Untersuchungen zu metabolisch und toxisch induzierter Beeinträchtigung der Gehirnaktivität des Hundes
INAUGURAL-DISSERTATION zur Erlangung des Grades einer
Doktorin der Veterinärmedizin - Doctor medicinae veterinariae -
(Dr. med. vet.)
vorgelegt von Christina Brauer
Soltau
Hannover 2009
1. Gutachter: Prof. Dr. med. vet. Andrea Tipold 2. Gutachter: Prof. Dr. Marion Hewicker-Trautwein
Tag der mündlichen Prüfung: 16.09.2009
Meiner Familie
I. Inhaltsverzeichnis
I. Inhaltsverzeichnis ... 5
II. Einleitung ... 7
III. Publikationen ... 12
A. Metabolic and toxic causes of canine seizure disorders: a retrospective study of 96 cases (2004-2008)... 12
Abstract... 13
Introduction ... 14
Materials and methods... 15
Results... 17
Discussion... 21
Conclusions ... 25
Conflict of interest statement... 26
Acknowledgements... 26
References... 26
B. Barbiturate intoxication in two dogs confirmed by toxicological urinalysis ... 31
Summary... 32
Introduction ... 32
Case Histories... 33
Discussion... 35
Conclusions ... 37
References... 38
IV. Zusammenfassung der Ergebnisse beider Studien ... 41
V. Übergreifende Diskussion... 43
VI. Zusammenfassung (englisch)... 48
VII. Zusammenfassung (deutsch) ... 50
VIII. Schrifttumsverzeichnis ... 52
IX. Abkürzungen... 59
X. Danksagung... 60
II. Einleitung
Anfälle gehören zu den häufigsten neurologischen Störungen beim Hund (Podell et al., 1995). Sie entstehen durch die paroxysmale, elektrische Entladung von Neuronen (Steffen und Jaggy, 1995a). Das klinische Erscheinungsbild reicht von subtilen Beeinträchtigungen (fokale Krampfanfälle) bis zu generalisierten tonisch- klonischen Krampfanfällen (Knowles, 1998). Als Epilepsie wird das wiederholte Auftreten von epileptischen Anfällen ohne nachweisbares morphologisches Substrat bezeichnet (Jaggy und Heynold, 1996). Je nach Ätiologie des Anfallsgeschehens wird eine Unterteilung in drei Kategorien vorgenommen: idiopathische bzw. primäre, symptomatische bzw. sekundäre und reaktive epileptische Anfälle (March, 1998). Als Status epilepticus wird ein 30 Minuten oder länger andauernder epileptischer Anfall bezeichnet (Podell, 1996). Zwei oder mehrere isolierte Krampfanfälle innerhalb von 24 Stunden werden als Cluster-Anfälle definiert (de Lahunta und Glass, 2009).
Idiopathische oder auch primäre Epilepsie bezeichnet das Auftreten von spontanen Krampfanfällen ohne nachweisbare Ursache wie z. B. eine Enzephalitis oder eine Neoplasie (Steffen und Jaggy, 1995a). Die Prävalenz wird in verschiedenen Studien zwischen 0,5 % und 5,0 % geschätzt (Berendt, 2004). Eine familiäre Präsdisposition bzw. eine genetische Grundlage wurde bei verschiedenen Rassen wie zum Beispiel beim Beagle (Bielfelt et al., 1971), Belgischen Schäferhund (van der Velden, 1968;
Oberbauer et al., 2003), Keeshond (Wallace, 1975; Hall und Wallace, 1996), Vizsla (Patterson et al., 2003), Labrador Retriever (Jaggy et al., 1998; Berendt, 2004) und Golden Retriever (Srenk et al., 1994) nachgewiesen. Es wird davon ausgegangen, dass unterschiedliche Vererbungsgänge für die Entwicklung der Epilepsie bei diesen Rassen verantwortlich sind (Berendt, 2004). Die meisten Hunde erkranken zwischen dem ersten und dem fünften Lebensjahr (Podell, 1996). Die idiopathische Epilepsie wird im Ausschlussverfahren diagnostiziert (de Lahunta und Glass, 2009; Fig. 1).
Verlaufen alle Untersuchungen ohne besonderen Befund, so besteht der starke Verdacht, dass eine idiopathische Epilepsie vorliegt. Sollte das Tier bei Krankheitsbeginn ungewöhnlich jung oder alt für eine idiopathische Epilepsie sein, so kann auch von kryptogener Epilepsie gesprochen werden, d. h. eine morphologische
Krankheitsursache wird vermutet, konnte aber nicht nachgewiesen werden (Berendt und Gram, 1999). Für Hunde, die an idiopathischer Epilepsie erkrankt sind, stehen unterschiedliche Behandlungsmöglichkeiten zur Verfügung. Eine Therapie sollte begonnen werden, sobald das Tier zwei oder mehr generalisierte epileptische Anfälle innerhalb von sechs Monaten gezeigt hat (Podell, 2004). Bisher gibt es in Deutschland kein für den veterinärmedizinischen Markt zugelassenes antiepileptisches Medikament. Zurzeit werden vor allem Phenobarbital, Kaliumbromid, Felbamat, Gabapentin, Zonisamid und Levetiracetam aus der Humanmedizin umgewidmet und mit unterschiedlichem Erfolg bei Hunden zur dauerhaften Therapie eingesetzt (Potschka et al., 2009).
Bei symptomatischen bzw. sekundären Krampfanfällen liegt eine strukturelle Veränderung im Bereich des Gehirns vor (March, 1998). Diese strukturellen Veränderungen können als Folge von Hämorrhagien, Entzündungen, Traumata, Anomalien, Neoplasien oder Speicherkrankheiten auftreten (Steffen und Jaggy, 1995c). Hunde mit symptomatischer Epilepsie bedürfen einer ätiologischen Therapie je nach Ursache zum Beispiel mit Antibiotika oder einer Chemotherapie und sollten zudem unterstützend antiepileptisch therapiert werden (Podell, 2004).
Reaktive Krampfanfälle sind Folge einer Entgleisung des Stoffwechsels, die durch unterschiedliche zu Grunde liegende Erkrankungen hervorgerufen werden kann.
Veränderungen im Körper, die zu solchen epileptischen Anfällen führen können, sind zum Beispiel Hypoglykämie, Hypoxie, Hypo- oder Hyperkalzämie, Hypo- oder Hypernatriämie, Hyperosmolalität, hepatische oder urämische Enzephalopathie und Schilddrüsenunterfunktion; zudem kann eine große Breite an toxischen Substanzen reaktive Krampfanfälle auslösen (Tab. 1; Cunningham, 1971; Fuhrer, 1990; Steffen und Jaggy, 1995b; O’Brien, 1998).
Intoxikationen gehören zu den häufigsten Notfällen in der veterinärmedizinischen Neurologie (Sigrist und Spreng, 2007), wobei das zentrale Nervensystem besonders anfällig für viele Toxine ist (Steffen und Jaggy, 1995b). Oft gehen Vergiftungen mit
einer akuten Entwicklung der klinischen Symptome einher (Dorman, 1993). Häufige Veränderungen sind Hyperaktivität, Muskeltremor, Hyperästhesie und Krampfanfälle (Steffen und Jaggy, 1995b). Der Zeitraum zwischen den einzelnen Anfällen ist oft durch abnorme neurologische Untersuchungen gekennzeichnet (Dorman, 1993).
