Non-motor symptoms in patients with isolated idiopathic and inherited dystonia LEJLA PARACKA

University of Veterinary Medicine Hannover

Department of Neurology, Hannover Medical School

Center for Systems Neuroscience

University of Veterinary Medicine Hannover

Department of Neurology, Hannover Medical School

Center for Systems Neuroscience

Non-motor symptoms in patients with isolated idiopathic and inherited

dystonia

THESIS

Submitted in partial fulfilment of the requirements for the degree

DOCTOR OF PHILOSOPHY

(PhD)

awarded by the University of Veterinary Medicine Hannover

by

Lejla Paracka

(Republic of Kosovo)

Hannover, Germany 2016

Supervisor: Prof. Dr. med. Florian Wegner

Supervisor group: Prof. Dr. med. Florian Wegner

Prof. Dr. med. Joachim K. Krauss

Prof .Dr. med. Eckart Altenmüller

1st evaluation Prof. Dr. med. Florian Wegner

Department of Neurology, Hannover Medical School, Hannover

Prof. Dr. med. Joachim K. Krauss

Department of Neurosurgery, Hannover Medical School, Hannover

Prof. Dr. med. Eckart Altenmüller

Institute of Music Physiology and Musician’s Medicine

2nd evaluation Prof. Dr. med. Alfons Schnitzler

Department of Neurology, University of Düsseldorf

Date of final exam: 21.10.2016

To my beloved family

Parts of this thesis have been submitted previously in:

Paracka L*, Wegner F*, Blahak C, Abdallat M, Dressler D, Karst M, Krauss JK.

(*Equal contribution). Subtle sensory abnormalities in patients with isolated idiopathic

and hereditary dystonia. Eur J Neurol. Currently under review

Paracka L, Kollewe K, Wegner F, Dressler D. Strategies to decrease injection site

pain in botulinum toxin therapy. J Neural Transm. Currently under review

Publications that are not included in this thesis:

Kollewe K, Escher CM, Wulff DU, Fathi D, Paracka L, Mohammadi B, Karst M,

Dressler D. Long-term treatment of chronic migraine with OnabotulinumtoxinA:

efficacy, quality of life and tolerability in a real-life setting. J Neural Transm. 2016

123:533-40.

Paracka L, Kollewe K, Dengler R, Dressler D. Botulinum toxin therapy for

hyperhidrosis: reduction of injection site pain by nitrous oxide/oxygen mixtures. J

Neural Transm. 2015 122:1279-82.

Parts of the thesis have been presented as posters in the following

events

20th International Congress of Parkinson’s Disease and Movement Disorders, Berlin

2016

3rd International Congress on Treatment of Dystonia, Hannover 2016

88. Kongress der Deutschen Gesellschaft für Neurologie (DGN), Düsseldorf 2015

60. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Klinische

Neurophysiologie und Funktionelle Bildgebung (DGKN), Düsseldorf 2016

Authors contributions:

Manuscript I: Subtle sensory abnormalities in patients with isolated idiopathic

and hereditary dystonia

L. Paracka did the conception and design of the study, recruited subjects, collected

data, performed statistical analysis, interpreted the data and wrote the manuscript. F.

Wegner concepted and designed the study, recruited the patients, collected and

interpreted data and contributed to the manuscript. C. Blahak, M. Karst and D.

Dressler recruited the patients, collected data and approved the manuscript. J.

Krauss supervised the research project, concepted and designed the study, recruited

patients and contributed essentially to the manuscript.

Manuscript II: Strategies to decrease injection site pain in botulinum toxin

therapy

L. Paracka concepted and designed the study, recruited the subjects, performed the

testing, collected data, performed the statistical analysis, interpreted the data and

wrote the manuscript. K. Kollewe and F. Wegner collected data and contributed to

the manuscript. D. Dressler supervised the research project, interpreted the data,

contributed essentially to the manuscript.

Contents

1. Introduction………………………………………………………………………….1

1.1. Definition..................................................................................................1

1.2. Classification of dystonia………………………………………………………1

1.3. Pathophysiology of idiopathic and inherited dystonia………………………....3

1.4. Clinical features and diagnosis of dystonia..…………………………………..5

1.5. Treatment and management of dystonia……………………………...…..…..7

1.5.1. Botulinum toxin……………………………………………...……………..7

1.5.2. Deep brain stimulation……………………………………………………..8

1.6. Processing sensory information from skin to the cortex……………………....9

2. Objectives…………………………………………………………………………..12

3. Manuscript I………………………………………………………………………..15

4. Manuscript II……………………………………………………………………….43

5. Appendix…………………………………………………………………………...53

6. General discussion……………………………………………………………….61

7. Summary……………………………………………………………………………69

8. Zusammenfassung………………………………………………………………..73

9. References………………………………………………………………………….77

Acknowledgements............................................................................................89

Abbreviations list

BDI Beck depression inventory

BFM Burke-Fahn-Marsden Dystonia Rating Scale

BoNT botulinum neurotoxin

BP bodily pain

CDT cold detection threshold

CPT cold pain threshold

DBS deep brain stimulation

DMA dynamic mechanical allodynia

FI forearm ischemia

FKKS Frankfurt body concept scale

GH general health

GPe external globus pallidus

GPi internal globus pallidus

HDI Hamilton depression inventory

HDT hot detection threshold

HPT hot pain threshold

IS ice spray

LAC local anesthetic cream

MH mental health

MMT mini metal test

MPT mechanical pain threshold

MPTT mechanical pain threshold test

NOO nitrous oxide/oxygen mixture

PF physical functioning

PPT pressure pain threshold

PSP pain sensitivity for pinprick

QST quantitative sensory testing

RE role emotional

RP role physical

RPST repetitive pain stimulation test

SAKA acceptance of one’s body by the others

SASE aspects of outer appearance

SDIS dissimilatory body processes

SF social functioning

SGKB body concept towards the health

SIAS Social Interaction Anxiety Scale

SKEF bodily efficiency

SKKO body contact

SNpr substantia nigra pars reticularis

SPBF care towards the body and functionality to taking care about the body

SPIN Social Phobia Inventory

SSAK self-acceptance of the body

SSEX sexuality

STN nucleus subthalamicus

TDT tactile detection threshold

TSL thermal sensory limen

TWSTRS Toronto Western Spasmodic Torticollis Rating Scale

V vitality

VT vibration threshold

WUR wind-up ratio

1. Introduction

1.1 Definition

Dystonia is a movement disorder characterized by sustained or intermittent muscle

contractions, causing abnormal, often repetitive movements, postures, or both.

Dystonic movements are typically patterned, twisting, and may be tremoulous.

Dystonia is often initiated or worsened by voluntary action and associated with

overflow muscle activation (Albaneze et al. 2013b). This disease was first interpreted

in 1911, when children of one family with evidence of involuntary movements

(Oppenheim 1911) and ‘’progressive torsion spasms’’ (Flatau 1911) were described.

However, its clinical recognition was officially obtained in 1975 during the First

International Symposium on Dystonia in New York, after which focal forms of

dystonia such as blepharospasm, writer’s cramp and torticollis were acknowledged

(Marsden 1976a,b,c).

1.2. Classification of dystonia

According to the new classification all dystonias are classified along two axes: clinical

characteristics and etiology (Balint and Bhatia 2014; Albanese et al. 2013). Clinical

characteristic represents the phenomenology of dystonia in a patient. It includes age

of onset, body distribution, temporal pattern and association with other disorders. The

second axis represents the etiology of dystonia and it covers anatomical changes

(degeneration, structural change or neither) and pattern of inheritance (inherited,

acquired and idiopathic). Primary dystonias include inherited dystonias and all

idiopathic dystonias. Secondary dystonias are dystonias that manifest from other

disease states or brain injury (Table 1).

2

Axis 1. Clinical characteristic

Age of onset Infancy (birth-2years)

Childhood (3-12 years)

Adolescence (13-20 years)

Early adulthood (21-40 years)

Late aduthood (>40 years)

Body distribution Focal

Segmental

Multifocal

Generalized

Hemidystonia

Temporal pattern Disease course Static

Progressive

Variability Persistent

Action specific

Diurnal

Paroxysmal

Associated features Isolated

Combined with other movement disorders

Associated with other neurological disorders and systemic diseases

Axis 2. Etiology

Nervous system pathology Structural lesion

Degeneration

No evidence

Pattern of inheritence Inherited Autosome-dominant

Autosome-recessive

X-linked

Mitochondrial

Aquired Perinatal brain trauma

Toxic

Infection

Neoplastic

Vascular

Drugs

Brain injury

Psychogenic

Idiopathic Sporadic

Familial

Table 1. New classification of dystonia (modified from Albanese et al. 2013b)

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1.3. Pathophysiology of idiopathic and inherited dystonia

As already mentioned before dystonia has different causes and they do not share the

same pathways of pathogenesis. Specific groups of dystonia have certain biological

impairments in the molecular, cellular, physiological and anatomical levels, which at

the end produce the final outcome (Prudente et al. 2014). It is believed that basal

ganglia modulate the movements through direct and indirect pathway. Briefly, the

direct striatomedial pallidonigral pathway is activated by glutaminergic projections

from sensorimotor cortex and by dopaminergic nigral pars compacta (SNpc)-striatal

projections. Activation of direct pathway inhibits internal globus palidus (GPi) and

substantia nigra pars reticularis (SNpr) by inhibitory gamma-amino butyric acid

(GABA) neurotransmitter. The GPi’s and SNpr’s lower inhibitory activity to the motor

part of the thalamus results in the increased activity of the thalamic projections to the

cortex. Higher firing frequency of neuronal groups in the cortex leads to the amplified

activity in the corticostriatal tract and in muscles, respectively. On the other side, in

the indirect pathway, dopamine binds to the D2 receptors of the striatum, which

causes declination of inhibition on the external globus pallidus (GPe) and nucleus

subthalamicus (STN), which in the next step activates cells in the GPi. GPi inhibits

the motor part of thalamus through GABA transmission, which decreases the

excitatory drive to the cortex. In dystonic patients there is an imbalance of direct and

indirect pathway (when direct pathway is overactive or indirect pathway is

underactive) that produces excessive movement and overflow of activity in muscles

(Hallett 2006).

The neuroimaging studies have contributed in understanding the anatomical basis of

dystonia. The recent studies have shown the increasing association of cerebellar

abnormalities in the physiology of dystonia as well (Prudende et al. 2014; Shakkottai

2014; Sadnicka et al. 2012). Abnormalities in the basal ganglia and their circuits and

4

also in cerebellum were found in different types of dystonia in functional imaging

studies even when the lesions were not detected by ordinary imaging techniques

(Lehericy et al. 2013; Zoons 2011; Neychev et al. 2011; Pantano et al. 2011;

Colosimo et al. 2005; Argyelan 2009; Carbon and Eidelberg 2009). Another fact that

supports the involvement of basal ganglia in pathophysiology of dystonia are

neurosurgical studies that have shown an improvement of dystonia by deep brain

stimulation of the GPi and pallidotomy (Moro et al. 2013; Vidailhet et al. 2012; Gross

2008).

In addition, dopaminergic dysfunction is a common cause of dystonia. Abnormal

dopaminergic release, a high level of dopaminergic neurons, non-responsiveness to

L-dopa, disorders of dopamine synthesis or transport can induce dystonias with

various phenotypes (Kurian et al. 2011; Fogel 2013; Balcioglu et al. 2007; Zhao et al.

2008; Page et al. 2010; Song et al.2012). This suggests that the levels of dopamine

either too much or to less, can cause dystonia (Breakefield et al. 2008).

There are three abnormalities that underlie the pathophysiological substrate in

dystonia: loss of inhibition, defects in the somatosensory integration and deranged

plasticity (Quartarone and Hallett 2013). Briefly, the surround inhibition is a neural

mechanism which can sharpen the desired movement by inhibiting the activity in

adjunct muscles (Beck et al. 2008; Berardelli et al. 1998). Surround inhibition is

reduced in focal hand dystonia and may contribute to the difficulties in focusing motor

command and to the overflow phenomenon (Beck et al. 2009; Hallett 2011).

Furthermore, defects in sensorimotor integration involve defects in sensory and

perceptual function. Basal ganglia and cerebellum play a role of filtering or ‘’sensory

gaiting’’ of the information that is passed to the motor system (Pastor et al. 2004).

Abnormalities in the perception of sensory information have been demonstrated in

temporal and spatial domains in focal, as well as in the generalized and inherited

5

dystonias (Tinazzi et al. 2009; Neychev et al. 2011; Molloy et al. 2003; Bara-Jimenez

et al. 2000; Kimmich et al. 2014). Moreover, functional imaging studies have revealed

abnormal somatotopic representation in the sensory cortex (Elbert et al. 1998;

Meunier et al. 2001). Additionally, plasticity mechanisms that help the brain to adapt

to the environment as a part of the learning process are abnormal in dystonic patients

(Quartarone et al. 2008). Abnormal plasticity has been reported in basal ganglia,

cerebellum and in cortex of the patients with dystonia (Quartarone et al. 2008;

Rothwell and Huang 2004; Thompson and Steinmetz 2009).

In summary, pathophysiology of dystonia is convoluted involving both basal ganglia-

thalamo-cortical and cerebello-thalamo-cortical networks. The role of each level of

those circuits and their implication in the subtypes of dystonia still remains unclear.

1.4. Clinical features and diagnosis of dystonias

According to the guidelines of the European Federation of Neurological Societies

(Albanese et al. 2011), there are a few major recommendations for diagnostics of

dystonia. Recognizing clinical features of dystonia is the first step of managing the

patients with dystonia since the clinical phenomenology remains the main basis for

the diagnosis and there is no specific diagnostic test. Albanese and Lalli (2012) have

proposed criteria and a structuralized flowchart on recognizing the features of

dystonia. Those criteria are:

1. Dystonic postures are twisted along its longitudinal axis and there is a

sensation of rigidity on the dystonic part of the body. This does not comply for

blepharospasm or laryngeal dystonia (Albanese and Lalli 2012).

2. Dystonic movements are involuntary and they may be twisting or a pull in a

preferred direction with repetitive and patterned altitude and are often prone to

6

lessen when a given posture is identified (‘’null point’’). They may be fast or

slow and may appear as tremor, chorea, tic or myoclonus.

