Studies on canine epilepsy: diagnostic workup including ... · Tierärztliche Hochschule Hannover...

Tierärztliche Hochschule Hannover Klinik für Kleintiere

Studies on canine epilepsy: diagnostic workup including advanced imaging techniques and new

treatment modalities

INAUGURAL – DISSERTATION

zur Erlangung des Grades einer Doktorin der Veterinärmedizin

- Doctor medicinae veterinariae -

( Dr. med. vet. )

vorgelegt von

Melanie Jambroszyk

aus Essen

Hannover 2008

II

Wissenschaftliche Betreuung: Univ.-Prof. Dr. med. vet. A. Tipold

Ein Teil des Projektes (Zusatztherapie mit Verapamil) wurde von Frau Univ.-Prof. Dr.

med. vet. H. Potschka, Institut für Pharmakologie, Toxikologie und Pharmazie,

Ludwig-Maximilians-Universität München, mitbetreut.

1. Gutachterin: Univ.-Prof. Dr. med. vet. A. Tipold

2. Gutachter: Univ.-Prof. Dr. med. vet. K. Feige

Tag der mündlichen Prüfung: 22.05.2008

Gefördert durch die Gesellschaft zur Förderung kynologischer Forschung e.V.

III

Meiner Familie gewidmet

„Die Kunst ist, einmal mehr aufzustehen, als man umgeworfen wird.“

Winston Churchill, 1874 – 1965

IV

Teile der hier vorliegenden Arbeit wurden bereits als Kongressbeitrag präsentiert:

ADD ON TREATMENT WITH PHENOBARBITAL AND A P-GLYCOPR OTEIN

INHIBITOR OR LEVETIRACETAM IN DOGS.

M. Jambroszyk1, H. Potschka2, A. Tipold1. 1Department of Small Animal Medicine

and Surgery, University of Veterinary Medicine Hannover, 2Institute of Pharmacology,

Toxicology and Pharmacy, Ludwig Maximilians University, Munich, Germany

In European Society and European College of Veterinary Neurology: Proceedings of

20th Anniversary Symposium “Infectious and Inflammatory Diseases of the Nervous

System in Animals”, Bern 27.-29-September 2007.

Table of content V

Table of content Page

Abbreviations............................................................................................................ VI

1 Introduction..........................................................................................................7

2 Literature review..................................................................................................9

2.1 Idiopathic and symptomatic epilepsy............................................................9

2.2 Pharmacoresistance in epilepsy.................................................................12

3 Material and Methods........................................................................................14

3.1 Evaluation of the distribution and trait of seizures ......................................14

3.1.1 Statistical analysis...............................................................................16

3.2 Treatment Study including treatment with PB and Verapamil- Pre-study ...16

3.3 Treatment Study including treatment with PB and Verapamil- Main-study.18

3.4 Treatment with PB and Levetiracetam .......................................................21

4 Results ..............................................................................................................22

4.1 Actual distribution and classification of seizures ........................................22

4.2 Treatment Study- Outcome of the Pre-Study .............................................30

4.3 Treatment Study- Outcome of the Main Study ...........................................31

4.3.1 Blood evaluation and side effects........................................................33

4.4 Add-on treatment with Levetiracetam.........................................................34

5 Discussion .........................................................................................................35

5.1 First part of the study..................................................................................35

5.2 Second part of the study (Treatment study) ...............................................38

6 Conclusion.........................................................................................................41

7 Summary ...........................................................................................................42

8 Zusammenfassung............................................................................................44

9 References ........................................................................................................47

10 Appendix ...........................................................................................................58

11 Acknowledgements ...........................................................................................76

VI Abbreviations

Abbreviations

AED Antiepileptic Drug

BBB blood brain barrier

CSF cerebrospinal fluid

ECG electrocardiogram

GABA gamma amino butyric acid

ILAE International League Against Epilepsy

KBr potassium bromide

MRI magnetic resonance imaging

MRT Magnetresonanztomographie

PB Phenobarbital

PGP P-glycoprotein

VER Verapamil

Introduction 7

1 Introduction

Epilepsy is one of the most common neurological diseases in dogs (SCHWARTZ-

PORSCHE et al. 1985, JAGGY and BERNARDINI 1998, CHANDLER 2006). It is

characterized by uncontrollable electric discharges of the neurons in the brain

(JAGGY and HEYNOLD 1996) and is defined as a condition of recurrent focal,

complex focal or generalized seizures (LECOUTEUR and CHILD 1989, PODELL et

al. 1996, HEYNOLD et al. 1997). Up to 10% of the dog population with neurological

disorders suffer from seizures of different causes (JAGGY and BERNARDINI 1998).

In veterinary medicine seizures can be categorized due to the etiologic background.

Epilepsy could be divided into three general categories according to the “Commission

on Classification and Terminology of the International League Against Epilepsy”

(ILAE) (ILAE 1989, ENGEL 2006). Concerning idiopathic epilepsy no underlying

causes are detectable during diagnostic work-up (SCHWARTZ-PORSCHE 1984,

JAGGY and BERNARDINI 1998, KNOWLES 1998, LICHT et al. 2002). Symptomatic

epilepsy is induced by an intracranial (secondary intracerebral) or a general

metabolic disease (secondary extracerebral) (JAGGY and HEYNOLD 1996). In

addition, patients, who most likely suffer from symptomatic seizures although no

abnormality could be found after a complete diagnostic work-up, are categorized to

the group of cryptogenic epilepsy (PODELL 1999). Last year at the ACVIM Meeting

in Seattle (25th ACVIM Forum, 2007, Seattle) a consensus statement was presented.

According to this statement the diagnosis of idiopathic epilepsy is confirmed, when

neurological and laboratory examinations are normal.

In the last years several studies have shown that magnetic resonance imaging (MRI)

has the capability to detect abnormalities in the brain more sensitively than computed

tomography (CT) (BRANT-ZAWADZKI et al. 1984, MATHEWS et al. 1989, MODIC

1991, KORTZ 1998, SNYDER et al. 2006). Therefore in human medicine the ILAE

recommends a high quality MRI in every epileptic patient to rule out any secondary

cause for seizure development (KUZNIECKY et al. 2002). In the current study we

evaluated, if MRI examinations are also recommended for every canine patient with

seizures.

8 Introduction

Diagnostic work-up and exclusion of extraneural metabolic diseases is followed by

treatment with antiepileptic drugs. Standard antiepileptic drugs (AED) are

Phenobarbital (PB) and potassium bromide (KBr) (FREY and LÖSCHER 1985,

PEARCE 1990, PODELL 1996, LÖSCHER 2003, GOVENDIR et al. 2005).

Nevertheless, about 30% of dogs with epilepsy are refractory to this

pharmacotherapy (SCHWARTZ-PORSCHE et al. 1985, PODELL and FENNER

1993, TREPANIER et al. 1998, RIECK et al. 2002, MUNANA 2004).

Pharmacoresistance to PB and/or KBr can be defined if no reduction in seizure

frequency of at least 50% is achieved despite adequate serum concentrations of the

AED (TREPANIER et al. 1998, REGESTA and TANGANELLI 1999). Despite the

introduction of several new antiepilepileptic drugs during the last two decades the

incidence of pharmacoresistance remains at a comparable level (REGESTA and

TANGANELLI 1999, BEGHI 2004, ROGAWSKI and LÖSCHER 2004). In veterinary

medicine the use of these new AEDs is limited due to very short half-lives or adverse

side effects (LÖSCHER 2003, GOVENDIR 2005). Furthermore, the costs for some of

these drugs are very high, thus limiting the use of this medication.

In the current study two approaches were pursued: Firstly, the diagnostic workup

including MRI studies in dogs with seizures was evaluated to give a recommendation

for private practice. Therefore, in retrospective part of the study the purpose was to

evaluate the actual distribution of idiopathic and symptomatic epilepsy in 343 patients

with seizures presented at the Department of Small Animal Medicine and Surgery,

University of Veterinary Medicine Hannover, after the introduction of MRI and to

evaluate the use of MRI studies in every patient with seizures.

In a second step a new therapeutic concept in pharmacoresistant dogs with epilepsy

was tested.

Literature review 9

2 Literature review

2.1 Idiopathic and symptomatic epilepsy

Up to 10 % of patients with neurological deficits suffer from seizures of different

causes (SCHWARTZ-PORSCHE et al. 1985, JAGGY and BERNARDINI 1998,

CHANDLER 2006). Diagnosing idiopathic epilepsy is still a demanding challenge,

because all other possible seizure-inducing diseases have to be excluded by the use

of different available diagnostic tools. Dysfunctions like vascular (e.g. stroke) and

inflammatory diseases (e.g. canine distemper encephalitis), trauma, anomaly

(primary hydrocephalus), neoplastic disorders (e.g. brain tumor) or degenerative

diseases (e.g. storage diseases) belong to the group of “secondary intracerebral”

disorders, whereas dysfunctions like hyperglycaemia (e.g. diabetes mellitus),

hypoglycaemia (e.g. insulinoma), hyperammoniaemia (e.g. liver shunt) or

hypothyroidism belong to the “secondary extracerebral” disorders (TIPOLD 1995,

THOMAS 1998, BAGLEY et al. 1999, SNYDER et al. 2006). Precise diagnostic work-

up is necessary to rule out secondary intra- and extracerebral disorders. The

common scheme of complete diagnostic workup in canine epilepsy is shown in

Figure 1. In veterinary medicine the incidence of brain tumors, inflammatory brain

diseases or anomalies is as high as in human medicine (MOORE et al. 1996,

SNYDER et al. 2006). Therefore the MRI should be used as a routine diagnostic tool

in diagnosing idiopathic epilepsy in veterinary medicine as well. This often fails

because of high costs, which result from the required general anaesthesia and

maintenance costs of the MRI (JAGGY and BERNARDINI 1998, BERENDT et al.

1999), but is especially recommended in older individuals (SMITH et al. 2007).

10 Literature review

Figure 1: Scheme of complete diagnostic workup in c anine epilepsy (Source: CVE 2007; 1 (5):

1-24)

In addition to brain lesions causing seizures, postictal MRI changes are described in

human and veterinary medicine (AYKUT-BINGOL et al. 1997, MELLEMA et al.

1999). Postictal changes are regions with hyperintensity in T2-weighted images with

only marginal mass effect (Figure 2). They occur in patients with generalized

physical and neurological

examination

Specific treatment of

internal diseases

Examination of the brain: EEG,

MRI and CSF

Specific treatment of

intracranial diseases

diagnosis of

IDIOPATHIC EPILEPSY

blood cell count, serum chemistry,

X-ray thorax and abdomen,

ultrasound heart/ abdomen… Diagnosis of internal diseases

Exclusion of internal diseases

Diagnosis of intracranial diseases

Exclusion of intracranial diseases

Diagnosis of idiopathic epilepsy

Literature review 11

seizures and cannot be detected in MRI control examinations. These reversible

changes are thought to be caused by a disturbance in the blood-brain-barrier, a local

cytotoxic/vasogenic brain edema or a cerebral dysregulation during seizure activity

(MONTE SECADES et al. 1994, AYKUT-BINGOL et al. 1997, SILVERSTEIN and

ALEXANDER 1998, MELLEMA et al. 1999).

Figure 2: Postictal changes- MRI study of a dog- tr ansversal plane, T2-weighted image,

arrowhead: symmetric hyperintense lesions in the ar ea of hippocampus (Source: Vet Radiol

Ultrasound 1999; 40 (6): 588-595)

12 Literature review

2.2 Pharmacoresistance in epilepsy

One hypothesis for the described pharmacoresistance in patients suffering from

refractory epilepsy is the overexpression of multidrug transporters in the blood brain

barrier (BBB) and in epileptic brain tissue (TISHLER et al. 1995, DOMBROWSKI et

al. 2001, SISODIYA et al. 2002). Recently, we got first evidence that an

overexpression of the multidrug transporter P-glycoprotein (PGP) is also present in

the canine epileptic brain (POTSCHKA, unpublished data).

The physiological function of multidrug transporters is to support the defence

mechanisms of the brain by limiting the influx of a broad spectrum of xenobiotics as

you can see in Figure 3 (FROMM 2000, LEE et al. 2001). P-glycoprotein for example

is normally found in the vicinity of blood vessels, especially on endothelial cell

membranes (RAO et al. 1999) and mainly transports planar, lipophilic, molecular

structures. As the vast majority of the current AEDs have planar and lipophilic

qualities (LEVY et al. 1995) many AEDs are likely to be PGP substrates.

Figure 3: The function of multidrug-transporters li ke P-glycoprotein and their inhibitors for

example Verapamil (Source: The Association of the B ritish Pharmaceutical Industry- ABPI)

Literature review 13

Therefore, overexpression of PGP can explain pharmacoresistance to a broad

spectrum of different AEDs with different mechanisms of action. The overexpression

of P-glycoprotein seems to prevent a sufficient brain penetration of the AEDs and

thus, is hypothesised to limit the AED concentrations reached at the target sites on

epileptic neurons (POTSCHKA et al. 2001, POTSCHKA and LÖSCHER 2001,

LÖSCHER and POTSCHKA 2002).

Experimental data indicate that seizure activity is the major factor inducing a transient

overexpression in the epileptic tissue (ZHANG 1999, SEEGERS et al. 2002).

Another hypothesis of pharmacoresistance in epilepsy is the possibility that GABA-

receptors lose their inhibitory function. In veterinary medicine most of the AEDs act

as a stimulant to the GABA-receptors. Therefore, the administration of AEDs with

completely different mechanisms, such as Levetiracetam (Figure 4), which is binding

at the synaptic vesicle protein (SV2A) instead of GABA-receptors (LYNCH et al.

2004, GILLARD et al. 2006) and which do not act as P-glycoprotein-substrate in

addition, could be recommended.

Figure 4: Chemical structure of Levetiracetam

So far it is not clear, whether a modulation of PGP function can be achieved by co-

administration of Verapamil in order to enhance brain penetration of PB and to

improve the clinical response to PB. The P-glycoprotein modulator inhibitor

Verapamil in combination with PB in patients with refractory epilepsy was expected to

reduce the pathological transporter efflux (POTSCHKA et al. 2002).

14 Material and Methods

3 MATERIAL AND METHODS

3.1 Evaluation of the distribution and trait of seizures

The records of 343 dogs were evaluated. These patients were presented at the

Department of Small Animal Medicine and Surgery, University of Veterinary Medicine

Hannover after introduction of magnetic resonance tomography (MRI) between

01/2004 and 09/2006 by reason of having seizures. The criteria for including patients

in the data collection were the occurrence of focal, complex focal or generalized

seizures and the existence of a physical examination, blood cell count and serum

chemistry. Detailed information about breed, gender, age of presentation, nature of

seizures (focal, complex-focal or generalized seizures, occurrence of clusters/status

epilepticus), age of seizures occurrence for the first time, seizure frequency and

results of physical, neurological and blood examination were recorded. In cases

where additionally ultrasound, MRI and/or an examination of the cerebrospinal fluid

(CSF) were performed, these results were included as well (Table 1).

Table 1: Performed examinations in 343 dogs with se izure activity

Examination number of dogs

physical examination 343

neurological examination 310

blood cell count/serum chemistry 343

thyroid hormone 211

ultrasound abdomen 155

ultrasound heart 112

CSF examination 140

MRI 145

Furthermore the final clinical diagnoses were listed and it was noted if dogs passed

away or had to be euthanized.

Material and Methods 15

After the collection of all data, the patients were divided into two groups to evaluate

the significance of MRI and other further examinations. The cases with a confirmed

diagnosis of idiopathic or symptomatic epilepsy were summarized in Group 1. The

following criteria were used to confirm the different diagnoses. In the case of

idiopathic epilepsy no interictal changes during physical and neurological

examination were found. Blood work, MRI and CSF examination were normal.

Metabolic or toxic disorders were verified by abnormal blood examination and/or

positive metabolic or toxicologic test results. Neoplastic, inflammatory, vascular

disorders and anomalies were diagnosed using MRI in combination with CSF

examination. Histopathological findings contributed to the diagnosis if available to

distinguish inflammatory and neoplastic lesions. Degenerative diseases were

confirmed by histopathological examination.

Group 2 contained all patients with a highly suspicious clinical diagnosis, which could

not be confirmed by further extensive testing. Reasons for incomplete diagnostic

investigation were reluctance of the owner or the dogs died respectively were

euthanized due to bad general condition before finishing diagnostic work-up. In this

group at least a clinical and neurological examination and laboratory testing was

performed as suggested by the consensus statement (25th Annual ACVIM Forum,

2007, Seattle).

Data of group 1 were compared to those of group 2 to evaluate the different

distribution of clinical diagnosis. A correlation between the results of neurological

examination (normal/ abnormal) and MRI findings (normal/ abnormal) was

additionally calculated.

MRI (1 Tesla, Magnetom, Siemens, Siemens AG, Erlangen, Germany) was

performed in 145 patients to exclude symptomatic epilepsy. These image sequences

were re-evaluated by a Diplomat, a Resident of the European College of Veterinary

Neurology and the author. In every case T1-weighted images with and without

contrast medium (Gadolinium) (Magnevist, Schering, Deutschland GmbH, Berlin,

Germany) and T2-weighted images were performed in sagittal, transversal and

dorsal planes. In the cases where FLAIR- and STIR-sequences were available, they

were included into the evaluation. Focus of the re-evaluation of the MRI-images was


to discover and compare the different MRI results as well as to detect possible

postictal changes which arise as hyperintens regions in T2-weighted images and

which are not typical for other brain diseases (MELLEMA 1999). To evaluate, if

postictal changes occur only shortly after seizure events, the time period between

last seizure event and MRI was noted. Control MRIs could not be done in the current

study because of reluctance of the owners to perform two long anaesthesias in dogs

with seizures. Postictal changes were defined as typical diffuse T2 hyperintense

region in the temporal lobes as described by MELLEMA et al. 1999.

3.1.1 Statistical analysis

The comparison of distribution of the clinical diagnoses in group 1 and 2 (confirmed

versus presumptive diagnosis) was made using the two-sided Chi-squared-test. To

prove a feasible correlation between MRI findings and the result of the neurological

examination and the occurrence of postictal changes in MRI, the kappa-index was

calculated. Linear regression gave information about a possible correlation between

the occurrence of postictal changes and the time period between the last seizure

event and performance of MRI. The statistical analysis was performed at the Institute

for Biometry, Epidemiology and Information Processing of the University of

Veterinary Medicine Hannover.

3.2 Treatment Study including treatment with PB and Verapamil- Pre-study

A permit was granted for both parts of the study under animal experiment number

33.42502/05-12.05 on 19 December 2005.

The pre-study was designed to investigate tolerability of a combined treatment with

PB and Verapamil. The combination was tested on 6 beagle dogs two years of age, 3


females and 3 males, with a bodyweight of 11-13 kg.

PB (Luminal/Luminaletten, Desitin, Germany) was applied by oral administration

once daily at a dosage of 4 mg/kg bodyweight. This resulted in a complete dosage of

45-50 mg PB per dog and day in the first part of the study. On day 30 of PB

administration the following initial examinations were performed: clinical and

neurological examination, blood cell count and blood chemistry (Laboratory

Department of Small Animal Medicine and Surgery, University of Veterinary Medicine

Hannover), measurement of blood pressure (NAIS Memoprint, Matsushita Electric

Works), electrocardiogram (ECG) (MAC 5000 marquette and MAC 1200 ST, GE

Medical Systems) and the examination of cerebrospinal fluid (CSF), which included a

cell count, the measurement of glucose concentration, total protein and PB

concentration in the CSF (Laboratory Department of Pharmacology and Toxicology,

University of Veterinary Medicine Hannover). CSF samples were taken under general

anaesthesia in lateral recumbency by puncture of the Cysterna magna.

All six dogs additionally received Verapamil twice daily (Verapamil-ratiopharm N 80,

Ratiopharm, Germany) at a dosage of 6.2–7.3 mg/kg bodyweight starting on day 32

after the beginning of the administration with PB. The Verapamil administration

resulted in a complete dosage of 160 mg per dog and day. On day 13 of this

combined application all above mentioned examinations and the measurement of PB

concentration in the CSF were repeated. After that the Verapamil administration was

stopped and PB administration was increased to 10 mg/kg bodyweight once a day to

determine whether adverse effects in patients treated with a high PB dosage might

occur. This resulted in a dosage of 115–130 mg PB per dog and day. Thirty days

after increasing the PB administration the dogs received again an add-on treatment

with Verapamil (6.6-7.3 mg/kg twice daily, 160 mg per dog and day). Forty-three days

following the increase in the PB dosage all examinations were repeated except for

the sampling and analysis of CSF as shown in Figure 5.


Figure 5: Study design pre-study

legend: PB= Phenobarbital, VER= Verapamil, bw= body weight

3.3 Treatment Study including treatment with PB and Verapamil- Main-study

The main study included 11 dogs from different breeds, which were considered to be

non-responders to PB treatment (Table 2). For inclusion in the study the dogs had to

fulfill the following criteria: generalised seizures (single generalised seizures,

clusters, status epilepticus), no benefit or poor seizure control despite a high serum

level of PB. The dogs had to display a seizure frequency of at least one seizure/

month and had to be treated only with PB, resulting in an adequate serum level

within the therapeutical range (65-130 µmol/l). Data concerning seizure frequency of

the previous 4 months were available and physical and neurological examinations

had to be without distinctive features. Dogs were examined according to the study

design shown in Figure 6.