Wird ein Tier im Status epilepticus vorgestellt, ohne dass es vorher jemals epileptische Anfälle gezeigt hat, so muss Vergiftung immer mit in die Liste der möglichen Differentialdiagnosen aufgenommen werden (Steffen und Jaggy, 1995b;
Zimmermann et al., 2009). Vergiftungen erfordern ein sofortiges Handeln, um bleibende Schädigungen möglichst abzuwenden. Zunächst sind eine Stabilisierung des Herz-Kreislauf-Systems und eine Dekontamination des Patienten mittels induzierter Emesis, Magenspülung und Verabreichung von Laxantien anzustreben;
gegebenenfalls müssen Antikonvulsiva verabreicht werden (Hall, 2008). Eine toxikologische Untersuchung des Patienten ist anzustreben, um eine Vergiftung definitiv nachzuweisen, da viele Patientenbesitzer vermuten, dass ihr Tier vergiftet wurde, ohne eine Giftaufnahme beobachtet zu haben (Poppenga und Braselton, 1990). Der Nachweis von toxikologisch wirksamen Substanzen im Patienten kann im Weiteren auch dazu dienen, die Vergiftungsquelle ausfindig zu machen, um andere Tiere und Menschen vor Intoxikationen mit der gleichen Substanz zu bewahren.
Eine umfassende diagnostische Abklärung eines Patienten mit Krampfanfällen ist die Voraussetzung für eine adäquate Therapie, die je nach zu Grunde liegender Ursache stark variieren kann (Podell, 1998). Hierzu gehören die ausführliche Anamneseerhebung, die exakte klinische und neurologische Untersuchung des Tieres und die umfassende Blutuntersuchung. Je nach Befund muss zur weiteren Untersuchung des Patienten in Narkose mittels Elektroenzephalographie, Magnetresonanztomographie und Liquoruntersuchung geraten werden (Berendt, 2004; Fig. 1).
Fig. 1. Diagnostisches Vorgehen bei epileptischen Anfällen.
Bei der idiopathischen Epilepsie handelt es sich um eine Auschlussdiagnose. Kann eine metabolische oder toxische Ursache für den epileptischen Anfall nachgewiesen werden, so handelt es sich um reaktives Krampfgeschehen. Sobald eine intrazerebrale Ursache nachgewiesen werden kann, wird von einer symptomatischen oder auch sekundären Epilepsie gesprochen. Verlaufen alle Untersuchungen ohne besonderen Befund, so liegt eine primäre oder auch idiopathische Epilepsie vor.
Ziel dieser Arbeit war es, durch retrospektive Auswertung aller Hunde mit reaktivem Krampfgeschehen und anderen toxisch bedingten Beeinträchtigungen des zentralen Nervensystems, das Auftreten der einzelnen metabolischen und toxischen Ätiologien zu analysieren, um dadurch neue Anhaltspunkte für eine adäquate Diagnosestellung, Prognose und Therapie zu erhalten.
Die erste Studie analysierte die Häufigkeit metabolischer und toxischer Ätiologien bei Hunden, die aufgrund eines Krampfgeschehens in der Klinik für Kleintiere der Tierärztlichen Hochschule Hannover in den Jahren 2004-2008 vorgestellt wurden.
Die zweite Studie beschreibt mit der toxikologischen Harnuntersuchung mittels Gaschromatographie-Massenspektrometrie eine Methode der toxikologischen Untersuchung, die zurzeit noch wenig in der Tiermedizin angewandt wird, jedoch über große diagnostische Möglichkeiten verfügt.
III. Publikationen
Die folgende Publikation wurde am 24.06.2009 im „The Veterinary Journal“
eingereicht.
A. Metabolic and toxic causes of canine seizure disorders: a retrospective study of 96 cases (2004-2008)
Christina Brauera, *, Melanie Jambroszykb, Andrea Tipolda
a Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173 Hannover, Germany
b Small Animal Practice Dr. Ehrhardt & Ehrhardt, Karlstr. 9, 44575 Castrop-Rauxel, Germany
* Corresponding Author. Tel.: +49 511-856-8301; fax: +49 511-856-7686.
E-mail address: christina.brauer@tiho-hannover.de (C. Brauer)
Abstract
A wide variety of intoxications and abnormal metabolic conditions can lead to reactive seizures in dogs. 877 patient records of dogs suffering from seizure disorders were reviewed, 96 of them were identified as cases with underlying metabolic or toxic aetiology including intoxications by varying substances, hypoglycaemia, electrolyte disorders, hepatic encephalopathy, hypothyroidism, uraemic encephalopathy, hypoxia and hyperglycaemia. Further, the incidence of underlying diseases was determined. The most common causes for reactive seizures were intoxications (39 %, 37 dogs) and hypoglycaemia (32 %, 31 dogs) with mean plasma glucose concentration ≤ 2.19 mmol/L at first presentation. Hypocalcaemia was the most frequent electrolyte disorder that caused reactive seizures (5%, 5 dogs). All five dogs had ionized calcium levels ≤ 0.69 mmol/L.
In conclusion, in this study on a large number of dogs with seizure disorders, 11 % of all investigated dogs suffered from metabolic or toxic disorders. This relatively high number supports the importance of a careful clinical workup in dogs presented for seizures for better planning of treatment strategies which may differ substantially depending on the underlying disease.
Keywords: epilepsy; hypoglycaemia; hypocalcaemia; metaldehyde;
organophosphates
Introduction
Seizures belong to the most common neurological disorders in dogs (Podell et al., 1995; March, 1998; Berendt, 2004). Based on aetiology, seizures have been grouped into three different categories, i.e. idiopathic, symptomatic and reactive (Podell, 1996). The latter have an extracranial origin and can be caused by a variety of different metabolic disturbances and intoxications (O'Brien, 1998). A status of recurrent seizures is defined as epilepsy (Berendt, 2004).
Reactive seizures as a result of altered brain function can be elicited by dysfunction of virtually any organ system (Boggs, 1997), leading to many metabolic and toxic differential diagnoses that have been described in the literature (Cunningham, 1971;
Fuhrer, 1990; Steffen and Jaggy, 1995; O'Brien, 1998; Tab. 1). Most of these conditions are reversible, depending on the underlying disease. Therefore, permanent antiepileptic drug therapy may only be initiated when seizures are uncontrolled despite therapy of the underlying disease. This is of special interest since most antiepileptic drugs (AEDs) can lead to side effects and/or interact with other drugs essential for the patient (Boggs, 1997). Therefore AEDs should only be applied if absolutely necessary.
To the authors’ knowledge, no data are published about the frequency of the underlying aetiology of reactive seizures in dogs. The purpose of this study was to describe frequent metabolic and toxic causes in dogs that are presented due to a seizure disorder.