3. Geste antagoniste is a voluntary physical gesture or position which temporarily

improves the dystonic posture (Poisson et al. 2012), especially early in the

disease course (Kagi et al. 2013). These movements are never forceful and

they do not push or pull the body part, but they represent a simple touch of the

eyelid, an eyebrow, a neck etc. The alleviation of dystonia lasts as long as the

trick lasts or reverses unconstrained slowly before its end.

4. Mirror movements are dystonic movements of the less affected side with

dystonia, which happen during the repetitive tasks of the affected side of the

body (finger tapping, writing, painting etc).

5. Motor overflow is a muscle contraction which accompanies, but is anatomically

distinct from the primary dystonic movement (Sitburana et al. 2009; Jedynak et

al. 1991). It can be observed at peak dystonic movements, ipsilaterally or

contralaterally, by inspection or EMG (Albanese et al. 2003).

The movement disorder society (MDS) Task Force on Rating Scales for Movement

Disorders Steering Committee identified 7 out of 36 scales and questionnaires who

meet the requirements to rate the motor symptoms of dystonia. The best identified

scale to rate the generalized dystonia is Burke-Fahn-Marsden Dystonia Rating Scale

(BFM). Cervical dystonia can be best rated with Toronto Western Spasmodic

Torticollis Rating Scale (TWSTRS) and cervical dystonia impact scale (CDIP-58).

Blepharospasm Disability Index (BSDI) for blepharospasm and Craniocervical

Dystonia Questionnaire (CDQ-24) for cervical dystonia and blepharospasm also meet

the criteria of the task force (Albanese et al. 2013).

After the recognition of dystonia, it is important to identify the specific type of dystonia

according to the classification scheme (Table 1) in order to provide the appropriate

7

management and treatment. When inherited dystonias are suspected genetic testing

should be performed.

Neurophysiological studies are not recommended for clinical diagnostics of dystonia

but may be used for clinical assessment by showing simultaneous activation of

agonist and antagonist muscles.

Brain imaging is not necessary for diagnosis of classical idiopathic dystonia.

Computerized tomography may reveal calcium and iron accumulation, magnetic

resonance imaging may help to identify the acquired dystonias (Meunier et al. 2003;

and pre-synaptic dopaminergic scan (DAT-SPECT or 18F-DOPA-PET) is useful to

diagnose Parkinson’s disease with dystonia and L-dopa responsive dystonia. This

may help to specify the tremor as well.

1.5. Treatment of dystonia

1.5.1. Botulinum toxin

Botulinum neurotoxin (BoNT) is considered the first line treatment for the focal

dystonias. It has a well controllable paralyzing effect on muscles. There are three

approved BoNT A medications: OnabotulinumtoxinA (onaBoNT-A),

incobotulinumtoxinA (incoBoNT-A) and AbobotulinumtoxinA (aboBoNT-A). One

approved BoNT type B medication (rimabotulinumtoxinB (rimaBoNT-B) is

recommended when antibodies against BoNT-A occur. According to the American

Academy of Neurology guidelines update summary (Simpson et al. 2016), BoNT is

shown to be effective in cervical dystonia, blepharospasm and upper limb dystonia. In

action specific dystonia (writer’s cramp) the effect of the treatment may not be

optimal, since the therapeutic area is narrow in the forearm (Dressler et al. 2015a).

Therefore, ultrasound and EMG guided injections are useful to enhance the accuracy

of the treatment of musician’s dystonia (van Vugt et al. 2014; Schuele et al. 2005).

8

Apart from the focal dystonias, the high-dose therapy has been introduced to treat

the more widespread dystonias (Dressler et al. 2015b).

The disadvantage of BoNT treatment is that the injection site pain during the

treatment may reduce the compliance especially after injections in the hand muscles

and in children. Moreover, effect of the treatment lasts 8-12 weeks and the treatment

has to be repeated regularly.

1.5.2. Deep brain stimulation (DBS)

Long-term electrical stimulation of the internal globus pallidus is considered an

effective treatment for dystonias (Krauss et al. 2004). It is mostly indicated in the

generalized dystonias or segmental forms, complex cervical dystonia, tardive

dystonia and where botulinum toxin was refractive to relieve symptoms (Kupsch et al.

2006; Capelle and Krauss 2009). In generalized dystonias GPi DBS brings relief of

symptoms in a range from 40-80 %. In a two year retrospective follow-up study of

GPi DBS patients, excellent motor and functional outcome was found (Isaias et al.

2008, 2009; Cif et al. 2010). Young patients with primary dystonia and tardive

dystonia, with shorter duration of the disease, have a better outcome of the pallidal

DBS (Moro et al. 2013; Mehdorn 2016). However, in children with secondary dystonia

the effect of the GPi DBS is controversial (Loher et al. 2001; Eltahawy et al.

2004;Krause et al. 2006; Alterman et al. 2007; Roubertie et al. 2012). GPi DBS in the

secondary dystonia has shown a less positive effect, presumably because it is a

more complex disorder and the DBS targets may be lesioned and dystonia is

progressive (Welter et al. 2010; Vidailhet et al. 2012).

The mechanism of action of deep brain stimulation is not fully understood. It is

believed that DBS influences the targeted structures and surrounding pathways,

resulting in excitatory and inhibitory effects that modulate the basal ganglia-thalamo-

9

cortical pathway. This prevents oscillatory activity and bursts resulting in improved

processing and reduction of disease symptoms (Huston et al. 2011; Hu and Stead

2014). Other targets for DBS in dystonia than GPi have also been suggested. Ostrem

et al. (2011) have reported positive outcome of bilateral STN stimulation in 9 patients

with cervical dystonia. The stimulation of ventral intermediate nucleus has also been

suggested for the dystonias with tremor, when tremor is the more disabling part of the

disease (Morishita et al. 2010).

1.6. Processing sensory information from skin to the cortex

Afferent inputs come from the specialized receptors that are located in the skin,

subcutaneous tissue, muscle, joints and viscera. They include nerve endings in the

skin associated with specializations that act as amplifiers or filters, and sensory

terminals associated with specialized transducing cells that influence the ending by

virtue of synapse-like contacts (Purves et al. 2001). Skin and subcutaneous receptors

can be divided into three groups: mechanoreceptors, nociceptors and

thermoreceptors depending on their selective sensitivity to respective stimuli (Light

and Perl 1993, Sinclair 1981). Mechanoreceptors are specialized to sense

mechanical forces from the skin and subcutaneous tissue. Thermoreceptors and

nociceptors represent branching nerve endings of the unmyelinated A and C

sensory fiber system. They are located in the dermis and epidermis and have a role

in transmitting pain and temperature sensations. Proprioreceptors are located in the

skeletal muscles, tendons and fiber capsules of the joints. They provide information

about the joint angle, muscle length, muscle tension and allow postural information

about the limbs. Hence, different qualities of sensations are processed by different

sensory fiber system. C sensory fiber system processes cold detection partly cold

10

Fig. 1. Major pathways for sensation. (a) Spinothalamic tract.

(b) Posterior column medial lemniscus pathway. (Adopted

from © 2011 Pearson Education, Inc)

and hot pain threshold and thermal sensory limen (ability to detect fast changes of

the temperature). A fibre system processes hot detection, hot and cold pain

threshold, crude mechanical touch and thermal sensory limen. Aß fibre system

processes light touch, vibration, pressure and dynamic mechanical allodynia

(Campbell et al. 1988, Beissner et al. 2010). After the receptors are irritated and the

action potential is induced, sensory transduction through the peripheral nerve is

triggered. The information is further carried on depending on the receptor system that

has been triggering the action potential. There are two sensory pathways that convey

information from the peripheral sensory nerve to the cortex. Fine touch, vibration,

two-point discrimination, position sense of the joints are transmitted by the posterior

column medial lemniscus pathway (PCML). Briefly, in PCML, the first order neurons

carrying proprioceptive or touch information synapse at the gracile and cuneate

nuclei of the medulla, axons from secondary order neurons decussate at this level

and travel up the brainstem to the cells of ventral posterior lateral nucleus (VPL) of

the thalamus (Davidoff 1989, Nathan et al. 1986). These cells as part of the third

order neurons, project to the primary somatic sensory cortex (Fig. 1A).

The second pathway that

caries sensory information is

the spinothalamic tract

(anterolateral tract). The

anterior part of the tract

carries information about

crude touch and the lateral

part conveys information for

pain and temperature.

11

Neurons of the dorsal root ganglion after entering the spinal cord, ascend and

descend one or two vertebral levels and they synapse in the substantia gelatinosa of

Rolando or the nucleus proprius. The second order neuron decussates to the other

side of the spinal cord and travels up to the different nuclei of the thalamus, where

they ultimately synapse with third-order neurons. The neurons of third order project to

the primary sensory cortex, cingulate cortex and insular cortex (Ropper and Samuels

2009). (Fig. 1B, adopted from © 2011 Pearson Education, Inc.).

12

2. Objectives

For a long time dystonia has been considered a pure motor disorder (Tamura et al.

2008). Recent evidence has postulated several non-motor features that accompany

dystonia (Stamelou et al. 2012; Peall et al. 2015; Conte et al. 2016; Kuyper et al.

2011). Sensory tricks or ‘’geste antagoniste’’, the voluntary movements that

temporarily improve dystonic posture or movement, indicate that afferent sensory

inputs are affected in the patients with dystonia (Quartone and Hallett 2013; Muller et

al. 2001; Schramm et al. 2007). Discomfort, pain and kinesthetic sensations can be

observed weeks or months before the dystonia appears (Martino et al. 2005),

although neurophysiological studies (neurographies and somatosensory evoked

potentials) show no impairments also in the late stage of the disease (Abbruzzese et

al. 2003). Basal ganglia and cerebellum have an influence in filtering or ‘’sensory

gaiting’’ the sensory information that is transmitted to the motor system (Kaji et al.

2001; Murase et al. 2000; Oulad Ben Taib et al. 2005). Since in dystonia there is a

disruption in the striato-thalamo-cortical-pathway it is not surprising that there are

impaired sensory and perceptual defects. Although there is a lot of evidence that

there are sensory abnormalities, the relationship between dystonia and sensory

abnormalities remains unclear. Moreover, the association of different qualities of

sensations that are carried by C, Aδ and Aß sensory systems with idiopathic and

hereditary dystonia has not been revealed yet. Furthermore, it is uncertain if these

sensory impairments are correlated to the age and to severity of motor symptoms.

The first line treatment of focal idiopathic dystonia is botulinum toxin. This treatment

is sometimes very painful, especially in the hand palm and on the foot soles. Since

this treatment is related to procedural pain and distress, this may reduce its

compliance (Paracka et al. 2015). Different analgesic procedures have been

proposed to reduce the Injection Site Pain during the treatment (ice-spray, nitrous

13

oxide, anesthetic cream), but there are no studies that compare all those procedures

intra-individually.

There is emerging evidence that psychiatric symptoms are present in a higher

prevalence in patients with primary dystonia. Due to the involvement of fronto-striatal

pathways in mood and behavioral regulations (Eldar and Niv 2015), it is not

surprising that mood instability and anxiety might occur in the dystonic patients.

Involuntary movements and twisted postures in dystonic patients cause slowness of

voluntary movement and substantial disfigurement. This may cause disability in the

patient’s everyday life and dissatisfaction with physical appearance. Embarrassment

from the patient’s physical appearance may interfere with the social interaction and

cause social avoidance and isolation (Jahanshahi et al. 2005; Page et al. 2007;

Lewis et al. 2008). It has been postulated that there is a higher risk of depression and

anxiety in patients with idiopathic and isolated inherited dystonias (Lewis 2008;

Heiman et al. 2004; Moraru et al. 2002; Lauterbach et al. 2004, Müller et al. 2002;

Gundel et al. 2003; Jahanshahi 1990a,b). However, different aspects of body

concept not related only to the physical appearance, but also the self-perception of

the body, efficiency and dissimilatory processes have not been thoroughly assessed

in these patients. Moreover, the correlation between different aspects of body

concepts and the severity of motor symptoms is still unknown.

Hence, objectives of this study are: 1. To analyze different sensory modalities in

patients with idiopathic and inherited dystonia by using Quantitative Sensory Testing

in the areas that are affected and not affected by the motor disorder. 2. To correlate

the sensory symptoms with the age of patients and severity of the disease. 3. To

analyze sensory symptoms intraindividually by comparing the sensory modalities

between sides more affected and less affected with motor symptoms. 4. To find the

most potent analgesic procedure for injection site pain reduction during botulinum

14

toxin treatment. 5. To evaluate the non-motor symptoms in patients with inherited and

idiopathic dystonia including mood, anxiety, quality of life and body concept.

15

3. Manuscript I

Subtle sensory abnormalities in patients with isolated idiopathic and hereditary

dystonia

Lejla Paracka1*, Florian Wegner1*, Christian Blahak2, Mahmoud Abdallat3, Dirk

Dressler1, Matthias Karst4, Joachim Kurt Krauss3

1Department of Neurology, Hannover Medical School, Hannover, Germany

2Department of Neurology, University of Heidelberg, Faculty of Medicine Mannheim,

Mannheim, Germany

3Department of Neurosurgery, Hannover Medical School, Hannover, Germany

4Department of Anesthesiology, Hannover Medical School, Hannover, Germany

*Contributed equally

Abstract

Sensory abnormalities are increasingly being recognized as an accompanying

symptom in patients with isolated idiopathic dystonia. The aim of this study was to

investigate whether sensory abnormalities could be related to age or the distribution

of motor symptoms in patients with primary dystonia. For this purpose we recruited

20 dystonic patients from which 8 had generalized dystonia, 7 cervical dystonia and 5

segmental dystonia with arm/hand involvement in dystonia. The patients with

involvement of the arm/hand in dystonia were divided into two groups: younger than

40 years (6 patients) and older than 40 years (7 patients). All patients with cervical

16

dystonia were older than 40 years. We used Quantitative Sensory Testing (QST) at

the back of the hand in all patients and at the shoulder in patients with cervical

dystonia. The main finding was impaired dynamic mechanical allodynia (DMA) and

thermal sensory limen (TSL). The other impairments were characteristic of the

subgroups. In hands of dystonic patients there was a significant increase for DMA

and thermal sensory limen in comparison to 19 matched healthy controls. Patients

younger than 40 years with arm/hand involvement in dystonia had a higher cold pain

threshold (CPT) and DMA, but decreased hot pain threshold (HPT) and wind-up ratio

(WUR). Older patients displayed a diminished cold detection threshold (CDT) and

WUR and higher TSL and DMA. The alterations were present on the clinically more

and less affected side, with a higher pronunciations on the side more affected with

dystonia. Patients with cervical dystonia showed a reduced hot detection threshold

(HDT) and CDT, enhanced TSL and DMA at the back of the hand, whereas the

shoulder QST only revealed increased CPT and DMA. Thus, in patients with primary

dystonia QST clearly shows several significant sensory abnormalities which partly

differed in age-groups and could also manifest in regions without motor symptoms.

