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In
Neurosurgery
BY
E ssam M oneer A li Rezk
Assistant Lecturer, Neurosurgery Department
Faculty of Medicine
Tanta University
Supervisors:
Prof. Dr.
Samy Mahmoud Tourky
Professor of Neurosurgery department
Faculty of Medicine
Tanta University
Prof. Dr.
Mohamed Yosri Elsenosy
Professor of Neuropsychiatry Department
Faculty of Medicine
Tanta University
Prof. Dr.
Ahmed Abd Elsalam Shakal
Professor of Neurosurgery department
Faculty of Medicine
Tanta University
Faculty of Medicine
Tanta University
2014
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I am greatly grateful to the staff m em bers of m y departm ent for their continuous
cooperation and assistance during this w ork.
Abstract
Background: Several drugs are available that can effectively treat the
symptoms of the Parkinson’s disease, but long term medical management is
often complicated by the appearance of levodopa-induced motor
complications. In the past years there has been an increasing interest in the
surgical therapies for Parkinson's disease. The most common functional
stereotactic neurosurgical procedures that are currently performed worldwide
for PD are surgical lesioning and deep-brain stimulation (DBS).
Objective: The aim of this study is to review and evaluate the different
modalities of stereotactic techniques, and their efficacy in the management of
idiopathic Parkinson’s disease.
Methodology: 60 patients (20 Egyptians and 40 Germans) with idiopathic
Parkinson’s disease (iPD) were treated with subthalamic nucleus (STN) deep
brain stimulation (DBS) in this study. Operative details, outcome, and
complications are recorded and analyzed.
Results: 60 patients (42 males & 18 females) were treated with subthalamic
nucleus (STN) deep brain stimulation (DBS). The efficacy of STN-DBS was
calculated as the percentage improvement of UPDRS-III total score from
baseline to postoperative conditions. 36/60 patients (60%) had good outcome
(50-75% improvement in off UPDRS III) and 24/60 patients had fair
outcome (25-50% improvement in off UPDRS III). There were no cases that
exhibited excellent or poor outcome. Postoperative mean L- Dopa equivalent
dose (LED) was reduced by 64.4% postoperatively. The mean rate of
improvement of postoperative L Dopa induced dyskinesia score was 83.6%.
The mean rate of improvement of off duration subscore was 71.4%.
Operative complications were noted in 18/60 patients (30%). They were
transient in 14/18 patients (77.8%).
Conclusion: Subthalamic nucleus stimulation by means of permanently
implanted brain electrodes is a very effective therapy for all the cardinal
features of Parkinson's disease. In appropriate patients, motor improvement is
accompanied by a significantly improved quality of life and a reduced
necessity for medication.
List of Contents
Contents Page
List of Tables III
List of Figures IV
List of Abbreviations VI
Introduction 1
Review of literature 3
Functional Anatomy and Physiology of the Basal Ganglia 3
• General Structure and connectivity of the Basal Ganglia 3
• Basal Ganglia Circuitry and Synaptic Connectivity 5
Inputs to the Basal Ganglia 5
Intrinsic Basal Ganglia Connections 8
Output Projections of the Basal Ganglia 10
The Pathology of Parkinson's Disease 12
• The neuropathological features of PD 12
• The mechanism of nigral neuronal death in PD 14
• The Pathophysiologic Model of Parkinson's disease 15
The Etiology of Parkinson's Disease 18
Clinical Features of Parkinson’s disease 20
• Classical motor features of PD 21
• Other features of PD 24
• Subtypes of PD 29
• The Clinical Rating Scales for Parkinson’s Patient 29
Role of brain imaging in the diagnosis of Parkinson’s disease 41
• Structural brain imaging approaches 41
• Functional brain imaging approaches 43
The Renaissance of Parkinson’s disease Surgery 47
• The pre-stereotactic open surgery era 47
- Cell-based therapies 51
- Gene therapy 52
Deep brain stimulation 53
II
List of Tables
III
List of Figures
IV
Figure (20) Subtypes of PD. 96
Figure (21) H &Y Stage of PD. 97
Figure (22) Overall outcome in 60 patients with PD operated upon. 106
Figure (23) Trajectory planning. In this axial T2-weighted scan, both 109
trajectories to the subthalamic nucleus are drawn in. The target
points are marked by crosses.
Figure (24) The location of the active electrode in relation to the stereotactic 109
frame was determined from intraoperative stereotactic X-rays
(anteroposterior and lateral) after final implantation of the
permanent stimulation electrode.
V
List of Abbreviations
123I-FP-CIT 123I-N-3- fluoropropyl-2 beta-carbomethoxy-3beta-(4-
PET iodophenyl) tropane PET
18F-dopa PET 18F-3,4-dihydroxyphenylalanine PET
18F-FDG PET 18F-fluorodeoxglucose PET
3D Three dimensional
AC anterior commissure
ACC The anterior cingulate cortex
AD Alzheimer’s disease
AEO Apraxia of eyelid opening
AIMS abnormal involuntary movement scale
BDI Beck Depression Inventory
bFGF basic fibroblast growth factor
BG basal ganglia
CAPSIT Core Assessment Program for Surgical Interventional
Therapies in Parkinson's disease
CBD corticobasal degeneration
CM centromedian nucleus
CM cingulate motor area
CSF Cerebrospinal fluid
CT Computerized tomography
DAT imaging dopamine active transporters imaging
DBS deep-brain stimulation
DLB Dementia with Lewy bodies
DLPFC dorsolateral prefrontal cortex
DRD dopa-responsive dystonia
DTBZ PET 18F-dihydrotetrabenazine PET
EGF epidermal growth factor
FDA Food and Drug Administration
FTD-P frontotemporal dementia with parkinsonism
GAD generalized anxiety disorder
GDNF glial cell line derived neurotrophic factor
GP globus pallidus
VI
GPe globus pallidus external segment
GPi globus pallidus internal segment
HD Huntington’s disease
IPG implanted pulse generator
JP juvenile Parkinsonism
LED Ldopa equivalent daily dose
M1 primary motor cortex
MADRS Montgomery and Asberg Depression Rating Scale
MCP midcommissural point
MCS motor cortex stimulation
MD mediodorsal nucleus
MDRS Mattis Dementia Rating Scale
MER microelectrode recording
MMSE Mini Mental Status Exam
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MRI Magnetic resonance imaging
MRS magnetic resonance spectroscopy
MSA multiple system atrophy
MSA-P Multiple system atrophy with predominant parkinsonian
features
MSNs medium spiny neurons
NAA Nacetylaspartate
OFC orbital frontal cortex
OKN optokinetic nystagmus
OR operative room
PAF pure autonomic failure
PC posterior commissure
PD Parkinson’s disease
PET positron emission tomography
PF parafascicular nucleus
PMC premotor cortex
PPN pedunculopontine nucleus
PSP progressive supranuclear palsy
RRF retrorubral field
VII
SF-36 36-Item Short Form Health Survey
SMA supplementary motor, area
SN substantia nigra
SNc substantia nigra pars compacta
SNc-d dorsal tier of the substantia nigra pars compacta
SNc-v ventral tier of the substantia nigra pars compacta
SNr substantia nigra pars reticulata
SPECT Single-photon emission computed tomography
STIR fast spin-echo short inversion time inversion-recovery
STN subthalamic nucleus
UKPDSBB United Kingdom Parkinson’s Disease Society Brain
Bank
UPDRS Unified Parkinson’s Disease Rating Scale
UPDRS ADL activities of daily living subscore of the Unified
Parkinson's Disease Rating Scale
VAmc ventral anterior nucleus magnocellular division
VIM nucleus ventralis intermedius of the thalamus
VPL nucleus ventral posterolateral thalamic nucleus
VTA ventral tegmental area
YOPD young-onset Parkinson’s disease
ZI zona incerta
VIII
Introduction 1
Introduction
Figure 1: The primary structures of the basal ganglia. (Fernando and Clemens, 2012).