Metabolic causes of seizures Selection of toxic causes of seizures
Hypoglycaemia Animal toxins
Hypoxia Caffeine and other Methylxanthines
Hyperthermia
Hyperosmolality
Hydrocarbons and Petroleum Distillates (e. g. ethylene glycol, methanol)
Hyponatraemia and Hypernatraemia Lead and other heavy metals Hypocalcaemia and Hypercalcaemia Mycotoxins
Hepatic encephalopathy Uraemic encephalopathy
Hyperlipoproteinaemia
Pesticides (e. g. Bromethalin,
Metaldehyde, Organophosphates and carbamates, Pyrethrins and
pyrethroids, Strychnine)
Hypothyroidism Plant toxins
Drugs
Tab 1. Extracranial causes of seizures in dogs
(adapted and modified from Cunningham, 1971; Fuhrer, 1990; Steffen and Jaggy, 1995; O'Brien, 1998)
Materials and methods
A total of 877 patient records of dogs suffering from seizure disorders presented to the Department of Small Animal Medicine and Surgery of the University of Veterinary Medicine Hannover between 2004 and 2008 were reviewed for underlying metabolic or toxic disturbances. Possible differential diagnoses are listed in Tab. 1. Seizures
were defined and found to be either generalized or focal with or without loss of consciousness.
Hypoglycaemia was defined to be responsible for the seizure disorder when dogs showed repeated low blood glucose levels and an underlying disease could be identified (e.g. neoplasia) or when animals presented while having a seizure had low blood glucose levels and immediately responded to intravenous glucose administration (Podell, 2004).
Hepatic encephalopathy had been diagnosed mainly through marked hyperammonaemia; diagnostic imaging of liver and abdominal blood vessels was performed with ultrasound and/or computed tomography (Hardy, 1992). Uraemic encephalopathy had been diagnosed by measuring of creatinine and urea concentrations in plasma and detection of an acute or chronic renal disease (Fenner, 1995). Electrolyte disorders were defined to be the reason for the seizure disorder when at least one of the concentrations of calcium, sodium or potassium was markedly de- or increased due to an underlying disease (Podell, 2004).
Hypothyroidism was regarded to be responsible for the seizure disorder when diagnosed either by a thyreotropin-releasing-hormone (TRH) stimulation test or when elevated thyroid-stimulating hormone (TSH) levels with concurrent low thyroxin levels were measured (Jaggy, 1990; Scott-Moncrieff, 2009). In cases of presumed hypoxia, anaesthesia had been performed for different operations prior to presentation as reported by the owners. Hyperglycaemic animals were concurrently presented with seizures, marked elevated blood glucose levels (e.g. due to concurrent diabetes mellitus) and hyperosmolality (O'Brien, 1998). Diagnosis of intoxication was made by toxicological analysis of urine (Maurer, 2004). Further, dogs were included when toxic material could be proven in stomach content or faeces, in case of concomitant affection of more than one animal in the same household or when owners observed their dog ingesting possible toxic substances. Low activities of cholinesterase were taken as a diagnostic measure for presumptive organophosphate or carbamate intoxication (Fikes, 1990).
Patient records of the included 96 cases were reviewed and data of signalement, physical and neurological examinations, blood cell count and serum biochemistry analysis, additional blood investigations (e.g. insulin, parathyroid hormone etc.), diagnostic imaging, treatment and outcome were evaluated. Occurrence of different aetiologies and underlying diseases were determined.
Results
Ninety-six out of 877 patients with seizures were included into this study. A definite metabolic or toxic disorder could therefore be established in about one tenth (11 %, 96/877) of all dogs presented for seizures. Thirty-nine of these dogs (41 %, 39/96), suffering from various metabolic or toxic diseases, were presented in status epilepticus. Seven dogs (7%, 7/96) had experienced generalized seizures without loss of consciousness and 47 dogs (49%, 47/96) generalized seizures with loss of consciousness. Only three dogs (3%, 3/96) were affected with focal seizures without loss of consciousness.
Thirty-one dogs (32 %, 31/96) were suffering from hypoglycaemia. Electrolyte disorders were responsible for seizures in ten dogs (10 %, 10/96). Hepatic encephalopathy with a concurrent seizure disorder occurred in nine dogs (9 %, 9/96).
Hypothyroidism was the suspected cause in three dogs (3 %, 3/96) and uraemic encephalopathy, hypoxia and hyperglycaemia each accounted for two seizuring dogs (each 2 %, 2/96). Intoxication was the most frequent diagnosis being detected in 37 dogs (39 %, 37/96, Fig.2).
Fig. 2. Occurrence of seizures due to metabolic and toxic conditions.
Intoxications (37 dogs) and hypoglycaemia (31 dogs) are the most frequent extracranial aetiologies of seizures.
Dogs of the hypoglycaemic group were further divided into different subgroups (Fig.
3). Hypoglycaemia was most frequently caused by insulinomas, suspected insulinomas or other tumours. These three aetiologies made up for 68 % (21/31) of all hypoglycaemic dogs. Mean age of all dogs in these subgroups was 10 years (range 7-16 years). Five dogs (16 %, 5/31) with a mean age of 3.4 months suffered from juvenile hypoglycaemia due to various underlying causes like starvation, gastrointestinal parasites and disturbances. Mean blood glucose concentration of all dogs in the hypoglycaemic group at time of first presentation was 2.19 mmol/L (range 0.55-3.5 mmol/L, reference range 3.9-6.1 mmol/L).
Fig. 3. Differential diagnoses for hypoglycaemia.
Most common differential diagnosis for hypoglycaemia and concurrent seizure disorders is neoplasia (21 dogs).
Electrolyte disorders were responsible for seizures in ten dogs. Of these, five showed marked hypocalcaemia with a mean ionized calcium concentration of 0.61 mmol/L (range 0.5-0.69 mmol/L, reference range 1.25-1.47 mmol/L). Causes for hypocalcaemia were found to be hypoparathyroidism, suspected hypoparathyroidism, lactation, protein losing enteropathy and iatrogenic hypocalcaemia after resection of a parathyroidea carcinoma. The other five dogs with electrolyte disorders suffered from Addison’s disease (2 dogs), overdosage of metildigoxin, excessive vomiting and severe systemic illness with marked elevation of serum potassium ion concentrations (6.46 mmol/L, reference range 3.5-5.1 mmol/L).
Hepatic encephalopathy due to portosystemic shunting occurred in nine dogs. Seven of them suffered from seizures before surgical intervention and two dogs exhibited seizures after incomplete ligature of the shunt vessels. The first of the latter two dogs developed the seizure disorder five years after surgery when serum ammonia concentrations were repeatedly elevated to 180 µmol/L (reference range < 58.8 µmol/L) at that time. The second dog showed seizures directly after surgery. Mean
ammonia serum levels of all nine dogs in this group at first presentation was 221.48 µmol/L (range 147.00-265.78 µmol/L).
Two dogs were presented after general anaesthesia for routine operations performed by referring veterinarians. Seizures developed in one dog subsequently to anaesthesia, in the other about eight hours later. Both dogs displayed partial seizures during clinical examination in our clinic. Partial oxygen pressure was normal in both dogs at the time of presentation and seizures resolved in both dogs 24 hours after admission.
Hyperglycaemia was found in two dogs with diabetes mellitus and concurrent seizures. Blood glucose concentrations at presentation were 102.12 mmol/L and 32.19 mmol/L, respectively. The first dog also suffered from renal disease and had a base excess of -15.6 mmol/L (reference range -4 to 4 mmol/L).