Introduction

The dystonias are a heterogenous group of movement disorders that are defined by

the nature of their abnormal movement (Jinnah et al. 2015). According to the modern

definition, dystonia represent a movement disorder, which is characterized by

sustained or intermittent muscle contractions causing abnormal, often repetitive

movements, postures, or both. Dystonic movements are typically patterned, twisting,

and may be tremulous. Dystonia is often initiated or worsened by voluntary action

and associated with overflow muscle activation (Albanese et al. 2013).

17

Idiopathic dystonia has been regarded as a basal ganglia disease and its circuits.

The pathophysiology of dystonia still remains unclear, but several mechanisms, such

as decreased inhibition, altered plasticity and dysfunction of oscillatory activity appear

to be involved (Quartarone and Hallett 2013). In addition, there is evidence of

involvement of sensory systems in the pathophysiology of dystonia. Imaging and

electrophysiological studies have revealed abnormalities in sensorimotor networks

(Carbon et al. 2008; Hallett 2006) and cerebello-thalamo-cortical pathways (Sako et

al. 2015; Argyelan et al. 2009).

Dystonic patients often complain about pain, although the clinical examination and

neurophysiological testing remains normal (Abbruzzese et al. 2003). They use certain

maneuvers in order to temporarily improve the motor symptoms. This phenomenon

has been recognized as sensory trick (e.g. geste antagoniste), suggesting an

important role of the sensory system in the complex pathophysiology of primary

dystonia (Berardelli et al. 1998).

Other hints for involvement of sensory systems in dystonia include abnormal sensory

processing (Walsh et al. 2007; Bradley et al. 2012) and altered temporal and spatial

discrimination of tactile stimuli (Kimmich et al 2014; Hutchinson et al. 2013; Tinazzi et

al. 2009; Bara-Jimenez et al. 2000; Molloy et al 2003).

Hence, we investigated the somatosensory integrity in patients with primary dystonia

using quantitative sensory testing (Rolke et al. 2006a). This method allows the

investigation of different sensory qualities such as heat, cold, paradox sensations

(the ability to differentiate the warmth and cold), touch, pain, pressure and vibrations,

which are transmitted by Aß, A and C fibers in the periphery. The aim of the study

was to assess sensory processing in patients with isolated primary dystonia in

relation to the patients’ age and motor symptoms.

18

Methods

Subjects

Twenty patients (10 men, mean age±SD 51.2±17.2 and 10 women mean age±SD

55.5±21.3) and 19 age and sex matched controls (10 men mean age±SD 49.3±18.7

and 9 women mean age±SD 48.1±19.0) were included in the study. Eight patients

had generalized dystonia, five segmental dystonia with arm/hand involvement, and

seven patients showed isolated cervical dystonia. Two of the patients had genetically

proven DYT1 hereditary dystonia. The other patients were classified as idiopathic

dystonia. According to the German Network for Neuropathic Pain sensory modalities

are age dependant and the cut off age of 40 years has been proposed (Rolke et al.

2006b). Hence, the patients were divided in the subgroup older than 40 years and

the subgroup younger than 40 years. Six patients with generalized dystonia were

younger than 40 years, including the two patients with DYT1 dystonia. The other

patients together with those with cervical dystonia and segmental dystonia were older

than 40 years. Three of seven patients with cervical dystonia reported shoulder or

neck pain, otherwise there were no pain symptoms or overt sensory deficit.

Exclusion criteria were polyneuropathy, cognitive disturbances or any other

neurological disease. Since the sensory perception may be influenced by botulinum

toxin treatment, the patients who received botulinum toxin within six months prior to

the testing were excluded from the study. All patients and controls signed written

informed consent. The ethics committee of Hannover Medical School approved this

study.

Neurophysiological and clinical assessment

In all patients standard nerve conduction velocity measurements to assess large

myelinated fibers was performed. Neurographies and nerve conduction velocities

19

conducted from ulnar, radial and sural nerves were normal in all patients.

Somatosensory evoked potentials were performed to exclude central sensory

pathway disturbance. The Burke-Fahn-Marsden Dystonie Rating Scale (BFM) was

used for all patients and Toronto Western Spasmodic Torticollis Rating Scale

(TWSTRS) in patients with cervical dystonia. Hand and arm dystonia was scored

using the BFM motor subscore for arm (0-16); arm/hand with the higher score was

characterized as clinically more affected side, the arm/hand with the lower score as

clinically less affected. Because of the bilateral involvement in cervical dystonia, the

shoulder was staged as one entity (the mean of both sides) for further analysis and

compared to controls. BFM and TWSTRS scores are expressed as means±SD.

Quantitative sensory testing

In all patients the quantitative sensory testing (QST) battery was applied according to

the protocol of the German Research Network of Neuropathic Pain (Rolke et al.

2006b). QST allows the assessment of specific myelinated A- and unmyelinated C-

fibers for temperature and pain, but also the evaluation of touch and vibration eliciting

activity in large myelinated A-fibers. It allows testing of sensory modalities not

assessable by conventional neurophysiological methods. QST uses various stimuli to

investigate the different sensory modalities such as the thermal test, mechanical

stimuli (pinprick set), stimuli for touch (Fray Hair filaments, cotton wool, Q-tip, brush),

vibration (tuning fork) and pressure (pressure pain algometer).

The testing of patients with arm/hand involvement in dystonia was compared to the

side less affected by motor symptoms of dystonia and to the normal values of healthy

controls. Since cervical dystonia most frequently involves bilateral contraction of neck

muscles, the mean QST parameters of both shoulders were calculated and

compared to age matched controls. In patients with cervical dystonia assessment

20

involved also QST of non-dystonic hands. In this case, the mean of both sides for all

sensory profiles was compared to the values of healthy controls.

Twelve tests were performed as previously described (Rolke et al. 2006a). Shortly,

thermal thresholds were measured with the thermal sensory analyzer (MEDOC,

Ramat Yishari, Israel). The cold detection threshold (CDT) and hot detection

threshold (HDT) were registered with decreasing or increasing temperature stimuli,

respectively, that were applied with a thermode of 3cm2. The baseline temperature of

the thermode was 32ºC, it increased and decreased the temperature by 1ºC/sec. For

detection thresholds, subjects were asked to press the stop button in the moment

they perceived the warm or cold stimuli. The same procedure was used for the

thermal sensory limen (TSL), a test of paradoxical heat sensations, only that the

changes of the temperature in the thermode was done consequently after the stop

button was pressed and the patients had to indicate verbally if it was warm or cold.

The TSL is designed to test paradoxical heat findings and the capability to detect fast

changes of the temperature. The cold and hot pain thresholds (CPT, HPT) were

measured by pressing the stop button when the sensation for cold or warm reached a

painful sensation (range 0ºC to 50ºC).

The tactile detection threshold (TDT) was recorded with a set of Frey filaments

(OptiHair MARSTOCKnervtest, Marburg, Germany) which exert forces of 0.25 to 512

mN. The patients had to indicate if they felt the stimuli with their eyes closed. The

filaments with smaller forces were gradually introduced and the threshold was

recorded where they lastly did not perceive any sensation. The final value was the

geometrical mean of 5 series of ascending and descending stimuli.

The mechanical pain threshold (MPT) was registered with a set of weighted pinprick

stimulators with a flat contact area of 0.25mm2 diameter inducing pressure forces of

8, 16, 32, 64, 128, 256 and 512mN (MRC Systems, Heidelberg, Germany). Using this

21

set of stimulators and escalating the stimulation force from 8mN, subjects were asked

to indicate the sharp sensation pain threshold. After determination of the sharp

sensation pain threshold the stimulation force was gradually reduced to determine

the dull sensation threshold. The ascending and descending stimuli were performed

five times and limits for dull and sharp were registered. The MPT threshold was the

geometrical mean of 5 series of ascending and descending stimuli (Baumgärtner et

al. 2002).

The mechanical pain sensitivity to pin prick stimuli (PSP) and dynamic mechanical

allodynia (DMA) was determined with a set of pinprick stimulators (MRC Systems,

Heidelberg, Germany) and the following tactile stimulators: cotton wool

(MEDIWOOD, megro GmbH, Wesel, Germany), a cotton Q-tip and a brush

(Somedic, Hörby, Sweden). Sensitivity to sharp pin prick sensation and to tactile

stimulators was determined. The subjects were asked to estimate the pain of the

stimuli (pinprick and tactile stimulators) from 0 to 100, whereby 0 represents no pain

(touch and no sharp sensation) and 100 represents the most unbearable intense

pain. Every sharp sensation had to be evaluated with a value larger than 0. The final

value was the arithmetical mean of the ratings across all stimuli (Baumgärtner et al.

2002).

The wind up ratio (WUR) was tested with the pinprick stimulator of 256 mN where

single stimuli were compared to 10 pinprick stimuli repeated at a 1/sec rate. The

testing was applied to five different skin sites (back of the hand or shoulder) and

subjects were asked to rate the pain from 0-100. The final WUR value was the ratio

between the 5 trains of 10 pinprick stimulations and 5 single stimuli.

The vibration detection threshold (VT) was determined with a Rydel Seiffer fork (c64

Hz, 8/8 scale) placed at processus styloideus ulnae or the acromion. The testing was

repeated 3 times and the final value was the arithmetical mean of 3 sensations.

22

The pressure pain threshold (PPT) represents the tenderness resistance of the

muscles. PPT was recorded by pressure pain algometry (Somedic Algometer, Hörby,

Sweden). This device has the ability to quantify the tenderness of muscles. It

contains a rubber disc with an area of 1cm2 that displays the pressure on a specific

part of the body. The assessment was performed on M. abductor pollicis brevis and

M. trapezius.

Neuropsychological examination

The patients and the controls underwent neuropsychlogical testing for cognition (Mini

Mental Score) and attention (Trail Making Test) as such impairment may interfere

with the results of the QST testing.

Statistical analysis

To determine the data distribution the Shapiro-Wilk test and visualisation assessment

were performed. Normally distributed data were analysed as raw data and with 95%

confidence interval. Non-normally distributed data were log10 transformed in order to

reach the normalization. Test for normality was carried out in each sequence of the

analysis and if log10 transformation was performed. To compare both sides to the

normal values throughout different QST parameters, z-transformation was used for

each subject according to the formula z-score=(Xsingle patient – Meancontrols)/SDcontrols.

QST parameters for hand were first analysed for all patients (n=20), including

patients with isolated cervical dystonia (n=7). The mean of both sides of the hands

was compared to the mean of both hands of controls. Next, 13 patients with

arm/hand involvement in dystonia were compared with controls in relation to the

clinically more or less affected side and age. Additionally, the subgroups of patients

older (n=7) and younger the 40 years (n=6) with arm/hand involvement in dystonia

23

were compared with controls in association with the clinically more or less affected

side and age. The mean of both sides of the shoulder QST in patients with cervical

dystonia was compared to the mean of the shoulder QST of the age matched

controls. The same procedure was done in the hand QST for patients with cervical

dystonia. Z-scores greater than 2 were reported as gain of sensory function and

values below 2 were reported as loss of sensory function.

Correlation analysis between BFM and QST values of the hand and TWSTRS and

QST values of the shoulder was performed with Spearman-Rho test. For statistical

analyses and visualisation of data we used SPSS (IBM Deutschland, Ehningen,

Germany). Two-sided p-values <0.05 were considered statistically significant.

Results

The mean BFM motor score for all patients was 16.4±9.3, (generalised 28.3±5.7,

segmental 11.3±4.1, cervical dystonia 6.0±2.2). A significant difference (p=0.023) in

the arm BFM subscore was registered comparing the more affected dystonic

arm/hand (7.5±3.8) against the less affected arm/hand (3.7±2.8) in patients with

involvement of arm/hand dystonia (n=13). The mean in TWSTRS motor score for

patients with cervical dystonia was 8.6±2.5 (n=7).

There was no significant correlation between BFM and any QST score (Table 1). The

correlation of TWSTRS with QST of the shoulder was insignificant as well (Table 1).

The hand QST was first analysed for all dystonic patients, including the patients with

isolated cervical dystonia. As indicated above, in patients with cervical dystonia the

mean of both sides was calculated and compared to the normal values.

The hands of dystonic patients showed a sensory gain for dynamic mechanic

allodynia and thermal sensory limen in comparison to the matched controls (n=20,

Fig. 1A, Table 2).

24

In order to analyse more homogenously the effect of dystonia in sensory functions,

the patients with cervical dystonia were excluded during the next calculations.

Compared to healthy controls the QST detected sensory loss for cold detection

threshold on the clinically more affected side, as well as sensory gain for dynamic

mechanical allodynia bilaterally (n=13, Fig. 1B, Suppl. Table 1).

In the patients older than 40 (n=7, Fig. 1C, Suppl. Table 2) there was a sensory loss

for cold detection threshold and wind up ratio, but increased sensitivity for thermal

sensory limen and for dynamic mechanical allodynia. The QST in patients younger

than 40 (n=6, Fig. 1D, Suppl. Table 3) showed increased sensitivity for cold pain

threshold and dynamic mechanical allodynia whereas hot pain threshold and wind up

ratio were reduced. There was no significant difference between clinically more or

less affected sides in both age-groups.

In the hand QST of the 7 patients with isolated cervical dystonia a sensory decrease

for cold and hot detection thresholds was found as well as increased sensation for

allodynia and thermal sensory limen compared to controls (Fig. 1E, Suppl. Table 4).