0 days 30 32

first

examination

45

second

examination

75 88

third

examination

VER add-on

treatment

PB treatment

4mg/kg bw

PB treatment alone

10 mg/kg bw

VER add-on

treatment


Figure 6: Study design main-study, legend: PB= unde r Phenobarbital treatment alone

The initial examination included the same tests as in the pre-study: physical and

neurological examination, blood cell count and serum chemistry, measurement of

blood pressure and ECG. In cases with bradycardia, cardiac murmur or an irregular

heartbeat, blood pressure under reference range and/or an abnormal ECG, patients

were not allowed to participate in the study because of a potential for increased side

effects of Verapamil.

After giving the owners general instructions and having them sign a contract the

Verapamil administration started at a dosage of about 1 mg/kg twice daily additionally

- 4 - 3 - 2 - 1 1 2 3 4

control examinations

1 2 3 4

Levetiracetam add - on treatment

months

months

PB treatment Verapamil add- on treatment

initial examination


to the PB treatment. The Verapamil dosage was reduced in comparison to the pre-

study since the first study participant developed severe bradycardia as an adverse

side effect. Every four weeks after the first Verapamil administration controls were

performed and the initial examinations were repeated four times. Before beginning

with the co-administration of PB and Verapamil and at the last control examination

the PB serum level was measured (Alomed, Radolfzell-Böhringen). Following the

fourth examination participation in a long-term study was optional for the owners, if

the dog responded well to the combined treatment and no side effects occurred.

Dogs with a reduction in seizure frequency of at least 50 % during the period of

combined treatment with PB and Verapamil compared to the 4-month period without

Verapamil were classified as Verapamil-responders. The following data were

evaluated: number of Verapamil-responders, development of seizure severity,

seizure duration and possible side effects.


3.4 Treatment with PB and Levetiracetam

In Verapamil-non-responders an add-on treatment with Levetiracetam (10-15 mg/kg

three times daily) was tested following discontinuation of Verapamil. If no seizure

reduction was observed in response to this initial dosage the Levetiracetam dosage

was increased to 20 mg/kg bodyweight three times daily. Additional diagnostic work-

up such as computed tomography (CT), magnetic resonance imaging (MRI) and CSF

analysis was performed in half of the cases to rule out symptomatic epilepsy. In the

other dogs further examinations could not be performed because of reluctance of the

owners.

Table 2: Patient information and Phenobarbital plas ma level before and after combined

treatment with Verapamil

Case Breed Gender

Weight

(kg)

Age of

1st

seizure

(yr)

Age at

study entry

(yr)

seizure

type

length of PB

medication before

study entry

PB plasma

pre VER add-

on

PB plasma

after the

study

Additional

diagnostic

workup

1 GS m 30,5 1,75 3,5 tc 20 90.1 µmol/l

2 H f 37,5 3,1 4,5 tc, foc 11 109.2 µmol/l CT, CSF

3 AT m 9,3 1,75 2,25 tc 5 135 µmol/l

4 CB f 16 2,75 3,75 tc 8 135.9 µmol/l CT, CSF

5 BP f 13,3 4,5 7,5 tc 34 158.2 µmol/l MRI, CSF

6 S f 40 1,8 3,5 tc, foc 20 147.5 µmol/l 160 µmol/l

7 CB m 42 4,2 7,1 tc 36 95 µmol/l 110 µmol/l

8 CB m 41 1 5 tc 42 65 µmol/l 124 µmol/l

9 BP m 14 3,25 7,25 tc 45 174 µmol/l 164 µmol/l

10 FB f 14 0,9 1,2 tc 4 89 µmol/l 87 µmol/l MRI, CSF

11 CB f 15,5 1,5 3,2 tc 21 180 µmol/l 134 µmol/l MRI, CSF

legend: GS= Gordon Setter, H= Hovawart, AT= Austral ian Terrier, CB= Crossbreed, BP= Bergé

de Pyrenée, S= Giant Schnauzer, FB= French Bulldog, m= male, f= female, yr= years, tc=

generalised tonic-clonic seizures, foc= focal seizu res, PB= Phenobarbital, VER= Verapamil,

MRI= magnetic resonance imaging, CT= computed tomog raphy, CSF= cerebrospinal fluid

analysis, = drop out

22 Results

4 RESULTS

4.1 Actual distribution and classification of seizures

A total of 343 dogs suffering from generalized, focal or complex focal seizures met

the criteria for inclusion in the study. Of these 343 dogs, 150 dogs (43.7%) were

female and 103 dogs (56.3%) as shown in the figure 7.

Figure 7: Distribution of gender

legend: f= intact female, fn= neutered female, m= i ntact male, mn= neutered male

Over eighteen breeds were represented in addition to 77/343 crossbred dogs

(22.5%). The distribution of frequently occurring breeds is shown in figure 8; large

breed dogs were seen more frequently than small breed dogs. Information about the

age when the first seizure appeared in the dogs could be gathered in 337 cases.

Fourty three dogs (12.8%) were younger than one year, 91 dogs (27%) were older

than six years and the main part of 203 dogs (60.2%) were between one and six

years old.

distribution of gender

f

fn

m

mn

Results 23

5.2%

22.5%

48.3%4.7%

4.7%

4.1%

4.1%

3.2%

3.2%

miscellaneous breeds

Crossbreed

Golden Retriever

Dachshund

Jack Russel Terrier

Labrador Retriever

German Shepherd

Schnauzer

Beagle

Figure 8: Distribution of different breeds sufferin g from seizure activity.

The character of the seizures was evaluated in all cases. The main part (304 dogs;

88.6%) suffered from generalized seizures (tonic-clonic, tonic, clonic) whereas a

differentiation between primary and secondary generalized seizures could not made

retrospectively. Fourteen dogs (4.1%) suffered from focal and 8 (2.3%) dogs suffered

from complex-focal seizures exclusively. Ten dogs (2.9%) were afflicted with the

combination of generalized and focal seizures, whereas 2 dogs (0.6%) suffered from

the combination of focal and complex-focal seizures. Only in 1 dog (0.3%) all three

forms of seizuring (generalized, focal and complex-focal) occurred. Seizure

frequency could be evaluated in 328 dogs. The other dogs were admitted because of

sudden onset of clusters or status epilepticus. Most of the dogs (124/328; 37.9%)

had only 2-3 seizures at the time of the neurological consultation and the exact

frequency could not be determined. The seizure frequency of the other 204 dogs is

described in Figure 9.

Furthermore, 49.9% (171/343) of the whole study population suffered from cluster

runs whereas 12.5% (43/343) experienced a status epilepticus in life before. Of the

whole patient population 34 dogs (9.9%) had to be euthanized because of the

24 Results

severity of their seizures and the seizure frequency, and 4 patients (1.2%) died due

to bad general condition.

Figure 9: Seizure frequency of 204 dogs

In every patient blood cell count and serum chemistry was performed. In 63.3% of

the population (217/343) both examinations were unremarkable whereas in 36.7%

(126/343) different abnormalities could be found. The diagnoses of dogs with

metabolic-toxic diseases and seizure activity are summarized in table 3.

0

10

20

30

40

50

60

70

dogs

monthly weekly every second week 1-2/ year <1/ year daily

Results 25

Table 3: Dogs with metabolic-toxic diseases and sei zure activity (confirmed diagnoses)

diagnosis number of dogs

intoxication 16

hypothyreosis 10

insulinoma 6

Cushing’s disease 4

diabetes mellitus 4

liver shunt 3

sick sinus syndrom 2

hypoparathyoidism 2

Addison’s disease 1

hypoxy 1

hyocalemia after birth 1

others 1

total 50

In general the whole population could be divided into two groups. 212 patients were

summarized in group 1 (61.8%) and the clinical diagnosis was considered to be

confirmed according to the described criteria. In group 2 (131 dogs) diagnoses were

only presumed because of incomplete diagnostic work-up. Two-sided Chi-squared-

test could show a significant different distribution of etiological background

(p=0.0005). In group 2 a suspicion of idiopathic epilepsy was more frequently

diagnosed, than in cases with complete diagnostic work-up of group 1. Furthermore,

diseases like anomalies, vascular and degenerative diseases were not diagnosed in

group 2. In figure 10 the distribution of different disease categories causing seizures

is shown in a comparative way for group 1 and 2.

26 Results

A: group 1

different disease categories- confirmed diagnoses

idiopathic

vascular

inflammatory

trauma

anomaly

metabolic-toxic

neoplastic

degenerative

B: group 2

different disease categories- presumed diagnoses

idiopathic

vascular

inflammatory

trauma

anomaly

metabolic-toxic

neoplastic

degenerative

Figure 10 A+B: Different disease categories of grou p 1- confirmed and group 2- presumed

diagnoses

Neurological examination was performed in 310 dogs. The other cases had to be

sedated because of severe seizure activity. In 214 of the 310 dogs, the neurological

examination was unremarkable whereas in 96 dogs neurological deficits occurred

such as ataxia, proprioceptive deficits, absent menace response, vestibular signs,

strabismus/nystagmus, anisocoria, hypermetria, circling, opisthotonus, and/or

paraparesis/ tetraparesis. In 145 dogs a neurological examination as well as a MRI

examination was performed. In these cases the result of the neurological

Results 27

examination (normal/ abnormal) was compared with the results of MRI (normal/

abnormal). Kappa-index was calculated and a slight correlation existed (kappa-index

0.1358). Ninety three of the 145 dogs did not show neurological deficits and 76 of

them had a normal MRI additionally. Nevertheless, in 17 dogs MRI abnormalities

could be found despite a normal neurological examination. In these 17 cases either

an intracerebral neoplasia or an inflammatory disease was detected. In contrast,

neurological deficits could be shown in 52 of the 145 dogs. Sixteen of them had

abnormal findings in MRI whereas 36 dogs had a normal MRI. These results are

illustrated in Table 4.

Table 4: Correlation between the results of neurolo gical examination and MRI

neurological examination unremarkable neurological examination abnormal number of dogs: 93 number of dogs: 52

normal MRI results

abnormal MRI results

normal MRI results

abnormal MRI results

76 17 36 16

Neurological deficits were found in 36 cases with normal further examinations. In

these cases these signs did not resolve in all cases until 1 to 5 days. Therefore they

were not considered as postictal findings in all of these cases.

In addition to the evaluation of the diagnoses of these 145 MRI-series, attention was

turned to the existence of postictal changes in MRI-sequences. Presumed postictal

changes occurred in 10/145 cases (Figure 11). There was no correlation between

postictal changes and normal or abnormal MRI (neoplasia, inflammatory lesion,

anomaly) (kappa-index -0.0640).

28 Results

Figure 11: Presumed postictal changes: MRI of a dog - transversal plane, T2-weighted image

Albeit a certain tendency could be seen, a correlation between the occurrence of

postictal changes and the period between the last seizure event and performance of

the MRI (p=0.1911) could not be proven. In table 5 the time period between the last

seizure event and the MRI performed in cases with postictal changes is listed.

Table 5: patients with postictal changes in MRI- da ys between last seizure event and performed

MRI

Patient days between seizure event and MRI

1 4

2 4

3 1

4 1

5 16

6 2

7 2

8 8

9 1

10 1

Results 29

Examination of cerebrospinal fluid (CSF) was performed in 140 dogs. 90% of the

dogs (126/140) had a normal CSF without an elevated number of cells (0-2 cells/µl).

Six dogs (4.3%) had a slightly increased (3-10 cells/µl) and 8 dogs (5.7%) had a

moderate to severe increased number of cells in CSF.

An overview about the context between the age at onset of seizures and the results

of the neurological examination, the CSF analysis and the performed MRI in 135

dogs is shown in Table 6.

The probability is higher in dogs older than 6 years of age that a normal neurological

examination is accompanied by abnormal MRI results.

Table 6: results of neurological examination, exami nation of the CSF and the existence of

abnormal MRI findings in 135 patients

number of dogs age at onset of

seizures

results neuro

examination result CSF analysis normal MRI

results abnormal MRI

results

< 1y abnormal abnormal 1 1

abnormal normal 2 1

normal abnormal 0 0 normal normal 6 1

1y > 6y abnormal abnormal 2 2 abnormal normal 17 4

normal abnormal 0 1

normal normal 40 5

> 6y abnormal abnormal 1 0

abnormal normal 8 5

normal abnormal 3 1

normal normal 25 9

30 Results

4.2 Treatment Study- Outcome of the Pre-Study

All beagle dogs were in good constitution and alert during the whole study period.

Between days 32 to 40 the dogs developed slight diarrhoea. Initial and control

examinations were altogether unremarkable. Bradycardia (64 heartbeats per minute)

was observed during the third control examination in dog 1. Furthermore, a decrease

in blood pressure was found in three of the dogs during the course of the study. In

ECGs no abnormal findings could be observed (Table 7).

Table 7: Count of heart rate and results of blood p ressure measurement in six healthy beagle

dogs

Dog Gender Heart rate blood pressure

1st

examination

2nd

examination

3rd

examination

1st

examination

2nd

examination

3rd

examination

1 m 112 100 64 174/129 131/75 112/80

2 f 132 140 120 160/124 131/105 138/109

3 m 100 140 116 170/133 167/107 157/85

4 m 100 84 88 144/99 133/89 135/81

5 f 120 120 106 175/107 168/112 197/135

6 f 100 132 100 192/111 133/90 120/97

legend: m= male, f= female, heart rate= heartbeats per minute, blood pressure= systolic arterial

blood pressure/ diastolic arterial blood pressure i n mm/Hg

The CSF examinations were unremarkable. Cell count, glucose concentration and

total protein were all within the reference ranges in both CSF samples of each dog.

The measurement of PB concentration in serum and CSF did not result in any

elevation of PB concentration in CSF after the combined treatment with PB and

Verapamil over 14 days (Table 8).

Results 31

Table 8: Phenobarbital level in serum and cerebrosp inal fluid before (1 st examination) and 13

days after combined treatment of Phenobarbital and Verapamil (2 nd examination) in six healthy

beagle dogs

dog 1st examination 2nd examination

PB plasma (µg/ml) PB CSF (µg/ml) PB plasma (µg/ml) PB CSF (µg/ml)

1 8,02 5,77 8,65 5,52

2 11,22 5,40 11,63 6,24

3 12,86 8,05 14,41 7,72

4 12,03 8,18 13,00 8,24

5 13,11 7,76 10,75 6,29

6 11,69 6,68 12,94 7,44

legend: PB= Phenobarbital, CSF= cerebrospinal fluid

Blood examinations: three dogs (2, 5 and 6) had slightly elevated leukocytes (13.0-

14.2 103/µl, reference range 6.0-12.0 103/µl) at the last control examination. Two of

these dogs (5, 6) additionally developed decreased haemoglobin concentration under

reference range (14.1 g/dl, 11.9 g/dl, reference range 15.0-19.0 g/dl), which was

combined with a decreased hematocrit of 33 % (reference range 40.0-55.0%) in dog

6. In addition, five of the six dogs showed slightly elevated liver enzymes (ALT 69-

419 U/l, reference range < 50 U/l; GLDH 98,6 U/l, reference range < 6 U/l; ALP 238-

337 U/l, reference range <150 U/l) at the third blood examination. Both previous

blood examinations had revealed that all values had been within the reference range

before.

4.3 Treatment Study- Outcome of the Main Study

Patients’ medium age at the beginning of the first seizures was 2.4+0.8 years.

Medium bodyweight was 24.8+8 kg. All these dogs were considered to be

pharmacoresistant to PB and had at least generalised seizures every four weeks.

32 Results

Further information concerning all patients such as age at first seizure, age at study

entry, seizure type, length of time previously treated with PB, serum concentration at

study entry and after the study period of four months is provided in Table 2.

Six of the eleven patients completed the four-month observation period with

combined treatment with PB and Verapamil. Three dogs discontinued the study

because they developed heavy cluster seizures (Figure 12). In Patient 1 these

clusters started 7 days after beginning with add-on therapy with Verapamil directly.

Clusters had never appeared before in this patient. In Patient 2 cluster seizures had

occurred before the study, but after 6 weeks of combined treatment a run of clusters

of higher severity than before was observed despite seizure frequency having

decreased from 4.5 to 2 seizures/ month. In Patient 3 cluster seizures had been

known as well, but after 8 weeks of combined treatment heavier cluster seizures with

a higher number of generalised seizures/ 24 hours appeared in this patient, too. The

seizure frequency increased from 2 to 2.3 seizures/ month. All three patients had to

receive intravenously barbiturates to stop cluster seizures. Verapamil treatment was

discontinued in these cases and Levetiracetam add-on treatment was recommended.

In addition, two more patients did not complete the study because seizure frequency

did not change satisfactorily. Patient 4 stopped the study after 10 weeks. The seizure

frequency of this patient decreased from 2 to 1.3 seizures/ month. However, the

intensity and duration of the seizures increased. Patient 5 left the study after 9 weeks

because seizure frequency increased from 1.6 to 2.3 seizures/ month. The remaining

six patients completed the arranged observation period. One out of these six dogs

was a responder (Patient 7). The other five dogs were non-responders. The medium

seizure frequency before the beginning of the combined treatment with PB and

Verapamil was 1.4 seizures/ month (range 0.8 to 2.3) which increased to 1.8

seizures/ month (range 1.4 to 2.3). Furthermore, the intensity of the seizures

worsened at the end of the observation period in two of the dogs. In the dogs

suffering from cluster seizures before the study the number of seizures per day could

not be reduced with add-on treatment with Verapamil.

Results 33

Figure 12: Seizure frequency before and during Vera pamil and Levetiracetam add-on treatment

legend: PB= under Phenobarbital treatment alone

4.3.1 Blood evaluation and side effects

The PB serum concentration was evaluated before and after the four-month study

period. PB serum levels were not increased (Table 2). Regarding side effects in the

circulatory system severe bradycardia of 35 heartbeats per minute occurred in

Patient 11 two days after beginning with add-on therapy with Verapamil at a dosage

of 2 mg/kg bodyweight twice daily. The dosage was immediately lowered to 1 mg/kg

bodyweight twice daily. After this reduction the dog was in good constitution and

frame of mind and all circulatory values were in reference ranges during the further

study period. In two more patients a slight decrease in blood pressure could be

observed. However, values were still within the reference range and no clinical signs

occurred. Complete blood cell count and serum chemistry were performed in all

patients at every control examination. With the exception of a slight increase in liver

0

1

2

3

4

5

1 2 3 4 5 6 7 8 9 10 11

patients

seiz

ures

/ mon

th

PB Verapamil add-on Levetiracetam add-on Cluster

34 Results

enzymes in four and an increase of eosinophilic granulocytes in two (1760 – 1900/µl,

reference range < 1500/µl) out of eleven patients no further changes were observed.

One patient developed slight anaemia (haemoglobin 14.1 g/dl, hematocrit 39%,

erythrocytes 5.74 106/µl, reference range 6.0-9.0 106/µl) without clinical signs.

4.4 Add-on treatment with Levetiracetam

The 8 Verapamil non-responders (dogs 2, 3, 4, 5, 6, 9, 10 and 11) were treated with

Levetiracetam additionally to PB after Verapamil had been discontinued. As initial

dosage the dogs received 10-15 mg/kg bodyweight three times daily (VOLK et al.

2007).

If seizure frequency was not reduced for at least 50 % the dosage of Levetiracetam

was increased to 20 mg/kg bodyweight three times daily.

A subpopulation of 3 out of these 8 dogs (dogs 3, 4 and 10) could be classified as

Levetiracetam-responders. In Patient 3 seizure frequency was reduced from 2.1 to

0.5 seizures/ month. However, the number of cluster seizures could not be reduced.

The seizure frequency in Patient 4 decreased from 2 to 1 seizure/ month. In addition,

the severity of the seizures could also be reduced subjectively. The third responder

was Patient 10. After beginning with Levetiracetam add-on therapy no more seizures

for the four-month observation period appeared. However, after seven months cluster

seizures occurred once despite Levetiracetam treatment. The other five dogs had to

be classified as non-responders. The medium seizure frequency before the

beginning of the combined treatment with PB and Levetiracetam had been 2.25

seizures/month (range 1.5 to 3.8) which increased to 2.7 seizures/ month (range 1.8

to 3.9). The subjectively examined severity of the seizures could be reduced in all

cases. In the dogs suffering from cluster seizures the number of seizures per day

could not be reduced by using Levetiracetam as add-on therapy.

Discussion 35

5 Discussion

5.1 First part of the study

Epilepsy is one of the most common neurological diseases in dogs (SCHWARTZ-

PORSCHE et al. 1985, JAGGY and BERNARDINI 1998, CHANDLER 2006). The

etiological background of seizures is categorized into three different classes - the

idiopathic, the symptomatic and the cryptogenic epilepsy. In the idiopathic epilepsy

no detectable causes can be demonstrated after complete diagnostic work-up. The

symptomatic epilepsy is induced by an intracerebral or extracerebral disease and

cryptogenic epilepsy consists of patients in which symptomatic epilepsy is assumed

though no abnormalities are detectable (PODELL et al. 1995).

First goal in the present study was to analyse a large group of patients suffering from

seizures and classify the etiological background of the seizures according to the

Vitamin D-scheme (JAGGY 2005). All the patients were divided into two groups. In

group 1 in 212 patients a confirmed diagnosis could be established. The other 131

patients in group 2 did not undergo complete diagnostic work-up and etiologic causes

could only be presumed.