Thirty-seven dogs out of the 96 dogs in this study (39 %, 37/96) suffered from toxicosis. Metaldehyde intoxication occurred in seven dogs (19 %, 7/37), organophosphate or carbamate poisoning in six (16 %, 6/37) and ethylene glycol intoxication in two (5 %, 2/37). Mean cholinesterase level in organophosphate or carbamate poisoning was 354 U/L (range 55-700 U/L, reference range 1500-3000 U/L). One dog with organophosphate intoxication had a history of three recurrent seizures occurring in intervals of four weeks. Because of seizure appearance the referring veterinarian had suspected intoxication and induced a toxicological examination of the dog’s vomit. This examination had been negative. After presentation to our clinic a toxicological urinalysis detected parathion, an organophosphate. The other 22 dogs in this group had different aetiologies of intoxication. Three of them (8 %, 3/37) were living in households with other pets showing the same clinical signs. Six animals (16 %, 6/37) had eaten garbage, mouldy food, a decayed animal, compost or dunghill leading to the presumptive diagnosis of mycotoxicosis. Seven dogs (19 %, 7/37) had been observed while ingesting an unknown substance. Of the other six dogs (16 %, 6/31) in this group, two dogs had eaten faeces of horses previously treated with ivermectine or moxidectine, one had been suspected to suffer from strychnine poisoning, one had eaten pieces of yew, one had been bitten by a swarm of bees, and one dog had
eaten silage (Fig. 4). Urine of two dogs underwent toxicological analysis diagnosing metaldehyde and parathion intoxication, respectively. Twenty-two of all 37 intoxicated dogs (59 %) were presented in status epilepticus.
Fig. 4. Differential diagnoses for intoxication.
Most common confirmed intoxications are metaldehyde and organophosphate or carbamate intoxications.
Discussion
Various extracranial metabolic or toxic insults can result in reactive seizures (March, 1998). Not all mechanisms of seizure release through toxins or metabolic diseases are understood so far. Some toxins disturb the well-balanced system of inhibition and excitation in the nervous system; some interfere with energy metabolism (O'Brien, 1998). Energy metabolism can also be changed by metabolic diseases leading to modified osmolality or production of endogenous toxins (O'Brien, 1998). Clinical onset in metabolic and toxic diseases is often acute, progressive and accompanied with symmetrical signs (Garosi, 2004). In the current study, 11 % of all dogs presented to our clinic between 2004 and 2008 for seizure disorders suffered from reactive seizures due to metabolic or toxic disturbances. This number is similar to a
study performed by Podell et al. (1995) who examined a total of 50 dogs of which five dogs were afflicted with reactive seizures.
Status epilepticus was seen in less than half (41%) of all dogs in this study.
Therefore metabolic and toxic disturbances also have to be considered as a differential diagnosis in cases with single generalized seizures although reactive epileptic seizures have a 1.57 times higher odds for status epilepticus in comparison to idiopathic epilepsy (Platt and Haag, 2002).
Intoxication was the most often differential diagnosis confirmed or highly suspected in 37 dogs in this study. Seven of them suffered from metaldehyde intoxication.
Metaldehyde is a common compound of snail and slug baits. Clinical signs most often seen in this toxicosis are seizures, hyperthermia, tachycardia and muscle tremors (Yas-Natan et al., 2007). The exact mechanism of metaldehyde intoxication is currently not understood (Richardson et al., 2003).
Organophosphate or carbamate insecticides facilitate cholinergic stimulation through inhibition of acetylcholine esterase (O'Brien, 1998). A wide variety of cholinesterase- inhibiting compounds exists including insecticide dips and sprays, household, garden, or agricultural products (Murphy, 1994). Diagnosis in the current study had been established by clinical signs, direct measurement of cholinesterase activity and in one case by toxicological urinalysis.
Antifreeze solutions often contain 95 % ethylene glycol (Thrall et al., 1995) and uptake can provoke seizures (O'Brien, 1998). Central nervous system dysfunction is caused by glycoaldehyde, a metabolite of ethylene glycol, through inhibition of respiration, glucose metabolism, serotonin metabolism, and alteration of amine concentrations (Thrall et al., 1995).
Hypoglycaemia caused seizures in 31 dogs. The brain is the most important obligate consumer of glucose and its stores of glycogen and capacity to utilize amino acid pools are limited (Leifer and Peterson, 1984). In the present study, more than two thirds of all patients with hypoglycaemia and concurrent seizures suffered of neoplastic disorders, making this differential diagnosis most likely in hypoglycaemic elderly dogs that have not been treated with insulin. This age preference is supported by other studies about dogs with insulin-secreting and nonislet cell tumours in which
mean ages of dogs were 9.4 to 11.2 years (Leifer et al., 1985; Leifer et al., 1986;
Trifonidou et al., 1998). Hypoglycaemia and seizures appearing in young dogs lead to the most likely diagnosis of transient juvenile hypoglycaemia, usually precipitated by cold, starvation, or gastrointestinal disturbances (Johnson and Atkins, 1980) which could be confirmed by our study. Four of five dogs were typical breeds for this subgroup being Chihuahuas and Yorkshire Terriers (Leifer and Peterson, 1984). In addition, insulin overdosage causing iatrogenic hypoglycaemia has to be kept in mind when examining a dog suffering from seizures.
Hypocalcaemia had been the most often differential diagnosis in dogs with seizures and concurrent electrolyte disturbances. Interestingly, clinical signs in children with ionized serum calcium concentrations ≤ 2.50 mg/dL (0.62 mmol/L) included seizures, muscle fasciculations and restlessness (Sorell et al., 1975). These findings correspond to our results: all dogs with seizures due to hypocalcaemia had ionized calcium concentrations of ≤ 0.69 mmol/L. Measurement of the ionized portion of serum calcium is necessary to establish the correct diagnosis since this is the physiologically active form (Kornegay, 1982).
Two dogs suffered from Addison’s disease. Seizures due to hypoadrenocorticism have been described in the literature as consequence of concurrent hypoglycaemia (Levy, 1994; Syme et al., 1998) which occurs in approximately 25 % of dogs with hypoadrenocorticism (Levy, 1994).
Hepatic encephalopathy occurred in 9 % of all dogs in this study. The mechanism of hepatic encephalopathy is not completely understood so far. Different theories have been proposed of which the most favoured ones are that (1) ammonia acts as a putative neurotoxin; (2) monoamine transmission (serotonin, tryptophan) is perturbed; (3) amino acid neurotransmission is imbalanced and (4) an endogenous benzodiazepine-like substance exists (Maddison, 1992). Of these entire factors one alone is not capable to induce hepatic encephalopathy itself, so it has been proposed that certain factors have to act synergistically (Hardy, 1992). Ammonia seems to be one of the more important factors in inducing hepatic encephalopathy and can be easily determined when a patient is presented. Consequently, clinical signs and laboratory results have to be analysed in conjunction. Two dogs in this study suffered
from seizures after shunt ligature. In one of them hepatic encephalopathy can definitely be seen as the eliciting factor because ligature of the shunt vessel was only partial and ammonia concentrations were still markedly elevated five years after initial operation. In the other dog seizures started right after operation and were still present when ammonia concentrations started to normalize. This symptom has been described before (Matushek et al., 1990; Yool et al., 2002) and the actual underlying mechanism still remains unclear (Tisdall et al., 2000). Adaptation of the brain to an altered metabolism prior to surgery and inability to react to rapid changes after shunt ligature has been proposed as theory for this clinical problem (Matushek et al., 1990).