In the shoulder QST of 7 patients with cervical dystonia a higher score for cold pain

threshold and dynamic mechanical allodynia was detected in comparison to controls

(Fig. 1F, Suppl. Table 5).

Z-scores of the clinically more affected arm/hand showed a higher shift from normal

than the clinically less affected arm/hand in all instances compared to controls (Fig.

1B-D). In the older dystonic patients the shift of the more affected arm/hand from

healthy control level was much more apparent than of the less affected arm/hand

(Fig. 1C). In younger patients the differences of z-scores between sides tended to be

lower (Fig. 1D).

25

Figure 1

Fig 1. Means of z-scores of QST: A. Hand QST in all dystonic patients (n=20); B. Hand QST in patients with dystonic arm/hand

involvement (n=13) after exclusion of cervical dystonia patients; C. Hand QST in patients older than 40 (n=7); D. Hand QST in

patients younger than 40 (n=6); in all groups (B-D) there is no significant sensory difference between clinically more and less

affected sides; E. Hand QST in patients with cervical dystonia (n=7); F. Shoulder QST in patients with cervical dystonia (n=7).

QST parameters: Cold detection threshold (CDT), hot detection threshold (HDT), thermal sensory limen (TSL), cold pain

threshold (CPT), hot pain threshold (HPT), tactile detection threshold (TDT), mechanical pain threshold (MPT), mechanical pain

sensitivity for pinprick (PSP), dynamic mechanical allodynia (DMA), wind up ratio (WUR), vibration threshold (VT), pressure pain

threshold (PPT). Z-scores higher than 2 are considered as sensory gain and z-scores below 2 are considered as sensory loss.

26

Discussion

Our study shows that QST may detect subtle sensory abnormalities in dystonic

patients in absence of overt sensory symptoms. The alteration of sensory function

was registered on modalities that are transmitted by C fibre (cold detection, partly

cold and hot pain threshold and thermal sensory limen), A fibre (hot detection, hot

and cold pain threshold, thermal sensory limen) sensory systems (Beissner et al.

2010) and predominantly by the Aß fibre (dynamic mechanical allodynia) sensory

system (Campbell et al. 1988).

The main findings in the hand QST of all investigated patients was increased

dynamic mechanical allodynia and thermal sensory limen. Some other sensory

modalities (cold and hot detection, cold and hot pain threshold, thermal sensory limen

and wind up ratio) were relevant for subgroups. Decreased sensations for cold and

hot detection threshold confirm the abnormalities that were found in a previous QST

study (Suttrup et al. 2011), although in our study there was no abnormality for

mechanical pain threshold and pain sensitivity for pinprick in our patients. Moreover,

our patients showed increased dynamic mechanical allodynia in comparison to

controls, in contrary to the study by Suttrup et al. (2011), where none of the patients

showed this impairment. In that study only patients with writer’s cramp were

assessed and only the affected side with dystonic motor symptoms showed sensory

abnormalities. In our study we have assessed patients with generalized, segmental

and cervical dystonia. We have found sensory alterations on both sides at the back of

the hand with a more accentuated distribution on the clinically more affected side,

although there was no significant difference between sides. However, the findings

were diverse in age-groups, the younger patients showed increased cold pain and

decreased hot pain threshold, whereas we found reduced cold detection and

enhanced thermal sensory limen in the older patients.

27

Interestingly, we detected subtle sensory impairments on hands of patients with

isolated cervical dystonia. These findings suggests that sensory impairment in these

patients is present regardless of the motor distribution of the disease contrary to the

study from Suttrup et al. (2011), where only the clinically affected dystonic region

showed deterioration of QST modalities. To our knowledge, for the first time the

shoulder QST was done in patients with cervical dystonia. Our results showed

increased dynamic mechanical allodynia and cold pain threshold compared to

matched healthy controls suggesting that this localization is also suitable for further

sensory examinations in patients with dystonia.

Dynamic mechanical allodynia enhancement was the most consistent finding in our

investigated patients. It is a stimulus evoked pain (Sandkühler 2009) that is induced

by light touch (brush, cotton wool and Q tip). However, our patients perceived those

light stimuli as sharp, not as painful. They had only altered perception of the quality of

the stimuli, not touch induced pain or hyperalgesia. Moreover, allodynia for punctuate

stimuli (pain sensitivity for pinprick) was not found in our dystonic patients. Therefore,

pathophysiological mechanisms that have been proposed for DMA in peripheral and

central neuropathic pain or in post stroke pain cannot explain the impairment of this

sensory modality in dystonic patients.

In addition, although we have demonstrated that the somatosensory processing is

also impaired in clinically distant areas, the z-scores of the arm/hand more affected

with dystonia showed a higher shift from the values of the controls than the arm/hand

less affected by dystonia in all its domains. These findings were more expressed in

the older patients, although they were not statistically significant. Interestingly, in

younger patients the differences of z-scores between sides tended to be lower, which

may suggest a slight enhancement of sensory subtle abnormalities with increasing

age of dystonic patients.

28

There was no significant correlation between the motor score of the disease (BFM

scale, TWSTRS) with QST parameters. This may indicate that there is a generalized

subtle sensory deficit in dystonic patients independent from motor symptoms. Loss of

sensitivity in temporal and spatial discrimination in patients with primary dystonia has

been demonstrated in previous studies (Bara-Jimenez et al. 2000; Scontrini et al.

2009; Bradley et al. 2012, Hutchinson et. al 2013) and in the non-affected body

regions as well (Molloy et al. 2003; Putzki et al. 2006; Fiorio et al. 2008). Abnormal

spatial discrimination thresholds were found even in unaffected relatives (siblings and

children) of patients with sporadic adult onset dystonia (Walsh et al. 2007, 2009).

However, deficits in spatial discrimination threshold are not detected in DYT1 and

DYT6 dystonic patients, which means that there is an endophenotypic trait of sensory

abnormalities in patients with hereditary dystonia (Deik et al. 2012; Molloy et al.

2003). Moreover, the abnormalities in temporal perception of consecutive stimuli

have been shown in unaffected DYT1 carriers, which implies that sensory deficits in

dystonia are not a mere consequence of abnormal movements, but may occur before

overt motor manifestations (Fiorio et al 2007). Additionally, botulinum toxin and GPi-

DBS did not appear to normalise temporal discrimination threshold in patients with

cervical dystonia, which means that this finding is likely to be causal in the genesis,

rather than epiphenomena secondary to abnormal motor activity (Sadnicka et al.

2013, Scontrini et al 2011).

The mechanism of occurrence of these QST impairments is uncertain. Pathogenesis

of dystonia could help understand the appearance of QST impairments in these

patients. It is known that the defect in sensorimotor integration plays a major role in

pathophysiology of dystonia (Quartarone et Hallett 2013). Basal ganglia have an

important role in the modulation of sensory stimuli and a direct influence in the

somatosensory integration (Kaji 2001; Graybiel 2004; Ding et al. 2010). Furthermore,

29

cerebellum receives input from the spinal cord and influences the somatosensory

system (Oulad Ben Taib et al 2005; Daskalakis et al. 2004). Functional imaging

studies have revealed abnormalities in basal ganglia, pathways to and from basal

ganglia and also in cerebellum in dystonic patients, even when lesions were not

evident by ordinary clinical imaging methods (Lehericy et al. 2013; Zoons et al 2011,

Neychev et al. 2011; Argyelan et al 2009; Niethammer et al 2011; Carbon et al.

2010).

Furthermore, alterations in the somatosensory cortex related to deranged

somatotopic representation, such as abnormal cortical finger representation and

disordered homuncular arrangement were found in patients with focal dystonia

(Catalan et al. 2012, Elbert et al. 1998, Bara-Jimenez et al 1998) and have been

seen in both hemispheres as well (Meunier et al. 2001). Additionally, abnormal

plasticity has been demonstrated in several types of dystonia (Quartarone et al

2008). Although plasticity is a normal property of the nervous system, maladaptive

plasticity could occur as a result of intrinsic defects in plasticity mechanism or

breakdown of these mechanisms (Neychev et al. 2011). Abnormal plasticity leads to

changes in the connectivity of the sensory and motor networks resulting in abnormal

sensory and motor functions.

These complex structural and functional changes of the brain of dystonic patients

may contribute to the sensory alterations that we have detected with QST. Our

findings may suggest that the deranged somatosensory integration and plastic

changes can lead to the less reliable differentiation of somatosensory stimuli

(dynamic mechanical allodynia, temperature thresholds) and slower detection of the

sensation (thermal sensory limen), and that these abnormalities may partly increase

with age of the patient. Whether these impairments are a consequence of a deficit of

30

global sensorimotor integration or of the specific levels of the loop, or even a process

of maladaptive plasticity, remains unclear.

Moreover, it is speculative if these QST changes represent a primary sensory lesion

or a reaction to maladjusted central changes in the patients with dystonia. The further

analysis of the separate subtypes of dystonia may elucidate the understanding of

sensory impairment in these patients and the possible endophenotypic trait of

sensory changes in the subgroups. Finally, future studies should be addressed to the

clarification of the role of specific parts of the thalamo-striato-cortical and cerebello-

thalamo-cortical pathways in the development of sensory changes in dystonic

patients.

Conclusion

Subtle sensory abnormalities can be detected by QST testing in patients with primary

dystonia. These impairments are partly age dependent and are not correlated with

the severity of motor symptoms. Moreover, these findings can be detected regardless

of the distribution of motor symptoms and are likely a characteristic of the disease.

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35

BFM

TWSTRS

Spearman P-value Spearman P-value

CDT -0.161 0.522 -0.186 0.489

HDT -0.232 0.355 0.021 0.939

TSL 0.187 0.457 -0.132 0.939

CPT -0.435 0.71 -0.429 0.097

HPT 0.084 0.741 0.379 0.148

TDT 0.186 0.459 -0.533 0.34

MPT -0.164 0.543 -0.349 0.202

DMA 0.355 0.205 0.633 0.09

PSP 0.163 0.545 0.209 0.456

WUR 0.091 0.746 -0.528 0.098

VT 0.313 0.238 -0.507 0.10

PPT 0.258 0.374 0.127 0.679

Table 1. Correlation of Burke-Fahn-Marsden Dystonia Rating Scale (BFM) and

Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). P value is

considered significant when p<0.05. Abbreviations: Cold detection threshold (CDT),

hot detection threshold (HDT), thermal sensory limen (TSL), cold pain threshold

(CPT), hot pain threshold (HPT), tactile detection threshold (TDT), mechanical pain

threshold (MPT), mechanical pain sensitivity for pinprick (PSP), dynamic mechanical

allodynia (DMA), wind up ratio (WUR), vibration threshold (VT), pressure pain

threshold (PPT).

36

QST

parameters

Dystonic patients

raw

Controls

raw

Dystonic patients

log

Controls

log

p

values

CDT(ºC) -2.29±1.6 -1.43±0.51

0.055

HDT(ºC) 3.63±2.2 2.42±1.61 0.49±0.24 0.53±0.06 n.s.

TSL(ºC) 5.89±3.08 3.56±1.96 0.51±0.19 0.32±0.22 0.04

CPT(ºC) 17.47±9.19 13.61±8.66

n.s.

HPT(ºC) 42.51±4.16 44.12±2.55

n.s.

TDT(mN) 3.02±2.45 1.26±1.27 0.39±0.31 0.31±0.18 n.s

MPT(mN) 71.17±107±4 49.60±32.88 1.56±0.72 1.58±0.36 n.s.

PSP 1.3±1.2 1.15±0.85 0.33±0.18 0.31±0.14 n.s.

DMA 0.13±0.0627 0.01±0.03 0.05±0.02 0.004±0.001 0.001

WUR(ratio) 2.64±1.77 1.94±0.26 0.34±0.25 0.28±0.06 n.s.

VDT(/8) 7.32±0.58 7.75±0.48 0.19±1.16 0.08±0.13 n.s.

PPT(kPa) 340.0±81.7 367.6±119.57

n.s.

Table. 2. Hand QST of all dystonic patients (n=20) compared to matched healthy controls

(n=19) showing the raw data and log transformed parameters of non-normally distributed

data. QST parameters are given as means±SD. P values are related to raw data when the

data are normally distributed and to log transformed data when they are non-normally

distributed. Abbreviations: Cold detection threshold (CDT), hot detection threshold (HDT),

thermal sensory limen (TSL), cold pain threshold (CPT), hot pain threshold (HPT), tactile

detection threshold (TDT), mechanical pain threshold (MPT), mechanical pain sensitivity for

pinprick (PSP), dynamic mechanical allodynia (DMA), wind up ratio (WUR), vibration

threshold (VT), pressure pain threshold (PPT).

37

Supplement

Tables

Suppl. Table 1. Hand QST of patients with hand involvement in dystonia (n=13), after

exclusion of patients with cervical dystonia only, compared to matched healthy controls

(n=19). There is no significant sensory difference between patients’ clinically more affected

and less affected arm/hand. QST parameters are shown as means ± SD. P values are

related to raw data when the data are normally distributed and to log transformed data when

they are non-normally distributed.

Abbreviations: Cold detection threshold (CDT), hot detection threshold (HDT), thermal

sensory limen (TSL), cold pain threshold (CPT), hot pain threshold (HPT), tactile detection

threshold (TDT), mechanical pain threshold (MPT), mechanical pain sensitivity for pinprick

(PSP), dynamic mechanical allodynia (DMA), wind up ratio (WUR), vibration threshold (VT),

pressure pain threshold (PPT).

QST

parameter

Dystonic patients

clinically more

affected arm/hand

raw

Dystonic patients

clinically less

affected

arm/hand raw

Controls raw

Dystonic

patients

clinically more

affected

arm/hand log

Dystonic

patients

clinically

less affected

arm/hand log

Controls log

p values

clinically

more

affected

arm/hand

p values

clinically

less

affected

arm/hand

CDT(ºC) -2.69±2.38 -2.31±1.17 -1.43±0.51 0.98±0.06 0.94±0.16 1.02±0.02 0.052 n.s.

HDT(ºC) 3.17±1.66 3.17±1.89 2.42±1.61 1.62±0.04 1.63±0.05 1.64±0.02 n.s. n.s.

TSL(ºC) 6.12±2.46 6.02±4.38 3.56±1.96 0.75±0.18 0.68±0.31 0.51±0.19 0.01 n.s.