Regarding our data it can be stated, that 50 % of the patients with confirmed

diagnosis suffered from idiopathic epilepsy. In the other 50 % of the patients seizures

were a symptom of another primary disease. MRI diagnosis, established by the

examination of a large number of cases, did not change the figure, since the number

of patients with idiopathic epilepsy is similar to the number in former studies, which

range from 25 % over 40 % to 53 % of all epileptic dogs (PODELL et al. 1995,

JAGGY and BERNARDINI 1998, BERENDT and GRAM 1999). In our study about 24

% of the patients with symptomatic epilepsy suffered from metabolic-toxic diseases

like liver-shunts, hypothyroidism and other organic disorders, about 10 % had brain

tumors and 8.5 % suffered from inflammatory brain diseases. In our case load more

dogs had brain tumors than it was observed in most of previous studies (MOORE et

al. 1996, SNYDER et al. 2006). The same could be found for metabolic-toxic

36 Discussion

diseases (PODELL et al. 1995). The introduction of MRI seems to enhance the

diagnosis of brain tumors. Most of the brain tumors were observed in German

Shepherds (4/11 dogs) and Boxers (3/5 dogs). This matches with former studies

where Boxers were most affected amongst other breeds (HEIDNER et al. 1991,

BAGLEY et al. 1999). The German Shepherd is one of the most common breeds in

Germany with 16.000 to over 29.000 puppies per year in the last 10 years

(VERBAND FÜR DAS DEUTSCHE HUNDEWESEN, 2007) which could explain the

high number of German Shepherds with brain tumors. Anomalies were found only in

pure bred dogs and never appeared in any crossbred dog. Finally, we could not rule

out cryptogenic epilepsy in patients with an abnormal neurological examination

despite a normal CSF analysis and a normal MRI. This is in agreement with the study

of Berendt and Gram, 1999.

We compared group 2 (with a presumed diagnosis) with group 1 (with a confirmed

one). The results of the two-sided Chi-squared-test show that the distribution of the

differential diagnoses between the two groups is significant different. In group 2, 75%

of the dogs were classified to have idiopathic epilepsy, in only 25% symptomatic

epilepsy was suspected. Therefore most probably neoplastic, inflammatory and

metabolic-toxic diseases were underdiagnosed. Furthermore no anomaly and no

vascular diseases were suspected in group 2. In conclusion we can propose that a

complete diagnostic work-up is highly recommended for an exact diagnosis of the

cause for occurring seizures. Beyond we tested the capability of the neurological

examination to predict abnormalities in MRI or CSF examination respectively to

predict idiopathic epilepsy. Calculated kappa-index shows only a slight correlation.

Nevertheless, we could show that an unremarkable neurological examination is

mostly accompanied by a normal MRI, whereas abnormal MRI findings mainly occur

if the neurological examination is abnormal. This result confirms a former study

where correlation between the age and the results of neurological examination, CSF

analysis and MRI were tested (BUSH et al. 2002). Therefore, it can be proposed that

CSF analysis and MRI is indicated in dogs with seizures particularly if the

neurological examination is abnormal. Only in dogs older than 6 years of age a

tendency could be shown that MRI findings occur despite a normal neurological

Discussion 37

examination. According to the consensus statement, ACVIM, Seattle 2007, idiopathic

epilepsy could be diagnosed already by normal physical and neurological

examination and an unremarkable blood work. We could show in our study that older

dogs more frequently had MRI abnormalities despite a normal neurological

examination. Therefore MRI is recommended especially for dogs with seizures over 6

years of age even if financial aspects have frequently to be considered in private

practice (JAGGY and BERNARDINI 1998).

Concomitant we wanted to discover the occurrence of presumed postictal changes.

Postictal changes are described as hyperintens regions in T2-weighted images

without special mass effect. Their specific feature is their disappearance in control

MRI. It is thought that postictal changes are caused by a disturbance in the blood-

brain-barrier, a local cytotoxic/vasogenic brain edema or a cerebral dysregulation

during seizure activity (MONTE SECADES et al. 1994, AYKUT-BINGOL et al. 1997,

SILVERSTEIN and ALEXANDER 1998, MELLEMA et al. 1999). In our study

presumed postictal changes were found in 10 patients while MRI sequences were re-

evaluated. We had not the possibility to confirm that these changes disappeared in

control MRIs. Due to the fact that no control MRIs had been done, the occurrence of

postictal changes could only be assumed and interpretation of postictal changes can

be subjective. Re-evaluation was performed in a blinded way by a Diplomat and a

Resident of the European College of Veterinary Neurology to minimize the level of

error and evaluate in the most possible objective way. The occurrence of postictal

changes seems to be more probable when MRI is performed directly after the last

seizure event. However, calculating the linear regression in the present study no

significant correlation between the occurrence of postictal changes and the time

period between the last seizure event and performance of MRI could be seen. In our

study presumed postictal changes were found, when MRI studies were performed

contemporary 1 to 4 days after the last seizure event. Altogether postictal changes

seem to be rare findings compared to the total number of performed MRIs in our

study.

38 Discussion

5.2 Second part of the study (Treatment study)

In veterinary medicine about 30 % of the patients who suffer from epilepsy are

refractory to the treatment with common AEDs, such as PB and KBr (SCHWARTZ-

PORSCHE et al. 1985, PODELL and FENNER 1993, TREPANIER et al. 1998,

RIECK et al. 2002, MUNANA 2004).

In former studies an overexpression of multidrug-transporters in the BBB and in brain

tissue was identified both in rats and humans with refractory epilepsy (TISHLER et al.

1995, DOMBROWSKI et al. 2001, SISODIYA et al. 2002, POTSCHKA et al. 2004,

VOLK and LÖSCHER 2005). It is hypothesised that the overexpression of

transporters such as P-glycoprotein can limit brain penetration rates of AEDs

including PB. Refractoriness to AEDs can be the consequence of insufficient

concentrations at the target sites in the epileptic brain. A few experimental studies

with epileptic rats with pharmacoresistant or difficult-to treat epilepsy were performed

in which the efficacy of P-glycoprotein-inhibitors could be shown, which preclude the

pathological transporter efflux of AED (CLINCKERS et al. 2005, BRANDT et al. 2006,

VAN VLIET et al. 2006 ).

To tie in with these former experimental studies in rats it was the aim of our study to

evaluate the efficacy and tolerability of the co-administration of the P-glycoprotein-

inhibitor Verapamil with PB in dogs who suffer from naturally recurrent severe seizure

activity.

To fulfill the inclusion criteria of the study only dogs with refractory epilepsy were

examined. Generalised seizures occurred at least every four weeks, serum levels of

PB had to be within the normal and high range respectively. In a pre-study a good

tolerability of combination using higher dosage of PB and Verapamil than usually

applied, was demonstrated. No severe side effects occurred in the six beagle dogs

except for one of them which developed slight bradycardia. However, PB levels in

CSF did not increase after add-on treatment with Verapamil. It is possible that the

inhibition of the P-glycoprotein only affects PB concentrations in epileptic foci of

affected patients. VAN VLIET et al. (2007) showed in a recent study an increased

Phenytoin level after inhibition of P-glycoprotein with Tariquidar, which is a highly

Discussion 39

selective inhibitor, especially in brain regions with PGP-overexpression. This would

explain why the PB levels in CSF did not increase in the six healthy beagle dogs. On

the other hand, it is also possible that competitive inhibitors of the low affine first

generation, like Verapamil, could not inhibit P-glycoprotein efficiently at dosages

which are tolerable in dogs.

In our main-study population only one responder could be observed out of eleven

patients, whose seizure frequency improved up to 75 % in the designed observation

period and the last five months of the long-term follow-up. Five of the included

patients discontinued the intended observation period due to ineffectiveness of the

treatment. Three out of these five patients developed severe cluster seizures. In the

five remaining patients who completed the four-month observation period a

significant decrease in the seizure frequency did not occur. In general, a worsening

of the seizure severity could be observed subjectively by the owners in most of the

participants. In one patient mutual reaction concerning the circulatory system

occurred in form of severe bradycardia which disappeared after the dosage of

Verapamil was decreased. All the other patients were in good constitution over the

whole study period and no further side effects were seen.

The reason why the seizure frequency could not be reduced by treatment with the P-

glycoprotein inhibitor Verapamil in this study is not known. A possible explanation

would be that the Verapamil dosage in our study was too low to inhibit the

overexpressed multidrug transporters. Although no severe adverse effects occurred

in the beagle group of the pre-study, which were treated with a higher dosage of

Verapamil, we could not increase the Verapamil dosage in the epileptic patients due

to life-threatening side effects concerning the circulatory system as was the case in

Patient 11. The low dosage might have prevented the PB level reaching the effective

levels in the affected brain tissue to advance the accumulation of the AED in epileptic

foci. Noncompetitive inhibitors of the third generation such as Tariquidar (BRANDT et

al. 2006, VAN VLIET et al. 2007) might be more effective. This has also been

indicated by studies with P-glycoprotein-inhibitors in human cancer patients.

It is not clear, if either the medication failed or multidrug transporter overexpression

did not contribute to refractoriness in most of the dogs included in the study.

Another presumptive hypothesis in refractoriness is that the GABA-receptors lose

40 Discussion

their inhibitory function in general (DEISZ 2002, BECK 2007). The GABA-receptor is

the most important inhibitory receptor in the central nervous system. The

neurotransmitter gamma-aminobutyric acid (GABA) ligates on GABA-receptors which

induces an opening of the potassium channels causing a hyperpolarisation of the cell

membrane. Furthermore, calcium channels are blocked so that no more excitatory

transmitters can be discharged. Therefore, an achieved adequate PB level due to an

inhibition of the multidrug transporters could not have a positive effect concerning the

seizure frequency if the GABA-receptors lose their inhibitory function. Therefore,

eight Verapamil non-responders were treated with Levetiracetam as the add-on

therapy after Verapamil had been discontinued. Levetiracetam is an AED which has

recently been developed in human medicine. It is binding at the synaptic vesicle

protein (SV2A) instead of at GABA-receptors (LYNCH et al. 2004, GILLARD et al.

2006). Therefore, Levetiracetam is the only AED whose mechanism of action is

completely different to that of the common AEDs. Furthermore there is evidence from

rat studies that Levetiracetam is not a substrate of P-glycoprotein (POTSCHKA et al.

2004).Three out of eight dogs could be classified as Levetiracetam-responders in PB

pharmacoresistant dogs. In two dogs a reduction in seizure frequency of 50 % and

75 %, respectively could be achieved. One of these patients was even seizure-free

over a seven-month period before cluster seizures occurred. Thus, in accordance

with the study from VOLK et al. (2007) Levetiracetam proved to be a useful add-on

medication only in a subpopulation of PB non-responders. However, VOLK et al.

showed that the development of tolerance is a problem not only in treatment with

Zonisamid (VON KLOPMANN et al. 2005, VON KLOPMANN et al. 2007), but also in

treatment with Levetiracetam.

When interpreting the data of the present study the applied inclusion criteria (normal

physical and neurological examination and normal blood work) were used according

to the consensus statement, ACVIM, Seattle, 2007. In five patients, additional tests

such as MRI, CT and CSF analysis were performed to rule out intracranial diseases

as other causes than idiopathic epilepsy responsible for the severe

pharmacoresistance. In the remaining cases intracranial diseases could not be

dismissed completely as a reason for pharmacoresistance.

Conclusion 41

6 Conclusion

In summary, the performance of imaging techniques such as CT and MRI seems to

enhance the diagnosis of symptomatic epilepsy and is recommended in patients

suffering from seizures. The age and the results of neurological examination could be

used to predict if MRI is recommended and could be abnormal. Postictal changes are

a rare finding and occur mostly when the time spare between MRI performance and

last seizure event is under 4 days.

The current study indicates also that the P-glycoprotein-inhibitor Verapamil is not

appropriate for preventing pathological efflux of PB in most dogs at the dosage used.

Since at a higher dosage severe cardiac side effects were seen, this add-on

medication cannot be recommended in dogs. It is not clear, if either the medication

failed or multidrug transporter overexpression did not contribute to refractoriness in

the dogs included in this study with the exception of one case. In general,

pharmacoresistance is regarded as a multifactorial phenomenon in an entire patient

population. Subpopulations, as found in this small study, may exist. Therefore, single

cases might respond to P-glycoprotein-inhibitors or to medications not acting on the

GABA-receptor. Levetiracetam seems to be a valuable add-on medication in a

subpopulation of canine non-responders to phenobarbital.

42 Summary

7 Summary

Jambroszyk, Melanie:

Studies on canine epilepsy: diagnostic workup including advanced imaging

techniques and new treatment modalities

Up to 10% of the dog population with neurological disorders suffer from seizures of

different causes. Because further studies showed that the incidence of symptomatic

epilepsy caused by brain tumors, inflammatory brain diseases or anomalies is as

high as in human medicine, MRI is recommended as a routine diagnostic tool in

diagnosing idiopathic epilepsy in veterinary medicine.

The purpose of this retrospective part of the study was to evaluate the actual

distribution of idiopathic and symptomatic epilepsy in 343 patients with seizures

presented at the Department of Small Animal Medicine and Surgery, University of

Veterinary Medicine Hannover, after the introduction of MRI.

Two-sided Chi-squared-test could show a significant different distribution of

etiological background (p=0.0005). In presumed cases a suspicion of idiopathic

epilepsy was more frequently diagnosed, than in cases with complete diagnostic

work-up. Concerning the confirmed diagnoses altogether 145 dogs had a

neurological examination as well as a MRI examination. In these cases kappa-index

was calculated and a slight correlation exists concerning the result of the neurological

examination and the result of MRI (kappa-index 0.1358). Supposed postictal changes

could be found in the MRI-sequences of 10 patients. A correlation whether postictal

changes are associated with normal or abnormal MRI results could not be

established (kappa-index -0.0640) as well as a correlation between the occurrence of

postictal changes and the period between last seizure and MRI (p=0.1911). The

performance of imaging techniques such as CT and MRI seems to enhance the

diagnosis of symptomatic epilepsy and is recommended in patients suffering from

seizures, especially at an age over 6 years. Postictal changes are a rare finding and

occur mostly when the time between MRI performance and last seizure event is

under four days.

Summary 43

In 30% of epileptic dogs, treatment with Phenobarbital (PB) and/or potassium

bromide (KBr) does not result in adequate seizure control. Modulation of efflux of p-

glycoprotein function may therefore help to overcome drug-refractoriness.

In the present study we tested whether add-on treatment with the P-glycoprotein

modulator Verapamil restores PB efficacy in patients with refractory epilepsy. The

study was divided into two parts: a) in six healthy beagle dogs side effects and

compatibility of these drugs as well as the influence on plasma and cerebrospinal

fluid (CSF) levels of PB was investigated; b) in eleven dogs with refractory epilepsy,

which were considered to be non-responders to PB, add-on treatment with Verapamil

(1 mg/kg bwt twice daily) was tested. In those patients in which no improvement of

seizure control could be achieved, Verapamil was discontinued and Levetiracetam

was applied as add-on medication.

In healthy beagle dogs no side-effects regarding clinical and neurological

examination, blood pressure and blood examination could be observed except for

one dog which developed bradycardia. PB levels in CSF did not increase after add-

on treatment with Verapamil. In the second part of the study clinical and neurological

examination, blood cell count and serum chemistry, measurement of blood pressure

and ECG were performed at the time point of inclusion in the study and during control

examinations every four weeks for four months in all patients.

In five of the eleven dogs add-on treatment was discontinued before the end of the

four-month period because of either severe cluster seizures or lack of an

improvement in seizure control. From the remaining six patients only one dog

responded with a 75% reduction in seizure frequency. One of the eleven patients

developed severe bradycardia. No further side effects were seen.

Following discontinuation of Verapamil eight of the non-responders received add-on

treatment with Levetiracetam (10-20 mg/kg bwt three times daily) for three to eight

months. Three of these dogs could be classified as responders.

This prospective study may indicate that the P-glycoprotein inhibitor Verapamil is not

appropriate for preventing pathological efflux of PB in dogs at the dosage used.

Levetiracetam proved to be a useful add-on medication in a subpopulation of PB

non-responders.

44 Zusammenfassung

8 Zusammenfassung

Jambroszyk, Melanie:

Studien zur Epilepsie des Hundes: Von der Diagnosestellung mit neuen

bildgebenden Verfahren bis zur innovativen Behandlungsstrategie

In einer Hundepopulation mit neurologischen Krankheiten treten bei etwa 10% der

Tiere Krampfanfälle auf. Frühere Studien zeigen, dass die Inzidenz der

symptomatischen Epilepsie, welche durch Gehirntumore, entzündliche

Gehirnerkrankungen und Missbildungen verursacht wird, genauso hoch ist wie in der

Humanmedizin. Deswegen sollte die Magnetresonanztomographie (MRT) als

Routineuntersuchung in der Veterinärmedizin ebenso wie in der Humanmedizin

eingesetzt werden. Zusätzlich zu den zahlreichen Gehirnläsionen sind postiktale

Veränderungen beschrieben. Diese sind durch in T2-gewichteten Sequenzen

hyperintense Bereiche gekennzeichnet, wobei nur ein geringgradiger Masseneffekt

zu sehen ist. Diese postiktalen Veränderungen treten vor allem bei Patienten auf,

welche unter generalisierten Krampfanfällen leiden, wobei sie bei

Kontrolluntersuchungen mittels MRT nicht mehr existieren.

Das Ziel dieses retrospektiven Teils der Untersuchung war, das aktuelle Verhältnis

zwischen idiopathischer und symptomatischer Epilepsie zu evaluieren. Hierfür

wurden 343 Patienten in die Untersuchungen mit einbezogen, welche aufgrund von

Krampfanfällen in der Klinik für Kleintiere der Tierärztlichen Hochschule Hannover

nach Einführung der Magnetresonanztomographie vorgestellt wurden.

Mittels Chi-Quadrat-Test konnte eine signifikant unterschiedliche Verteilung der

Patienten hinsichtlich des ätiologischen Ursprungs errechnet werden (p=0,0005). In

der Gruppe der Hunde, bei denen nach klinisch-neurologischer Untersuchung und

Abklärung von Stoffwechselerkrankungen nur eine Verdachtsdiagnose gestellt

werden konnte, wurde die Diagnose der idiopathischen Epilepsie signifikant häufiger

gestellt als bei den Tieren bei denen eine komplette diagnostische Aufarbeitung mit

modernen bildgebenden Verfahren durchgeführt wurde.

Zusammenfassung 45

In der Gruppe der gesicherten Diagnosen wurden bei 145 Hunden sowohl eine

neurologische Untersuchung als auch eine MRT durchgeführt. In diesen Fällen

wurde der Kappa-Index errechnet und eine leichte Korrelation zwischen dem

Resultat der neurologischen Untersuchung und dem Ergebnis der MRT bestätigt

(Kappa-Index 0,1358). Vermutete postiktale Veränderungen wurden in den MRT-

Sequenzen von 10 Patienten gefunden. Eine Korrelation, dass postiktale

Veränderungen mit einem pathologischen Befund in der MRT zusammenhängen,

konnte nicht bewiesen werden (Kappa-Index -0,0640). Dieses gilt auch für einen

Zusammenhang zwischen dem Auftreten von postiktalen Veränderungen und dem

Zeitraum zwischen dem letzten Krampfanfall und der Untersuchung mittels MRT

(p=0,1911). Eine Tendenz war zu erkennen, dass postiktale Veränderungen

vermehrt auftreten, wenn die MRT in den ersten vier Tagen nach dem letzten

Krampfanfall durchgeführt wurde.

Bei ungefähr 30% der Hunde, die unter Krampfanfällen leiden, bringt eine Therapie

mit Phenobarbital und/oder Kaliumbromid keine ausreichende Kontrolle der

Anfallsfrequenz. Eine Modulation der Funktion von P-Glycoprotein-Rezeptoren

könnte gegebenenfalls einen Beitrag dazu leisten, dass der lokale Spiegel wirksamer

Antiepileptika im Gehirn erhöht wird. In diesem prospektiven Teil der Studie wurde

getestet, ob eine Kombinationstherapie des P-Glykoprotein-Modulators Verapamil

die Effektivität der Behandlung mit Phenobarbital bei Patienten mit

Pharmakoresistenz wieder herstellt.

Diese Studie wurde in zwei Teile gegliedert. In der Vorstudie wurden sechs gesunde

Beagle mit Phenobarbital und Verapamil behandelt und Verträglichkeit,

Nebenwirkungen und die Beeinflussung des Phenobarbitalspiegels in Serum und

Liquor cerebrospinalis dokumentiert. In dieser Vorstudie konnten keine

Nebenwirkungen in Bezug auf klinische und neurologische Untersuchung, Blutdruck-

Kontrolle und Blutuntersuchung festgestellt werden. Lediglich ein Hund entwickelte

eine Bradykardie. Der Phenobarbitalspiegel im Liquor cerebrospinalis stieg jedoch

nicht an, nachdem Verapamil zusätzlich verabreicht wurde. Zum anderen wurden in

die Hauptstudie 11 Patienten mit refraktärer Epilepsie aufgenommen. Diese

Patienten reagierten nicht adäquat auf die Behandlung mit Phenobarbital allein, so

46 Zusammenfassung

dass eine Kombinationstherapie mit Verapamil (1mg/kg zweimal täglich) eingeleitet

wurde. Bei den Patienten bei denen dadurch kein positiver Effekt vermerkt werden

konnte, wurde Verapamil abgesetzt und eine Kombinationstherapie mit

Phenobarbital und Levetiracetam durchgeführt. In der Hauptstudie wurde jeweils eine

klinische Allgemeinuntersuchung, eine neurologische Untersuchung, eine

Blutuntersuchung, Messung von Blutdruck und ein EKG bei Eintritt in die Studie und

anschließend alle vier Wochen bei allen elf Patienten durchgeführt. Bei fünf der elf

Patienten konnte die Behandlung mit Phenobarbital und Verapamil nicht weiter

durchgeführt werden, da entweder schwere Clusteranfälle auftraten oder keine

Verbesserung der Anfallsfrequenz erreicht werden konnte. Von den verbleibenden

sechs Patienten sprach mit einer 75%igen Reduktion der Anfallsfrequenz lediglich

einer ausreichend auf diese Therapie an und konnte somit als Responder betrachtet

werden. Ein weiterer dieser elf Patienten entwickelte eine sehr schwere Bradykardie.