Three dogs in this study were diagnosed with seizures due to hypothyroidism.
Several reports about dogs with acute seizures due to atherosclerosis associated with primary hypothyroidism exist (Patterson et al., 1985; Zeiss and Waddle, 1995;
Blois et al., 2008). In all these reports ataxia, circling and head tilt often preceded more severe clinical signs like seizures, tetraparesis and coma and all dogs subsequently died or had to be euthanized. In 1990, Jaggy described a series of five dogs with refractory epilepsy in which therapy of hypothyroidism led to seizure free follow-up periods of six to 24 months. If these dogs also suffered from a mild, reversible form of atherosclerosis could not be proven. Scott-Moncrieff (2009) stated that “there is little evidence to suggest that hypothyroidism is a common cause in seizure disorders in dogs”. Our study supports this statement since there were only three dogs in which the seizures disorder could be connected to hypothyroidism.
Uraemic encephalopathy in dogs is probably caused by a combination of different factors like depressed cerebral oxygen consumption, cerebral acidosis, cerebral hypoxia, increased brain calcium levels, accumulation of toxic organic acids, increased phosphorus levels and non-specific increased cerebral membrane permeability or some not yet discovered “uraemia toxin” (Wolf, 1980). Although seizures due to uraemic encephalopathy include only a small portion of all cases in the current study (2 %) it is important to keep this differential diagnosis in mind when an epileptic dog is presented. Anticonvulsant therapy has to be adjusted accordingly to this condition since some antiepileptic drugs are excreted renally (Fenner, 1995)
and protein binding of other drugs such as several antibiotics may be changed in renal failure (O'Brien, 1998).
Hypoxic seizures can occur after respiratory or cardiac distress (Cunningham, 1971).
Brain oxygen supply may be diminished through decreased circulation or oxygen- saturation of the blood (Steffen and Jaggy, 1995). Exact protocols of anaesthesia were not available of the two dogs in this study presented with seizures due to presumed hypoxia. However, seizures resolved 24 hours after admission to our clinic in both dogs, which is most likely seen in dogs that suffered from short oxygen depletion and reversible insults on the cellular level (Steffen and Jaggy, 1995). On the other hand, prolonged anoxic episodes may as well lead to permanent epilepsy (O'Brien, 1998).
Hyperglycaemia can induce seizures through alteration of osmolality (O'Brien, 1998) which is more common than seizure development through diabetic ketoacidosis (Boggs, 1997) and was detected in only a low percentage in the present study.
Treatment of fluid and electrolyte alterations as well as therapy of the underlying disease is often sufficient to avoid further acute seizures (Boggs, 1997). Owners of diabetic dogs have to be aware of this complication.
Conclusions
The current study points out that metabolic and toxic conditions still have to be considered when a dog suffering from a seizure disorder is presented. Metabolic or toxic aetiologies seem to be responsible for about one tenth of all seizure disorders.
Exclusion of these possible differential diagnoses is important for planning therapeutic regimens and for justifying use of antiepileptic drugs. Complete history, clinical and neurological examinations and blood investigation are essential parts of the diagnostic work-up in a seizuring dog to confidently rule out metabolic or toxic causes.
Conflict of interest statement
None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.
Acknowledgements
The authors would like to thank Dr. Veronika Stein, Dr. Thilo von Klopmann, Dr.
Cornelia Flieshardt, and Dr. Henning Schenk for their precise maintenance of medical records and the referring veterinarians for their confidence and support.
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Die folgende Publikation wurde im „Journal of Small Animal Practice“ (2009), 50, 423-425 veröffentlicht.
B. Barbiturate intoxication in two dogs confirmed by toxicological urinalysis
C. Brauer1, A. Tipold1, H. Desel2, V.M. Stein1
1Department of Small Animal Medicine and Surgery University of Veterinary Medicine Hannover, Germany Bischofsholer Damm 15
D-30173 Hannover, Germany
2GIZ-Nord Poisons Centre and Toxicological Service Laboratory
University Medical Centre Göttingen – Georg-August-Universität Göttingen Robert-Koch-Str. 40
D-37075 Göttingen, Germany
Corresponding author:
Christina Brauer
Department of Small Animal Medicine and Surgery University of Veterinary Medicine Hannover, Germany Bischofsholer Damm 15
D-30173 Hannover, Germany Tel.: 0049-511-856-8301 Fax: 0049-511-856-7686
E-mail: christina.brauer@tiho-hannover.de
Summary
Two dogs presented within 24 hours to the Department of Small Animal Medicine and Surgery at the University of Veterinary Medicine Hannover for sudden onset of neurological abnormalities following a walk in the same park. One dog was observed ingesting a piece of meat. Analysis of urine by gas chromatography-mass spectrometry (GC-MS) from each of the dogs identified the presence of barbiturates.
Both dogs recovered with supportive treatment. This is the first report to describe the use of toxicological urinalysis with GC-MS for the diagnosis of barbiturate intoxication in dogs.
Introduction
Intoxications are frequent emergencies in veterinary neurology (Sigrist and Spreng 2007). Therapy usually consists of decontamination, through inducing emesis or binding of the toxicant to activated charcoal, and supportive care (Hall 2008). Since a sample of the toxic material is often unavailable, a definitive diagnosis potentially can be determined through toxicological analysis of the urine (Poppenga and Braselton 1990). Detecting and eliminating the source of intoxication prevents other animals and humans, especially children, from being exposed.
Intoxication is often a suspicion rather than a direct observation, therefore making toxicological analysis useful for confirmation. Gas chromatography-mass spectrometry is a particularly useful analytical technique as it is available through veterinary toxicological laboratories and has the ability to detect many different substances (Poppenga and Braselton 1990). Urine is considered the diagnostic sample of choice for screening and identification of unknown drugs or toxicants (Maurer 2004).
Until 1996, pentobarbital was widely used as a hypnotic in human medicine in Germany. The high risk of drug dependency and abuse warranted removal of this
drug from the market. Preparations are still available today for use in veterinary medicine for anaesthesia, therapy of intractable seizures and also for euthanasia (Plumb 2002). Albeit phenobarbital is used very rarely as an antiepileptic drug in human medicine, it is the initial drug of choice for maintenance therapy for idiopathic epilepsy in veterinary medicine (Plumb 2002, Podell 1998). This report describes two cases of barbiturate intoxication in dogs confirmed by GC-MS analysis of urine.
Case Histories Case 1
A one-year-old, male intact, dachshund, weighing 7.8 kg, was presented for progressive apathy, weakness of the hind limbs and swaying of the head. Six hours prior to presentation the dog exhibited normal behaviour and had been taken for a walk by his owners. During the walk the owners observed their dachshund ingesting a piece of meat.
The clinical examination only revealed severe apathy and perpetual yawning.
Neurological examination revealed tetraparesis with normal conscious proprioception, absent bilateral menace responses, and diminished spinal reflexes in all four limbs. A multifocal lesion of metabolic-toxic aetiology according to the DAMNITV-scheme (Garosi 2004) was suspected.