CPT(ºC) 16.22±8.97 16.42±8.09 13.61±8.66

n.s. n.s.

HPT(ºC) 41.42±3.88 43.14±4.5 44.12±2.55

n.s. n.s.

TDT(mN) 15.45±46.21 10.63±32.73 1.26±1.27 0.58±0.32 0.44±0.56 0.29±0.2 n.s. n.s.

MPT(mN) 74.82±147.19 40.77±36.08 49.6±32.88 1.47±0.54 1.42±0.45 0.29±0.36 n.s. n.s.

PSP 1.61±1.45 0.12±0.82 1.15±0.85 0.35±0.24 0.33±0.15 0.29±0.18 n.s. n.s.

DMA 0.14±0.08 0.12±0.05 0.01±0.03 0.05±0.02 0.05±0.02 0.03±0.02 0.001 0.001

WUR(ratio) 2.59±1.67 2.7±1.91 1.94±0.26 0.33±0.28 0.34±0.29 0.31±0.03 n.s. n.s.

VDT(/8) 7.24±0.68 7.54±0.58 7.75±0.48 0.22±0.19 0.10±0.15 0.05±0.14 n.s. n.s.

PPT(kPa) 348.67±73.05 358.89±103.51 367.6±119.57 2.53±0.09 2.54±0.20 2.54±0.20 n.s. n.s.

38

Suppl. Table 2. Hand QST of patients older than 40 with hand involvement in dystonia (n=7)

compared to age matched healthy controls (n=10). There is no significant sensory difference

between patients’ clinically more affected and less affected arm/hand. QST parameters are

shown as means ± SD. P values are related to raw data when the data are normally

distributed and to log transformed data when they are non-normally distributed.

Abbreviations: Cold detection threshold (CDT), hot detection threshold (HDT), thermal

sensory limen (TSL), cold pain threshold (CPT), hot pain threshold (HPT), tactile detection

threshold (TDT), mechanical pain threshold (MPT), pain sensitivity for pinprick (PSP)

dynamic mechanical allodynia (DMA), wind up ratio (WUR), vibration threshold (VT),

pressure pain threshold (PPT).

QST

parameter

Dystonic

patients

clinically more

affected

arm/hand raw

Dystonic

patients

clinically less

affected arm

raw Controls raw

Dystonic

patients

clinically more

affected

arm/hand log

Dystonic

patients

clinically less

affected

arm/hand log Controls log

p values

clinically

more

affected

arm/hand

p values

clinically

less

affected

arm/hand

CDT(ºC) -2.49±1.29 -2.85±3.03 -1,13±0,32 0,64±0,13 0.59±0.31 0.49±0.05 0.011 n.s.

HDT(ºC) 3.48±1.98 3,06±2,41 1,85±0,54 0,47±0,25 0.37±0.31 0.25±0.15 0.046 n.s.

TSL(ºC) 6.28±2.64 6.29±5.57 2.87±0.99 0.76±0.19 0.65±0.39 0.44±0.12 0.004 n.s.

CPT(ºC) 13.2±7.65 14.13±7.09 17.91±8.97 1.21±0.26 1.16±0.22 0.95±0.41 n.s. n.s.

HPT(ºC) 42.95±3.98 44.49±3.62 43.33±3.13

n.s. n.s.

TDT(mN) 3.02±4.11 1.68±2.04 0.76±0.42 0.44±0.38 0.33±0.29 0.23±0.11 n.s. n.s.

MPT(mN) 25.39±24.33 28.5±28.8 44.77±35.21 1.29±0.39 1.25±0.47 1.51±0.39 n.s. n.s.

MPS 2.19±1.86 1.4±1.12 1.24±1.08 0.41±0.27 0.34±0.19 0.31±0.18 n.s. n.s.

DMA 0.17±0.09 0.14±0.06 1.24±0.05 0.06±0.03 0.05±0.02 0.007±0.02 0.005 0.008

WUR(ratio) 1.57±0.09 1.99±1.01 1.91±1.98 0.17±0.17 0.25±0.22 0.27±0.04 0.009 n.s.

VDT(/8) 7,11±0,58 7.39±0.68 7.58±0.61 0.25±0.15 0.15±0.17 0.12±0.16 n.s. n.s.

PPT(kPa) 342.8±70.57 368.2±131.15 327.87±139.38 n.s. n.s.

39

Suppl. Table 3. Hand QST of patients younger than 40 with hand involvement in dystonia

(n=7) compared to age matched healthy controls (n=10). There is no significant sensory

difference between patients’ clinically more affected and less affected arm/hand. QST

parameters are shown as means ± SD. P values are related to raw data when the data are

normally distributed and to log transformed data when they are non-normally distributed.

Abbreviations: Cold detection threshold (CDT), hot detection threshold (HDT), thermal

sensory limen (TSL), cold pain threshold (CPT), hot pain threshold (HPT), tactile detection

threshold (TDT), mechanical pain threshold (MPT), pain sensitivity for pinprick (PSP)

dynamic mechanical allodynia (DMA), wind up ratio (WUR), vibration threshold (VT),

pressure pain threshold (PPT).

QST

parameter

Dystonic

patients

clinically more

affected

arm/hand raw

Dystonic

patients

clinically less

affected arm

raw Controls raw

Dystonic

patients

clinically more

affected

arm/hand log

Dystonic

patients

clinically less

affected

arm/hand log Controls log

p values

clinically

more

affected

arm/hand

p values

clinically

less

affected

arm/hand

CDT(ºC) -2.01±1.02 -2.42±0.45 -1.76±0.47 0.59±0.05 0.64±0.05 0.57±0.05 n.s. n.s.

HDT(ºC) 2.69±0.95 3.04±0.70 3.07±2.29 0.41±0.10 0.47±0.10 0.41±0.26 n.s. n.s.

TSL(ºC) 5.88±2.42 5.59±1.73 4.34±2.59

n.s. n.s.

CPT(ºC) 22.9±6.99 20.08±9.01 8.71±5.31 0.73±0.40 0.86±0.40 1.32±0.11 0.002 0.045

HPT(ºC) 40±3.31 40.99±5.34 44.81±1.55

0.007 n.s.

TDT(mN) 6.47±10.14 5.01±8.25 1.83±1.69 5.26±8.67 4.21±3.26 0.4±0.21 n.s. n.s.

MPT(mN) 131.32±214.44 55.43±41.53 55.11±31.77 1.69±0.38 1.63±0.38 1.65±0.33 n.s. n.s.

MPS 1.15±0.65 1.08±0.24 1.04±0.54 0.329±0.05 0.314±0.0512 0.29±0.10 n.s. n.s.

DMA 0.12±0.01 0.11±0.01 0.012±0.016 0.041±0.001 0.04±0.001 0.013±0.012 0.001 0.001

WUR(ratio) 3.61±1.79 3.44±2.37 1.98±0.33 0.51±0.29 0.45±0.29 0.29±0.07 0.039 n.s.

VDT(/8) 7.4±0.83 7.73±0.43 7.94±0.11 0.16±0.19 0.08±0.13 0.02±0.04 n.s. n.s.

PPT(kPa) 356±86.38 347.25±72.90 413±78.64 n.s. n.s.

40

QST

parameter

Cervical

dystonia raw

Controls

raw

Cervical

dystonia log

Controls

log p values

CDT(ºC) -2.03±1.08 -1.13±0.33 0.44±0.18 0.58±0.03 0.04

HDT(ºC) 4.17±1.77 1.85±0.54 0.58±0.21 0.28±0.148 0.03

TSL(ºC) 5.65±2.21 2.89±0.99

0.06

CPT(ºC) 17.48±10.61 17.91±8.97

n.s.

HPT(ºC) 42.29±4.02 43.33±3.14

n.s.

TDT(mN) 4.13±7.61 2.76±1.41 0.44±0.43 0.23±0.11 n.s.

MPT(mN) 77.49±57.35 44.77±35.21 1.78±0.36 1.51±0.39 n.s.

MPS 1.58±1.83 1.24±1.08 0.344±0.261 0.313±0.183 n.s.

DMA 0.13±0.07 0.024±0.052 0.052±0.026 0.01±0.022 0.02

WUR(ratio) 2.21±0.91 1.91±0.19 0.49±0.12 0.46±0.02 n.s.

VDT(/8) 7.13±0.29 758±0.61

n.s.

PPT(kPa) 330±86.38 327.87±139.38 n.s.

Suppl. Table 4. Hand QST in patients with cervical dystonia (n=7) compared to age matched

healthy controls (n=9). The QST values represent the mean of both sides of the hands. QST

parameters are given as means ± SD. P values are related to raw data when the data are

normally distributed and to log transformed data when they are non-normally distributed.

Abbreviations: Cold detection threshold (CDT), hot detection threshold (HDT), thermal

sensory limen (TSL), cold pain threshold (CPT), hot pain threshold (HPT), tactile detection

threshold (TDT), mechanical pain threshold (MPT), mechanical pain sensitivity for pinprick

(PSP), dynamic mechanical allodynia (DMA), wind up ratio (WUR), vibration threshold (VT),

pressure pain threshold (PPT).

41

QST

parameter

Cervical dystonia

raw

Controls

raw

Cervical

dystonia log

Controls

log p values

CDT(ºC) -1.57±0.81 -2.09±0.33

n.s.

HDT(ºC) 4.05±1.47 4.21±2.23 0.56±0.17 0.58±0.18 n.s.

TSL(ºC) 5.51±2.29 7.93±4.34 0.71±0.18 0.87±0.19 n.s.

CPT(ºC) 19.38±8.75 9.27±4.41

0.008

HPT(ºC) 44.28±4.38 45.91±2.02

n.s.

TDT(mN) 5.35±7.39 3.69±3.93 0.53±0.46 0.57±0.29 n.s.

MPT(mN) 35.23±32.03 45.42±13.76 1.38±0.41 1.64±0.12 n.s.

PSP 0.63±0.52 0.67±0.12 -0.39±0.33 -1.77±0.07 n.s.

DMA 0.634±0.055 0.03±0.032 0.052±0.021 0.01±0.015 0.001

WUR(ratio) 2.09±1.37 2.16±0.28 0.26±0.25 0.33±0.06 n.s.

VDT(/8) 7.2±0.44 6.92±0.69

n.s.

PPT(kPa) 429.4±132.32 470.75±126.96 n.s.

Suppl. Table 5. Shoulder QST in patients with cervical dystonia (n=7) compared to age

matched healthy controls (n=9). The QST values represent the mean of both sides of the

shoulder. QST parameters are given as means ± SD. P values are related to raw data when

the data are normally distributed and to log transformed data when they are non-normally

distributed. Abbreviations: Cold detection threshold (CDT), hot detection threshold (HDT),

thermal sensory limen (TSL), cold pain threshold (CPT), hot pain threshold (HPT), tactile

detection threshold (TDT), mechanical pain threshold (MPT), mechanical pain sensitivity for

pinprick (PSP), dynamic mechanical allodynia (DMA), wind up ratio (WUR), vibration

threshold (VT), pressure pain threshold (PPT).

42

43

4. Manuskript II

Strategies to decrease injection site pain in botulinum toxin therapy

Lejla Paracka1, Katja Kollewe1, Florian Wegner1, Dirk Dressler1

1Movement Disorders Section, Department of Neurology, Hannover Medical School

Hannover, Germany

Key Words: Botulinum Toxin, Therapy, Injection Site Pain, Reduction

Abstract

Botulinum toxin (BT) is now used for numerous indications including dystonias,

spasticity, cerebral palsy, hyperhidrosis, cosmetics and chronic migraine. It has to be

injected into its target tissues thus causing injection site pain (ISP). We wanted to

compare the efficacy of various analgesic interventions suggested for ISP reduction.

In 13 healthy controls pain thresholds in the fingertips II and III bilaterally were

determined in the Mechanical Pain Threshold Test (MPTT) and the Repetitive Pain

Stimulation Test (RPST) at baseline and under nitrous oxide/oxygen (NOO), ice

spray (IS), local anaesthetic cream (LAC) and forearm ischaemia (FI).

All analgesic interventions studied produce statistically significant and robust

analgesic effects in the MPTT and the RPST. NOO had stronger analgesic effects

than the other interventions, although this superiority was statistically significant only

in the RPST and not against IS.

Additionally considering duration, localisation and penetration depth of the analgesic

effect, hyperhidrosis treatment may benefit from NOO, IS and LAC. In palmar

hyperhidrosis FI is possible and also reduces BT washout. Cosmetic indications may

44

also benefit from NOO and LAC. For BT therapy of spasticity, dystonia and tremor

only NOO may offer intramuscular analgesic effect. Its systemic and prolonged effect

is also an advantage in wide-spread injections in several body parts.

Future studies are necessary to test the influence of penetration depth and

combinations of analgesic interventions.

Introduction

Therapeutic use of botulinum toxin (BT) has expanded into many medical specialties

where it is used for numerous indications including dystonias, spasticity, cerebral

palsy but also hyperhidrosis, cosmetics and chronic migraine. Due to its mode of

action and its biological properties BT has to be injected into its target tissues.

Depending on the particular target tissue, this can be unpleasant for the patient. Over

the years several methods have been proposed to reduce this injection site pain

(ISP). We wanted to compare the analgesic efficacy of some of them.

Methods

Design: The pain sensitivity of the index and third fingertip was investigated without

and with four analgesic interventions.

Subjects: 13 healthy controls (7 males aged 36.3±8.3y, 6 females aged 36.0±10.2y)

gave informed consent and were included in the study. All of them underwent

neurological examination, electroneurography and somatosensory evoked potential

testing to exclude sensory pathway abnormalities.

45

Study parameters: Pain sensitivity was the study parameter. It was measured as the

pain threshold determined by the Mechanical Pain Threshold Test (MPTT) and by the

Repetitive Pain Stimulation Test (RPST).