The basic cortical-BG pathway flows from the cortex through BG structures, to
the thalamus and back to cortex. The striatum, and, to a lesser extent, the STN, are the
main input stations, while GPi and SNr function as output nuclei. This basic pathway is
Review of Literature 4
further divided into two circuits: (1) A direct circuit in which the striatum projects to the
GPi/SNr and back to cortex via the thalamus; and (2) an indirect circuit via the GPe
which projects to the STN, then from the STN to the GPi/SNr and back to cortex via the
thalamus. (Smith et al., 1998)
Furthermore, the output neurons of the GPi and SNr project to specific brainstem
structures (superior colliculus, lateral habenular nucleus, pedunculopontine nucleus
[PPN], parvicellular reticular formation) that provide descending projections to motor
nuclei in the medulla and spinal cord. STN, PPN, thalamus, and cortical projection
neurons are excitatory (glutamatergic), whereas other neurons intrinsic to the basal
ganglia are inhibitory (GABAergic). The GPi and SNr projections to the thalamus are
GABAergic and tend to inhibit thalamocortical feedback which, in turn, is excitatory
(glutamatergic). (Haber, 1986)
Figure 2: The Circuitry of the basal ganglia. The cerebral cortex (and thalamus) projects to the
striatum (excitatory pathways). The striatum also receives dopaminergic projections from the
substania nigra’s pars compacta (SNc). The striatum inhibits the globus pallidus (GP) as well as
the substantia nigra’s pars reticulata (SN pr). The STN sends excitatory projections to the GPi,
GPe & SNpr. GPi or SN pr inhibits (GABAergic) the thalamus. The thalamus projects to the
cortex (also excitatory). The direct path leads to less inhibition of the thalamus, (i.e. the striatum
inhibits GPi which in turn inhibits its normal (inhibitory) action on the thalamus, thus leading to
greater excitation from the thalamus to the cortex. This allows for sustain actions or initiation of
action. The indirect path excites the GPi thereby increasing its inhibition of the thalamus and thus
suppresses unwanted movements. (Fernando and Clemens, 2012)
Review of Literature 5
*Corticostriatal Projections
The main input to the striatum is from cortex. The frontal cortex is often
considered the cortex of action and divided into regions that mediate motivation and
emotion (limbic), cognitive, and motor control.
Afferent projections to the striatum terminate in a general topographic manner,
such that the dorsolateral striatum receives cortical input from sensory-motor areas, the
central striatum receives input from associative cortical areas, and the ventromedial
striatum receives input from limbic areas. Dendritic spines of striatal output neurons are
the main targets of corticostriatal afferents (Kemp and Powell, 1971).
The dorsolateral putamen (the post-commissural region of the putamen) and
caudate nucleus form the striatal area associated with motor control. This region receives
input from the motor, premotor, supplementary motor, and cingulate motor cortices. The
dorsolateral prefrontal cortex (DLPFC) plays an important role in executive functions.
The DLPFC projects primarily to the rostral central region of the caudate nucleus.
Consistent with input from this cortical area, cells in the head of the caudate nucleus
discharge during the delayed portion of the task resembling activity observed in the
DLPFC. Furthermore, imaging studies support the idea that the head of the caudate is
instrumental in delayed tasks, particularly in specific working memory tasks. Taken
together, a particularly large part of the head of the caudate nucleus nucleus is involved in
working memory and strategic planning processes (Fuster, 2000).
The anterior cingulate cortex (ACC) and orbital frontal cortex (OFC) are involved
in different aspects of emotional expression, reward-based behaviors, error prediction and
the choice between short and long-term gains (Hadland et al., 2003).
The OFC and ACC project primarily to the rostral and ventral striatum (the
medial caudate nucleus, the medial and ventral rostral putamen, and the nucleus
accumben). The entire reward-related striatum, as defined by ACC/OFC inputs, occupies
a large rostral region and encompasses at least 22% of the entire striatum (Haber et al.,
2006).
Review of Literature 7
*Thalamostriatal Projections
Most thalamic nuclei send topographically organized glutamatergic projections to
the striatum. Projections from the caudal intralaminar nuclear group, the centromedian
(CM) and the parafascicular (PF) nuclei are by far the most prominent among these
inputs. Compared to corticostriatal inputs, the CM/PF-striatal projections are more
focused and give rise to a significantly larger number of terminals than individual
corticostriatal axons. Projections from CM/ PF to the striatum are more focused, more
massive and innervate preferentially the dendritic shafts of striatal projection neurons
(Smith et al., 2004). CM and PF may provide feedback information to the basal ganglia.
In addition, it is proposed that the CM and PF supply striatal neurons with information
that have attentional values (Minamimoto and Kimura, 2002).
*Cortico-Subthalamic Projections
The STN receives a direct afferent projection from cortex. This pathway is
referred to as the hyperdirect pathway. Through this connection, information from cortex
reaches the STN prior to that from the GPe whose signal first must pass through the
striatum. The cortico-subthalamic projection is exclusively ipsilateral, and arises in large
part from the primary motor cortex (M1), with lesser contributions from prefrontal
cortex, premotor cortex (PMC), supplementary motor, area (SMA), and cingulate motor
Review of Literature 8
area (CM). M1-afferents are confined to the dorsolateral part of STN, while afferents
from the other motor areas innervate mainly the medial third of the nucleus. The M1-
STN projection is somatotopically organized with the face area projecting laterally, the
arm area centrally and the leg area medially. This somatotopic organization has been
reported in the STN of humans with Parkinson’s disease undergoing microelectrode
mapping during functional neurosurgical procedures. Input from the supplementary
motor area (SMA) to the STN shows a somatotopy which is reversed to the one from M1
(Nambu et al., 2002).
*Thalamo-Subthalamic Projections
A second source of excitatory inputs to the STN arises from CM/PF, although the
relevance of this finding for primate anatomy remains disputed. (Lanciego et al., 2004)
*Striatofugal projections
Striatofugal pathways are divided into the so-called direct and indirect striatofugal
projections, named after their presumed connection patterns to the basal ganglia output
nuclei GPi and SNr. The direct pathway arises from striatal MSNs that project directly to
neurons of GPi and SNr. The indirect pathway involves a striatal projection to GPe, and
subsequent projections to GPi and SNr. A portion of the indirect pathway passes through
the intercalated STN (Alexander and Crutcher, 1990).