Blood results showed a mild leucocytosis (16.7 x 10^9 leucocytes/l; reference range 6.0-12.0 x 10^9 leucocytes/l) due to lymphocytosis (5.1 x 10^9 lymphocytes/l;
reference range 0.9-3.6 x 10^9 lymphocytes/l). Radiographs of the thorax and abdomen, ultrasonography of the abdomen and an electrocardiogram to rule out any further involvement of the cardiovascular and gastrointestinal system were unremarkable.
Supportive treatment was started with intravenous 0.9 % sodium chloride solution (4 ml/kg/h constant rate infusion (CRI); Isotonische Natriumchlorid-Lösung ad us vet; B.
Braun Melsungen AG, Germany), and a single dose of furosemide (4 mg/kg IV;
Dimazon Lösung, intervet, Germany) to increase diuresis. Since the gag reflex was
intact, a single dose of activated charcoal (128 mg/kg PO; Kohle-Kompretten; Merck, Germany) was administered for absorption of the suspected toxicant. Emesis was not considered due to the timing post ingestion.
Urine collected within 24 hours of suspected toxicant exposure was submitted for a systematic toxicological screening analysis (Maurer 2004) to the toxicological service laboratory at the University Medical Centre Göttingen. Gas chromatography-mass spectrometry revealed 3`-hydroxypentobarbital, a metabolite of pentobarbital.
The dog gradually improved over the next 16 hours with only mild residual neurological deficits. It was discharged two days later.
Case 2
One day after presentation of the dachshund (case 1), a 12-year-old, female neutered, small Munsterlander, weighing 14.6 kg, was presented with similar symptoms as dog 1. Five hours prior to examination the dog had been taken for a walk in the same park as dog 1. Afterwards it developed progressive weakness of all four limbs. At the time of presentation the dog was disoriented and running into objects.
The clinical examination of the dog revealed mild apathy and disorientation. A full neurological examination was performed approximately 12 hours after admission and revealed a mild tetraparesis with diminished conscious proprioception of the hindlimbs, mild ataxia of all four limbs, and diminished bilateral menace responses.
The lesion was localized to the forebrain with metabolic-toxic aetiology as the most likely diagnosis considering the history.
Initial blood analysis showed moderate leucocytosis (21.5 x 10^9 leucocytes/l) with mature neutrophilia (18.49 x 10^9 segmented neutrophils/l, reference range 3.6-9.0 x 10^9 segmented neutrophils/l), base excess of -10.3 mmol/l (reference range -4 to +4 mmol/l) and blood glucose concentration of 9.88 mmol/l (reference range 3.9-6.1 mmol/l). Radiographs of the thorax and abdomen to rule out any further involvement of the cardiovascular and gastrointestinal system were unremarkable. After admission to the hospital therapy was started with an intravenous balanced electrolyte solution (4 ml/kg/h CRI; Sterofundin; B. Braun Melsungen AG, Germany)
for stabilization, and a single dose of furosemide (2 mg/kg IV) to stimulate diuresis.
Due to the fact that the gag reflex was normal, a single dose of activated charcoal (68 mg/kg PO) was administered in order to absorb any toxicant left in the gastro- intestinal tract. Emesis was not performed due to the time delay from potential ingestion of the toxicant and presentation at the clinic. The dog’s neurological condition improved continuously. While recovering it became very agitated and was sent home for further convalescence in its familiar surroundings.
The toxicological analysis of the urine with GC-MS, sampled within 24 hours after initiation of signs, revealed pentobarbital, phenobarbital, diethylenglycolmonobutylether, benzalkonium chloride, benzotriazole and benzylchloride.
Discussion
This case report described two cases of barbiturate intoxication in dogs confirmed by toxicological screening of urine. Gas chromatography-mass spectrometry of urine is a valuable tool for detection of a toxicological agent since many substances are excreted via the kidneys and accumulate in the urine. The method described screens for about 6,000 different toxicological substances in the sample (Pharmakologisch- toxikologisches Servicezentrum Universität Göttingen 2006, Maurer 2004).
Barbiturates are metabolized by microsomal P450 enzymes in the liver and excreted in the urine with approximately 25% as the unchanged compound (Bischoff 2007, Volmer 2008). Uptake of barbiturates can therefore be verified via urinalysis, which has gained widespread acceptance as the test of choice in human medicine (Poppenga and Braselton 1990). Although it took about three to five days from sampling of the urine until the diagnosis of barbiturate intoxication was established, this information was important for further cases presented to our animal hospital. One month after admission of the dogs described above another dog presented to our department exhibiting the same clinical signs. Given the history of this dog walking in the same park as the dogs described in this case report, consideration was given to
being exposed to the same source of the toxicant. The concern for human safety, especially children, and other animals warrants searching for the possible source of intoxication. The described method is therefore very valuable for identifying these sources (Poppenga and Braselton 1990).
Pentobarbital and phenobarbital are derivatives of barbituric acid. Pentobarbital belongs to the class of short-acting barbiturates whereas phenobarbital belongs to the class of long-acting barbiturates (Bischoff 2007). Most small animal exposures to these substances occur as a result of accidental ingestion of human or veterinary prescription preparations (Volmer 2006). In addition, ingestion of tissue from euthanized animals has been described before (Fucci and others 1986, Humphreys and others 1980, Reid 1978). Dog 1 was observed ingesting a piece of meat, which could be the source of its exposure. The source of dog 2 is unknown but suspected to be similar to dog 1 since it was taken to the same park, exhibited the same signs after the walk, and the toxicological analyses of the urine of both dogs showed pentobarbital. Barbiturates are known to be well absorbed orally (Volmer 2006).
Onset of clinical signs depends on the route of administration, the barbiturate involved, and the absence or presence of food in the stomach (Bischoff 2007). Time to onset after oral administration of short-acting barbiturates is 10-30 minutes. The onset time after oral administration for long-acting barbiturates can be up to an hour (Kisseberth and Trammel 1990). In these two cases the owners recognized the first signs of intoxication about five to six hours after the suspected exposure. Recent food intake or the lack of identification of early clinical signs by the owners might explain the discrepancy in time of onset of clinical signs.
Various other substances were detected in the urine of dog 2.
Diethylenglycolmonobutylether (butyldiglycol) is a water soluble organic solvent typically used in surface cleaning agents (Roempp Online 2007), and many other products. Benzalkonium chloride is a cationic detergent that can cause local or systemic effects depending on concentration and on dose, respectively (Kore and Kiesche-Nesselrodt 1990). Benzylchloride is a basic chemical used in industry for various creations of different products, e.g. disinfectants, pigments, scents and synthetic penicillin. It can cause inflammation and ulceration of the gastrointestinal
tract mucous membranes (BG Chemie 1997). Benzotriazole is used as a corrosion inhibitor and in cooling agents; in high concentrations it can cause central nervous system (CNS) effects (Baumann and Rothardt 1999). It is not proven whether these substances came from the same source as the barbiturates but disinfectants were not used in the owner’s home. Gas chromatography-mass spectrometry is a very sensitive method in detecting substances; however it provided only a qualitative examination when using urine as sample material. Since no local effects occurred at the mucous membranes we concluded that these chemicals were not responsible for any clinical signs. However, it cannot be ruled out that benzotriazole intoxication contributed to the neurological status at admission in dog 2.