Wurde Verapamil aufgrund von Nebenwirkungen oder fehlendem Erfolg abgesetzt,

so folgte eine Behandlung mit Phenobarbital und Levetiracetam (10-20mg/kg dreimal

täglich) über vier bis acht Monate (8 Hunde). Drei dieser 8 Hunde konnten als

Levetiracetam-Responder klassifiziert werden.

Der Teil dieser Studie, der sich mit neuen Behandlungsstrategien beschäftigt hat,

deutet an, dass der P-Glykoprotein-Inhibitor Verapamil in der hier verwendeten

Dosierung nicht angemessen dazu beiträgt, die Frequenz der Krampfanfälle zu

reduzieren. Levetiracetam scheint ein geeignetes Medikament zu sein um einen Teil

der Hund mit pharmakoresistenter Epilepsie erfolgreich behandeln zu können.

References 47

9 References

AYKUT-BINGOL, C., TEKIN, S., INCE D. and AKTAN, S. (1997):

Reversible MRI lesions after seizures.

Seizure, 6, 237-239

BAGLEY, R.S., GAVIN, P.R., MOORE, M.P., SILVER, G.M., HARRINGTON, M.L.

and CONNORS, R.L. (1999):

Clinical signs associated with brain tumors in dogs: 97 cases (1992-1997).

Journal of the American Veterinary Medical Association, 215, 818-819

BECK, H. (2007):

Plasticity of antiepileptic drug targets.

Epilepsia, 48, 14-18

BEGHI, E. (2004):

Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent

guidelines.

Lancet Neurology, 3, 618-621

BERENDT, M., HOGENHAVEN, H., FLAGSTAD, A. and DAM, M. (1999):

Electroencephalography in dogs with epilepsy: similarities to human seizures.

Acta Neurologica Scandinavica, 99, 276-283

BRAND-ZAWADSKI, M., BADAMI, J.P., MILLS, C.M., NORMAN, D. and NEWTON,

T.H. (1984):

Primary intracranial tumor imaging: a comparison of magnetic resonance and CT.

Radiology, 150, 435-440

48 References

BRANDT, C., BETHMANN, K., GASTENS, A.M. and LÖSCHER, W. (2006):

The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle

in a rat model of temporal lobe epilepsy.

Neurobiology of Disease, 24, 202-211

BUSH, W.W., BARR, C.S., DARRIN, E.W., SHOFER, F.S., VITE, C.H. and

STEINBERG, S.A. (2002):

Results of cerebrospinal fluid analysis, neurological examination findings, and age at

the onset of seizures as predictors for results of magnetic resonance imaging of the

brain in dogs examined because of seizures: 115 cases (1992-2000).

Journal of American Veterinary Medical Association, 220, 781-784

CHANDLER, K. (2006):

Canine epilepsy: what can we learn from human seizure disorders?

The Veterinary Journal, 172, 207-217

CLINCKERS, R., SMOLDERS, I., MEURS, A., EBINGER, G. and MICHOTTE, Y.

(2005):

Quantitative in vivo microdialysis study on the influence of multidrug transporters on

the blood-brain barrier passage of oxcarbazepine: concomitant use of hippocampal

monoamines as pharmacodynamic markers for the anticonvulsant activity.

Journal of Pharmacology and Experimental Therapeutics, 314, 725-731

DEISZ, R.A. (2002):

Cellular mechanisms of pharmacoresistance in slices from epilepsy surgery.

The Novartis Foundation Bulletin, 243, 186-199

DOMBROWSKI, S.M., DESAI, S.Y., MARRONI, M., CUCILLO, L., GOODRICH, K.,

BINGAMAN, W., MAYBERG, M.R., BENGEZ, L. and JANIGRO, D. (2001):

Overexpression of multiple drug resistance genes in endothelial cells from patients

with refractory epilepsy.

Epilepsia, 42, 1501-1506

References 49

ENGEL, J. (2006):

Report of the ILAE Classification Core Group.

Epilepsia, 47, 1558-1568

FLUEHMANN, G., DOHERR, M.G. and JAGGY, A. (2006):

Canine neurological diseases in a referral hospital population between 1989 and

2000 in Switzerland.

Journal of Small Animal Practice, 47, 582-587

FREY, H.H. and LÖSCHER, W. (1985):

Pharmacokinetics of anti-epileptic drugs in the dog: a review.

Journal of Veterinary Pharmacology and Therapeutics, 8, 219-233

FROMM, M.F. (2000):

P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS

accumulation of drugs.

International Journal of Clinical Pharmacology and Therapeutics, 38, 69-74

GILLARD, M., CHATELAIN, P. and FUKS, B. (2006):

Binding characteristics of Levetiracetam to synaptic vesicle protein 2A (SV2A) in

human brain an in CHO cells expressing the human recombinant protein.

European Journal of Pharmacology, 356, 102-108

GOVENDIR, M., PERKINS, M. and MALIK, R. (2005):

Improving seizure control in dogs with refractory epilepsy using gabapentin as an

adjunctive agent.

Australian Veterinary Journal, 83, 602-608

HEYNOLDS, Y., FAISSLER, D., STEFFEN, F. and JAGGY, A. (1997):

Clinical epidemiological and treatment results of idiopathic epilepsy in 54 Labrador

Retrievers: a long-term study.


50 References

ILAE (1989):

Commission on Classification and Terminology of the International League Against

Epilepsy. Proposal for revised clinical and electroencephalographic classification of

epileptic seizures.


JAGGY, A. and HEYNOLD, Y. (1996):

Die idiopathische Epilepsie des Hundes.

Schweizer Archiv für Tierheilkunde, 138, 523-531

JAGGY, A. and BERNARDINI, M. (1998):

Idiopathic epilepsy in 125 dogs: a long-term study- clinical and

electroencephalographic findings.


KATHMANN, I. and JAGGY, A. (2003):

Idiopathische oder symptomatische Epilepsie?

Praktischer Tierarzt, 84, 588-592

KNOWLES, K. (1998):

Idiopathic epilepsy.

Clinical Techniques in Small Animal Practice, 13, 144-151

KORTZ, G.D. (1998):

Brain imaging- CT or MRI- which one and why.

In: Proceedings of the 16th Annual Veterinary Medical Forum, San Diego, California,

May 22-25. pp 290-291

KUZNIECKY, R., ANDERMANN, F. and SPENCER, D. (2002):

Sailing into the 21st century: magnetic resonance techniques in epilepsy.

Epilepsia, 43 (Suppl.1), 1-3

References 51

LECOUTEUR, R.A. and CHILD, G. (1989):

Clinical management of epilepsy in dogs and cats.

Problems in veterinary medicine, 1, 578-595

LEE, G., DALLAS, S., HONG, M. and BENDAYAN, R. (2001):

Drug transporters in the central nervous system: brain barriers and brain

parenchyma considerations.

Pharmacological Reviews, 53, 569-596

LEVY, R.H., MATTSON, R.H. and MELDRUM, B.S. (1995)

Antiepileptic drugs. 4th edn. New York: Raven Press

LICHT, B.G., LICHT, M.H. and HARPER, K.M. (2002):

Clinical presentations of naturally occurring canine seizures: similarities to human

seizures.

Epilepsy & Behaviour, 3, 460-470

LÖSCHER, W. and POTSCHKA, H. (2002):

Role of multidrug transporters in pharmacoresistance to antiepileptic drugs.

Journal of Pharmacology and Experimental Therapeutics, 301, 7-14

LÖSCHER, W. (2003):

Pharmakologische Grundlagen zur Behandlung der Epilepsie bei Hund und Katze.

Der Praktische Tierarzt, 84, 574-586

LYNCH, B.A., LAMBENG, N., NOCKA, K., KENSEL-HAMMES, P., BAIJAALIEH,

S.M., MATAGNE and A., FUKS, B. (2004):

The synaptic vesicle protein SV2A is the binding site fort he antiepileptic drug

levetiracetam.

Proceedings of the National Academy of Sciences of the United States of America,

101, 9861-9866

52 References

MATHEWS, V.P., KUHARIK, M.A., EDWARDS, M.K., D’AMOUR, P.G., AZZARELLI,

B. and DREESEN, R.G. (1989):

Gd-DTPA-enhanced MR imaging of experimental bacterial meningitis: evaluation and

comparison with CT.

American Journal of Roentgenology, 152, 131-136

MELLEMA, L.M., KOBLIK, P.D., KORTZ, G.D., LECOUTEUR, R.A., CHECHOWITZ,

M.A. and DICKINSON, P.J. (1999):

Reversible magnetic resonance imaging abnormalities in dogs following seizures.

Veterinary Radiology and Ultrasound, 6, 588-595.

MODIC, M.T. (1991):

Advances in contrast-enhanced MR imaging- neurologic applications.

American Journal of Neuroradiology, 156, 239-245

MONTE SECADES, R., BRANAS FERNANDES, F., CORTES LAINO, J., PULPEIRO

RIOS, J. and MARTINEZ VASQUEZ, F. (1994):

Reversible changes in magnetic resonance images in two cases of complex partial

status epilepticus.

Neurologia, 9, 427-430

MOORE, M.P., BAGLEY, R.S., HARRINGTON, M.L. and GAVIN, P.R. (1996):

Intracranial tumors.

Veterinary Clinics of North America, 26, 759-777

MUNANA, K. (2004):

Managing the refractory epileptic.

Proceedings of the 22nd ACVIM forum. June 9 to 12, 2004, Minneapolis, USA. Pp

361-363.

References 53

PEARCE, L.K. (1990):

Potassium bromide as an adjunct to Phenobarbital for the management of

uncontrolled seizures in dogs.

Progress in Veterinary Neurology, 1, 95-101

PODELL, M. and FENNER, W.R. (1993):

Bromide therapy in refractory canine idiopathic epilepsy.

Journal of Veterinary Internal Medicine, 7, 318-327

PODELL, M., FENNER, W.R. and POWERS, J.D. (1995):

Seizure classification in dogs from a nonreferral-based population.


PODELL, M. (1996):

Seizures in dogs.

Veterinary Clinics of North America: Small Animal Pratice, 26, 779-809.

PODELL, M. (1999):

Epilepsy and seizure classification: A lesson from Leonardo.

Journal Veterinary Internal Medicine, 13, 3-4

POTSCHKA, H., FEDROWITZ, M. and LÖSCHER, W. (2001):

P-Glycoprotein and multidrug resistance-associated protein are involved in the

regulation of extracellular levels of the major antiepileptic drug carbamazepine in the

brain.

Neuroreport, 12, 3557-3560

POTSCHKA, H. and LÖSCHER, W. (2001):

Multidrug resistance-associated protein is involved in the regulation of extracellular

levels of phenytoin in the brain.

Neuroreport; 12, 2387-2389

54 References

POTSCHKA, H., VOLK, H. and LÖSCHER, W. (2004):

Pharmacoresistance and expression of multidrug transporter P-glycoprotein in

kindled rats.

Neuroreport, 15, 1657-1661

RAO, V.V., DAHLHEIMER, J.L., BARDGETT, M.E., SNYDER, A.Z., FINCH, R.A.,

SARTORELLI, A.C. et al. (1999):

Choroid plexus epithelial expression of MDR1 P-glycoprotein and multidrug

resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-

permeability barrier.

Proceedings of the National Academy of Sciences of the United States of America,

96, 3900-3905

REGESTA, G. and TANGANELLI, P. (1999):

Clinical aspects and biological bases of drug-resistant epilepsies.

Epilepsy Research, 34, 109-122

RIECK, S., LÖSCHER, W., RUNDFELDT, C. and TIPOLD, A. (2002):

Wirkung verschiedener antiepileptischer Substanzen beim Hund.

Tierärztliche Praxis, 3, 91-92

ROGWASKI, M.A. and LÖSCHER, W. (2004):

The neurobiology of antiepileptic drugs. Nature reviews.

Neuroscience, 5, 553-564

SCHWARTZ-PORSCHE (1984):

Epilepsie- Diagnose, Differentialdiagnose und Therapie.

Kleintierpraxis, 29, 67-82

SCHWARTZ-PORSCHE, D., LÖSCHER, W. and FREY, H.H. (1985):

Therapeutic efficacy of Phenobarbital and primidone in canine epilepsy: a

comparison.

Journal of Veterinary Pharmacology and Therapeutics, 8, 113-119

References 55

SEEGERS, U., POTSCHKA, H. and LÖSCHER, W. (2002):

Transient increase of P-glycoprotein expression in endothelium and parenchyma of

limbic brain regions in the kainate model of temporal lobe epilepsy.

Epilepsy Research, 51, 257-268

SILVERSTEIN, A.M. and ALEXANDER, J.A. (1998):

Acute postictal cerebral imaging.

American Journal of Neuroradiology, 19, 104-108

SISODIYA, S.M., LIN, W.-R., HARDING, B.N., SQUIER, M.V., KEIR, G. and THOM,

M. (2002):

Drug resistance in epilepsy: expression of drug resistance proteins in common

causes of refractory epilepsy.

Brain, 125, 22-31

SNYDER, J.M., SHOFER, F.S., VAN WINKLE, T.J. and MASSICOTTE, C. (2006):

Canine intracranial primary neoplasia: 173 cases (1986-2003)

Journal of Veterinary Internal Medicine, 20, 669-675

TIPOLD, A. (1995):

Diagnosis of inflammatory and infectious diseases of the central nervous system in

dogs: a retrospective study.

Journal of Veterinary Medicine, 9, 204-314

TISHLER, D.M., WEINBERG, K.T., HINTON, D.R., BARBARO, N., ANNETT, G.M.

and RAFFEL, C. (1995):

MDR1 gene expression in brain of patients with medically intractable epilepsy.

Epilepsia, 36, 1-6

THOMAS, W.B. (1998):

Inflammatory diseases of the central nervous system in dogs.

Clinical Techniques in Small Animal Practice 13, 167-178

56 References

TREPANIER, L.A., VAN SCHOICK, A., SCHWARK, W.S. and CARRILLO, J. (1998):

Therapeutic serum drug concentrations in epileptic dogs treated with potassium

bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996).


VAN VLIET, E.A., VAN SCHAIK, R., EDELBROEK, P.M., REDEKER, S., ARONICA,

E., WADMANN, W.J., MARCHI, N., VEZZANI, A. and GORTER, J.A. (2006):

Inhibition of the multidrug transporter P-glycoprotein improves seizure control in

phenytoin-treated chronic epileptic rats.


VAN VLIET, E.A., VAN SCHALK, R., EDELBROEK, P.M., VOSKUYL, R.A.,

REDEKER, S., ARONICA, E., WADMANN, W.J. and GORTER, J.A. (2007):

Region-specific overexpression of P-glycoprotein at the blood-brain barrier affects

brain uptake of Phenytoin in epileptic rats.

Journal of Pharmacological and Experimental Therapeutics, 322, 141-147

VOLK, H., POTSCHKA, H. and LÖSCHER, W. (2005):

Immunohistochemical localisation of P-glycoprotein in rat brain and detection of its

increased expression by seizures are sensitive to fixation and staining variables.

Journal of Histochemistry and Cytochemistry, 4, 517-531

VOLK, H. and LÖSCHER, W. (2005):

Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced

brain expression of P-glycoprotein compared with rats with drug-responsive seizures.

Brain, 128, 1358-1368

VOLK, H., MATIASEK, L.A., FELIU-PASCUAL, A.L., PLATT, S.R. and CHANDLER,

K. (2007):

The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs.

The Veterinary Journal, available online 30 April 2007.

References 57

VON KLOPMANN, T., SIMON, D. and TIPOLD, A. (2005):

Zonisamid add-on therapy for canine refractory epilepsy: Benefit of „Honey-Moon

Effect“.

In: Proceedings of 18th Annual European College of Veterinary Neurologist

Symposium, Munich, Germany.

VON KLOPMANN, T., RAMBECK, B. and TIPOLD, A. (2007):

Prospective study of zonisamid therapy for refractory idiopathic epilepsy in dogs.


ZHANG, L., ONG, W.Y. and LEE, T. (1999):

Induction of P-glycoprotein expression in astrocytes following intracerebrovetricular

kainate injections.

Experimental Brain Research, 126, 509-516

58 Appendix

10 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

11

LRM

20.1

2.20

0127

.1.2

004

757

2,07

gene

ral

0,5

zwei

wun

auffä

llig

21

SC

HM

30.8

.199

521

.3.2

004

3081

8,44

gene

ral

7zw

eiw

unau

ffälli

g3

1M

IXM

K1.

1.19

903.

3.20

0451

0213

,98

gene

ral

13un

auffä

llig

41

SO

NS

TM

6.1.

2002

3.3.

2004

777

2,13

gene

ral

1,5

mon

atl

unau

ffälli

g5

1M

IXM

12.1

1.20

025.

3.20

0447

31,

30ko

mpl

.1,

5w

öche

ntl

unau

ffälli

g6

1T

EC

KE

LM

17.5

.199

29.

3.20

0442

5211

,65

gene

ral/f

okal

6tg

lab

norm

al7

1W

HW

TM

K19

.9.2

002

12.3

.200

453

31,

46ge

nera

l1,

5tg

lun

auffä

llig

81

MIX

M1.

6.19

9512

.3.2

004

3161

8,66

gene

ral

9tg

lun

auffä

llig

92

MIX

M11

.3.2

001

15.3

.200

410

842,

97ge

nera

l1,

5w

öche

ntl

unau

ffälli

g10

2G

RM

K5.

1.19

9716

.3.2

004

2591

7,10

gene

ral

7m

onat

lun

auffä

llig

111

RO

TT

M22

.7.1

997

19.3

.200

423

976,

57ge

nera

l1

mon

atl

unau

ffälli

g12

2JR

TM

1.1.

1995

19.3

.200

433

189,

09ge

nera

l7

vier

telj

unau

ffälli

g13

2M

ÜN

ST

M1.

1.20

0323

.3.2

004

442

1,21

gene

ral

0,25

wöc

hent

lun

auffä

llig

141

SE

TT

ER

M11

.9.2

001

23.3

.200

491

22,

50ge

nera

l2,

5m

onat

lun

auffä

llig

151

DS

HM

8.1.

2004

23.3

.200

475

0,21

kom

pl.

0,2

tgl

unau

ffälli

g16

1M

IXW

1.1.

2000

30.3

.200

415

294,

19ge

nera

l4

wöc

hent

lun

auffä

llig

171

MIX

W5.

12.2

003

31.3

.200

411

60,

32ge

nera

l/fok

al0,

3er

stm

als

unau

ffälli

g18

1D

SH

WK

15.2

.199

91.

4.20

0418

465,

06ge

nera

l4,

5un

auffä

llig

192

SO

NS

TW

K4.

3.20

015.

4.20

0411

113,

04ge

nera

l2,

5w

öche

ntl

unau

ffälli

g20

1T

EC

KE

L1.

1.19

9122

.3.2

004

4761

13,0

4ge

nera

l12

zwei

wun

auffä

llig

211

SO

NS

TM

K1.

1.19

996.

4.20

0418

955,

19ge

nera

l1

tgl

unau

ffälli

g22

2T

EC

KE

LM

28.1

.199

56.

4.20

0433

089,

06ko

mpl

.9

wöc

hent

lun

auffä

llig

231

BC

M6.

6.20

0211

.4.2

004

665

1,82

gene

ral

2m

onat

lun

auffä

llig

241

LRM

9.4.

2002

12.4

.200

472

31,

98ge

nera

l2

erst

mal

sun

auffä

llig

251

SO

NS

TW

30.5

.200

113

.4.2

004

1033

2,83

gene

ral

3er

stm

als

unau

ffälli

g26

2S

ON

ST

MK

18.7

.200

113

.4.2

004

985

2,70

gene

ral

1m

onat

lun

auffä

llig

271

MIX

M12

.7.2

001

15.4

.200

499

32,

72ge

nera

l2,

5m

onat

lun

auffä

llig

281

BC

MK

12.6

.200

220

.4.2

004

668

1,83

gene

ral

1,5

unau

ffälli

g29

1S

ON

ST

M15

.7.1

996

25.4

.200

428

007,

67ge

nera

l8

erst

mal

sun

auffä

llig

301

MÜ

NS

TW

1.1.

1999

26.4

.200

419

155,

25ge

nera

l5

mon

atl

unau

ffälli

g31

2M

IXM

30.7

.199

63.

5.20

0427

937,

65ge

nera

l7

wöc

hent

lun

auffä

llig

321

SO

NS

TM

11.1

1.19

964.