*Pallido-Subthalamo-Pallidal Loops
In addition to this GABAergic striatal input, there is the well-characterized
glutamatergic input from the STN nucleus to all pallidal components. Terminals from
STN intermingle with the much larger GABAergic innervation from the striatum. One
population of STN cells project to all three target regions, the GPi, GPe, and SN; a
second population, the largest, sends axons to the GPi and GPe; a third group of cells
innervates only the GPe. The GPe projects primarily to the STN, via the subthalamic
Review of Literature 9
fasciculus. It also projects to the striatum, to the internal pallidal segment, and to the
midbrain. Neurons in the GPe segment have been further classified according to their
projection targets: those that target the STN and SNr; those that target the internal pallidal
segment and STN; and those that target the striatum (Carpenter et al., 1981).
2. Dopaminergic Projections
*Pallidofugal Pathways
The motor territory of the basal ganglia output nuclei is mostly contained within
GPi. The GPi project directly to the thalamus and brainstem. These projection fibers are
divided into the pallidotegmental fibers and two bundles to the thalamus, the ansa
lenticularis bundle, and the lenticular fasciculus bundle. Fibers in the ansa lenticularis
arise from the outer portion of the GPi, forming a clearly defined bundle that sweeps
ventromedially and rostrally, around the internal capsule and continuing caudally to
merge with Forel’s field H. Fibers of the lenticular fasciculus arise from the medial
portion of the GPi, traverse the internal capsule, and form a discrete bundle, ventral to the
zona incerta. This bundle joins the ansa lenticularis in Forel’s field H and both fiber
groups then become part of the thalamic fasciculus to terminate in different thalamic
nuclei (Kuo and Carpenter, 1973).
Sensorimotor information is conveyed almost exclusively to the posterior part of
the ventrolateral nucleus. Via the thalamus, sensorimotor output from GPi is projected
towards the supplementary motor, area SMA, primary motor cortex (M1), and premotor
cortex PM cortical area. A large portion of GPi neurons also sends axon collaterals to the
noncholinergic portion of the PPN. The PPN, in turn, gives rise to descending projections
to the pons, medulla, and spinal cord as well as prominent ascending projections to the
basal ganglia, the thalamus and the basal forebrain (Sakai et al., 2002).
*Nigrofugal Pathways
The SNr cells are GABAergic and, like the pallidum, are primarily large neurons
with long, thick dendrites. Based on the arrangement of striatal inputs and nigral outputs,
the SNr can be subdivided into a dorsolateral sensorimotor and a ventromedial
associative territory. Most SNr output to the thalamus appears to be related to non-motor
functions. However, neurons in the lateral part of the SNr project preferentially to the
lateral posterior region of the ventral anterior nucleus magnocellular division (VAmc)
and to different parts of the mediodorsal nucleus (MD). These areas of the thalamus are
predominately related to posterior regions of the frontal lobe including the frontal eye
field and areas of the premotor cortex, respectively (Ilinsky et al., 1985).
Review of Literature 11
Other SNr projections reach PPN, the superior colliculus and the medullary
reticular formation. Nigro-tegmental projections terminate predominantly on
noncholinergic neurons in the medial two-thirds of the PPN. Nigro collicular fibers arise
primarily from the lateral SNr and terminate mainly on tectospinal neurons in the
intermediate layers of the superior colliculus. The nigro-collicular system is thought to
play a role in the regulation of visual saccades and the control of eye movements
associated with specific behavioral tasks. The nigro-reticular projection terminates in the
parvicellular reticular formation, which is directly connected with orofacial motor nuclei
(Wurtz and Hikosaka, 1986).
Review of Literature 12
Figure 4: Circuit diagram for direct & indirect pathways. Neurotransmitters: Ach, acetylcholine;
DA, dopamine; Glu, glutamate; Enk, enkaphalin; SP, substance P. Nuclei: SNc, substantia nigra
pars compacta; SNr, substantia nigra pars retriculata; GPe, globus pallidus pars externa; GPi,
globus pallidus pars interna; STN, subthalamic nucleus; VL, ventral lateral nucleus; VA, ventral
anterior nucleus (Fernando and Clemens, 2012).
In the classical model of basal ganglia function, a balance between two opposing
pathways in the motor circuit, the direct and indirect pathways, regulates normal
voluntary movement. Both pathways begin with neurons in cortical motor areas
projecting to the putamen, which in turn sends signals that ultimately terminate in the
internal segment of the globus pallidus (GPi). Putamenal output in the indirect pathway,
however, travels through the external segment of the globus pallidus (GPe) and
subthalamic nucleus (STN) before it reaches the GPi, whereas the direct pathway projects
directly from the putamen to the GPi. The majority of GPi output is directed toward the
thalamus, which sends projections to the supplementary motor area, the premotor cortical
Review of Literature 16
area, and the primary motor cortex. Activation of the direct pathway decreases the normal
inhibitory outflow from the GPi to the thalamus, leading to increased cortical motor
activation and the facilitation of voluntary movement. In contrast, stimulation of the
indirect pathway causes inhibition of the GPe, disinhibition of STN excitatory fibers, and
an increase in the inhibitory outflow from the GPi onto the thalamus, resulting in
decreased output to the motor cortex and suppression of voluntary movement
(Wichmann and DeLong, 2003).
The exact mechanism by which the basal ganglia interpret the information
flowing through these two opposing motor circuit pathways to control normal movement
is unclear. Two theories have been proposed: scaling and focusing. In the scaling
hypothesis, movement is controlled by temporally changing activity in the basal ganglia.
For example, putamenal output would first facilitate a particular movement by
disinhibiting the thalamus through the direct pathway, and subsequently stop the ongoing
movement by causing the same GPi neurons to increase inhibition of the thalamus
through the indirect pathway. The resulting sequence of facilitation and inhibition would
regulate the amplitude or velocity of individual movements. Neurons with short latency
responses to movement could play such a role. In the focusing hypothesis, movement is
allowed to proceed by stimulation of the direct pathway, whereas extra, unnecessary
movements are suppressed by activity in the indirect pathway. The most common change
in GPi activity during movement is increased activity. Thus, suppression of unintended
movements may be a particularly important role of the basal ganglia (Albin et al., 1989).