The basic principles for successful treatment for barbiturate and other intoxications include decontamination if recent exposure, monitoring, symptomatic and supportive therapy (Bischoff 2007). Emetics may be given to asymptomatic animals (Bischoff 2007). For animals exhibiting severe depression, emesis is contraindicated because of the risk of aspiration (Volmer 2006). In animals with CNS depression intubation and gastric lavage are more appropriate (Bischoff 2007). However, these methods were not considered in these dogs due to delay in presentation. Activated charcoal has been shown to bind barbiturates and decrease mortality (Kisseberth and Trammel 1990). A beneficial effect on the clearance of phenobarbital has been demonstrated with repeated doses of activated charcoal (Boldy and others 1986).
Fluid therapy is indicated to maintain cardiac and renal function (Bischoff 2007) and furosemide application can be used to force diuresis (Hall 2008). The animals described in this case report recovered quickly using symptomatic and supportive therapy schedules.
Conclusions
Toxicological screenings can help to find the accurate diagnosis in a suspected intoxication and should be carried out regularly in veterinary medicine. However, since GC-MS is usually not carried out quantitatively, clinical findings and the
pathogenesis of toxic agents have to correlate with each other in order to verify the diagnosis.
References
Baumann, W. & Rothardt, T. (1999) Bezeichnungen, Handelsnamen, Anwendungsbereiche und Eigenschaften von Druckereichemikalien, 2nd edn.
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IV. Zusammenfassung der Ergebnisse beider Studien
Im ersten Teil dieser Arbeit wurde das Auftreten von reaktiven epileptischen Anfällen analysiert. In den Jahren 2004 bis 2008 wurden 877 Hunde aufgrund eines Krampfgeschehens in der Klinik für Kleintiere der Tierärztlichen Hochschule Hannover vorgestellt. Bei 96 dieser 877 Hunde (11 %) konnte ein reaktives Anfallsgeschehen diagnostiziert werden, so dass sie in die Studie aufgenommen wurden.
Neununddreißig Hunde (41 %, 39/96) wurden im Status epilepticus in die Klinik eingeliefert. Einzelne generalisierte Anfälle wurden bei 54 Hunden registriert. Ein Bewusstseinsverlust trat bei 47 (49 %, 47/96) von diesen Hunden ein, sieben (7 %, 7/96) waren während dieses Krampfgeschehens weiterhin ansprechbar. Drei Hunde (3 %, 3/96) zeigten lediglich fokale Anfälle ohne Bewusstseinsverlust.
Bei 37 Hunden (39 %, 37/96) waren Intoxikationen unterschiedlichster Art für das Krampfgeschehen verantwortlich. Bei 31 Hunden (32 %, 31/96) führte eine Hypoglykämie zum Krampfanfall. Elektrolytverschiebungen waren bei 10 Hunden (10
%, 10/96) dafür verantwortlich. Eine hepatische Enzephalopathie mit gleichzeitigem Anfallsgeschehen trat bei neun Hunden (9 %, 9/96) auf. Eine Hypothyreose wurde bei drei Hunden (3 %, 3/96) als Ursache vermutet. Eine urämische Enzephalopathie, Hypoxie oder Hyperglykämie wurde bei jeweils zwei krampfenden Hunden (2 %, 2/96) nachgewiesen (Fig. 2).
Intoxikation war mit 37 betroffenen Hunden die häufigste Ursache für reaktive Anfälle in dieser Studie. Sieben Hunde (19 %, 7/37) erlitten eine Metaldehyd-Vergiftung nach Schneckenkornaufnahme, jeweils sechs Hunde (16 %, 6/37) zeigten Krampfanfälle nach Organophosphat-/Carbamat- oder vermutlicher Mycotoxin-Vergiftung. Letztere hatten verschimmeltes Futter oder Müll, verweste Tiere, Kompost oder Mist gefressen. Die Cholinesteraseaktivität war bei den sechs Hunden, die Organophosphate bzw. Carbamate aufgenommen hatten, durchschnittlich auf einen Wert von 354 U/l (Spannweite 55-700 U/l, Referenzbereich 1500-3000 U/l) reduziert.
Ein Hund dieser Gruppe hatte wiederholt über einen Zeitraum von einem halben Jahr
im Abstand von ein bis zwei Monaten die gleiche akute Symptomatik gezeigt. Vom überweisenden Tierarzt war bereits beim zweiten Anfallsgeschehen Erbrochenes des Hundes in ein Labor zur toxikologischen Untersuchung gesendet worden. Diese Untersuchung verlief ohne besonderen Befund. Nach der Vorstellung in der Klinik für Kleintiere der Tierärztlichen Hochschule Hannover wurde eine toxikologische Untersuchung des Urins eingeleitet, wodurch die Aufnahme von Parathion nachgewiesen wurde.
Sieben Hunde (19 %, 7/37) wurden beim Fressen einer unbekannten Substanz von ihren Besitzern beobachtet und krampften in zeitlichem Zusammenhang zu dieser Aufnahme. Zwei Tiere hatten Frostschutzmittel getrunken (5 %, 2/37). Drei Hunde (8
%, 3/37) lebten in Haushalten, in denen andere Tiere (mehrere Hühner, eine Katze, ein Hund) kurz zuvor die gleichen akuten Symptome gezeigt haben. Sowohl die Katze als auch der Hund waren bereits vor der Vorstellung des anderen Tieres verstorben. Die restlichen sechs Hunde (16 %, 6/37) vergifteten sich mit unterschiedlichen Substanzen, zwei hatten Pferdekot von Pferden gefressen, die zuvor mit Ivermectin oder Moxidectin entwurmt worden waren. Ein Hund erlitt eine Strychninvergiftung. Ein Hund hatte Eibe gefressen, ein anderer Silage. Der letzte Hund dieser Gruppe war zuvor in einen Schwarm Bienen geraten und von mehreren Tieren gestochen worden (Fig. 3). Von den 39 Hunden in dieser Studie, die im Status epilepticus vorgestellt worden sind, entfielen 22 Hunde auf die Gruppe der Intoxikationen.
Der zweite Teil dieser Arbeit beschäftigte sich mit zwei Hunden bei denen mittels Gaschromatographie und anschließender Massenspektrometrie (GC-MS) eine Vergiftung mit Pentobarbital nachgewiesen wurde. Beide Hunde wurden aufgrund einer progressiven Verschlechterung des Allgemeinbefindens mit zunehmender Apathie und Gangschwäche innerhalb von 24 Stunden in der Klinik vorgestellt. Bei beiden Hunden führte eine unterstützende Therapie mit Aktivkohleeingabe und Infusionen zu umgehender Besserung des klinischen Bildes. Aufgrund der Tatsache, dass der erste Hund von seinem Besitzer bei einem Spaziergang sechs Stunden vor der Vorstellung hier in der Klinik bei der Aufnahme von Fleisch beobachtet wurde
und der zweite Hund vor seiner Erkrankung im selben Park spazieren gegangen war, wurde bei beiden Hunden eine toxikologische Untersuchung des Harns eingeleitet.
Diese wies bei beiden Tieren Pentobarbital nach.
V. Übergreifende Diskussion
Diese Arbeit unterstreicht zum einen die Bedeutung einer umfassenden diagnostischen Abklärung von Hunden mit Krampfgeschehen und weist zum anderen auf die große diagnostische Aussagekraft der toxikologischen Harnuntersuchung hin.