5.20

0426

937,

38ge

nera

l4

zwei

wun

auffä

llig

331

SC

HM

1.1.

2001

5.5.

2004

1204

3,30

gene

ral

3er

stm

als

unau

ffälli

g34

1M

IXM

1.9.

1993

8.5.

2004

3847

10,5

4ge

nera

l11

erst

mal

sun

auffä

llig

352

SO

NS

TM

23.5

.200

310

.5.2

004

347

0,95

foka

l/kom

plex

1w

öche

ntl

abno

rmal

361

HU

SK

YW

4.11

.200

010

.5.2

004

1266

3,47

gene

ral

4tg

lun

auffä

llig

371

BE

AG

LEM

3.3.

2000

11.5

.200

415

084,

13ge

nera

lun

auffä

llig

381

SO

NS

TM

10.1

1.20

0311

.5.2

004

181

0,50

gene

ral

0,5

wöc

hent

lun

auffä

llig

391

CO

CK

ER

MK

1.7.

1998

13.5

.200

421

125,

79ge

nera

l1

mon

atl

unau

ffälli

g40

2S

ON

ST

M15

.7.2

001

14.5

.200

410

192,

79ge

nera

l3

mon

atl

unau

ffälli

g

Appendix 59

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e1

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l19

.2.2

004

5.2.

2004

idio

path

isch

nein

0ne

inne

inid

iopa

this

chne

in2

unau

ffälli

gun

auffä

llig

post

ikta

l25

.3.2

004

24.3

.200

4id

iopa

this

chne

in1

nein

jaid

iopa

this

chja

3un

auffä

llig

unau

ffälli

g3.

3.20

04id

iopa

this

chne

in1

nein

jaid

iopa

this

chne

in4

unau

ffälli

gun

auffä

llig

post

ikta

l5.

3.20

043.

3.20

04id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in5

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l12

.3.2

004

7.3.

2004

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

6un

auffä

llig

unau

ffälli

gne

inja

met

.-to

x.ne

in7

unau

ffälli

gun

auffä

llig

post

ikta

l12

.3.2

004

11.3

.200

4A

nom

alie

nein

0ne

inja

Ano

mal

ieja

8un

auffä

llig

post

ikta

l15

.3.2

004

12.3

.200

4ne

opla

stis

chne

in0

jane

inne

opla

stis

chja

9un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in10

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in11

unau

ffälli

gun

auffä

llig

3.6.

2004

2.5.

2004

idio

path

isch

nein

0ne

inne

inm

et.-

tox.

nein

12un

auffä

llig

unau

ffälli

gne

inja

idio

path

isch

nein

13un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in14

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l31

.3.2

004

15.3

.200

4id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

15ab

norm

alne

inja

Ano

mal

ieja

16ab

norm

alab

norm

alpo

stik

tal

2.4.

2004

30.3

.200

4id

iopa

this

chne

in6

jane

inde

gene

rativ

ja17

unau

ffälli

gne

inja

entz

ündl

ich

nein

18un

auffä

llig

unau

ffälli

g7.

4.20

04id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

19un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in20

abno

rmal

post

ikta

l6.

4.20

043.

4.20

04id

iopa

this

chne

in0

nein

jam

et.-

tox.

vers

torb

en21

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l6.

4.20

0430

.3.2

004

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

22un

auffä

llig

unau

ffälli

gne

inja

idio

path

isch

nein

23un

auffä

llig

unau

ffälli

gpo

stik

tal

14.4

.200

411

.4.2

004

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

24un

auffä

llig

abno

rmal

jane

inm

et.-

tox.

nein

25un

auffä

llig

unau

ffälli

gpo

stik

tal

16.4

.200

413

.4.2

004

vask

ulär

nein

0ne

inja

vask

ulär

nein

26un

auffä

llig

abno

rmal

nein

jam

et.-

tox.

nein

27un

auffä

llig

unau

ffälli

g15

.4.2

004

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

28ab

norm

alun

auffä

llig

12.5

.200

4id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in29

unau

ffälli

gun

auffä

llig

post

ikta

l26

.4.2

004

25.4

.200

4id

iopa

this

chne

in0

nein

jam

et.-

tox.

nein

30un

auffä

llig

abno

rmal

post

ikta

l27

.4.2

004

25.4

.200

4id

iopa

this

chne

in1

nein

jaid

iopa

this

chja

31un

auffä

llig

unau

ffälli

gne

inja

met

.-to

x.ne

in32

unau

ffälli

gun

auffä

llig

29.8

.200

3id

iopa

this

chne

in1

nein

jaid

iopa

this

chne

in33

abno

rmal

abno

rmal

jane

inid

iopa

this

chja

34ab

norm

alun

auffä

llig

post

ikta

l17

.5.2

004

16.5

.200

4ne

opla

stis

chne

in0

nein

jane

opla

stis

chne

in35

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in36

unau

ffälli

gun

auffä

llig

post

ikta

l10

.5.2

004

10.5

.200

4id

iopa

this

chne

in1

nein

jaid

iopa

this

chne

in37

unau

ffälli

gun

auffä

llig

11.5

.200

4id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

38un

auffä

llig

unau

ffälli

gpo

stik

tal

24.5

.200

423

.5.2

004

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

39ab

norm

alab

norm

alpo

stik

tal

13.5

.200

413

.5.2

004

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

40un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in

60 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

412

GR

MK

18.7

.200

117

.5.2

004

1019

2,79

gene

ral

2w

öche

ntl

unau

ffälli

g42

1D

SH

W23

.4.2

003

25.5

.200

439

21,

07ge

nera

l1

mon

atl

unau

ffälli

g43

1Y

OR

KW

9.4.

2002

27.5

.200

476

82,

10ge

nera

l/kom

plex

2er

stm

als

unau

ffälli

g44

2B

CW

21.1

.200

431

.5.2

004

130

0,36

gene

ral

0,25

erst

mal

sun

auffä

llig

452

MIX

M1.

1.19

981.

6.20

0423

106,

33ge

nera

l6

erst

mal

sun

auffä

llig

462

MIX

WK

15.1

2.20

001.

6.20

0412

463,

41fo

kal

2,5

mon

atl

unau

ffälli

g47

2JR

TM

31.8

.199

84.

6.20

0420

745,

68ge

nera

l6

erst

mal

sab

norm

al48

1D

SH

W25

.5.1

998

6.6.

2004

2171

5,95

gene

ral

6tg

lun

auffä

llig

491

TE

CK

EL

W28

.4.2

001

7.6.

2004

1119

3,07

gene

ral

2m

onat

lun

auffä

llig

501

SC

HW

K1.

10.2

002

7.6.

2004

606

1,66

gene

ral

2er

stm

als

unau

ffälli

g51

2S

ON

ST

M12

.8.2

003

8.6.

2004

296

0,81

kom

pl.

0,5

erst

mal

sun

auffä

llig

521

JRT

W1.

1.19

9910

.6.2

004

1959

5,37

gene

ral

5er

stm

als

abno

rmal

532

HU

SK

YW

25.1

1.19

9810

.6.2

004

1995

5,47

gene

ral

6er

stm

als

abno

rmal

541

MIX

WK

1.1.

1994

19.6

.200

437

6810

,32

gene

ral

10er

stm

als

unau

ffälli

g55

1JR

TM

K1.

1.19

9721

.6.2

004

2690

7,37

gene

ral

5un

auffä

llig

561

SO

NS

TW

26.6

.200

121

.6.2

004

1075

2,95

gene

ral/f

okal

4er

stm

als

unau

ffälli

g57

1B

RA

CK

EM

1.4.

2003

22.6

.200

611

613,

18ge

nera

l1

mon

atl

unau

ffälli

g58

1M

IXW

26.1

.200

429

.6.2

004

153

0,42

gene

ral

0,5

wöc

hent

lun

auffä

llig

592

SO

NS

TM

K23

.5.2

000

5.7.

2004

1482

4,06

foka

l3

mon

atl

unau

ffälli

g60

2S

ET

TE

RM

16.5

.200

16.

7.20

0411

303,

10ge

nera

l3

erst

mal

sun

auffä

llig

612

DS

HM

20.1

1.19

966.

7.20

0427

467,

52ge

nera

l6,

5jä

hrl

unau

ffälli

g62

2M

IXW

K1.

1.19

9612

.7.2

004

3071

8,41

gene

ral

7jä

hrl

unau

ffälli

g63

1S

ON

ST

MK

1.6.

2002

19.7

.200

476

82,

10ge

nera

l2

zwei

wun

auffä

llig

641

LRM

K1.

3.20

0227

.7.2

004

866

2,37

gene

ral

2m

onat

lun

auffä

llig

652

MIX

M24

.2.1

993

28.7

.200

441

1411

,27

foka

l11

tgl

unau

ffälli

g66

1H

US

KY

WK

27.1

0.19

9528

.7.2

004

3151

8,63

gene

ral

9er

stm

als

unau

ffälli

g67

1S

ON

ST

M28

.7.1

998

29.7

.200

421

615,

92ge

nera

l6

erst

mal

sun

auffä

llig

682

SO

NS

TM

20.7

.200

12.

8.20

0410

922,

99ge

nera

l3

erst

mal

sun

auffä

llig

692

LRW

K19

.4.2

000

2.8.

2004

1543

4,23

foka

l4

erst

mal

sun

auffä

llig

702

SO

NS

TM

1.9.

2003

2.8.

2004

331

0,91

foka

l1

mon

atl

unau

ffälli

g71

2S

ON

ST

WK

1.1.

2000

2.8.

2004

1651

4,52

foka

l4,

5er

stm

als

unau

ffälli

g72

2S

ON

ST

WK

1.4.

2000

2.8.

2004

1561

4,28

gene

ral

4er

stm

als

unau

ffälli

g73

2S

ON

ST

MK

12.6

.199

93.

8.20

0418

515,

07ge

nera

l5

erst

mal

sun

auffä

llig

741

MIX

WK

4.4.

1998

9.8.

2004

2285

6,26

gene

ral

6er

stm

als

unau

ffälli

g75

1H

US

KY

W1.

6.20

0110

.8.2

004

1149

3,15

gene

ral

3er

stm

als

unau

ffälli

g76

2B

OX

ER

W1.

1.20

0316

.8.2

004

585

1,60

gene

ral

1,5

erst

mal

sun

auffä

llig

771

DS

HM

1.9.

1999

18.8

.200

417

874,

90ge

nera

l3

mon

atl

unau

ffälli

g78

2G

RW

1.11

.200

223

.8.2

004

652

1,79

gene

ral

2m

onat

lun

auffä

llig

791

GR

MK

7.3.

2002

23.8

.200

488

62,

43ge

nera

l2,

5w

öche

ntl

unau

ffälli

g80

2JR

TW

K1.

1.19

9923

.8.2

004

2032

5,57

gene

ral

5er

stm

als

unau

ffälli

g

Appendix 61

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e41

abno

rmal

unau

ffälli

gne

inne

inid

iopa

this

chne

in42

unau

ffälli

gun

auffä

llig

post

ikta

l2.

6.20

0431

.5.2

004

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

43ab

norm

alpo

stik

tal

28.5

.200

427

.5.2

004

idio

path

isch

nein

0ne

inne

inid

iopa

this

chne

in44

abno

rmal

jane

inm

et.-

tox.

nein

45un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in46

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

47un

auffä

llig

nein

nein

met

.-to

x.ne

in48

unau

ffälli

gun

auffä

llig

post

ikta

l7.

6.20

046.

6.20

04ne

opla

stis

chne

in0

nein

jane

opla

stis

chne

in49

unau

ffälli

gun

auffä

llig

8.2.

2005

idio

path

isch

nein

2ne

inne

inid

iopa

this

chne

in50

unau

ffälli

gun

auffä

llig

post

ikta

l9.

6.20

047.

6.20

04id

iopa

this

chne

in0

nein

jaid

iopa

this

chja

51ab

norm

alun

auffä

llig

nein

nein

idio

path

isch

nein

52ab

norm

alab

norm

alni

cht p

ostik

tal

10.6

.200

431

.5.2

004

neop

last

isch

nein

220

nein

nein

neop

last

isch

ja53

abno

rmal

jaja

met

.-to

x.ne

in54

unau

ffälli

gun

auffä

llig

post

ikta

l30

.6.2

004

29.6

.200

4id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

55un

auffä

llig

abno

rmal

nich

t pos

tikta

l22

.6.2

004

2.6.

2004

idio

path

isch

nein

3ne

inne

inid

iopa

this

chne

in56

abno

rmal

abno

rmal

nein

nein

met

.-to

x.ne

in57

unau

ffälli

gun

auffä

llig

post

ikta

l24

.6.2

004

21.6

.200

4id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in58

abno

rmal

abno

rmal

post

ikta

l29

.6.2

004

27.6

.200

4en

tzün

dlic

hne

in0

nein

jaen

tzün

dlic

hne

in59

abno

rmal

unau

ffälli

gne

inne

inid

iopa

this

chne

in60

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

61un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in62

abno

rmal

unau

ffälli

gne

inne

inid

iopa

this

chne

in63

unau

ffälli

gun

auffä

llig

28.7

.200

4en

tzün

dlic

hne

in0

nein

jaen

tzün

dlic

hne

in64

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

65un

auffä

llig

nein

nein

met

.-to

x.ne

in66

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

9.8.

2004

4.8.

2004

entz

ündl

ich

nein

1ne

inja

dege

nera

tivne

in67

abno

rmal

abno

rmal

nich

t pos

tikta

l29

.7.2

004

23.7

.200

4ne

opla

stis

chne

in0

nein

jane

opla

stis

chja

68ab

norm

alab

norm

alja

nein

idio

path

isch

ja69

abno

rmal

unau

ffälli

gne

inne

inm

et.-

tox.

nein

70un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in71

unau

ffälli

gun

auffä

llig

nein

nein

met

.-to

x.ne

in72

unau

ffälli

gun

auffä

llig

nein

jam

et.-

tox.

nein

73un

auffä

llig

nein

nein

met

.-to

x.ne

in74

abno

rmal

unau

ffälli

gne

inne

inm

et.-

tox.

nein

75un

auffä

llig

abno

rmal

post

ikta

l11

.9.2

004

9.8.

2004

idio

path

isch

nein

0ne

inne

inid

iopa

this

chne

in76

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

77un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

18.8

.200

412

.8.2

004

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

78un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in79

unau

ffälli

gun

auffä

llig

post

ikta

l5.

10.2

004

3.10

.200

4id

iopa

this

chne

in1

nein

jaid

iopa

this

chne

in80

unau

ffälli

gab

norm

alne

inne

inid

iopa

this

chne

in

62 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

811

DS

HM

19.4

.200

324

.8.2

004

485

1,33

gene

ral

0,2

mon

atl

unau

ffälli

g82

1S

ON

ST

W10

.2.2

001

24.8

.200

412

743,

49ge

nera

l2

mon

atl

unau

ffälli

g83

2R

OT

TM

1.5.

1999

26.8

.200

419

155,

25ge

nera

l5

wöc

hent

lun

auffä

llig

842

PU

DE

LM

1.1.

1991

1.9.

2004

4920

13,4

8ge

nera

l13

erst

mal

sun

auffä

llig

851

WH

WT

MK

12.8

.199

66.

9.20

0429

047,

96ge

nera

l5

vier

telj

unau

ffälli

g86

2S

CH

M1.

1.19

946.

9.20

0438

4510

,53

gene

ral

8un

auffä

llig

871

MIX

W1.

1.19

998.

9.20

0420

475,

61ge

nera

l/fok

al5,

5er

stm

als

unau

ffälli

g88

2Y

OR

KM

1.11

.199

113

.9.2

004

4632

12,6

9ge

nera

l13

erst

mal

sun

auffä

llig

892

BE

AG

LEW

15.4

.200

414

.9.2

004

149

0,41

gene

ral

0,5

erst

mal

sun

auffä

llig

902

CO

CK

ER

WK

6.6.

1996

25.9

.200

429

898,

19ge

nera

l7

vier

telj

unau

ffälli

g91

1B

OX

ER

M1.

1.20

0125

.9.2

004

1344

3,68

gene

ral

3,5

mon

atl

unau

ffälli

g92

2S

ON

ST

W6.

2.20

0127

.9.2

004

1311

3,59

gene

ral

2,5

wöc

hent

lun

auffä

llig

931

BC

WK

13.8

.199

628

.9.2

004

2925

8,01

gene

ral

5w

öche

ntl

unau

ffälli

g94

2S

ON

ST

M7.

8.19

951.

10.2

004

3294

9,02

gene

ral

9er

stm

als

unau

ffälli

g95

2C

OC

KE

RW

1.1.

2000

4.10

.200

417

134,

69ge

nera

l3,

5vi

erte

ljun

auffä

llig

962

MIX

M1.

1.19

985.

10.2

004

2434

6,67

gene

ral

5,5

wöc

hent

lun

auffä

llig

972

MÜ

NS

TM

1.3.

2003

11.1

0.20

0458

01,

59ge

nera

l0,

75un

auffä

llig

981

LRM

K24

.12.

2002

28.9

.200

463

41,

74ge

nera

l1,

5zw

eiw

unau

ffälli

g99

1P

UD

EL

WK

10.1

2.19

9712

.10.

2004

2462

6,75

gene

ral/f

okal

3vi

erte

ljun

auffä

llig

100

1M

IXW

25.1

0.20

0014

.10.

2004

1429

3,92

gene

ral

4vi

erte

ljun

auffä

llig

101

1JR

TM

K20

.10.

1999

15.1

0.20

0417

954,

92ge

nera

l1,

5vi

erte

ljun

auffä

llig

102

1M

IXM

1.5.

1999

25.1

0.20

0419

745,

41ge

nera

l3

vier

telj

unau

ffälli

g10

31

SO

NS

TW

K29

.9.1

999

7.11

.200

418

385,

04ge

nera

l5

erst

mal

sun

auffä

llig

104

2B

CM

15.1

.200

09.

11.2

004

1734

4,75

gene

ral

2vi

erte

ljun

auffä

llig

105

2S

ET

TE

RM

12.6

.199

711

.11.

2004

2669

7,31

gene

ral

7,5

erst

mal

sun

auffä

llig

106

1B

OX

ER

M7.

5.20

0319

.11.

2004

552

1,51

gene

ral

1,5

zwei

wab

norm

al10

72

YO

RK

WK

3.1.

1995

22.1

1.20

0435

599,

75ge

nera

l9,

5m

onat

lun

auffä

llig

108

1W

HW

TW

K1.

5.19

9423

.11.

2004

3802

10,4

2ge

nera

l10

erst

mal

sun

auffä

llig

109

2LR

MK

1.10

.199

923

.11.

2004

1852

5,07

gene

ral

2zw

eiw

unau

ffälli

g11

02

SO

NS

TW

K3.

4.19

9525

.11.

2004

3472

9,51

gene

ral

9ha

lbj

unau

ffälli

g11

11

BE

AG

LEM

25.3

.200

126

.11.

2004

1321

3,62

gene

ral

2vi

erte

ljun

auffä

llig

112

1D

SH

M27

.10.

2002

29.1

1.20

0475

22,

06ge

nera

l2

wöc

hent

lun

auffä

llig

113

2T

EC

KE

LW

27.4

.200

130

.11.

2004

1293

3,54

gene

ral

3,5

mon

atl

unau

ffälli

g11

42

SO

NS

TM

17.7

.200

37.

12.2

004

500

1,37

gene

ral

1,5

zwei

wun

auffä

llig

115

2M

IXM

14.1

1.19

967.

12.2

004

2903

7,95

gene

ral

8zw

eiw

unau

ffälli

g11

61

LRW

6.2.

2004

7.12

.200

430

10,

82ge

nera

l0,

75er

stm

als

unau

ffälli

g11

72

SO

NS

TM

5.11

.200

214

.12.

2004

759

2,08

gene

ral

1,5

vier

telj

unau

ffälli

g11

81

SO

NS

TM

8.4.

2003

15.1

2.20

0460

71,

66ge

nera

l1,

5m

onat

lun

auffä

llig

119

2S

ON

ST

M23

.6.1

999

16.1

2.20

0419

735,

41ge

nera

l5,

5er

stm

als

unau

ffälli

g12

01

SO

NS

TW

15.1

0.19

9424

.12.

2004

3669

10,0

5ge

nera

l6

mon

atl

unau

ffälli

g

Appendix 63

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e81

unau

ffälli

gab

norm

alpo

stik

tal

24.8

.200

423

.8.2

004

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

82un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

26.8

.200

42.

8.20

04A

nom

alie

nein

nein

nein

Ano

mal

iene

in83

unau

ffälli

gun

auffä

llig

nein

jane

opla

stis

chne

in84

abno

rmal

abno

rmal

nein

nein

neop

last

isch

ja85

abno

rmal

abno

rmal

nein

jam

et.-

tox.

nein

86un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in87

abno

rmal

abno

rmal

nich

t pos

tikta

l10

.9.2

004

6.9.

2004

entz

ündl

ich

ja0

nein

nein

entz

ündl

ich

nein

88un

auffä

llig

abno

rmal

nein

nein

neop

last

isch

nein

89ab

norm

alun

auffä

llig

nein

nein

idio

path

isch

nein

90un

auffä

llig

abno

rmal

nein

jaid

iopa

this

chne

in91

unau

ffälli

gab

norm

alpo

stik

tal

27.4

.200

424

.9.2

004

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

92ab

norm

alun

auffä

llig

nein

jaid

iopa

this

chne

in93

unau

ffälli

gun

auffä

llig

post

ikta

l29

.9.2

004

26.9

.200

4id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in94

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

95un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in96

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in97

abno

rmal

unau

ffälli

gne

inja

idio

path

isch

nein

98un

auffä

llig

unau

ffälli

g12

.10.