Based on the model of basal ganglia function described above, an imbalance
between the direct and indirect pathways accounts for the clinical manifestations of
Parkinson's disease. The release of dopamine from nerve terminals in the striatum
appears to stimulate the direct pathway and inhibit the indirect pathway, thus effectively
facilitating movement. Consequently, degeneration of the dopaminergic nigrostriatal
pathway, as seen in Parkinson's disease, would result in decreased dopamine receptor
activation and disinhibition of the indirect pathway, leading to increased activity in the
STN and GPi. The increased inhibitory outflow from GPi on the thalamus would
decrease cortical motor activation, with the end result being slowed movements, or
bradykinesia. There is considerable evidence supporting the classical model for the
Review of Literature 17
Familial PD
A minority of patients with the typical clinical picture of PD have a positive
family history compatible with a Mendelian (autosomal dominant or autosomal recessive)
inheritance. As a rule, age at onset in many (but not all) of these patients is younger than
that of patients with sporadic disease, but no other specific clinical signs or symptoms
distinguish familial from sporadic cases. Genetic research of the past 15 years, in
particular the mapping and cloning of a number of genes that cause, when mutated,
monogenically inherited forms of the disorder, has shown that PD is actually not a
disease entity but rather a heterogeneous group of diseases associated with a spectrum of
clinical and pathological changes (Marder et al., 2003).
Table 1: Genes and Loci Linked to Familial Parkinson's disease (Vila and Przedborski, 2004).
Chromosomal Gene/ Inheritance Atypical PD Features Lewy
Locus Location Bodies
Protien
PARK1 4q21 Alpha- AD Early onset 40 Yes
synuclein Lower prevalence of
tremor
PARK2 6q25 Parkin AR Early juvenile onset 20-40 Mostly
More frequent dystonia negative
PARK3 2p13 Unknown AD Dementia in some patients Yes
Rapid progression
PARK4 4p15 Alpha- AD Early onset 30-60 Unknown
synuclein Rapid progression
Dementia
Autonomic dysfunction
Postural tremor
PARK5 4p14 UCH-L1 AD None Unknown
or failure of levodopa therapy, do not manifest until later in the course of the disease
(Hughes et al., 1992).
In PD, the onset of symptoms and signs is frequently asymmetrical in the limbs. It
is more common for features to be symmetrical in other parkinsonian disorders except
CBD, where the classical phenotype typically presents in a very asymmetrical fashion.
Another disorder that, by definition, has a unilateral presentation and always maintains
profound asymmetrical features is hemiatrophyhemiparkinsonism. Evaluation of
asymmetric limb size is critical to this diagnosis. The onset of symptoms in PD is usually
subtle, and progression is slow. The course of the common parkinson-plus syndromes
tends to be more rapid and aggressive than PD, and an alternative diagnosis should
always be considered in cases of “malignant Parkinson’s disease” (referring to disease
course). Abrupt symptom onset should raise a consideration of other diagnoses such as
vascular disease, encephalitis or Wilson’s disease (Testa et al., 2001).
progresses, these movements become less coordinated, with frequent hesitation or arrests
(Gelb et al., 1999).
Rigidity
Rigidity is a hypertonic state that is commonly seen in disorders of the basal
ganglia and is defined as unvarying increased resistance within the range of passive
movement about a joint. Clinical series have reported that rigidity occurs in 89 to 99% of
patients with PD. The “cogwheel” phenomenon is a particular type of rigidity occurring
in PD, and it refers to rhythmic brief increases in resistance that are palpated during
passive movement (Hughes et al., 1993).
Cogwheeling is thought to be tremor superimposed on rigidity. It is a common
misconception that a patient must have cogwheeling on examination to merit a diagnosis
of PD. Many instead will have “lead pipe” rigidity, which is smooth throughout the entire
range of motion (Lance et al., 1963).
Rigidity affects both limb and axial musculature and contributes to the postural
deformities seen in PD. The stooped or “simian” posture and lateral tilt of the trunk are
common sequelae of axial rigidity. In some patients, severe forward flexion of the
thoracolumbar spine occurs, a phenomenon known as “camptocormia.” It is
controversial, however, whether camptocormia is due to rigidity of the iliopsoas and
spinal muscles or a rare and extreme example of a typically parkinsonian postural
deformity. Common complaints of patients that can be attributed in part to rigidity
include difficulty turning over in bed or standing up from a chair, and muscle cramps or
pain (Djaldetti et al., 1999).
Tremor
Tremor is perhaps the most obvious manifestation of PD, causing James
Parkinson to label the disease he was describing the “shaking palsy.” (Parkinson, 1817).
Tremor is defined as an involuntary rhythmic oscillation of a body region that is
produced by alternating contractions of reciprocally innervated muscles. The typical
tremor in PD is a rest tremor; present mainly when the patient is relaxed and when the
tremulous limb is not engaged in purposeful activities. However, as PD progresses, it is
Review of Literature 23
not unusual to observe a postural or action component to the tremor and, in severe cases;
it may be difficult to tell whether the tremor is primarily resting or postural (Scott et al.,
1970).
Tremor is the most frequent presenting symptom of PD and commonly described
as “pill rolling” because of the unique, 4 to 6 Hz rhythmic oscillation of flexion and
extension movements of the thumb and fingers in the style of the early pharmacists who
rolled or rounded hand-made pills into little balls by using the thumb and forefinger.
Head tremor is unusual in PD, and some experts in the field think that prominent head
tremor in the setting of otherwise classical PD is evidence of coexistent etiology (Pal et
al., 2002).
The typical tremor of PD tends to start unilaterally in the hand, subsequently
involving the ipsilateral leg or the contralateral arm. On average, the tremor spreads
bilaterally six years after the onset of symptoms, and the side initially affected continues
to have more tremor than the contralateral side (Scott et al., 1970).
Postural instability
Postural instability, or impairment of centrally mediated postural reflexes, is a
fourth cardinal feature of PD, usually appearing for the first time several years after the
onset of the first symptom. Initially, postural instability may be subtle and found only on
neurologic exam with the “pull” test. Patients may take extra steps backward to remain
upright (retropulsion), or they may fall backward. In more severe cases, patients may not
be able to move their feet at all to maintain balance and may make no other corrective
movements to protect against a fall, resulting in falling “en bloc” like a plank of wood
(Munhoz et al., 2004).
With further deterioration of postural reflexes, the gait may show signs of
festination, defined by Parkinson as “an irresistible impulse to take much quicker and
shorter steps, and thereby to adopt unwillingly a running pace”. As the postural righting
reflexes become impaired, falling and injury to head, joints, and peripheral nerves is a
serious risk (Parkinson, 1817).
Patients with parkinsonian features who present with early postural instability,
falls, or gait difficulty should be evaluated for another parkinsonian disorder, such as PSP
Review of Literature 24
or MSA. In PSP, postural instability is an early manifestation (usually with falls within
the first year of presentation) (Litvan et al., 1997).
►Other features of PD
Sensory Symptoms
Parkinson’s disease (PD) is, with good reason, conventionally considered a
movement disorder. However many patients with PD do experience unpleasant
sensations, and for some these sensory symptoms are the biggest problem. Numbness is
the most common term used by patients with PD to describe unwanted somatic
sensations. Other patients describe tingling, others burning, yet others itching or crawling
(Snider et al., 1976).
Another dysesthesia, fairly specific to PD, is the unpleasant restless sensation in
muscle or skin that impels the patient to contract the muscle. The sensation mimics in
character the experience of patients with restless legs syndrome, though the heredity, age
of onset, and associated features are not identical (Ondo et al., 2002).
finding, and those who propose cortical Lewy body pathology as the critical pathological
change (Emre, 2003).