For the MPTT (Greenspan & McGillis 1991) the pain threshold was determined by a

set of weighted pinprick stimulators with a flat contact area of 0.25mm in diameter

producing pressure forces of 8, 16, 32, 64, 128, 256 and 512mN (MRC Systems,

Heidelberg, Germany) on the fingertip. Escalating the pressure force subjects were

asked to indicate when the sensation started to feel sharp (sharp threshold, given in

mN). After determination of the sharp threshold the pressure force was then gradually

reduced and the subjects were asked to indicate when the sensation started to feel

dull (dull threshold, given in mN). This ascending and descending stimulation scheme

was performed five times and all sharp and dull thresholds were registered. The

MPTT pain threshold for each finger tip was the geometric mean of five ascending

and descending stimulation schemes (Baumgärtner et al. 2002) calculated according

to the formula: 𝐺𝑀�� = √𝑦1 × 𝑦2 × …𝑦𝑛𝑛 .

MPTT pain thresholds were determined for fingertips II and fingertips III of both

hands. The final MPTT pain threshold (given in mN) was the mean value of the

MPTT pain thresholds for fingertip II and fingertip III on the right side and fingertip II

and fingertip III on the left side. Final MPTT pain thresholds were calculated for the

baseline, i.e. without analgesic intervention, and for each analgesic intervention. The

analgesic intervention 'forearm ischemia' could not be tested with the MPTT, because

of the duration of the testing procedure.

The RPST was also performed with the above described weighted pinprick stimulator

set (MRC Systems, Heidelberg, Germany). Repetitive stimuli (2Hz for five seconds)

46

with increasing pressure forces of 8, 16, 32, 64, 128, 256 and 512mN were applied to

the fingertip and subjects were asked to indicate at what pressure force pain was felt

(pain threshold, given in mN). The final RPST pain threshold (given in mN) was the

mean value of the RPST pain thresholds for fingertip II and fingertip III on the right

side and fingertip II and fingertip III on the left side. Final RPST pain thresholds were

calculated for the baseline and for each analgesic intervention.

Analgesic interventions: All subjects underwent a series of analgesic interventions

after their baseline pain sensitivity was assessed. First analgesic intervention was

application of an equiproportional fixed mixture of nitrous oxide and oxygen (NOO,

Livopan®, Linde Gas Therapeutics, Unterschleißheim, Germany). NOO was inhaled

by the subjects for 5 minutes before and throughout the testing procedure. Total

inhalation time was usually 15-20min. Second analgesic intervention was ice spray

(IS, Eisspray-ratiopharm 150ml). IS was applied 5s before testing and it was re-

applied every 30s onto the fingertip. Third analgesic intervention was forearm

ischemia (FI). For this the blood pressure cuff of a sphygmomanometer was

positioned on the upper extremity over the biceps brachii muscle, set to a pressure of

20mm Hg over the systolic pressure and held for 5min. Fourth analgesic intervention

was the application of a lidocaine 2.5%/prilocaine 2.5% local anaesthetic cream

(LAC, Emla®, AstraZeneca, Wedel, Germany). LAC was applied 40min prior to the

testing. During this period, subjects were instructed not to wash their hands and not

to touch anything.

Statistical Analysis: To determine the data distribution the Shapiro-Wilk test and

visualisation assessment were used. Normally distributed data were analysed by

applying the One-way ANOVA test. For statistical analyses and visualisation of data,

SPSS (IBM Deutschland, Ehningen, Germany) was used. Two-sided p values <0.05

47

Fig. 1. Pain threshold in the Mechanical Pain Threshold Test (MPTT) under various analgesic interventions. All

analgesic interventions tested produce a statistically significant reduction of the pain threshold. There was no

statistically significant difference between the different analgesic interventions. Abbreviations: LAC (local

anaesthetic cream), NOO (equiproportional fixed mixture of nitrous oxide and oxygen), IS (Ice spray). Median

± 95% confidence interval. *=p<0.05

were considered statistically significant. Comparisons were calculated between each

analgesic intervention and the baseline and in between all analgesic interventions.

Results

The effects of the analgesic interventions on pain sensitivity as tested in the MPTT

are shown in Figure 1. In the MPTT all patients responded to all analgesic

interventions performed. NOO reduced the pain sensation from the baseline of

39±36.9mN to 190.14±96.6mN (p<0.001), LAC to 177.7±108.5mN (p<0.001) and IS

to 173.4±111.3mN (p=0.001). There was no statistically significant difference

between the analgesic effects of these analgesic interventions.

48

Fig. 2. Pain threshold in the Repetitive Pain Stimulation Test (RPST) under various analgesic interventions. All

analgesic interventions (except FI) produce a statistically significant reduction of the pain threshold. NOO had

stronger analgesic effects than LAC and FI, but not against IS. Abbreviations: LAC (local anaesthetic cream),

NOO (equiproportional fixed mixture of nitrous oxide and oxygen), IS (Ice spray), FI (forearm

ischaemia).Median ± 95% confidence interval, *=p<0.05

The effects of the analgesic interventions on pain sensitivity as tested in the RPST

are shown in Figure 2. In the RPST, again, all patients responded to all analgesic

interventions. NOO reduced the pain sensation from the baseline of 96±39.25mN to

512±236.7mN (p<0.001), LAC to 256±92.32mN (p=0.008) and IS to 256±148.3mN

(p=0.009). The FI reduction to 192±71.8mN (p=0.08) was statistically not significant.

NOO showed statistically significant superiority over LAC (p=0.03) and FI (p<0.001)

and a tendency against IS (p=0.08). No adverse effects were registered during the

analgesic procedures.

Discussion

Several analgesic interventions have been proposed for ISP reduction during BT

therapy including dermal application of local anaesthetic creams (Carruthers &

Carruthers 2005) or ice spray (Elibol et al. 2007), forearm ischemia (Dressler 2000)

and inhalation of nitrous oxide/oxygen mixtures (Paracka et al 2015). Our study is the

49

first comparing various analgesic interventions including NOO against each other.

Our data show that all analgesic interventions studied produce statistically significant

and robust analgesic effects in the MPTT and the RPST. Analgesic effects are

similar. NOO, however, had stronger analgesic effects than the other interventions

tested, although this superiority was statistically significant only in the RPST and not

against IS.

A previously published study compared local anaesthetic cream, ice and vapocoolant

spray and found comparable effects of ice and EMLA cream. However, spray did not

offer pain relief (Fung et al. 2012).

Choosing an appropriate analgesic intervention for a specific procedure starts with a

comparison of analgesic potency. Our study shows superior analgesic effects of

NOO against LAC and FI and - as a trend only - against IS.

Other aspects shown in Table 1, however, also need to be discussed when choosing

an appropriate analgesic intervention. Considering the duration of the analgesic

effect, NOO and LAC produce continuous and long-lasting effects, whereas the

effects of FI and IS are short-lasting. Concerning the localisation of the analgesic

effect, NOO offers wide-spread systemic effects, whereas the effects of LAC, IS and

FI are local. For anatomic reasons, FI can only be used in the forearm. Considering

the penetration depth, NOO and FI may also reach deeper muscular tissues,

whereas analgesic effects of LAC and IS seem to be more restricted to superficial

tissues. NOO and LAC consume moderate costs and time, whereas cost and time

consumption are low for IS and FI.

50

Analgesic

intervention

Duration of

effect

Localisation

of effect

Penetration

depth

Costs Time

consumption

Use for botulinum

toxin therapy

NOO long

expandable

systemic probably high moderate moderate dermal applications

muscular applications

FI short regional

forearm only

probably high low low dermal applications

muscular applications

LAC long local probably low moderate moderate dermal applications

IS short local probably low low low dermal applications

Table 1. Suitability of various analgesic interventions for botulinum toxin therapy. Abbreviations: LAC (local

anaesthetic cream), NOO (equiproportional fixed mixture of nitrous oxide and oxygen), IS (Ice spray), FI (forearm

ischaemia).

BT therapy of hyperhidrosis may benefit from NOO, IS and LAC. In palmar

hyperhidrosis FI is possible and at the same time also reduces the BT washout at the

injection site. BT therapy for cosmetic indications may also benefit from NOO and

LAC as the targeted muscle tissue is very superficial and can easily be reached.

Application of IS in facial cosmetic procedures may be difficult because of eye

protection. For BT therapy of spasticity, dystonia and tremor, where skeletal muscles

are targeted, NOO, LAC and IS may reduce the pain arising from the skin

penetration, but only NOO may offer an additional intramuscular analgesic effect.

NOO's systemic effect also is an advantage when dystonia and spasticity requires

wide-spread injections in several body parts.

For multiple dermal injections in pain sensitive areas such as the face, the palms and

the feet and in children, use of appropriate analgesia is frequently required and - if

offered - will increase the patient’s compliance to undergo BT therapy.

NOO shows superior analgesic effects and it also reaches deeper structures in

comparison to the other analgesics giving it an advantage in muscular BT injections.

51

Additional analgesic strategies such as pH reduction of the reconstituted BT drugs

may also be used (Dressler et al 2016).

Future studies are necessary to test the influence of penetration depth and

combinations of analgesic interventions to further improve analgesic effects.

Conflict of Interest: The authors report no conflict of interest.

References

1. Baumgärtner U, Magerl W, Klein T, Hopf HC, Treede RD (2002) Neurogenic

hyperalgesia versus painful hypoalgesia: two distinct mechanisms of

neuropathic pain. Pain 96:141-151.

2. Carruthers A, Carruthers J (2005) Single-center, double-blind, randomized

study to evaluate the efficacy of 4% lidocaine cream versus vehicle cream

during botulinum toxin type A treatments. Dermatol Surg 31:1655-1659.

3. Dressler D (2000) Botulinum Toxin Therapy. Thieme Verlag, Stuttgart, New

York

4. Dressler D, Sadberi FA, Bigalke H (2016) Botulinum Toxin Therapy: Reduction

of Injection Site Pain by pH-Normalisation. J Neural Transm 123:527-31

5. Elibol O, Ozkan B, Hekimhan PK, Cağlar Y (2007) Efficacy of skin cooling and

EMLA cream application for pain relief of periocular botulinum toxin injection.

Ophthal Plast Reconstr Surg 23:130-133.

6. Fung S, Phadke CP, Kam A, Ismail F, Boulias C (2012) Effect of Anesthetics

on Needle Insertion Pain During Botulinum Toxin Type A Injections for Limb

Spasticity. Arch Phys Rehabil 93:1643-1647.

52

7. Greenspan JD, McGillis SLB (1991) Stimulus features relevant to the

perception of sharpness and mechanically evoked cutaneous pain.

Somatosens Mot Res 8:137–147.

8. Paracka L, Kollewe K, Dengler D, Dressler D (2015) Botulinum toxin therapy

for hyperhidrosis: reduction of injection site pain by nitrous oxide/oxygen

mixtures. J Neural Transm 122:1279-1282.

53

5. Appendix

Psychiatric symptoms in patients with isolated idiopathic and inherited

dystonia

Methods

Patients: The study was comprised of twenty patients (10 males aged 51.2±17.2 and

10 females aged 55.5±21.3 years) with the average disease duration of 11.47±16.27

years. Eight patients had generalized dystonia, five segmental dystonia, and seven

patients showed isolated cervical dystonia. Two of the patients were diagnosed with

DYT1 hereditary dystonia. All other subjects were classified as idiopathic dystonia.

Exclusion criteria were dystonias related to other diseases. Patients were evaluated

by Burke-Fahn-Marsden Dystonia Rating Scale (BFM) and Toronto Western

Spasmodic Torticollis Rating Scale (TWSTRS) motor examination to stage the

disease severity. Informed consent to participate was obtained after the approval by

the ethics committee of Hannover Medical School. Mini mental state test was done in

all patients to evaluate cognitive impairment. Patients were asked to perform the

standardized scales SF36 (quality of life), Beck depression inventory, social phobia

scale, social phobia anxiety scale and Frankfurter body concept scale. The structural

interview for Hamilton depression inventory was also used to objectively measure the

mood.

Materials

SF36

54

The short form health survey is designed to survey the quality of life in medical

outcome research (Ware et al 1992). SF36 is a multi-item scale that assesses

physical and mental well-being including eight health concepts: 1) limitations in

physical activities because of health problems; 2) limitations in social activities

because of physical or emotional problems; 3) limitations in usual role activities

because of physical health problems; 4) bodily pain; 5) general mental health

(psychological distress and well-being); 6) limitations in usual role activities because

of emotional problems; 7) vitality (energy and fatigue); and 8) general health

perceptions (Ware et al. 1992). The values of dystonic patients were then compared

to the normal values from the surveys that correspond to German population (Ellert et

al. 1999, 2004; Ware et al. 1998).

Beck depression inventory (BDI)

BDI is a questionnaire, a self-rating depression inventory, consisting of 21 items that

cover affective and somatic symptoms of depression (Beck et al. 1961). Scores

between 0-9 represent no depression, 10-18 mild depression, 19-29 moderate to

severe depression, and scores from 30-63 indicate severe depression (Beck et al.

1988). The test is designed in a way that the patients have to define how they felt in

the past week.

Hamilton depression inventory (HDI)

HDI is a semi structured diagnostic interview, which is performed by a healthcare

professional. It consists of 21 items and it contains somatic symptoms and relatively

few affective and cognitive symptoms (Hamilton 1960; Williams et al. 2001, Shafter et

al. 2006). Score of 0-7 indicates no depression, 8-16 mild depression, 17-23

moderate depression and 24 or higher severe depression (Zimmerman et al 2013).

55

Social phobia inventory (SPIN)

The SPIN is a 17-item self-rating scale for social anxiety disorder (social phobia). It

includes 17 items assessing symptoms of social anxiety disorder (fear, avoidance,

physiological arousal) (Connor et al. 2000). Scores less than 20 represent no social

phobia, 21-30 mild, 31-40 moderate, 41-50 severe, 51 and above very severe social

phobia.

Social interaction Anxiety Scale (SIAS)

SIAS measures social interaction anxiety and assesses anxiety during the interaction

with others (friends, opposite sex, strangers). This includes fears of being inarticulate,

sounding boring, sounding stupid, not knowing what to respond, and being ignored

(Mattick and Clark 1998). It includes 20 items and scores higher than 43 represent

probable social anxiety.

Frankfurt body concept scale (FKKS)

This scale evaluates the perception of the body image and self-concept, how the

body and inner and outer appearance is perceived by the subject. It consists of 64

items, divided in 8 subscales: body concept towards the health (SGKB), care towards

the body and functionality to taking care about the body (SPBF), bodily efficiency

(SKEF), body contact (SKKO), sexuality (SSEX), self-acceptance of the body

(SSAK), acceptance of one’s body by the others (SAKA), aspects of outer

appearance (SASE) and dissimilatory body processes (SDIS). Values for each

subscore were compared with the mean score of the German population survey

(Deusinger 1998).