2004

idio

path

isch

nein

0ne

inne

inid

iopa

this

chne

in99

unau

ffälli

gab

norm

alpo

stik

tal

15.1

0.20

0412

.10.

2004

idio

path

isch

nein

1ne

inne

inid

iopa

this

chne

in10

0un

auffä

llig

abno

rmal

post

ikta

l3.

2.20

041.

2.20

05id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in10

1un

auffä

llig

unau

ffälli

g4.

11.2

004

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

102

unau

ffälli

gun

auffä

llig

nein

jam

et.-

tox.

nein

103

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l8.

11.2

004

15.1

0.20

04ne

opla

stis

chne

in63

nein

nein

neop

last

isch

nein

104

abno

rmal

abno

rmal

nein

nein

idio

path

isch

nein

105

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

106

unau

ffälli

gab

norm

alni

cht p

ostik

tal

23.1

1.20

0419

.11.

2004

idio

path

isch

ja24

jaja

entz

ündl

ich

ja10

7ab

norm

alab

norm

alne

inne

inm

et.-

tox.

nein

108

abno

rmal

jaja

met

.-to

x.ja

109

unau

ffälli

gab

norm

alne

inne

inid

iopa

this

chne

in11

0un

auffä

llig

abno

rmal

nein

nein

entz

ündl

ich

nein

111

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in11

2un

auffä

llig

abno

rmal

nich

t pos

tikta

l14

.12.

2004

9.12

.200

4id

iopa

this

chne

in1

nein

jane

opla

stis

chja

113

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in11

4un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in11

5un

auffä

llig

unau

ffälli

gne

inja

idio

path

isch

nein

116

abno

rmal

unau

ffälli

gpo

stik

tal

9.12

.200

47.

12.2

004

vask

ulär

nein

1ne

inja

vask

ulär

nein

117

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

118

unau

ffälli

gun

auffä

llig

26.4

.200

5id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

119

unau

ffälli

gab

norm

alne

inja

idio

path

isch

nein

120

unau

ffälli

gab

norm

alpo

stik

tal

24.1

2.20

0424

.12.

2004

idio

path

isch

nein

jane

inid

iopa

this

chne

in

64 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

121

1H

US

KY

W1.

5.20

0426

.12.

2004

235

0,64

gene

ral

0,75

erst

mal

sun

auffä

llig

122

2S

ON

ST

W7.

5.20

004.

1.20

0516

774,

59ge

nera

l4,

5ha

lbj

unau

ffälli

g12

31

JRT

M1.

1.19

9811

.1.2

005

2530

6,93

gene

ral/f

okal

4m

onat

lun

auffä

llig

124

2T

EC

KE

LM

19.4

.199

811

.1.2

005

2422

6,64

gene

ral

4un

auffä

llig

125

1B

EA

GLE

M10

.5.1

990

12.1

.200

552

8214

,47

gene

ral

15,5

erst

mal

sab

norm

al12

61

TE

CK

EL

MK

28.6

.199

612

.1.2

005

3074

8,42

gene

ral

9er

stm

als

unau

ffälli

g12

72

MIX

W1.

5.20

0417

.1.2

005

256

0,70

gene

ral

1er

stm

als

abno

rmal

128

1B

OX

ER

WK

12.5

.199

419

.1.2

005

3847

10,5

4ge

nera

l11

erst

mal

sun

auffä

llig

129

1S

CH

WK

1.1.

1992

19.1

.200

546

9812

,87

gene

ral

13er

stm

als

unau

ffälli

g13

02

MIX

M1.

8.20

0420

.1.2

005

169

0,46

gene

ral

0,5

erst

mal

sun

auffä

llig

131

1R

OT

TW

1.4.

1998

24.1

.200

524

536,

72ge

nera

l6,

5er

stm

als

unau

ffälli

g13

21

JRT

MK

16.1

0.19

9725

.1.2

005

2619

7,18

gene

ral

7w

öche

ntl

unau

ffälli

g13

31

WH

WT

W21

.2.1

993

25.1

.200

542

9411

,76

gene

ral

11,5

wöc

hent

lab

norm

al13

41

CO

CK

ER

M14

.1.1

999

1.2.

2005

2177

5,96

gene

ral

6er

stm

als

unau

ffälli

g13

52

MIX

W10

.10.

2004

3.2.

2005

113

0,31

foka

l0,

3er

stm

als

unau

ffälli

g13

61

SO

NS

TM

23.7

.199

53.

2.20

0534

309,

40ge

nera

l10

wöc

hent

lun

auffä

llig

137

2Y

OR

KM

13.7

.199

67.

2.20

0530

848,

45ge

nera

l1,

5vi

erte

ljun

auffä

llig

138

1M

IXW

K8.

8.19

957.

2.20

0534

199,

37ge

nera

l9

zwei

wun

auffä

llig

139

1S

ON

ST

W1.

1.20

018.

2.20

0514

774,

05ge

nera

l4

wöc

hent

lun

auffä

llig

140

1M

ÜN

ST

M17

.11.

2001

8.2.

2005

1161

3,18

gene

ral

3m

onat

lun

auffä

llig

141

2B

EA

GLE

M10

.7.2

004

18.2

.200

521

80,

60ge

nera

l0,

75er

stm

als

unau

ffälli

g14

22

SO

NS

TM

1.6.

2002

28.2

.200

598

72,

70ge

nera

l2,

5vi

erte

ljun

auffä

llig

143

1M

IXM

1.10

.199

51.

3.20

0533

909,

29ge

nera

l9

erst

mal

sun

auffä

llig

144

1G

RM

27.1

1.20

046.

3.20

0599

0,27

gene

ral

0,25

erst

mal

sun

auffä

llig

145

1M

IXM

16.1

2.20

048.

3.20

0582

0,22

gene

ral

0,25

erst

mal

sun

auffä

llig

146

1S

CH

M1.

1.20

0121

.3.2

005

1520

4,16

gene

ral

4w

öche

ntl

unau

ffälli

g14

72

DS

HW

7.9.

2003

21.3

.200

555

41,

52ge

nera

l1,

5zw

eiw

unau

ffälli

g14

81

TE

CK

EL

M1.

6.19

9622

.3.2

005

3171

8,69

gene

ral

4m

onat

lab

norm

al14

91

DS

HM

30.9

.199

523

.3.2

005

3413

9,35

gene

ral

9,5

erst

mal

sab

norm

al15

01

GR

M29

.3.1

998

3.4.

2005

2524

6,92

gene

ral

4m

onat

lab

norm

al15

11

MIX

WK

1.6.

2003

5.4.

2005

664

1,82

gene

ral

1vi

erte

ljun

auffä

llig

152

1M

IXW

11.1

1.20

0211

.4.2

005

870

2,38

foka

l2,

5tg

lab

norm

al15

31

MIX

M1.

1.20

0012

.4.2

005

1901

5,21

gene

ral

5zw

eiw

unau

ffälli

g15

42

MIX

M1.

1.20

0112

.4.2

005

1541

4,22

gene

ral

3,5

mon

atl

unau

ffälli

g15

52

SO

NS

TW

1.1.

2003

13.4

.200

582

22,

25ge

nera

l2

mon

atl

unau

ffälli

g15

62

SO

NS

TM

27.1

2.20

0215

.4.2

005

828

2,27

gene

ral

2m

onat

lun

auffä

llig

157

1C

OC

KE

RW

K1.

6.19

9718

.4.2

005

2837

7,77

kom

pl.

8er

stm

als

unau

ffälli

g15

82

GR

WK

2.3.

1997

18.4

.200

529

268,

02ge

nera

l8,

5er

stm

als

unau

ffälli

g15

91

MIX

M1.

1.19

9918

.4.2

005

2267

6,21

gene

ral

5,5

vier

telj

unau

ffälli

g16

01

MIX

WK

1.3.

1996

25.4

.200

532

949,

02fo

kal

9w

öche

ntl

unau

ffälli

g

Appendix 65

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e12

1un

auffä

llig

abno

rmal

nein

nein

entz

ündl

ich

ja12

2ab

norm

alun

auffä

llig

nein

nein

idio

path

isch

nein

123

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

11.1

.200

57.

1.20

05en

tzün

dlic

hne

in1

nein

jaen

tzün

dlic

hne

in12

4un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in12

5ab

norm

alun

auffä

llig

nein

nein

met

.-to

x.ne

in12

6un

auffä

llig

unau

ffälli

gne

inja

idio

path

isch

nein

127

unau

ffälli

gab

norm

alne

inne

intr

aum

atis

chne

in12

8un

auffä

llig

abno

rmal

post

ikta

l19

.1.2

005

18.1

.200

5ne

opla

stis

chne

in1

nein

jane

opla

stis

chja

129

unau

ffälli

gun

auffä

llig

post

ikta

l20

.1.2

005

19.1

.200

5id

iopa

this

chja

5ne

inja

idio

path

isch

nein

130

unau

ffälli

gab

norm

alne

inja

idio

path

isch

nein

131

unau

ffälli

gun

auffä

llig

nein

nein

met

.-to

x.ne

in13

2ab

norm

alun

auffä

llig

nein

nein

met

.-to

x.ne

in13

3ab

norm

alun

auffä

llig

post

ikta

l28

.1.2

005

28.1

.200

5id

iopa

this

chne

in6

nein

jam

et.-

tox.

nein

134

unau

ffälli

gun

auffä

llig

post

ikta

l3.

2.20

052.

2.20

05en

tzün

dlic

hne

in0

nein

nein

entz

ündl

ich

nein

135

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in13

6ab

norm

alab

norm

alni

cht p

ostik

tal

4.2.

2005

29.1

.200

5id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in13

7un

auffä

llig

unau

ffälli

gne

inja

idio

path

isch

nein

138

unau

ffälli

gab

norm

alni

cht p

ostik

tal

8.2.

2005

10.1

.200

5id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

139

abno

rmal

abno

rmal

post

ikta

l9.

2.20

058.

2.20

05id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in14

0un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

9.2.

2005

10.1

.200

5id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

141

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in14

2un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in14

3un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

9.3.

2005

20.2

.200

5id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

144

unau

ffälli

gab

norm

alpo

stik

tal

9.3.

2005

6.3.

2005

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

145

abno

rmal

unau

ffälli

gne

inja

entz

ündl

ich

nein

146

abno

rmal

unau

ffälli

gpo

stik

tal

10.1

0.20

059.

10.2

005

idio

path

isch

ja0

jaja

idio

path

isch

nein

147

abno

rmal

abno

rmal

nein

jaid

iopa

this

chne

in14

8un

auffä

llig

abno

rmal

nich

t pos

tikta

l31

.3.2

005

15.3

.200

5id

iopa

this

chja

1ne

inja

idio

path

isch

nein

149

unau

ffälli

gab

norm

alpo

stik

tal

24.3

.200

523

.3.2

005

neop

last

isch

nein

2ne

inja

neop

last

isch

ja15

0un

auffä

llig

unau

ffälli

gpo

stik

tal

4.4.

2005

2.4.

2005

idio

path

isch

ja0

jaja

idio

path

isch

nein

151

abno

rmal

unau

ffälli

gne

inja

met

.-to

x.ne

in15

2un

auffä

llig

abno

rmal

post

ikta

l13

.4.2

005

11.4

.200

5id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in15

3un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

12.4

.200

58.

4.20

05id

iopa

this

chne

inne

inne

inid

iopa

this

chne

in15

4ab

norm

alun

auffä

llig

nein

nein

idio

path

isch

nein

155

abno

rmal

unau

ffälli

gne

inne

inid

iopa

this

chne

in15

6un

auffä

llig

unau

ffälli

gne

inja

idio

path

isch

nein

157

unau

ffälli

gun

auffä

llig

19.4

.200

5id

iopa

this

chne

in0

idio

path

isch

nein

158

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in15

9ab

norm

alun

auffä

llig

nein

jam

et.-

tox.

nein

160

abno

rmal

unau

ffälli

g18

.5.2

005

neop

last

isch

nein

34ne

inja

neop

last

isch

nein

66 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

161

1S

ON

ST

MK

1.1.

1997

25.4

.200

529

948,

20ge

nera

l8

erst

mal

sun

auffä

llig

162

1JR

TW

1.8.

2003

29.4

.200

562

81,

72ge

nera

l1,

5er

stm

als

unau

ffälli

g16

32

LRM

K19

.4.1

998

2.5.

2005

2533

6,94

gene

ral

1m

onat

lun

auffä

llig

164

1M

IXM

10.1

1.20

042.

5.20

0517

20,

47ge

nera

l0,

5er

stm

als

unau

ffälli

g16

52

MIX

M8.

12.1

996

9.5.

2005

3031

8,30

gene

ral

8,5

tgl

unau

ffälli

g16

62

SO

NS

TW

K30

.3.2

003

16.5

.200

576

62,

10ge

nera

l2

erst

mal

sab

norm

al16

71

SO

NS

TM

1.2.

2005

18.5

.200

510

70,

29ge

nera

l0,

25er

stm

als

unau

ffälli

g16

81

GR

M27

.7.2

001

19.5

.200

513

723,

76ge

nera

l0,

75m

onat

lun

auffä

llig

169

2W

HW

TW

K1.

1.19

9719

.5.2

005

3018

8,27

gene

ral

8,5

erst

mal

sun

auffä

llig

170

1W

HW

TM

6.11

.199

422

.5.2

005

3796

10,4

0ge

nera

l10

,5er

stm

als

abno

rmal

171

2M

IXM

K25

.5.2

002

23.5

.200

510

782,

95ge

nera

l2

unau

ffälli

g17

21

LRW

K1.

11.2

003

24.5

.200

556

31,

54ge

nera

l1,

5er

stm

als

abno

rmal

173

1R

OT

TM

1.1.

1998

25.5

.200

526

647,

30ge

nera

l7,

5er

stm

als

unau

ffälli

g17

41

TE

CK

EL

M20

.6.1

999

27.5

.200

521

375,

85ge

nera

l/kom

plex

6er

stm

als

unau

ffälli

g17

51

MIX

M18

.10.

1998

30.5

.200

523

826,

53ge

nera

l6,

5er

stm

als

unau

ffälli

g

176

1M

IXM

12.9

.200

530

.5.2

005

-102

-0,2

8ge

nera

l / fo

kal/

kom

plex

6tg

lun

auffä

llig

177

1B

EA

GLE

W24

.1.2

003

6.6.

2005

852

2,33

gene

ral

2ha

lbj

unau

ffälli

g17

82

YO

RK

W3.

1.20

028.

6.20

0512

353,

38ge

nera

l2

erst

mal

sun

auffä

llig

179

2M

IXM

K1.

1.19

9610

.6.2

005

3399

9,31

gene

ral

6w

öche

ntl

unau

ffälli

g18

01

TE

CK

EL

W13

.6.1

994

10.6

.200

539

5710

,84

gene

ral

11er

stm

als

abno

rmal

181

1S

ON

ST

WK

17.8

.199

813

.6.2

005

2456

6,73

gene

ral

3m

onat

lun

auffä

llig

182

1LR

WK

6.5.

2003

14.6

.200

575

82,

08ge

nera

l1,

5vi

erte

ljun

auffä

llig

183

1S

CH

M21

.8.2

003

15.6

.200

565

41,

79ge

nera

l2

erst

mal

sun

auffä

llig

184

1S

ON

ST

WK

26.1

0.19

9921

.6.2

005

2035

5,58

gene

ral

5jä

hrl

unau

ffälli

g18

51

MIX

M25

.1.1

998

23.6

.200

526

687,

31ge

nera

l4,

5zw

eiw

abno

rmal

186

2S

ON

ST

W12

.12.

2003

29.6

.200

555

71,

53ge

nera

l0,

5ha

lbj

unau

ffälli

g18

71

SO

NS

TM

1.1.

1996

30.6

.200

534

199,

37ge

nera

l7

wöc

hent

lun

auffä

llig

188

1S

ON

ST

M22

.5.1

994

11.7

.200

540

0910

,98

gene

ral

11er

stm

als

unau

ffälli

g18

91

MIX

WK

1.1.

1992

11.7

.200

548

7013

,34

gene

ral

13,5

erst

mal

sab

norm

al19

02

HU

SK

YM

K26

.5.1

999

19.7

.200

522

136,

06ge

nera

l4,

5zw

eiw

unau

ffälli

g19

11

CO

CK

ER

M27

.7.1

997

19.7

.200

528

727,

87ge

nera

l8

erst

mal

sun

auffä

llig

192

1S

ON

ST

WK

26.9

.199

621

.7.2

005

3175

8,70

gene

ral

4m

onat

lun

auffä

llig

193

2B

EA

GLE

WK

15.3

.200

425

.7.2

005

490

1,34

gene

ral/f

okal

1w

öche

ntl

unau

ffälli

g19

41

SO

NS

TM

18.1

2.19

9925

.7.2

005

2017

5,53

gene

ral

3w

öche

ntl

unau

ffälli

g19

51

SO

NS

TM

21.1

.200

426

.7.2

005

545

1,49

gene

ral

1zw

eiw

unau

ffälli

g19

61

SO

NS

TM

10.1

1.19

9626

.7.2

005

3136

8,59

gene

ral

6zw

eiw

unau

ffälli

g19

71

MIX

WK

1.1.

2002

27.7

.200

512

863,

52ge

nera

lun

auffä

llig

198

1M

IXW

8.3.

2003

1.8.

2005

863

2,36

gene

ral

2vi

erte

ljun

auffä

llig

199

1S

ON

ST

MK

6.5.

2002

15.8

.200

511

793,

23ge

nera

l3

mon

atl

unau

ffälli

g20

02

TE

CK

EL

M10

.1.2

002

18.8

.200

512

983,

56ge

nera

l3,

5zw

eiw

unau

ffälli

g

Appendix 67

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e16

1ab

norm

alun

auffä

llig

post

ikta

l25

.4.2

005

25.4

.200

5id

iopa

this

chne

in2

nein

jaid

iopa

this

chne

in16

2un

auffä

llig

abno

rmal

nich

t pos

tikta

l3.

5.20

0530

.4.2

005

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

163

unau

ffälli

gab

norm

alne

inja

entz

ündl

ich

nein

164

unau

ffälli

gne

inja

entz

ündl

ich

ja16

5un

auffä

llig

abno

rmal

nein

nein

neop

last

isch

nein

166

abno

rmal

abno

rmal

nein

nein

met

.-to

x.ne

in16

7ab

norm

alne

inne

inA

nom

alie

nein

168

unau

ffälli

gab

norm

al8.

6.20

05id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in16

9un

auffä

llig

unau

ffälli

gja

jaid

iopa

this

chne

in17

0un

auffä

llig

abno

rmal

post

ikta

l24

.5.2

005

22.5

.200

5ne

opla

stis

chne

inja

jane

opla

stis

chve

rsto

rben

171

unau

ffälli

gun

auffä

llig

idio

path

isch

nein

172

abno

rmal

jane

inm

et.-

tox.

nein

173

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

22.6

.200

517

.6.2

005

idio

path

isch

nein

0ne

inja

met

.-to

x.ne

in17

4un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

2.6.

2005

18.5

.200

5id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in17

5un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

30.5

.200

525

.5.2

005

neop

last

isch

nein

0ja

nein

neop

last

isch

nein

176

unau

ffälli

gun

auffä

llig

post

ikta

l16

.6.2

005

16.6

.200

5id

iopa

this

chne

in2

nein

jaid

iopa

this

chne

in17

7un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

7.6.

2005

17.5

.200

5id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

178

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

179

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in18

0un

auffä

llig

abno

rmal

jane

inm

et.-

tox.

nein

181

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

24.6

.200

55.

5.20

05id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

182

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

5.7.

2005

5.6.

2005

idio

path

isch

nein

1ne

inne

inid

iopa

this

chne

in18

3un

auffä

llig

abno

rmal

post

ikta

l16

.6.2

005

15.6

.200

5id

iopa

this

chne

in1

nein

jaid

iopa

this

chne

in18

4un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

28.6

.200

53.

6.20

05id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

185

unau

ffälli

gpo

stik

tal

24.6

.200

522

.6.2

005

idio

path

isch

ja1

jaja

idio

path

isch

ja18

6un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in18

7ab

norm

alun

auffä

llig

6.7.

2005

idio

path

isch

nein

nein

nein

met

.-to

x.ja

188

abno

rmal

nein

jam

et.-

tox.

ja18

9un

auffä

llig

abno

rmal

nich

t pos

tikta

l12

.7.2

005

7.7.

2005

neop

last

isch

nein

1ne

inne

inne

opla

stis

chne

in19

0ab

norm

alun

auffä

llig

nein

jaid

iopa

this

chne

in19

1ab

norm

alab

norm

alne

inne

inm

et.-

tox.

nein

192

abno

rmal

abno

rmal

nich

t pos

tikta

l16

.8.2

005

2.7.

2007

idio

path

isch

nein

1ne

inja

neop

last

isch

nein

193

unau

ffälli

gne

inja

idio

path

isch

nein

194

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

23.8

.200

518

.7.2

005

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

195

abno

rmal

abno

rmal

post

ikta

l28

.7.2

005

27.7

.200

5id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in19

6ab

norm

alab

norm

alpo

stik

tal

11.8

.200

511

.8.2

005

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

197

unau

ffälli

gab

norm

alni

cht p

ostik

tal

2.8.