Respiratory Dysfunction
Parkinson’s disease (PD) affects the respiratory tract at all levels from the upper
airway down to the pulmonary tissue itself. Pneumonia and pulmonary embolism are the
most frequent cause of death both in historical and more contemporary series (Mosewich
et al., 1994).
Hypophonia can be considered a cardinal sign of PD, since it is a direct effect of
bradykinesia and rigidity of the vocal cords and pharyngeal muscles. It is a very common
sign with more than 70% of patients experiencing problems with speech and voice.
Patients report that this can be one of the most disabling aspects of the disease. The voice
in PD is monotonous, hypophonic, stuttering, and sometimes more rapid than normal
(“tachyphemia”) with the patient frequently needing to repeat sentences. They are often
unwilling to speak on the phone or go out in public places for fear of being unable to
make them understood (Hanson et al., 1984).
of saliva in the mouth, or (alternatively) dry mouth, jaw muscle rigidity, and involuntary
jaw movements are problems that may be encountered by the person with PD. Contrary
to many patients’ perceptions, saliva production is not increased in PD and is actually, in
most instances, diminished. Rather, the salivary excess is the consequence of inefficient
and infrequent swallowing. Drooling is embarrassing and frustrating for PD patients and
may produce a reluctance to go out in public (Bagheri et al., 1999).
Swallowing may also be impaired but is only rarely a source of major disability in
early stage disease. Parkinsonian dysphagia is due to bradykinesia of the pharyngeal
musculature. Dysphagia is common in the late stages of all parkinsonian disorders. Early
swallowing difficulties should raise concerns about a diagnosis other than PD (e.g., PSP,
MSA, infarcts) (Clarke et al., 1998).
Perhaps the first hint that patients with PD might have impaired gastric emptying
(gastroparesis) can be found in the 1981 report of Evans and colleagues, who, although
not specifically studying PD, identified delayed gastric emptying in a group of elderly
individuals, 55% of whom did have PD, compared to young controls (Evans et al.,
1981).
Multiple studies have documented is slowed colonic transit of fecal material in
PD. The pathophysiological basis of constipation in PD has not been completely clarified.
Both central and peripheral factors may be operative. Anorectal dysfunction,
characterized by excessive straining and often accompanied by pain and a sense of
incomplete evacuation, is actually the more prevalent form of bowel dysfunction in PD.
(Bassotti et al., 2000)
Sleep disorders
The sleep architecture can be almost normal in the early stages of PD. The
abnormal sleep features associated with more advanced PD include a change of sleep
stage patterns, abnormal motor activity, and disturbed breathing patterns.
Polysomnography studies have demonstrated increased sleep latency with frequent
awakenings, leading to a reduced total sleep time with decreased sleep-efficacy
(Chokroverty, 1996).
Review of Literature 29
►Subtypes of PD
The marked variability of clinical expression and rate of progression among
patients with PD has led some investigators to conclude that PD is not one disease but a
cluster of diseases subsumed under the umbrella of a single label. PD is estimated to
affect 2 to 3 percent of the population over the age of 65. PD is uncommon in people
younger than 40, and when it occurs, Wilson’s disease (WD), Huntington’s disease (HD),
or dopa-responsive dystonia (DRD) are the principal alternative diagnoses to consider. In
the western hemisphere, only about 4 to 6 percent of patients with PD presenting to
referral clinics are below age 40, with approximately twice that number presenting in
Japan. By convention, patients with onset of symptoms between the ages of 21 and 40
have young-onset Parkinson’s disease (YOPD), and patients with onset younger than age
21 have juvenile Parkinsonism (JP). YOPD has the same underlying Lewy body (LB)
pathology as the disease of later onset, whereas JP may be a different disease, based on
observations in a few autopsied cases showing nigrostriatal degeneration without LB
pathology (De Rijk et al., 1997).
Clinical investigators have attempted to organize the heterogeneity of PD’s
natural history by creating somewhat artificial “subgroups,” mainly to prognosticate
outcome. Thus, age of onset (e.g., YOPD) and symptom predominance (tremor versus
postural instability/gait disorder versus akinetic-rigid, and so forth) have become the
principal headings in this taxonomy. Tremor predominance, like young age of onset,
tends to be associated with a more benign course, with slower progression and less
neuropsychologic impairment (Zetusky et al., 1985).
Status Exam (MMSE) and the Mattis Dementia Rating Scale (MDRS) (Mattis, 1988);
measures of executive functioning and attention; and measures of instrumental functions
(visuospatial function and language function). It is recommended also by the CAPSIT-PD
to have a psychiatric evaluation including the Minnesota Multiphasic Inventory
(Hathaway and McKinley, 1991) and the Montgomery and Asberg depression rating
scale (Montgomery and Asberg, 1975) to exclude patients with a high risk for
psychiatric complications after surgery.
Table 2: Modified Hoehn and Yahr staging (Hoehn and Yahr, 1967).