Sie legt dar, dass eine weite Bandbreite an unterschiedlichen Entgleisungen des Stoffwechsels und viele unterschiedliche Toxine zu Krampfanfällen führen können.
An einer großen Anzahl von Hunden konnte gezeigt werden, dass 11 % aller Hunde, die aufgrund eines Krampfgeschehens in der Klinik für Kleintiere der Tierärztlichen Hochschule Hannover von 2004 bis 2008 vorgestellt wurden, reaktive epileptische Anfälle zeigten. Dieses Ergebnis stimmt mit einer Studie von Podell et al. (1995) überein, in der fünf von 50 untersuchten Hunden reaktive Krampfanfälle zeigten.
Ein akuter und progressiver Krankheitsbeginn mit symmetrischen neurologischen Symptomen spricht für eine metabolische oder toxische Erkrankung (Garosi, 2004).
Dieses wurde durch die vorliegende Arbeit bestätigt, in der alle bis auf drei Hunde generalisierte Krampfanfälle, teilweise bis hin zum Status epilepticus, erlitten. Auch die mit Pentobarbital vergifteten Hunde wiesen generalisierte Symptome auf. Ein Status epilepticus trat bei weniger als der Hälfte (41 %) aller Tiere mit reaktivem Krampfgeschehen auf. Obgleich Tiere, die reaktive epileptische Anfälle zeigen, eine 1,57 fach höhere Chance haben, einen Status epilepticus zu entwickeln, als Hunde, die an idiopathischer Epilepsie leiden (Platt und Haag, 2002), zeigt diese Studie, dass das Auftreten von isolierten generalisierten Krampfanfällen kein Hinweis dafür ist, dass es sich nicht um ein reaktives Geschehen handelt.
Nicht alle Pathomechanismen, die zu reaktiven Krampfanfällen führen, wurden bis heute aufgeklärt. Viele Toxine stören das Gleichgewicht von Exzitation und Inhibition im Gehirn und führen so zur unkontrollierten Entladungen der Neurone (O’Brien, 1998). Metabolische Erkrankungen können den Energiemetabolismus im Gehirn
beeinflussen, indem sie zu veränderter Osmolalität oder Produktion endogener Toxine führen (O’Brien, 1998).
Intoxikation war im ersten Teil dieser Arbeit mit 37 betroffenen Hunden die häufigste Differentialdiagnose. Bei sieben dieser Tiere konnte eine Metaldehydintoxikation nachgewiesen werden. Metaldehyd wird häufig zur Schneckenabwehr in Gärten eingesetzt und führt in den meisten Fällen zu Muskeltremor, Hyperthermie, Tachykardie und Krampfanfällen (Yas-Natan et al., 2007). Der genaue Wirkmechanismus von Metaldehyd konnte bisher nicht nachgewiesen werden (Richardson et al., 2003). Organophosphate und Carbamate führen zu einer cholinergen Stimulation durch die direkte Inhibition der Cholinesterase (O’Brien, 1998). Sie werden ebenfalls häufig im Garten und in der Landwirtschaft eingesetzt und dienen der Insektenabwehr (Murphy, 1994). Frostschutzmittel enthalten bis zu 95 % Ethylenglykol (Thrall et al., 1995) und eine orale Aufnahme führt oft zu epileptischen Anfällen (O’Brien, 1998). Der Metabolit Glykoaldehyd ruft Veränderungen des Glukose- und Serotoninmetabolismus hervor und kann zudem die Atmung hemmen (Thrall et al., 1995).
Häufig vermuten Besitzer, dass ihr Tier vergiftet wurde, jedoch haben sie selten die Giftaufnahme direkt beobachtet. Deswegen ist in solchen Fällen eine exakte Diagnosestellung von großer Bedeutung für Besitzer und Tier. In der zweiten Studie wurde aufgezeigt, dass mittels toxikologischer Urinuntersuchung eine exakte Diagnose der Vergiftung erfolgen kann. Prinzipiell können durch GC-MS bis zu 6.000 toxische Substanzen nachgewiesen werden (Maurer, 2004; Pharmakologisch- toxikologisches Servicezentrum Universität Göttingen, 2006). Diese Methode ist vor allem in der Humanmedizin weit reichend akzeptiert und Methode der Wahl (Poppenga et al., 1990). Gerade die aufgezeigten Fälle verdeutlichen die Wichtigkeit der toxikologischen Untersuchung, da hier mit Pentobarbital eine Substanz nachgewiesen wurde, die in Deutschland seit 1996 nicht mehr als humanmedizinisches Präparat erhältlich ist, sprich seit 13 Jahren nur noch unter strengster Kontrolle im veterinärmedizinischen Bereich verwendet wird. Auch ein Fall in der ersten Studie zeigt die hohe Aussagekraft der toxikologischen Harnuntersuchung mittels GC-MS, da von einem vergifteten Tier bereits Erbrochenes
mit negativem Befund untersucht worden war und erst die Analyse des Urins eine Vergiftung mit Parathion nachweisen konnte. Urin ist somit das Untersuchungsgut der Wahl für das Aufdecken und Identifizieren unbekannter Substanzen (Maurer, 2004).
In 31 Fällen führte eine Unterzuckerung zu epileptischen Anfällen, wobei dieses bei 21 Hunden durch eine Neoplasie hervorgerufen wurde oder der starke Verdacht bestand, dass eine Neoplasie vorlag. Bei älteren Hunden, die wegen Krampfanfällen durch Hypoglykämie vorgestellt werden und die keine Behandlung mit Insulin aufgrund eines Diabetes mellitus erfahren, muss folglich immer der starke Verdacht eines tumorösen Geschehens bestehen. Dieses steht in Einklang mit mehreren Studien in der Literatur, in denen das Durchschnittsalter bei Hypoglykämie- induzierenden Neoplasien zwischen 9,4 und 11,2 Jahren lag (Leifer et al., 1985, Leifer et al., 1986, Trifonidou et al., 1998). Im Gegensatz dazu steht die Junghundehypoglykämie, die in der vorliegenden Arbeit bei fünf Hunden festgestellt wurde. Vier dieser Hunde waren Chihuahuas und Yorkshire Terrier und somit typische Rassen für dieses Phänomen (Leifer et al., 1984), das durch Kälte, Abmagerung, gastrointestinale Störungen und Parasiten hervorgerufen werden kann (Johnson und Atkins, 1980).
Hypokalzämie war die häufigste Elektrolytverschiebung in dieser Arbeit und führte bei fünf Hunden zu Krampfanfällen. Bei allen Tieren war die Konzentration des ionisierten Kalziums ≤ 0,69 mmol/l. Dieses stimmt mit Werten aus der Humanmedizin überein. In einer Studie an Kindern wurde gezeigt, dass neurologische Symptome ab Kalzium-Konzentrationen von ≤ 0,62 mmol/l auftreten können (Sorell et al., 1975).
Eine hepatische Enzephalopathie führte bei neun Hunden zu epileptischen Anfällen.
Der Pathomechanismus der hepatischen Enzephalopathie wurde bisher nicht aufgeklärt. Mehrere Auslöser wurden vermutet (Maddison, 1992), wobei es wahrscheinlich ist, dass nicht eine Theorie alleine das Auftreten von Krampfanfällen erklären kann. Somit besteht weiterhin der Verdacht, dass mehrere Faktoren