2005

25.7

.200

5id

iopa

this

chja

nein

jaid

iopa

this

chne

in19

8un

auffä

llig

unau

ffälli

gne

inne

inm

et.-

tox.

nein

199

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l16

.8.2

005

7.8.

2005

idio

path

isch

nein

1ja

jaid

iopa

this

chne

in20

0un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in

68 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

201

2M

ÜN

ST

M29

.1.1

998

22.8

.200

527

237,

46ge

nera

l4,

5m

onat

lun

auffä

llig

202

2M

IXM

K3.

10.1

996

25.8

.200

532

028,

77ge

nera

l8

halb

jun

auffä

llig

203

1M

IXM

K1.

4.20

041.

9.20

0551

01,

40ge

nera

l1,

5er

stm

als

unau

ffälli

g20

42

MIX

M1.

1.19

985.

9.20

0527

647,

57ge

nera

l7,

5er

stm

als

unau

ffälli

g20

52

BC

M1.

10.1

999

6.9.

2005

2135

5,85

gene

ral

2zw

eiw

unau

ffälli

g20

62

SO

NS

TW

24.1

0.19

9913

.9.2

005

2119

5,81

gene

ral

6er

stm

als

unau

ffälli

g20

71

MIX

W1.

1.19

9415

.9.2

005

4214

11,5

5ge

nera

l11

,5m

onat

lun

auffä

llig

208

2S

ON

ST

M1.

7.20

0019

.9.2

005

1878

5,15

gene

ral

5er

stm

als

unau

ffälli

g20

91

SO

NS

TW

K22

.4.2

001

20.9

.200

515

884,

35ge

nera

l4

mon

atl

unau

ffälli

g21

02

BR

AC

KE

WK

10.9

.199

920

.9.2

005

2170

5,95

gene

ral

4,5

zwei

wun

auffä

llig

211

1JR

TW

6.6.

2005

20.9

.200

510

40,

28ge

nera

l0,

25er

stm

als

abno

rmal

212

1C

OC

KE

RM

K25

.8.2

002

26.9

.200

511

113,

04ge

nera

l3

mon

atl

unau

ffälli

g21

31

SO

NS

TM

6.5.

2005

6.10

.200

515

00,

41ge

nera

l0,

25tg

lab

norm

al21

42

MIX

W12

.12.

2004

8.10

.200

529

60,

81ge

nera

l1

erst

mal

sun

auffä

llig

215

1S

ON

ST

M17

.11.

2003

13.1

0.20

0568

61,

88ge

nera

l2

mon

atl

unau

ffälli

g21

61

SO

NS

TW

1.6.

1992

16.1

0.20

0548

1513

,19

gene

ral

13tg

lun

auffä

llig

217

2M

IXM

9.8.

2000

24.1

0.20

0518

755,

14ge

nera

l2

zwei

wun

auffä

llig

218

2LR

M1.

1.20

0024

.10.

2005

2093

5,73

gene

ral

3,5

jähr

lun

auffä

llig

219

1M

IXM

1.5.

2000

25.1

0.20

0519

745,

41ge

nera

l0,

5ha

lbj

unau

ffälli

g22

01

MIX

M1.

1.20

0226

.10.

2005

1375

3,77

gene

ral

3m

onat

lun

auffä

llig

221

1M

IXW

K1.

1.19

981.

11.2

005

2820

7,73

gene

ral

7w

öche

ntl

abno

rmal

222

1R

OT

TW

5.9.

1997

1.11

.200

529

368,

04ge

nera

l7

erst

mal

sun

auffä

llig

223

2M

IXM

27.4

.200

411

.11.

2005

554

1,52

gene

ral

1m

onat

l22

41

SE

TT

ER

M28

.2.1

999

14.1

1.20

0524

146,

61ge

nera

l5,

5vi

erte

ljun

auffä

llig

225

2B

EA

GLE

M4.

4.20

0114

.11.

2005

1660

4,55

gene

ral

1,5

mon

atl

unau

ffälli

g22

62

LRM

19.1

0.20

0314

.11.

2005

745

2,04

gene

ral/f

okal

1,5

mon

atl

unau

ffälli

g22

72

PU

DE

LM

15.9

.199

616

.11.

2005

3301

9,04

gene

ral

9ha

lbj

unau

ffälli

g22

81

DS

HW

13.1

0.19

9618

.11.

2005

3275

8,97

gene

ral

9er

stm

als

unau

ffälli

g22

91

YO

RK

WK

31.3

.200

029

.11.

2005

2039

5,59

gene

ral/f

okal

2,5

unau

ffälli

g23

01

BO

XE

RW

16.1

2.19

932.

12.2

005

4306

11,8

0ge

nera

l12

erst

mal

sun

auffä

llig

231

1M

IXW

1.1.

2002

6.12

.200

514

153,

88ge

nera

ler

stm

als

unau

ffälli

g23

22

MIX

M16

.10.

1997

8.12

.200

529

328,

03ge

nera

l7,

5vi

erte

ljun

auffä

llig

233

2M

ÜN

ST

M15

.12.

1996

12.1

2.20

0532

378,

87ge

nera

l9

erst

mal

sun

auffä

llig

234

1S

ON

ST

M1.

2.20

0512

.12.

2005

311

0,85

gene

ral

0,5

zwei

wab

norm

al23

51

TE

CK

EL

M12

.3.2

004

13.1

2.20

0563

11,

73ge

nera

l1,

5zw

eiw

unau

ffälli

g23

61

BR

AC

KE

WK

1.3.

2003

19.1

2.20

0510

082,

76ge

nera

l1,

5w

öche

ntl

unau

ffälli

g23

71

MIX

M6.

10.2

005

20.1

2.20

0574

0,20

gene

ral

0,25

erst

mal

sun

auffä

llig

238

2M

IXW

5.8.

1995

22.1

2.20

0537

3710

,24

gene

ral

10er

stm

als

unau

ffälli

g23

91

GR

WK

9.2.

1995

30.1

2.20

0539

2110

,74

foka

l11

erst

mal

sun

auffä

llig

240

1R

OT

TM

K1.

1.19

9830

.12.

2005

2879

7,89

gene

ral

8er

stm

als

unau

ffälli

g

Appendix 69

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e20

1un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in20

2ab

norm

alun

auffä

llig

nein

nein

idio

path

isch

nein

203

abno

rmal

nein

nein

met

.-to

x.ne

in20

4un

auffä

llig

abno

rmal

nein

nein

met

.-to

x.ne

in20

5ab

norm

alab

norm

alne

inne

inid

iopa

this

chve

rsto

rben

206

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

207

abno

rmal

abno

rmal

nein

nein

met

.-to

x.ne

in20

8un

auffä

llig

abno

rmal

nein

nein

entz

ündl

ich

nein

209

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l27

.9.2

005

20.9

.200

5id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

210

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in21

1ab

norm

alab

norm

alpo

stik

tal

21.9

.200

521

.9.2

005

idio

path

isch

nein

nein

jaen

tzün

dlic

hja

212

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l25

.10.

2005

24.9

.200

5id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

213

abno

rmal

abno

rmal

post

ikta

l7.

10.2

005

7.10

.200

5id

iopa

this

chne

in24

nein

jaen

tzün

dlic

hve

rsto

rben

214

unau

ffälli

gab

norm

alne

inja

idio

path

isch

nein

215

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l14

.10.

2005

15.9

.200

5id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

216

abno

rmal

jaja

met

.-to

x.ja

217

abno

rmal

unau

ffälli

gne

inne

inid

iopa

this

chne

in21

8un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in21

9un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in22

0un

auffä

llig

unau

ffälli

gne

inne

inm

et.-

tox.

nein

221

abno

rmal

abno

rmal

post

ikta

l2.

11.2

005

31.1

0.20

05ne

opla

stis

chne

inne

inne

inne

opla

stis

chja

222

abno

rmal

abno

rmal

4.11

.200

5id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in22

3ab

norm

alun

auffä

llig

nein

nein

idio

path

isch

nein

224

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l14

.11.

2005

1.11

.200

5id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

225

unau

ffälli

gun

auffä

llig

jane

inid

iopa

this

chne

in22

6un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in22

7ab

norm

alab

norm

alja

jane

opla

stis

chja

228

unau

ffälli

gun

auffä

llig

post

ikta

l18

.11.

2005

17.1

1.20

05ne

opla

stis

chne

in0

nein

nein

neop

last

isch

nein

229

unau

ffälli

gab

norm

alpo

stik

tal

13.1

2.20

0512

.12.

2005

idio

path

isch

nein

0ne

inne

inid

iopa

this

chne

in23

0un

auffä

llig

post

ikta

l5.

12.2

005

2.12

.200

5ne

opla

stis

chne

inne

inja

neop

last

isch

nein

231

abno

rmal

nein

nein

met

.-to

x.ne

in23

2un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in23

3un

auffä

llig

unau

ffälli

gne

inja

idio

path

isch

nein

234

unau

ffälli

gun

auffä

llig

post

ikta

l20

.12.

2005

19.1

2.20

05id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in23

5ab

norm

alun

auffä

llig

nich

t pos

tikta

l20

.12.

2005

14.1

2.20

05id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

236

unau

ffälli

gun

auffä

llig

post

ikta

l19

.12.

2005

18.1

2.20

05id

iopa

this

chja

0ne

inja

idio

path

isch

nein

237

abno

rmal

nich

t pos

tikta

l29

.12.

2005

22.1

2.20

05id

iopa

this

chne

in0

nein

jam

et.-

tox.

nein

238

abno

rmal

abno

rmal

nein

nein

neop

last

isch

nein

239

unau

ffälli

gun

auffä

llig

nein

jam

et.-

tox.

nein

240

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

3.1.

2006

30.1

2.20

05id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

70 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

241

2S

ON

ST

M22

.8.2

000

9.1.

2006

1937

5,31

kom

pl.

5tg

lun

auffä

llig

242

2B

RA

CK

EW

6.6.

2005

10.1

.200

621

40,

59ge

nera

l0,

5zw

eiw

unau

ffälli

g24

32

YO

RK

M9.

6.20

0011

.1.2

006

2012

5,51

gene

ral

0,5

tgl

unau

ffälli

g24

42

SO

NS

TM

23.9

.200

116

.1.2

006

1553

4,25

gene

ral

4ha

lbj

unau

ffälli

g24

51

SO

NS

TW

1.1.

1996

17.1

.200

636

169,

91ge

nera

l11

wöc

hent

lun

auffä

llig

246

1LR

W25

.9.1

997

17.1

.200

629

928,

20ge

nera

l4

halb

jun

auffä

llig

247

1M

IXM

17.1

0.19

9226

.1.2

006

4779

13,0

9ge

nera

l13

erst

mal

sab

norm

al24

81

GR

W19

.12.

2004

31.1

.200

640

21,

10ge

nera

l1

zwei

wab

norm

al24

92

SC

HW

10.2

.200

131

.1.2

006

1791

4,91

gene

ral

5w

öche

ntl

unau

ffälli

g25

02

SO

NS

TM

21.5

.200

32.

2.20

0697

12,

66ge

nera

l1,

5zw

eiw

unau

ffälli

g25

11

GR

M1.

9.20

042.

2.20

0651

11,

40ge

nera

l1,

5er

stm

als

abno

rmal

252

1M

IXW

1.1.

2000

3.2.

2006

2192

6,01

gene

ral/k

ompl

ex5

tgl

unau

ffälli

g25

31

YO

RK

W15

.3.1

996

3.2.

2006

3558

9,75

gene

ral

10er

stm

als

unau

ffälli

g25

42

TE

CK

EL

W23

.8.1

994

5.2.

2006

4122

11,2

9ge

nera

l11

,5er

stm

als

abno

rmal

255

2M

IXM

K6.

12.2

000

6.2.

2006

1860

5,10

gene

ral

5er

stm

als

unau

ffälli

g25

61

SO

NS

TW

14.4

.200

59.

2.20

0629

50,

81ge

nera

l1

zwei

wun

auffä

llig

257

1JR

TM

18.1

.200

315

.2.2

006

1107

3,03

gene

ral

1,5

zwei

wun

auffä

llig

258

1M

IXM

K1.

1.19

9828

.2.2

006

2937

8,05

gene

ral

8er

stm

als

unau

ffälli

g25

92

MIX

WK

1.1.

1999

5.3.

2006

2584

7,08

gene

ral

6w

öche

ntl

unau

ffälli

g26

02

MIX

WK

1.9.

1990

7.3.

2006

5586

15,3

0ge

nera

l15

,5er

stm

als

abno

rmal

261

2B

OX

ER

WK

7.3.

2002

7.3.

2006

1440

3,95

kom

pl.

m

onat

lun

auffä

llig

262

1S

ON

ST

M5.

3.19

9813

.3.2

006

2888

7,91

foka

l8

erst

mal

sun

auffä

llig

263

2S

ON

ST

M23

.4.2

005

14.3

.200

632

10,

88ge

nera

l1

erst

mal

sun

auffä

llig

264

2S

ON

ST

MK

17.4

.199

516

.3.2

006

3929

10,7

6ge

nera

l10

,5zw

eiw

unau

ffälli

g26

51

SO

NS

TW

K19

.1.2

002

31.3

.200

615

124,

14ge

nera

l4

mon

atl

unau

ffälli

g26

61

SO

NS

TW

17.4

.200

52.

4.20

0634

50,

95ge

nera

l1

erst

mal

sab

norm

al26

72

BE

AG

LEM

26.3

.200

32.

4.20

0610

862,

98ge

nera

l3

erst

mal

sun

auffä

llig

268

2S

ON

ST

MK

29.1

0.20

033.

4.20

0687

42,

39ge

nera

l1

vier

telj

unau

ffälli

g26

91

GR

M4.

11.2

005

6.4.

2006

152

0,42

gene

ral

0,25

tgl

unau

ffälli

g27

02

WH

WT

W27

.6.2

001

10.4

.200

617

234,

72ge

nera

l4

wöc

hent

lun

auffä

llig

271

1B

EA

GLE

M30

.4.2

004

13.4

.200

670

31,

93ge

nera

l2

vier

telj

unau

ffälli

g27

22

SO

NS

TW

3.5.

2002

13.4

.200

614

203,

89ge

nera

l4

jähr

lun

auffä

llig

273

2S

ON

ST

M14

.9.2

004

18.4

.200

657

41,

57ge

nera

l1,

5w

öche

ntl

unau

ffälli

g27

41

MIX

WK

19.7

.199

918

.4.2

006

2429

6,65

gene

ral

6vi

erte

ljun

auffä

llig

275

1S

ET

TE

RW

1.1.

1996

19.4

.200

637

0810

,16

gene

ral

10er

stm

als

abno

rmal

276

1S

CH

M14

.1.2

005

25.4

.200

646

11,

26ge

nera

l0,

25tg

lun

auffä

llig

277

1M

IXW

K1.

11.1

996

25.4

.200

634

149,

35ge

nera

l9,

5er

stm

als

unau

ffälli

g27

81

SO

NS

TW

22.1

2.20

0225

.4.2

006

1203

3,30

gene

ral

3er

stm

als

unau

ffälli

g27

91

TE

CK

EL

WK

30.4

.200

6

foka

l11

mon

atl

unau

ffälli

g28

01

MIX

MK

30.6

.199

55.

5.20

0639

0510

,70

gene

ral

11er

stm

als

unau

ffälli

g

Appendix 71

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e24

1ab

norm

alun

auffä

llig

nein

nein

idio

path

isch

nein

242

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in24

3ab

norm

alun

auffä

llig

nein

nein

idio

path

isch

nein

244

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

245

abno

rmal

unau

ffälli

gne

inne

inm

et.-

tox.

nein

246

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l18

.1.2

006

1.12

.200

5id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

247

abno

rmal

post

ikta

l26

.1.2

006

26.1

.200

6va

skul

ärne

in0

jaja

vask

ulär

nein

248

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l16

.3.2

006

10.3

.200

6id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

249

abno

rmal

unau

ffälli

gne

inne

inid

iopa

this

chne

in25

0un

auffä

llig

unau

ffälli

gne

inja

idio

path

isch

nein

251

abno

rmal

jane

inm

et.-

tox.

nein

252

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

7.2.

2006

3.2.

2006

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

253

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l7.

2.20

063.

2.20

06id

iopa

this

chne

in1

jaja

idio

path

isch

nein

254

abno

rmal

abno

rmal

jane

inne

opla

stis

chja

255

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

256

unau

ffälli

gun

auffä

llig

post

ikta

l8.

3.20

068.

3.20

06id

iopa

this

chne

in0

jaja

idio

path

isch

nein

257

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l16

.2.2

006

16.1

.200

6id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in25

8ab

norm

alja

jade

gene

rativ

ja25

9ab

norm

alab

norm

alja

jaen

tzün

dlic

hne

in26

0ab

norm

alun

auffä

llig

jane

inid

iopa

this

chne

in26

1un

auffä

llig

unau

ffälli

gid

iopa

this

chne

in26

2un

auffä

llig

unau

ffälli

gne

inne

inm

et.-

tox.

nein

263

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

264

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

265

abno

rmal

unau

ffälli

gne

inne

inm

et.-

tox.

nein

266

unau

ffälli

gne

inne

inm

et.-

tox.

nein

267

abno

rmal

unau

ffälli

gja

nein

idio

path

isch

nein

268

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

269

unau

ffälli

gun

auffä

llig

post

ikta

l7.

4.20

065.

4.20

06id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in27

0un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in27

1un

auffä

llig

unau

ffälli

gpo

stik

tal

18.7

.200

615

.7.2

006

idio

path

isch

nein

0ne

inne

inid

iopa

this

chne

in27

2un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in27

3un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in27

4un

auffä

llig

unau

ffälli

gpo

stik

tal

20.4

.200

620

.4.2

006

neop

last

isch

nein

0ne

inja

neop

last

isch

ja27

5un

auffä

llig

jaja

met

.-to

x.ja

276

abno

rmal

abno

rmal

27.4

.200

6A

nom

alie

nein

0ne

inja

Ano

mal

ieja

277

unau

ffälli

gpo

stik

tal

26.4

.200

625

.04.

200

idio

path

isch

nein

0ja

jaid

iopa

this

chne

in27

8un

auffä

llig

abno

rmal

post

ikta

l27

.4.2

006

25.4

.200

6en

tzün

dlic

hne

in6

nein

jaen

tzün

dlic

hne

in27

9ab

norm

alne

inja

met

.-to

x.ne

in28

0ab

norm

alun

auffä

llig

12.5

.200

6id

iopa

this

chne

in0

nein

nein

met

.-to

x.ne

in

72 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

281

2S

CH

M30

.3.2

002

9.5.

2006

1479

4,05

gene

ral

3,5

jähr

lun

auffä

llig

282

1M

IXM

30.3

.200

610

.5.2

006

400,

11ge

nera

l0,

2tg

lab

norm

al28

32

SO

NS

TM

21.1

0.20

0514

.5.2

006

203

0,56

gene

ral

0,5

erst

mal

sun

auffä

llig

284

1S

ON

ST

W13

.5.2

004

15.5

.200

672

21,

98ge

nera

l1,

5zw

eiw

abno

rmal

285

1S

ON

ST

W1.

2.19

9520

.5.2

006

4069

11,1

5ge

nera

l11

erst

mal

sab

norm

al28

61

PU

DE

LM

1.1.

2000

24.5

.200

623

036,

31ge

nera

l5,

5er

stm

als

unau

ffälli

g28

72

DS

HM

K1.

11.2

003

29.5

.200

692

82,

54ge

nera

l2,

5er

stm

als

unau

ffälli

g28

81

BC

M19

.1.2

005

30.5

.200

649

11,

35ge

nera

l1

wöc

hent

lun

auffä

llig

289

2P

UD

EL

M29

.10.

2000

31.5

.200

620

125,

51ge

nera

l4,

5m

onat

lun

auffä

llig

290

1S

ON

ST

WK

1.7.

1993

31.5

.200

646

5012

,74

gene

ral/f

okal

13er

stm

als

unau

ffälli

g29

12

TE

CK

EL

M11

.11.

2002

31.5

.200

612

803,

51ge

nera

l2,

5zw

eiw

unau

ffälli

g29

21

BO

XE

RM

K1.

1.20

003.

6.20

0623

126,

33ge

nera

l6,

5w

öche

ntl

unau

ffälli

g29

31

MIX

M1.

3.19

996.

6.20

0626

157,

16fo

kal/k

ompl

ex6

unau

ffälli

g29

41

BE

AG

LEW

28.4

.200

69.

6.20

0641

0,11

gene

ral

0,2

tgl

unau

ffälli

g29

51

MIX

M1.

1.19

9813

.6.2

006

3042

8,33

gene

ral

2m

onat

lun

auffä

llig

296

1JR

TW

30.9

.200

418

.6.2

006

618

1,69

gene

ral

2er

stm

als

unau

ffälli

g29

71

HU

SK

YW

K1.

1.20

0019

.6.2

006

2328

6,38

gene

ral

5un

auffä

llig

298

2T

EC

KE

LM

27.4

.200

419

.6.2

006

772

2,12

gene

ral

2m

onat

lun

auffä

llig

299

2B

RA

CK

EW

16.3

.200

323

.6.2

006

1177

3,22

gene

ral

2,5

mon

atl

unau

ffälli

g30

01

SO

NS

TW

1.1.