1. Intellectual impairment
0 = none
1 = mild, consistent forgetfulness
2 = moderate, difficulty with complex problems
3 = severe, disorientation for time & place
4 = severe, help with personal care. Cannot be left alone
2. Thought disorder
0 = none
1 = vivid dreaming
2 = “benign" hallucination with insight retained
3 = hallucination or delusions without insight
4 = persistent hallucination, delusions, or florid psychosis
3. Depression
0 = not present
1 = periods of sadness or guilt > normal, never sustained for days/weeks
2 = sustained depression for >1 week
3 = vegetative symptoms (insomnia, anorexia, weight loss)
4 = vegetative symptoms and suicidal thoughts
Review of Literature 32
4. Motivation/Initiative
0 = normal
1 = less assertive than usual, more passive
2 = loss of initiative/disinterest in elective activities
3 = loss of initiative/disinterest in routine activities
4 = withdrawn, complete loss of motivation
5. Speech
0 = Normal
1 = Mildly affected
2 = Moderately affected. Sometimes asked to repeat statements
3 = Severely affected. Frequently asked to repeat statements
4 = Unintelligible most of the time
6. Salivation
0 = Normal
1 = Slight saliva excess. Some night-time drooling
2 = Moderately excessive saliva; minimal drooling
3 = Marked excess saliva with some drooling
4 = Marked drooling, requires constant tissue/handkerchief
7. Swallowing
0 = Normal
1 = Rare choking
2 = Occasional choking
3 = Requires soft food
4 =Requires nasogastric tube or gastrostomy feeding
8. Handwriting
0 = Normal
1 = Slightly slow or small
2 = Moderately slow/small; all words are legible
3 = Severely affected; not all words are legible
4 = The majority of words are not legible
10. Dressing
0 = Normal
1 = Somewhat slow, but no help needed
2 = Occasional assistance with buttons, arms in sleeves
3 = Considerable help, can do some things alone
4 = Helpless
Review of Literature 33
11. Hygiene
0 = Normal
1 = Somewhat slow, no help needed
2 = Help to shower/bathe
3 = Assistance for washing hair, brushing teeth & hair
4 =Foley catheter or pads
12. Turning in bed & adjusting bed clothes
0 = Normal
1 = Somewhat slow & clumsy, no help needed
2 = Turns alone or adjusts sheets, but with difficulty
3 = Can initiate, but not turn or adjust sheets alone
4 = Helpless
13. Falling
0 = None
1 = Rare falling
2 = Occasionally falls, < 1 per day
3 = Falls on average once per day
4 = Falls > once per day
15. Walking
0 = Normal
1 = Mild difficulty. May not swing arm or may drag leg
2 = Moderate difficulty, but requires no assistance
3 = Severe disturbance, requires assistance
4 = Cannot walk, even with assistance
18. Speech
0 = Normal
1 = Slight loss of expression, diction or volume
2 = Monotone, slurred but understandable
3 = Marked impairment, difficult to understand
4 = Unintelligible
22. Rigidity (judged on passive movement of major joints with patient relaxed in the sitting
position)
Rigidity - neck
0 = Absent
1 = Slight, detectable only with mirror movements
2 = Mild to moderate
3 = Marked, but full range of movement easily achieved
4 = Severe, range of movement achieved with difficulty
23. Finger taps (patient taps thumb with index finger in rapid succession with widest amplitude
possible)
24. Hand movements (Patient opens & closes hands in rapid succession with widest amplitude
possible)
Hand movements – Right hand
0 = Normal
1 = Mild slowing and/or reduction in amplitude
2 = Definite & early fatiguing; occasional arrests
3 = Frequent hesitation in initiation or arrests in movement
4 = Can barely perform the task
28. Posture
0 = Normal erect
1 = Slightly stooped; could be normal for older person
2 = Moderately stooped; can be slightly leaning to 1 side
3 = Severely stooped with kyphosis; can be moderately leaning to one side
4 = Marked flexion with extreme abnormality of posture
29. Gait
0 = Normal
1 = Walks slowly, short steps but no festination
2 = Walks with difficulty but without assistance; festination, short steps or propulsion
3 = Severely disturbed gait; requires assistance
4 =Cannot walk even with assistance
31. Body bradykinesia & hypokinesia (slowness, hesitancy, decreased arm swing, small
amplitude & poverty of movement)
0 = None
1 = Minimal slowness, deliberate character, possibly reduced amplitude
2 = Mild slowness, poverty or small amplitude of movement
3 = Moderate slowness, poverty or small amplitude of movement
4 = Marked slowness, poverty or small amplitude of movement
Review of Literature 38
A. DYSKINESIAS
32. Duration: What proportions of the waking day are dyskinesias present?
0 = None
1 = 1 – 25% of the day
2 = 26 – 50% of the day
3 = 51 – 75% of the day
4 =76 – 100% of the day
B. CLINICAL FLUCTUATIONS
36. Are any ‘off’ periods predictable as to timing after medication dosing?
0 = No 1 = Yes
37. Are any ‘off’ periods unpredictable as to timing after medication dosing?
0 = No 1 = Yes
39. What percentage of the waking day is the patient ’off’ on average?
0 = None
1 = 1 – 25% of the day
2 = 26 – 50% of the day
3 = 51 – 75% of the day
4 =76 – 100% of the day
Review of Literature 39
C. OTHER COMPLICATIONS
*Timed Testing
The following four timed tests (Langston et al., 1991) should be performed in
both the best “on” and practically defined “off” conditions:
• Pronation-Supination Test
This timed test of motor performance records the time in seconds required for the
patient to perform 20 successive cycles of alternating tapping movements of the palm and
dorsum of the hand on the knee while seated with both feet flat on the floor.
• Hand/Arm Movement between Two Points
This timed test performance records the time in seconds required for the patient to
tap the index finger of the right or left hand between 2 points on a table surface placed 30
cm apart horizontally. The test should be performed independently for each hand, and for
consistency, each test should begin with the left target.
• Finger Dexterity
The time required for tapping the thumb with the forefinger and then with each
finger in rapid succession for 10 times should be measured in seconds with each hand
independently.
• Stand-walk-sit-test
This timed performance test of postural and gait control records the time in
seconds required to stand up from a chair, walk seven meters, turn, walk back to the
chair, and sit down. This test should be performed twice and the faster time should be
recorded as the final result.
Standard MRI
Conventional MRI is normal in patients with idiopathic PD without dementia, as
standard MRI sequences have proved unable to detect definitive abnormalities in the
basal ganglia structures. Several researchers have used MRI sequences designed to reveal
changes in midbrain as post-mortem studies in PD have shown an increase in iron
concentration in the substantia nigra (SN). PD demonstrates a decrease in the width of the
pars compacta results from increased iron deposition in this area. Oikawa et al. concluded
that iron changes in the substantia nigra are better demonstrated on the proton density
weighted spin echo and fast spin-echo short inversion time inversion-recovery (STIR)
than on the T2 weighted images (Oikawa et al., 2002).
Probably more useful on the screening MR are specific findings in patient with
Parkinson plus diseases. Multiple system atrophy with predominant parkinsonian features
(MSA-P) has putaminal hypointensities and atrophy (Figure 5). Atrophy in the putamen
is not associated with PD. Another findings associated with MSA-P are mild to severe
brain stem and cerebellar atrophy, abnormal signal in the middle cerebellar peduncles and
Review of Literature 42
the “hot cross bun” sign of the pons: cruciform degeneration of pontine fibers secondary
to brain stem atrophy in a patient (Figure 6). Progressive supranuclear palsy demonstrates
atrophy of the midbrain and of the frontal lobe. Asymmetrical atrophy in the posterior
frontal and parietal regions contralateral to the side of the clinical manifestations is
characteristic of corticobasal degeneration. Unfortunately, atrophy is either a subjective
finding by an expert or an objective, time-consuming finding involving postprocessing
exercises such as pixel counting (Bhattacharya et al., 2002).
Conventional MRI sequences are valuable as they will reveal structural lesions
such as basal ganglia tumors, granulomas, and calcification; vascular disease; altered
basal ganglia signal due to Wilson’s disease or manganism/ephedrine poisoning; and
hydrocephalus and allow them to be excluded as secondary causes of parkinsonism
(Hirobumi et al., 2002).
A B
Figure 5: A, Normal iron distribution, ie, globus pallidum hypointensity relative to the putamen
in a patient with a clinical diagnosis of Parkinson disease (axial section, 1.5 T, T2 weighting). B,
Reversal of normal iron distribution with severe putaminal hypointensity relative to the globus
pallidum (inset) in a patient with a clinical diagnosis of multiple-system atrophy with
predominant parkinsonism (axial section, 1.5 T, T2 weighting) (Bhattacharya et al., 2002).
Review of Literature 43
A B
Figure 6: A, Normal pons in a patient with a clinical diagnosis of Parkinson disease (axial
section, 1.5 T, T2 weighting). B, “Hot-cross bun” sign: cruciform degeneration of pontine fibers
secondary to brainstem atrophy (inset) in a patient with a clinical diagnosis of multiple-system
atrophy with predominant parkinsonism (axial section, 1.5 T, T2 weighting) (Bhattacharya et
al., 2002).