56

Statistical analysis

Cut-offs for BDI, HDI, SIAS, SPIN classification were used to compare depression,

social phobia and social interaction anxiety. An ANOVA test was used to compare

the SF36 and FKKS subscores with the normal values. The correlation between

motor scores (BFM and TWSTRS) and non-motor scales (BDI, HDI, SIAS, SPIN) and

all subscores for SF36 and FKKS was done with Spearman-Rho bivariate correlation

test. For statistical analyses and visualisation of data we used SPSS (IBM

Deutschland, Ehningen, Germany). Two-sided p-values <0.05 were considered

statistically significant.

Results

The mean age (±SD) of male patients with dystonia was 51.2±17.2 and of females

was 55.5±21.3 years. Disease duration was 11.5±16.3 years. The mean BFM score

of all patients and all subscores was 19.4±10.7. According to the mini mental state

test, our patients did not show the signs of dementia (28.2±1.4).

Based on the evaluation of self-reported BDI and structuralized interview HDI,

patients with idiopathic dystonia show signs of mild depression (12.0±7.2 and

8.1±5.1, respectively).

According to our results, a mild phobia (21.5±12.6) but no social interaction anxiety

(21.3±16.9) was observed.

Compared to the general population, dystonic patients reported lower scores of

quality of life in all areas (Fig. 1). The poorest score was registered for physical role

(p=0.002), general health (p=0.005), social functioning (p=0.03), emotional role

(p=0.025) and mental health (p=0.03) (Fig. 1). The physical summary score of

quality of life (PCS) was 41.2±5.9, whereas mental score of quality of life (MCS) was

39.7±9.3.

57

Fig. 1. Quality of life in patients with dystonia in comparison to healthy controls presented as

mean±SD. Abbreviations: Physical functioning (PF), role physical (RP), bodily pain (BP), general

health (GH), vitality (V), social functioning (SF), role emotional (RE), mental health (MH). *p<0.05.

Body concept perceived by the patients was significantly impaired in seven of its

domains in comparison to controls (Fig. 2): The lowest scores were registered for

functionality of bodily care (p=0.006), body contact (p=0.002), sexuality (p=0.001),

self-acceptance of the body (p=0.001), aspects of bodily appearance (p=0.0001) and

dissimilatory processes (p=0.04).

* p= 0,002 * p= 0,005 * p= 0,03 * p= 0,025 * p= 0,030

0

10

20

30

40

50

60

70

80

90

100

PF RP BP GH V SF RE MH

SF 36

Healthy controls

Dystonic patients

58

Fig. 2. Frankfurt body concept scale in comparison to the healthy controls presented as mean±SD.

Abbreviations: Body concept towards the health (SGKB), care towards the body and functionality to

taking care about the body (SPBF), bodily efficiency (SKEF), body contact (SKKO), sexuality (SSEX),

self-acceptance of the body (SSAK), acceptance of ones body by the others (SAKA), aspects of outer

appearance (SASE) and dissimilatory body processes (SDIS).*p<0.05

Table 1 summarises Pearsons correlations between BFM and depression, social

phobia and social interaction anxiety, all subscales for SF36 and FKKS. The severity

of motor symptoms had a significant effect on depression scores. There was a

positive correlation of motor scores and HDI (p=0.04) and BDI (p=0.008). There was

no significant correlation observed between motor scores and anxiety scores,

subscores for SF36 and FKKS.

59

Table 1. Correlation of motor score BFM (Burke-Fahn-Marsden Dystonia Rating Scale) with mood

scales, anxiety scales, body concept and quality of life.

In the next step, we wanted to determine how depression in dystonic patients is

related to anxiety, body concept and quality of life, depression scores were correlated

with the social phobia scores and subscores of quality of life and Frankfurt body

concept scales. Depression scores showed significant correlations (p<0.01) with

Pearson p value

Mood scales

Beck Depression Inventory 0.34 0.04

Hamilton Depression Inventory 0.70 0.008

Anxiety scales

Social Phobia Inventory 0.213 0.30

Social Interaction Anxiety Scale 0.67 0.67

Frankfurt body concept scales

Concept health 0.076 0.79

Body care and finctionality 0.268 0.35

Bodily efficiency 0.343 0.22

Body contact -0.14 0.96

Sexuality 0.163 0.57

Self acceptance of the body -0.145 0.62

Acceptance by the others 0.35 0.15

Acceptance of the appearance -0.23 0.32

Dissimilatory processes 0.212 0.44

Quality of life scales (SF36)

Physical functioning 0.42 0.23

Role physical 0.34 0.57

Bodily pain 0.23 0.66

General health -0.14 0.09

Vitality 0.23 0.65

Social functioning 0.34 0.72

Role emotional 0.43 0.08

Mental health 0.39 0.66

60

social phobia inventory (p=0.01, r=0.52), subscores of SF36 (physical role p=0.003,

r=-0.34; social functioning p=0.001, r =-0.24 and mental health p=0.002, r=-0.67) and

subscores for FKKS (sexuality 0.0001, r=-0.57, aspects of physical appearance

p=0.0003, r=-0.76 and dissimilatory processes p=0.007, r=-0.43).

In order to determine how body concept can affect the quality of life, different areas of

body concepts were correlated with physical summary score of quality of life (PCS

41.2±5.9) and mental score of quality of life (MCS 39.7±9.3). In our patients, lower

physical summary score was determined by lower ability to take care of the body

(p=0.002, r=0.53), lower body contact (p=0.0001, r=0.63) and dissimilatory processes

(p=0.0004, r=0.23). The decreased ability to accept the body (p=0.01, r=0.32),

reduced self-perceived sexuality (p=0.0029, r=0.54) and physical appearance

(p=0.007, r=0.43) affect the mental score of the quality of life. These results show

how strong the psychological symptoms influence the quality of life in dystonic

patients.

Finally, there was no correlation between anxiety scores and SF36 and FKKS.

61

6. General discussion

Several studies have revealed that primary dystonia apart from being a movement

disorder is related to many non-motor features (Peall et al. 2015; Stamelou et al.

2012; Fabbrini et al. 2010; Kuyper et al. 2011). In this study we investigated the

sensory symptoms by using the Quantitative Sensory Testing to assess sensory

processing in patients with isolated primary dystonia in relation to the patients’ age

and motor symptoms. Moreover, since the treatment with botulinum toxin in dystonic

patients is sometimes associated with pain in the injected region, we compared the

analgesic potency of several methods such as ice spray, nitrous oxide/oxygen

mixture, anesthetic cream and forearm ischemia to reduce injection site pain. Finally,

we examined psychiatric symptoms in dystonic patients such as mood, anxiety, body

concept and also their impact for the quality of life.

In the first part of the thesis, we demonstrated several subtle sensory abnormalities in

patients with isolated idiopathic and hereditary dystonia which we detected using the

Quantitative Sensory Testing (QST). We focused more on the specific qualities of

sensations which require higher differentiation of the stimuli and these findings were

analyzed in relation to the disease severity and age-dependency. The tested areas

were the back of the hand for all patients and shoulder for patients with cervical

dystonia. We investigated twelve sensory modalities, such as: Cold and hot detection

threshold (CDT and HDT), thermal sensory limen (TSL), cold and hot pain threshold

(CPT and HPT), tactile detection threshold (TDT), mechanical pain threshold (MPT),

dynamic mechanical allodynia (DMA), pain sensitivity for pinprick (PSP), wind-up

ratio (WUR), vibration threshold (VT) and pressure pain threshold (PPT). The main

finding was impaired DMA and TSL, whereas the other modalities were relevant for

subgroups (CDT, HDT, CPT, HPT, WUR). The impairments were found at the back

of the hand and at the shoulder.

62

DMA is pain in response to a non-nociceptive stimulus (Sandkühler 2009). Although

our patients did not perceive the light stimuli (brush, Q-tip, cotton wool) as painful,

they perceived them as sharp, suggesting that there is an impairment of sensory

perception in dystonic patients. Nevertheless, hyperalgesia for mechanical stimuli

(pain sensitivity for pinprick) was not registered in our patients.

The patients older than 40 years showed impaired CDT, TSL, DMA and WUR,

whereas the patients younger than 40 years showed abnormal sensitivity for CPT,

HPT, DMA and WUR. The abnormalities were found on the side more affected and

less affected with dystonia with the prevalent distribution on the clinically more

affected side. Additionally, our study shows not only impairments on the shoulder

QST, but also in the hand QST of the patients with isolated cervical dystonia, which

suggests that the presence of the sensory abnormalities is independent from the

dissemination of motor symptoms. This opposes the findings from Suttrup and al.

(2011), who found impairments only on the affected side of their patients with writer’s

cramp. We believe that these findings are different because the writer’s cramp as a

task specific dystonia can hardly be compared with our sample of patients

(generalised, segmental and isolated cervical dystonia) as they are heterogeneous in

aetiology.

Although both sides in our dystonia patients displayed impairments in the QST

values, the z-scores of the clinically more affected side showed a higher discrepancy

from normal values than of the clinically less affected side. This was revealed mostly

in patients older the 40 years. In the patients younger than 40 years the z-scores of

the QST values tended to be similar on both sides. In addition, we tested the

correlation of disease severity with the sensory symptoms in primary dystonia

patients. For this purpose we compared the Burke-Fahn-Marsden Dystonia Rating

Scale (BFM) and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)

63

with QST values of the dystonic patients. Our results show no dependency of motor

severity with the QST abnormalities which again indicates the overall impairment of

the sensory processing in patients with primary dystonia.

Behavioural studies have shown that temporal and spatial discrimination are

compromised in patients with various types of dystonia (Hutchinson et al. 2013;

Bradley et al. 2012; Bara-Jimenez et al. 2000; Scontrini et al. 2009). These findings

were confirmed in the clinically distant areas as well suggesting that abnormal

sensory processing is a fundamental disturbance in patients with primary dystonia

(Molloy et al. 2003; Putzki et al. 2006; Fiorio et al. 2008). The absence of impairment

for spatial discrimination in patients with DYT1 and DYT6 dystonia indicates that

specific sensory impairments may have an endophenotypic trait of the disease.

Moreover, abnormal temporal discrimination thresholds in non-manifesting relatives

of patients with DYT1 (Fiorio et al. 2007) and adult onset sporadic primary dystonia

demonstrate that sensory abnormalities may be a surrogate marker of the disease

(Walsh et al. 2007).

Defects in the sensorimotor integration and abnormal plasticity have been proposed

as pathophysiological mechanisms for dystonia and may explain the impairments in

sensory perception in these patients (Perruchoud et al. 2014, Quartarone et al.

2008). Disability to coherently organize bodily sensations and motor responses might

contribute to the alterations that we have detected with QST.

Our findings may suggest that the altered somatosensory integration and abnormal

plastic changes can lead to the less reliable distinction of somatosensory stimuli

(dynamic mechanical allodynia, temperature thresholds) and slower detection of the

sensation (thermal sensory limen) and are partly age dependent. However, these

changes are not correlated to the disease severity and to the distribution of motor

symptoms.

64

In the second part of the thesis we compared the potency of different analgesic

methods for reduction of injection site pain during treatment with botulinum toxin in

dystonic patients. We wanted to find the most suitable method to achieve short-term

modulation of pain which would facilitate the treatments that involve the areas that

are known to be more sensitive such as palm of the hand and sole of the foot. For

this purpose we compared the efficacy of ice-spray (IS), local anesthetic cream

(LAC), nitrous oxide/oxygen mixture (NOO) and forearm ischemia (FI) with the

mechanical pain threshold test (MPTT) test and repetitive pain stimulation test

(RPST). Our data show that all analgesic interventions studied, produce statistically

significant effects in the MPTT and the RPST. Analgesic effects in MPTT show

similar potency of NOO, IS and LAC to reduce the injection site pain (ISP). However,

in RPST, the stronger analgesic effects in comparison to LAC and FI was registered

for NOO. This effect was not observed for IS. Although different analgesic methods

have been proposed for ISP by using local anaesthetic cream (Carruthers &

Carruthers 2005), nitrous oxide (Paracka et al. 2015), forearm ischaemia (Dressler

2000) and ice spray (Elibol et al. 2007), their limitation was that they did not compare

the potency of different methods intraindividually. In our study we tested MPTT and

RPST under different analgesic methods in healthy controls.

The choice of the appropriate analgesic during the botulinum toxin treatment should

be made in relation to the region that is being injected and the properties of the

analgesic method. IS and FI have a short lasting effect, in contrary to NOO and LAC

that have long lasting effects. Furthermore, IS, FI and LAC have a local effect,

whereas NOO shows systemic effects. However, considering penetration depth

during the botulinum toxin treatment, NOO would be more effective for injection in the

deeper structures such as skeletal muscles in dystonia, spasticity and tremor,

because of its systemic effect, in contrast to LAC and IS which have superficial

65

effects. Additionally, LAC and NOO can be used for injections in the face. IS cannot

be used in this region, because of the eye protection. Moreover, FI could be used

only for injections in the hand and lower arm, because of anatomical reasons.

Injection site pain should be considered in patients who are treated with botulinum

toxin. A proper analgesic method could offer a better acceptance of the patient to

undergo the treatment.

Psychiatric symptoms related to patients with idiopathic and inherited dystonia

represent the third part of the thesis. Based on our results we confirm the previous

reports that dystonic patients have increased risk of depression and that the severity

of depression is not related to the disease duration (Fabbrini et al 2010). In our

sample of patients, most of the patients were in the range of mild depression. There

are different reports about the association of depression with the severity of dystonia.

In a previous study (Lewis et al. 2008) the correlation between depression and the

extent of dystonia was demonstrated, whereby patients with focal dystonia have

lower depression scores than those with hemi-dystonia, segmental or multi-focal

dystonia. Scheidt et al. (1996) have found a correlation between Tsui score for

cervical dystonia and depression. On the other hand, several publications have not

found a correlation between the depression and the severity of the disease (Gundel

et al 2003, Fabbrini et al 2010). In the present study we correlated the depression

scores with the overall dystonia motor score, regardless of the body part affected with

dystonia. We have found that depression is correlated to the total BFM score

according to both self-reported depression scale (BDI) and structuralized interview

(HDI).