2003

26.6

.200

612

553,

44ge

nera

l3,

5er

stm

als

abno

rmal

301

1M

IXW

1.5.

2003

26.6

.200

611

353,

11ge

nera

l1,

5w

öche

ntl

unau

ffälli

g30

21

RO

TT

M27

.4.1

998

27.6

.200

629

408,

05ge

nera

l7,

5m

onat

lab

norm

al30

31

SO

NS

TW

1.1.

1993

29.6

.200

648

5813

,31

gene

ral

13,5

tgl

unau

ffälli

g30

41

GR

W6.

7.19

9630

.6.2

006

3594

9,85

gene

ral

10er

stm

als

abno

rmal

305

1M

IXM

K1.

1.20

043.

7.20

0690

22,

47ge

nera

l2,

5w

öche

ntl

unau

ffälli

g30

62

GR

WK

1.5.

1996

3.7.

2006

3662

10,0

3ge

nera

l10

erst

mal

sun

auffä

llig

307

2M

IXW

1.1.

2001

3.7.

2006

1982

5,43

gene

ral

4vi

erte

ljun

auffä

llig

308

1S

ON

ST

W6.

1.20

066.

7.20

0618

00,

49ge

nera

l0,

2w

öche

ntl

unau

ffälli

g30

91

SC

HW

8.4.

2006

13.7

.200

695

0,26

gene

ral

0,25

erst

mal

sab

norm

al31

02

SO

NS

TM

K22

.4.1

999

14.7

.200

626

027,

13ge

nera

l3

mon

atl

unau

ffälli

g31

12

BO

XE

RW

29.7

.199

621

.7.2

006

3592

9,84

gene

ral/k

ompl

ex10

tgl

unau

ffälli

g31

21

JRT

M1.

5.19

9723

.7.2

006

3322

9,10

gene

ral

9er

stm

als

abno

rmal

313

1G

RW

K14

.11.

1998

24.7

.200

627

707,

59ge

nera

l7,

5m

onat

lun

auffä

llig

314

1S

ON

ST

WK

1.3.

1994

28.7

.200

644

6712

,24

gene

ral

12er

stm

als

unau

ffälli

g31

52

YO

RK

M14

.2.2

006

29.7

.200

616

50,

45ge

nera

l0,

5er

stm

als

unau

ffälli

g31

62

MIX

W1.

1.19

9430

.7.2

006

4529

12,4

1ge

nera

lun

auffä

llig

317

1Y

OR

KW

27.1

2.20

0530

.7.2

006

213

0,58

gene

ral

0,75

erst

mal

sab

norm

al31

82

GR

W16

.4.2

000

1.8.

2006

2265

6,21

gene

ral

6er

stm

als

unau

ffälli

g31

91

GR

M7.

8.19

973.

8.20

0632

368,

87fo

kal

9er

stm

als

unau

ffälli

g32

01

SO

NS

TM

13.4

.200

65.

8.20

0611

20,

31ge

nera

l0,

25er

stm

als

unau

ffälli

g

Appendix 73

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e28

1un

auffä

llig

unau

ffälli

gne

inne

inid

iopa

this

chne

in28

2ab

norm

alja

jaen

tzün

dlic

hja

283

abno

rmal

unau

ffälli

gne

inja

idio

path

isch

nein

284

abno

rmal

abno

rmal

nich

t pos

tikta

l11

.7.2

006

27.6

.200

6A

nom

alie

nein

0ne

inja

Ano

mal

iene

in28

5ab

norm

alab

norm

alpo

stik

tal

23.5

.200

620

.5.2

006

vask

ulär

nein

0ne

inne

inva

skul

ärne

in28

6ab

norm

alab

norm

alpo

stik

tal

26.5

.200

626

.5.2

006

idio

path

isch

nein

7166

nein

jaen

tzün

dlic

hja

287

abno

rmal

unau

ffälli

gne

inja

idio

path

isch

nein

288

unau

ffälli

gun

auffä

llig

post

ikta

l31

.5.2

006

28.5

.200

6id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in28

9ab

norm

alun

auffä

llig

nein

jaid

iopa

this

chne

in29

0ab

norm

alab

norm

alni

cht p

ostik

tal

1.6.

2006

22.5

.200

6ne

opla

stis

chne

inne

inja

neop

last

isch

nein

291

unau

ffälli

gab

norm

alne

inja

idio

path

isch

nein

292

unau

ffälli

gun

auffä

llig

post

ikta

l7.

7.20

066.

7.20

06ne

opla

stis

chne

inja

jane

opla

stis

chne

in29

3un

auffä

llig

unau

ffälli

gne

inne

inm

et.-

tox.

nein

294

abno

rmal

unau

ffälli

gpo

stik

tal

13.6

.200

612

.6.2

006

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

295

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l22

.6.2

006

4.6.

2006

idio

path

isch

nein

6ne

inne

inen

tzün

dlic

hne

in29

6ab

norm

alab

norm

alne

inja

met

.-to

x.ne

in29

7un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

27.6

.200

61.

6.20

06id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

298

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

299

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

300

unau

ffälli

gab

norm

alpo

stik

tal

26.6

.200

624

.6.2

006

Ano

mal

iene

inne

inne

inA

nom

alie

nein

301

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l5.

7.20

0629

.5.2

006

idio

path

isch

nein

0ja

jaid

iopa

this

chne

in30

2un

auffä

llig

unau

ffälli

gne

inja

neop

last

isch

nein

303

abno

rmal

unau

ffälli

gne

inja

met

.-to

x.ne

in30

4ab

norm

alun

auffä

llig

nein

nein

met

.-to

x.ne

in30

5ab

norm

alun

auffä

llig

post

ikta

l4.

7.20

052.

7.20

06id

iopa

this

chne

in1

nein

jaid

iopa

this

chne

in30

6un

auffä

llig

abno

rmal

nein

nein

neop

last

isch

nein

307

unau

ffälli

gun

auffä

llig

jaja

idio

path

isch

nein

308

unau

ffälli

gpo

stik

tal

6.7.

2005

6.7.

2006

idio

path

isch

nein

0ne

inja

idio

path

isch

nein

309

abno

rmal

abno

rmal

nein

nein

met

.-to

x.ne

in31

0ab

norm

alun

auffä

llig

nein

jaid

iopa

this

chne

in31

1un

auffä

llig

abno

rmal

jaja

neop

last

isch

nein

312

abno

rmal

abno

rmal

jaja

met

.-to

x.ne

in31

3un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

25.7

.200

617

.7.2

006

idio

path

isch

nein

0ne

inne

inid

iopa

this

chne

in31

4ab

norm

alab

norm

alni

cht p

ostik

tal

15.3

.200

628

.7.2

006

idio

path

isch

nein

16ne

inne

inen

tzün

dlic

hne

in31

5ab

norm

alab

norm

alne

inne

inm

et.-

tox.

nein

316

abno

rmal

abno

rmal

nein

nein

neop

last

isch

nein

317

abno

rmal

unau

ffälli

gne

inja

met

.-to

x.ne

in31

8ab

norm

alab

norm

alne

inne

inne

opla

stis

chja

319

unau

ffälli

gun

auffä

llig

post

ikta

l4.

8.20

063.

8.20

06ne

opla

stis

chne

in0

nein

nein

neop

last

isch

nein

320

abno

rmal

jaja

met

.-to

x.ne

in

74 Appendix

Nr.

Gru

ppe

Ras

seG

esch

lech

tG

ebur

tsd.

Vor

stel

lung

sdV

orst

ella

lter

dV

orst

ella

lter

yP

robl

emat

ikA

uftr

ittsa

lter

yF

requ

enz

allg

us

321

1S

ON

ST

M11

.9.2

004

7.8.

2006

686

1,88

gene

ral

2m

onat

lun

auffä

llig

322

1Y

OR

KM

K29

.7.2

000

10.8

.200

621

715,

95ge

nera

l6

tgl

unau

ffälli

g32

31

SO

NS

TM

7.6.

1999

14.8

.200

625

877,

09ge

nera

l7

mon

atl

unau

ffälli

g32

41

BR

AC

KE

M2.

10.2

003

17.8

.200

610

352,

84ge

nera

l1,

5vi

erte

ljun

auffä

llig

325

2R

OT

TW

9.4.

2006

21.8

.200

613

20,

36ge

nera

l0,

25er

stm

als

unau

ffälli

g32

62

JRT

W8.

5.20

0222

.8.2

006

1544

4,23

gene

ral

4zw

eiw

unau

ffälli

g32

71

SO

NS

TM

10.5

.199

722

.8.2

006

3342

9,16

gene

ral

9m

onat

lun

auffä

llig

328

2H

US

KY

M25

.6.2

005

22.8

.200

641

71,

14ge

nera

l1

wöc

hent

lun

auffä

llig

329

1M

ÜN

ST

M1.

1.20

0422

.8.2

006

951

2,61

gene

ral

2,5

erst

mal

sun

auffä

llig

330

1M

IXW

27.9

.200

128

.8.2

006

1771

4,85

gene

ral

5tg

lun

auffä

llig

331

2C

OC

KE

RW

11.2

.200

629

.8.2

006

198

0,54

gene

ral

0,25

vier

telj

unau

ffälli

g33

22

SO

NS

TM

5.11

.200

129

.8.2

006

1734

4,75

foka

l5

erst

mal

sun

auffä

llig

333

1M

IXW

19.1

2.20

032.

9.20

0697

32,

67ge

nera

l3

erst

mal

sun

auffä

llig

334

1D

SH

W23

.7.2

004

4.9.

2006

761

2,08

gene

ral

0,25

mon

atl

unau

ffälli

g33

51

JRT

W6.

3.19

975.

9.20

0634

199,

37ge

nera

l9

mon

atl

unau

ffälli

g33

61

MIX

W1.

5.19

947.

9.20

0644

4612

,18

kom

pl.

11,5

unau

ffälli

g33

71

LRW

5.5.

2005

11.9

.200

648

61,

33ge

nera

l1

mon

atl

unau

ffälli

g33

82

JRT

W13

.9.2

006

gene

ral

2w

öche

ntl

unau

ffälli

g33

91

GR

W10

.3.2

003

19.9

.200

612

693,

48ge

nera

l1

mon

atl

unau

ffälli

g34

01

MIX

MK

1.2.

2004

19.9

.200

694

82,

60ge

nera

l1,

5vi

erte

ljun

auffä

llig

341

1D

SH

W31

.12.

2005

22.9

.200

626

20,

72ge

nera

l0,

75er

stm

als

abno

rmal

342

1S

ON

ST

MK

22.5

.200

124

.9.2

006

1922

5,27

gene

ral

5m

onat

lun

auffä

llig

343

1B

RA

CK

EW

7.4.

2003

26.9

.200

612

493,

42ge

nera

l3,

5m

onat

lun

auffä

llig

Lege

nd:

Nr.

= n

umbe

r, G

rupp

e =

gro

up,

Ras

se =

bre

ed,

Ges

chle

cht

= g

ende

r, G

ebur

tsd.

= d

ate

of b

irth,

Vor

stel

lung

sd.

= d

ate

of p

rese

ntat

ion,

Vor

stel

lung

salte

r d

= a

ge a

t da

te o

f pr

esen

tatio

n in

day

s, V

orst

ellu

ngsa

lter

y =

age

at

date

of

pres

enta

tion

in y

ears

, P

robl

emat

ic =

kin

d of

seiz

ures

,, A

uftr

ittsa

lter

y =

age

whe

n fir

st s

eizu

re o

ccur

red,

Fre

quen

z =

freq

uenc

y, a

llg u

s =

phys

ical

exa

min

atio

n

LR =

Lab

rado

r R

etrie

ver,

SC

H =

Sch

nauz

er, M

IX =

mix

ed b

reed

, S

ON

ST

= m

isce

llane

ous,

TE

CK

EL=

dac

hshu

nd,

WH

WT

= W

esth

ighl

and

Whi

te

Ter

rier,

GR

= G

olde

n R

etrie

ver,

RO

TT

= R

ottw

eile

r, J

RT

= J

ack

Rus

sel

Ter

rier,

MÜ

NS

T =

Mün

ster

länd

er,

SE

TT

ER

= S

ette

r, D

SH

= G

erm

an

She

pher

d, B

C =

Bor

der

Col

lie, H

US

KY

= H

usky

, B

EA

GLE

= B

eagl

e, C

OC

KE

R =

Coc

ker

Spa

niel

, Y

OR

K =

Yor

kshi

re T

errie

r, B

RA

CK

E =

Bra

cke,

BO

XE

R =

Box

er, P

UD

EL

= P

oodl

e, M

= m

ale,

MK

= n

eute

red

mal

e, W

= fe

mal

e, W

K =

neu

tere

d fe

mal

e, g

ener

al =

gen

eral

ized

sei

zure

s, /f

okal

=

foca

l sei

zure

s, k

ompl

. =

com

plex

foc

al s

eizu

res,

zw

eiw

= e

very

sec

ond

wee

k, m

onat

l = m

onth

ly,

wöc

hent

l = w

eekl

y, t

gl =

dai

ly,

vier

telj

= e

very

3

mon

ths,

ers

tmal

s =

for

the

first

tim

e, h

albj

= e

very

6 m

onth

s, u

nauf

fälli

g =

unre

mar

kabl

e, a

bnor

mal

= a

bnor

mal

Appendix 75

Nr.

Labo

rne

uro

usm

rtD

atum

mrt

letz

ter

anfa

llm

rt D

iagn

ose

post

ikt.

Ver

änd.

Zel

len

liquo

rS

tatu

s ep

il.cl

uste

rE

nddi

agno

seE

utha

nasi

e32

1un

auffä

llig

abno

rmal

post

ikta

l8.

8.20

066.

8.20

06id

iopa

this

chne

in0

nein

jaid

iopa

this

chne

in32

2ab

norm

alab

norm

alpo

stik

tal

14.8

.200

613

.8.2

006

idio

path

isch

ja2

nein

jaid

iopa

this

chne

in32

3un

auffä

llig

unau

ffälli

gni

cht p

ostik

tal

22.8

.200

67.

8.20

06id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

324

unau

ffälli

gun

auffä

llig

nein

nein

idio

path

isch

nein

325

unau

ffälli

gun

auffä

llig

idio

path

isch

nein

326

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in32

7ab

norm

alun

auffä

llig

nein

jam

et.-

tox.

nein

328

unau

ffälli

gun

auffä

llig

nein

jaid

iopa

this

chne

in32

9ab

norm

alun

auffä

llig

jaja

met

.-to

x.ne

in33

0un

auffä

llig

nein

jam

et.-

tox.

nein

331

unau

ffälli

gun

auffä

llig

idio

path

isch

nein

332

unau

ffälli

gab

norm

alne

inja

entz

ündl

ich

nein

333

abno

rmal

abno

rmal

post

ikta

l2.

9.20

062.

9.20

06id

iopa

this

chne

inja

jam

et.-

tox.

nein

334

abno

rmal

unau

ffälli

gni

cht p

ostik

tal

14.9

.200

61.

4.20

06id

iopa

this

chne

inne

inne

inid

iopa

this

chne

in33

5un

auffä

llig

unau

ffälli

g6.

9.20

06id

iopa

this

chne

in0

nein

nein

idio

path

isch

nein

336

unau

ffälli

gab

norm

alpo

stik

tal

8.9.

2006

7.9.

2006

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

337

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l12

.9.2

006

30.8

.200

6id

iopa

this

chne

in1

nein

nein

idio

path

isch

nein

338

abno

rmal

abno

rmal

jaja

entz

ündl

ich

nein

339

unau

ffälli

gab

norm

alni

cht p

ostik

tal

20.9

.200

631

.8.2

006

idio

path

isch

nein

1ne

inja

idio

path

isch

nein

340

unau

ffälli

gun

auffä

llig

nich

t pos

tikta

l26

.9.2

006

15.9

.200

6id

iopa

this

chne

inne

inne

inid

iopa

this

chne

in34

1ab

norm

alab

norm

alni

cht p

ostik

tal

27.9

.200

622

.9.2

006

entz

ündl

ich

nein

1323

nein

jaen

tzün

dlic

hne

in34

2ab

norm

alun

auffä

llig

nein

jam

et.-

tox.

nein

343

abno

rmal

unau

ffälli

gpo

stik

tal

27.9

.200

625

.9.2

006

idio

path

isch

nein

0ne

inne

inid

iopa

this

chne

in

Lege

nd: N

r. =

Lab

or =

blo

od c

ell c

ount

and

ser

um c

hem

istr

y, n

euro

us=

neu

rolo

gica

l exa

min

atio

n, m

rt =

mag

netic

res

onan

ce im

agin

g, D

atum

mrt

= d

ate

of M

RI

perf

orm

ance

, le

tzte

r A

nfal

l = la

st s

eizu

re,

mrt

Dia

gnos

e =

mri

diag

nosi

s, p

ostik

t. V

erän

d. =

pos

ticta

l cha

nges

, Z

elle

n liq

uor

= c

ells

in C

SF

, S

tatu

s ep

il. =

sta

tus

epile

ptic

us,

clus

ter

= c

lust

er r

un,

End

diag

nose

= d

iagn

osis

, E

utha

nasi

e =

eut

hana

sia,

una

uffä

llig

= u

nrem

arka

ble,

abn

orm

al =

abn

orm

al,

post

ikta

l = p

ostic

tal,

nich

t po

stik

tal

= no

n po

stic

tal,

idio

path

isch

= i

diop

athi

c ep

ileps

y, v

ascu

lar

= va

scul

ar,

entz

ündl

ich

= in

flam

mat

ory,

tra

umat

isch

= t

raum

atic

, A

nom

alie

=

anom

aly,

met

.-to

x. =

met

abol

ic-t

oxic

, neo

plas

tisch

= n

eopl

astic

, deg

ener

ativ

e =

deg

ener

ativ

e, n

ein

= n

o, ja

= y

es, v

erst

orbe

n =

pas

sed

away

76 Acknowledgements

11 Acknowledgements

Mein ganz besonderer und herzlichster Dank gilt meiner Betreuerin Frau Prof. Dr.

Andrea Tipold. Ihre durchgehend engagierte und freundschaftliche Betreuung meiner

Arbeit hat den allergrößten Anteil an deren Gelingen.

Herrn Prof. Dr. Ingo Nolte danke ich für die Möglichkeit der Durchführung dieser

Arbeit in der Klinik für Kleintiere der Stiftung Tierärztliche Hochschule Hannover.

Bei der Gesellschaft zur Förderung kynologischer Forschung bedanke ich mich für

die zur Verfügung gestellte Projektförderung.

Meinen Neurologen danke ich ganz, ganz herzlich für die geduldigen Erklärungen

und all die schönen Stunden, in denen wir immer herzhaft lachen konnten.

Auch allen anderen Mitarbeitern der Klinik für Kleintiere der Stiftung Tierärztliche

Hochschule Hannover danke ich für die unkomplizierte und nette Zusammenarbeit.

Hervorzuheben wäre jedoch die stete Geduld von Frau Littmann und Frau Thum bei

der Weiterleitung meiner Patienten-Termine.

Herrn Dr. Martin Beyerbach aus dem Institut für Biometrie, Epidemiologie und

Informationsverarbeitung der Stiftung Tierärztliche Hochschule Hannover danke ich

für die Hilfe bei der statistischen Auswertung meiner Daten.

Bei meinen „Liebsten“ Ruthi und Karla möchte ich mich vor allem dafür bedanken,

dass sie immer für mich da waren und stets ein offenes Ohr für Probleme jeglicher

Art hatten. Alle (bzw. fast alle) Prüfungen miteinander durchzustehen schweißt doch

enorm zusammen. Ihr seid die Besten!!!

Meinen „Tiermedizinern“, mittlerweile in ganz Deutschland verstreut, danke für all die

schönen und lustigen Momente im Pylorus, auf dem Campus, beim Brunchen, beim

Vorglühen, auf den Parties, beim Katerfrühstück… diese Zeit kann uns keiner mehr

nehmen!

Acknowledgements 77

Der besten WG in Hannover (Karla, Hanna und Dirk) danke ich für schönen letzten 2

Jahre- es war einfach super mit euch!

All meinen Freunden aus dem Ruhrgebiet danke ich dafür, dass sie mir in den letzten

7 Jahren stets die Treue erwiesen und mich jetzt wieder mit offenen Armen

empfangen haben.

Bei meinem lieben Schulfreund Dipl.-Ing. Dominik Wegener bedanke ich mich sehr

für die tolle Hilfe beim Formatieren dieser Arbeit. Ohne dich wäre das nicht so

einfach geworden.

Bei meinem Bruder Carsten und meiner „Schwägerin“ Sarah bedanke ich mich

besonders für meine wundervolle Nichte Lea.

Zuletzt, jedoch nicht weniger wichtig, möchte ich mich bei meiner Mutter, Dietmar,

meinen Geschwistern und meinen Großeltern für all die schönen Momente

bedanken, die wir zusammen verbracht haben.

Ich danke euch, dass ihr sowohl in einfachen als auch in schwierigeren Zeiten immer

hinter mir standet und mich unterstützt habt wo ihr nur konntet.

Meinen beiden Schwestern Yvonne und Kerstin möchte ich noch sagen- ihr schafft

das schon! Ich glaube fest an euch…

Date post:	25-Jun-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

Studies on canine epilepsy: diagnostic workup including ... · Tierärztliche Hochschule Hannover...

Documents