Functional MRI
Functional MRI is increasingly used to investigate neurologic disorders such as
PD, because it is widely available, does not require radiation (so there is no limit on the
number of scans that can be performed), and it has sufficient temporal resolution to
Review of Literature 44
monitor dynamic changes. There are particular challenges in applying functional MRI to
PD. Head movement, a prominent feature in older adults, can result in significant
artifacts. Subjects with PD may have tremor, dyskinesias, or akathisia, which may make
it difficult for them to lay still for tens of minutes (Nandhagopal et al., 2008).
Figure 7: 123I-FP-CIT SPECT images of healthy volunteer and patient with early hemi-
PD. PD patient shows asymmetric bilateral loss of putamen DAT binding (Marek et al., 1996).
Review of Literature 45
Levels of putamen 18F-dopa uptake and DAT binding correlate inversely with
bradykinesia and rigidity of PD patients, but interestingly, not with tremor severity. This
suggests that parkinsonian tremor is not a direct consequence of nigrostriatal
degeneration. When clinically probable PD and essential tremor patients have been
compared, striatal DAT imaging with 123I-FP-CIT SPECT has been shown to
differentiate these conditions with a sensitivity and specificity of over 90% (Benamer et
al., 2000).
Several studies have examined the role of DAT imaging for determining whether
gray parkinsonian cases are associated with striatal dopamine deficiency. One of the
more common causes of confusion with PD is an adult-onset dystonic tremor, which can
present as an asymmetric resting arm tremor with impaired arm swing but without
evidence of true akinesia. In these patients, functional imaging should be considered to
avoid inappropriate medication with dopaminergic agents (Schneider, et al., 2007).
Imaging presynaptic dopaminergic terminal function with either striatal 18F-dopa
uptake or a DAT SPECT marker shows high sensitivity for detecting atypical
parkinsonian syndromes but only poor specificity for discriminating them from typical
PD. The typical gradient of loss of dopaminergic function in PD, where the head of the
caudate is relatively spared, is less evident in progressive supranuclear palsy and
corticobasal degeneration patients. In progressive supranuclear palsy, there is a more
symmetric pattern of nigrostriatal dysfunction than in other parkinsonian syndromes
(Burn et al., 1994).
18F-fluorodeoxglucose (18F-FDG PET) can be used to assess levels of resting
regional cerebral glucose metabolism. Absolute levels in the lentiform nucleus lie within
the reference range in PD. Measurements of resting glucose metabolism can be helpful
for separating typical from atypical parkinsonian syndromes. In typical idiopathic PD,
lentiform nucleus glucose metabolism is preserved or raised, whereas it is reduced in
most atypical cases (Figure 8) (Eckert et al., 2005).
Review of Literature 46
chorea (Spiegel and Wycis, 1950), followed by patients with choreoathetosis (Spiegel et
al., 1950). When no rigidity ensued, they lesioned the pallidum and ansa lenticularis
(pallidoansotomy) in parkinsonian patients (Spiegel and Wycis, 1953). Pallidotomy and
pallidoansotomy were then widely used in Parkinson’s disease.
In performing pallidotomy, Spiegel and associates worried about concomitant
damage to the internal capsule or the anterior choroidal artery that lay near the pallidum.
To avoid these risks, Spiegel and Wycis made lesions more distally at the junction of the
ansa lenticularis and lenticular fasciculus in Forel’s field H (Spiegel et al., 1963). A
variety of targets in the subthalamic area have been used to treat parkinsonian tremor,
include Forel’s fields H and H2, the zona incerta, and the prelemniscal radiations
(Mundinger, 1969).
Basal ganglia stereotactic surgery initially targeted the globus pallidus and the
ansa lenticularis until Hassler and Reichert selected the ventral lateral nucleus of the
thalamus and its surrounding area as the favored site for tremor reduction. In 1952, they
performed the first ventrolateral thalamotomy on a patient with PD (Hassler and
Riechert, 1954).
In the late 1950s, Lars Leksell modified his pallidotomy target from the classical
anterodorsal portion of the medial pallidum to the posteroventral pallidum. He reported
improvement of tremor and rigidity, but also saw ‘‘improved mobility in terms of
strength, range, speed and precision’’. This statement was taken to indicate an
improvement in bradykinesia. At the time, the larger community of functional
neurosurgeons overlooked the significance of these results (Svennilson et al., 1960).
The late 1960s and early 1970s witnessed a substantial decline in the number of
procedures performed for the treatment of Parkinson’s disease and for movement
disorders in general, largely as a result of the introduction of L-dopa. The surgical
treatment of Parkinson’s disease was limited to the treatment of tremor refractory to L-
dopa (thalamotomy) (Olanow, 2002).
In the late 1980s, Laitinen and his colleagues re-explored posteroventral
pallidotomy in 38 PD patients. (Laitinen et al., 1992) They reported significant
improvement in bradykinesia, rigidity, tremor, ambulation, speech, and drug-induced
dyskinesias. Their study was criticized due to lack of standardized clinical examinations
Review of Literature 49
and the absence of radiological evaluations regarding precise lesion placement. Since
then, there have been multiple other studies using standardized clinical rating scales that
have also reported significant improvement in parkinsonian symptoms with unilateral
pallidotomy. A large number of pallidotomies were performed with excellent clinical
results, particularly for unilateral procedures. In the 1990s pallidotomy was the most
common surgical procedure for PD (Lozano, 1996).
STN lesioning in humans was introduced with the hope that it would provide a
cost-effective method of achieving many of the benefits seen with STN DBS. In a pilot
study, Alvarez et al. reported their experience in 11 PD patients who underwent unilateral
dorsal subthalamotomy. There was a significant improvement in the UPDRS ADL and
motor scores in the “off” state at 12-mo follow-up (Alvarez et al., 2001).
(Siegfried and Lippitz, 1994). Preliminary reports from other centers have confirmed
those findings (Kumar et al., 2000).
Hyperactivity of the STN is considered a hallmark of PD. The STN has many
connections, including excitatory glutamatergic input directed at the GPi and substantia
nigra. In experimental parkinsonism, modulation of STN activity has been shown to have
therapeutic benefit (Bergman et al., 1990).
In 1994 the first reports of bilateral STN DBS in humans started to emerge,
demonstrating improvement in all of the cardinal signs and symptoms of Parkinson’s.
Benabid et al. have followed more than 50 patients with STN DBS for 1 yr who have
maintained benefit (Benabid et al., 1994).
In the Western world, DBS has virtually eliminated the practice of ablative
procedures and provided nothing less than dramatic improvement for many patients with
advanced PD and complications of drug therapy. STN DBS was first reported to have a
major impact on the symptoms of PD by Benabid and his colleagues and in the last
decade, numerous studies have confirmed the major impact of these procedures on the
symptoms of PD (Deuschl et al., 2006).