Moreover, our patients have reported higher prevalence of social phobia, which

overlaps with the strong evidence of an increased rate of anxiety personality disorder

including obsessive compulsive disorder and avoidant personality disorder in patients

66

with dystonia (Moraru et al, 2002, Cavallaro et al 2002, Gündel et al 2001). Increased

prevalence rate of obsessive compulsive disorder in patients with dystonia was

registered also in comparison to the healthy controls (Lencer et al 2009, Lehn et al

2014). In the present study the patients reported a mild social phobia, which is

ranged in the lower level of the mild scale. In addition, the prevalence of social

phobia is correlated to mood, but not to the severity of dystonia. Furthermore, in our

sample of patients there was no reported social interaction anxiety and no extensive

fear or embarrassment in common social interactions, in contrary to the other studies

where a high prevalence of comorbidity of lower social coping in patients with

dystonia was revealed (Gündel et al 2001). In a more recent study no higher

prevalence of anxiety in patients with focal dystonia than in the general population

was found (Fabbrini et al 2010). In contrary to these findings, in a study by Voon et

al. (2010), a higher rate of anxiety disorder was registered in musicians with dystonia

than in non-dystonic musicians. This can be explained by the greater psychiatric

burden that the musicians with dystonia carry in contrary to the non-dystonic

musicians (Conte et al 2016).

To our knowledge different qualities of body concepts have not been investigated

thoroughly in patients with dystonia. In the previous studies body concept in dystonic

patients was analyzed only in one of its components, e.g. the effect of the

disfigurement in the other psychiatric symptoms (Lewis et al 2008, Gündel et al

2001). In our study we have assessed the overall body concept including cognitive

and affective attitudes of body image. Self-evaluation of body image and the

components of the body concepts in dystonia patients were impaired in our study.

The attitude towards their bodily wellbeing is decreased. In addition, our patients

perceive themselves unable to take care of their body and to improve its functionality

suggesting a lack of attention and consideration of the body. Apart from the impaired

67

cognitive components of the body concept, there is the reduced affective dimension

of the body image. Dystonic patients find the physical contact with others

uncomfortable. Furthermore, their attitude towards their own attractiveness and

sexuality is very low. Moreover, aesthetic aspects of their appearance and body

processes make their body unacceptable to them.

Mood and body concept in dystonic patients seem to have an impact on each other,

since patients with decreased self-evaluation of affective components of body

concept have higher BDI and HDI scores. This means that the self-perceived

dissatisfaction with the body image in dystonic patients may lead to depression.

Interestingly, an impaired body concept does not necessarily lead to anxiety disorder,

since there was no correlation between body concept dimensions and anxiety scores.

There is evidence that the extent of dystonia is correlated with lower quality of life. In

a study done by Skogseid et al (2007), there was a correlation between TWSTRS

and lower quality of life in patients with cervical dystonia. Page et al. (2007) revealed

that the patients with generalized dystonia have lower quality of life than patients with

focal dystonia. In the present study we had a mixed group of the dystonic patients,

where BFM was the marker of severity of dystonia. Quality of life in our patients was

not determined by the severity of dystonia, as there was no correlation between BFM

score and areas of quality of life. The main impairments of the quality of life were

observed in the physical role (functionality), concepts of general health, social

functioning, emotions and mental health. Although in the previous studies depression

and anxiety appear to have a significant negative effect on quality of life (Page et al

2007, Pekmezovic et al 2009, Ben-Shlomo et al 2002), we have found negative

correlations of quality of life with depression only and not with the anxiety scores.

Social phobia scale was not correlated to any of the quality of life domains. However,

there is an increasing psychosomatic component which interferes with the quality of

68

life of the patients with dystonia. Disability to taking care of the body, discomfort and

impaired body contact and also dissimilatory processes are correlated with the

physical part of the quality of life scale. Lower self-acceptance of the body, lower self-

esteem towards sexuality and lower physical appearance determine the

psychological part of the quality of life. This means that quality of life in dystonic

patients is aggravated by these internal conflicts.

Although we have reported the increased prevalence of non-motor symptoms such

as depression, anxiety, decreased body concept and their effect on the quality of life,

little is known about the management of these symptoms in dystonic patients.

Therefore, it is important to recognize these non-motor symptoms early in the

disease course, since with adequate therapeutical management the quality of life in

these patients may increase again.

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7. Summary

Lejla Paracka

Non-motor symptoms in patients with idiopathic and inherited dystonia

Dystonias represent a movement disorder which is characterized by sustained or

intermittent muscle contractions causing abnormal, often repetitive movements,

postures, or both. Dystonic movements are typically patterned, twisting, and may be

tremulous. Dystonia is often initiated or worsened by voluntary action and associated

with overflowing muscle activation. Idiopathic dystonia has been regarded as a basal

ganglia disease and its circuits. The pathophysiology of dystonia still remains

unclear, but several mechanisms, such as decreased inhibition, altered plasticity and

dysfunction of oscillatory activity appear to be involved. Apart from being known as a

motor disorder, there is a growing evidence of occurrence of non-motor symptoms in

patients with primary dystonia. This is not surprising due to the involvement of the

cortico-striato-thalamo and cerebello-thalamo-cortical pathways in the

pathophysiology of dystonia.

In the first part of the study, we detected several sensory abnormalities by using

quantitative sensory testing (QST) in twenty patients with primary dystonia (8

general, 5 segmental and 7 isolated cervical dystonia). The QST was performed at

the back of the hand in all patients and at the shoulder in patients with cervical

dystonia. The main findings were increased dynamic mechanical allodynia (DMA)

and thermal sensory limen (TSL). DMA is a stimulus evoked pain, which is elicited by

light touch, whereas TSL represents the ability to detect fast changes of the

temperature. Our results show that younger patients with hand dystonia had a higher

cold pain threshold (CPT) and DMA, but decreased hot pain threshold (HPT) and

wind-up ratio (WUR), which represents pain threshold after repetitive stimuli. Older

patients displayed a diminished cold detection threshold (CDT) and WUR as well as

70

higher TSL and DMA. The alterations were present on the clinically more and less

affected side, with a higher pronunciation on the side more affected by dystonia.

Patients with cervical dystonia showed a reduced hot detection threshold (HDT) and

CDT, enhanced TSL and DMA on the back of the hand, whereas the shoulder QST

only revealed increased CPT and DMA. Thus, in patients with primary dystonia QST

clearly shows several subtle sensory abnormalities which partly differed in age-

groups and could also manifest in regions without motor symptoms (manuscript

submitted).

In the second part of the study, we tested the potency of different analgesic methods

for reduction of injection site pain during treatment with botulinum toxin in dystonic

patients. For this purpose we compared the efficacy of ice-spray (IS), local anesthetic

cream (LAC), nitrous oxide/oxygen mixture (NOO) and forearm ischemia (FI) with the

mechanical pain threshold test (MPTT) and repetitive pain stimulation test (RPST).

Our data show that all analgesic interventions studied, produce statistically significant

effects in the MPTT and the RPST. Most analgesic effects were similar, NOO,

however, had stronger analgesic effects than the other interventions tested, although

this superiority was statistically significant only in the RPST and not against IS. The

choice of the appropriate analgesic method during the botulinum toxin treatment

should be made depending on the region that is being injected and the properties of

the analgesic method (manuscript submitted).

In the third part of the study, psychiatric symptoms such as mood, anxiety and body

concept were examined in relation to the severity of the disease and quality of life in

dystonic patients. Our results show that patients with dystonia have higher

prevalence for mood instability and anxiety, but not for social interaction anxiety.

Moreover, the depression was correlated to the severity of motor symptoms and to

social phobia. Furthermore, we found impairments of the body concept in both

71

cognitive and affective subscores. In addition, there is an increasing psychosomatic

component which interferes with the quality of life of the patients with dystonia. Mood

and body concept have an impact on each other and negatively influence the

physical and psychological part of the quality of life scale (manuscript in preparation).

72

73

8. Zusammenfassung

Lejla Paracka

Nicht-motorische Symptome in Patienten mit idiopathischer und hereditärer

Dystonie

Dystonien repräsentieren eine Bewegungsstörung, die charakterisiert ist durch

anhaltende oder intermittierende Muskelkontraktionen, die eine abnormale, oft

repetitive Bewegung, Haltung oder beides verursachen. Dystone Bewegungen folgen

typischerweise einem Muster und können auch einen Tremor aufweisen. Eine

Dystonie wird oft initiiert oder verschlechtert durch eine willkürliche Bewegung und ist

assoziiert mit überschießender Muskelaktivierung. Idiopathische Dystonien werden

als eine Erkrankung der Basalganglien und ihrer neuronalen Verbindungen

angesehen. Die Pathophysiologie von Dystonien bleibt unklar, aber verschiedene

Mechanismen, wie verminderte Inhibition, veränderte Plastizität und Dysfunktion von

oszillatorischer Aktivität scheinen beteiligt zu sein. Neben der motorischen

Symptomatik gibt es vermehrt Hinweise auf das Bestehen von nicht-motorischen

Symptomen in Patienten mit primärer Dystonie. Dies erscheint nicht überraschend

aufgrund der Beteiligung von cortico-striato-thalamischen und cerebello-thalamo-

corticalen Bahnen in der Pathophysiologie der Dystonien.

Im ersten Teil der Studie wiesen wir verschiedene sensorische Auffälligkeiten durch

die Quantitative Sensorische Testung (QST) in 20 Patienten mit primärer Dystonie (8

generalisierte, 5 segmentale und 7 isolierte cervicale Dystonie) nach. Die QST wurde

auf dem Handrücken in allen Patienten durchgeführt, in Patienten mit cervicaler

Dystonie auch an der Schulter. Die Hauptergebnisse sind erhöhte Parameter für

dynamic mechanical allodynia (DMA) und thermal sensory limen (TSL). DMA ist ein

stimulusabhängiger Schmerz, der durch nur leichte Berührung induziert wird, TSL ist

74

die Fähigkeit, schnelle Temperaturveränderungen zu bemerken. Unsere Resultate

zeigen, dass jüngere Patienten mit Handdystonie einen höheren Schwellenwert für

schmerzhafte Kälte (cold pain threshold, CPT) und DMA, aber einen verringerten

Schwellenwert für schmerzhafte Hitze aufwiesen (hot pain threshold, HPT) und

verminderte Parameter für wind-up ratio (WUR), bei der die Schmerzhaftigkeit von

repetitiven Stimuli beurteilt werden soll. Ältere Patienten zeigten einen reduzierten

Schwellenwert für Kältedetektion (CDT) und geringere WUR sowie höhere TSL und

DMA. Diese sensorischen Veränderungen waren sowohl auf der klinisch mehr

betroffenen als auch auf der weniger betroffenen Seite vorhanden mit Akzentuierung

der stärker von Dystonie betroffenen Seite. Patienten mit cervicaler Dystonie hatten

einen verringerten Schwellenwert für Hitzedetektion (HDT) und CDT sowie verstärkte

TSL und DMA auf dem Handrücken, wogegen die QST der Schulter nur eine erhöhte

CPT und DMA nachwies. Daher zeigt QST in Patienten mit primärer Dystonie

unterschiedliche subtile sensorische Pathologien, die teilweise altersabhängig sind

und sich auch in Regionen ohne motorische Symptome manifestieren können

(Veröffentlichung eingereicht).

Im zweiten Teil der Studie testeten wir die analgetische Potenz von verschiedenen

Methoden zur Reduzierung von Injektionsschmerz während der Botulinumtoxin-

Therapie in Dystonie-Patienten. Dabei verglichen wir die Effektivität von Eisspray,

lokaler anaesthetischer Creme (LAC), einer Stickstoffoxid/Sauerstoff-Mischung

(NOO) und einer Unterarm-Ischämie (FI) mit Hilfe des mechanical pain threshold test

(MPTT) und des repetitive pain stimulation test (RPST). Unsere Daten zeigen, dass

alle analgetischen Methoden signifikante schmerzlindernde Effekte im MPTT und

RPST erzielen. Die meisten analgetischen Effekte waren ähnlich, NOO allerdings

hatte einen stärkeren Effekt als die anderen Methoden, obwohl die Überlegenheit nur

im RPST signifikant war. Die Wahl der geeigneten analgetischen Methode während

75

der Botulinumtoxin-Therapie sollte von der zu behandelnden Region und den

speziellen Eigenschaften der analgetischen Methode abhängig gemacht werden

(Veröffentlichung eingereicht).

Im dritten Teil der Studie untersuchten wir psychiatrische Symptome wie Stimmung,

Angst und das Körperkonzept in Relation zur Schwere der Erkrankung und

Lebensqualität von Dystonie-Patienten. Unsere Resultate zeigen, dass diese

Patienten eine höhere Prävalenz für Stimmungsschwankungen und Angst aufwiesen

ohne vermehrte soziale Interaktionsangst. Außerdem konnten die Depressionswerte

mit der Schwere der motorischen Symptome und einer Sozialphobie korreliert

werden. Des Weiteren fanden wir Einschränkungen im Körperkonzept sowohl in

kognitiven als auch in affektiven Werten. In unseren Patienten mit Dystonie war eine

vermehrte psychosomatische Komponente nachweisbar, die deutlich mit ihrer

Lebensqualität interferierte. Stimmung und Körperkonzept haben einen

wechselseitigen Einfluß aufeinander, der den physischen und psychologischen Teil

der Lebensqualität negativ beeinflußt (Veröffentlichung in Vorbereitung).

76

77

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Acknowledgments

I would like to take the opportunity to thank my main supervisor Prof. Dr. Florian

Wegner for his continuous motivation and support. I am grateful for his guidance,

ideas and advices throughout my PhD project.

Many thanks to Prof. Dr. Joachim K. Krauss and Prof. Dr. Eckart Altenmüller for their

support, advices, the lively discussions during the meetings, thoughtful suggestions

and supervision.

Special thanks to Prof. Dr. Reinhard Dengler for giving me the opportunity to perform

the PhD study in the Department of Neurology at the Hannover Medical School,

without whom my PhD project would not have been possible.

I would also like to thank the entire Department of Neurology for the friendly working

environment making me feel welcome from the first day I joined the team.

90