Chronic Motor Cortex Stimulation MCS has been used not only in relieving
refractory pain but also in improving a variety of movement disorders including PD,
tremor, and poststroke dystonia (Franzini et al., 2003).
Review of Literature 51
Single case reports, multicenter retrospective clinical review and small case series
of advanced PD patients treated with MCS have been reported with variable clinical
results. Arle and Shils reported a significant effect on overall motor performance as
assessed by UPDRS (Arle and Shils, 2008), while Cilia et al. found that extradural MCS
produced no motor benefit but subjective improvement involving mainly axial symptoms
as well as reduction in daily off time and dyskinesias (Cilia et al., 2007).
Guti´errez et al. confirmed the absence of significant modification of UPDRS III
scores with only mild daily life activities improvement and slightly reduction of the
Ldopa equivalent daily dose (LEDD) (Guti´errez et al., 2009).
Cell-based therapies
Cell-based therapies trying to restore the nigrostriatal dopamine projection have
been at the forefront of neuroscientific research for more than 2 decades, but clinical
trials using human fetal mesencephalic dopaminergic cells or other sources of
dopaminergic cells so far have not stood the test of sham-surgery controlled clinical trials
(Freed, 1983).
In addition, these approaches have resulted in uncontrollable off-medication
dyskinesias, and Lewy body degeneration has been observed in grafted fetal neurons.
Still, cell-based therapy may be one of the future approaches to physiological continuous
dopamine replacement in PD if alternative sources, in particular stem cells, can be
developed to a stage where routine clinical use will become safe and feasible. Recently,
neuronal stem cells that are multipotent and capable of self-renewal have been discovered
in both embryonic and adult brains, particularly in regions that undergo neurogenesis
beyond the developmental stages (Kordower et al., 2008).
These regions include the subventricular zone and hippocampal dentate gyrus, the
olfactory system and hippocampus, and other areas of the adult rat brain (Tropepe et al.,
1999). Neuronal stem cells can be propagated in culture in the presence of epidermal
growth factor (EGF) or basic fibroblast growth factor (bFGF, FGF-2) (Palmer et al.,
1995).
It has been suggested that when treated with the appropriate factors while cultured
in vitro, the adult neural stem cells can differentiate into DAergic neurons. However,
Review of Literature 52
despite the intensive research, there is currently no solid evidence that human adult stem
cells are really able to give rise to DAergic neurons. Further studies are needed to prove
the theoretical applicability of adult stem cells for derivation of DAergic neurons in vitro
(Daadi and Weiss, 1999).
Gene therapy
The same may apply to gene therapy using local intracerebral injections of viral
vectors carrying therapeutic genes. So far, small proof-of-concept studies have produced
encouraging results for lentiviral delivery of glutamic acid decarboxylase into the STN as
well as for viral delivery of dopamine-synthesizing enzymes to the putamen. Although a
phase II sham-controlled trial using intraputaminal viral delivery of neurturine to enhance
function and survival of dopaminergic terminals was disappointing, this program is still
ongoing (Berry and Foltynie, 2011).
Review of Literature 53
the DBS electrode is decreased by synaptic inhibition, DBS increases output from the
stimulated nucleus by directly activating the axons of the local projection neurons. As a
result, their intrinsic activity is replaced by high-frequency activity that is time-locked to
the stimulus and more regular in pattern. The stimulation-induced change in neuronal
patterns prevents transmission of pathologic bursting and oscillatory activity within the
basal ganglia network resulting in improved processing of sensorimotor information and
reduction of motor symptoms. These findings have led to the hypothesis that stimulation
may improve PD motor signs by regularizing or interrupting pathologic neuronal activity
from the basal ganglia allowing cortical motor areas to function in a more normal fashion
without interference from subcortical structures (Garcia et al., 2005).
Both experimental and modeling studies have shown that HFS replaces intrinsic
irregular activity with one that is time-locked to the stimulus. Only frequencies above 100
Hz provide symptom relief while frequencies below 20 Hz often worsen symptoms
probably because this just adds spikes to an already irregular pattern of spontaneous
firing (Garcia et al., 2005).
• muscular rigidity
• 4-6 Hz resting tremor
• postural instability not caused by primary visual, vestibular, cerebellar or
proprioceptive dysfunction
Step 2. Exclusion criteria for Parkinson’s disease (other signs of atypical and
secondary parkinsonian syndromes)
• History of repeated strokes with stepwise progression of parkinsonian features
• History of repeated head injury
• History of definite encephalitis
• Oculogyric crises
• Neuroleptic treatment at onset of symptoms
• More than one affected relatives
• Sustained remission
• Strictly unilateral features after 3 years
• Supranuclear gaze palsy
• Cerebellar signs
• Early severe autonomic involvement
• Early severe dementia with disturbances of memory, language, and praxis
• Babinski’s sign
• Presence of a cerebral tumour or communicating hydrocephalus on computed
tomographic scan
• Negative response to large doses of levodopa (if malabsorption excluded)
• Exposure of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
Step 3. Supportive prospective positive criteria for Parkinson’s disease (three or
more required for diagnosis of definite Parkinson’s disease)
• Unilateral onset
• Rest tremor present
• Progressive disorder
• Persistent asymmetry affecting the side of onset most
• Excellent response (70-100%) to levodopa
Review of Literature 57
a) General Health
The entire surgical procedure is an arduous and lengthy process. Some patients
can be in the operating room for eight hours or more. The surgery is physically
demanding, not only because of the length of the procedure, but also because patients
may be “off” of their routine PD medications during much of the procedure. Furthermore,
patients are awake for a significant portion of the surgery, and must be able to provide
appropriate feedback in the operating room. In order to tolerate this procedure, it is
essential that patients be in good general health. The presence of significant comorbid
medical illnesses such as severe cardiopulmonary disease, or poor renal or hepatic
function is relative contraindications to surgery. The risk of a hemorrhage is increased in
the setting of untreated hypertension, coagulopathy, or evidence on magnetic resonance
imaging (MRI) of significant small vessel ischemic disease or extensive cerebral atrophy
(Umemura et al., 2003).
Review of Literature 59
b) Cognitive Criteria
The presence of dementia or significant cognitive impairment is considered a
contraindication for surgery. The cognitive impairments must be sufficiently severe to
cause impairment in occupational and social functioning and represent a decline from a
previously higher level of functioning. Preoperative screening for dementia is mandatory.
Demented patients may be unable to provide appropriate feedback both intraoperatively
and postoperatively. Some clinicians exclude patients based on a Mattis Dementia Rating
Scale (MDRS) total score of ≤ 120–130/144 (Pollak, 2000).
c) Psychiatric Symptoms
Approximately 40% of Parkinson’s disease patients suffer from depression. The
literature is conflicting on the effect of surgical treatment on mood. Some studies suggest
improvement in mood after surgery; however, a growing body of literature suggests, in
some individuals, that depression and anxiety can worsen after surgery. It seems
reasonable to assume that before proceeding with surgery, mood disorders should be
effectively treated with medication. In many instances, reduction of antiparkinsonian
medication or addition of an atypical antipsychotic agent will improve these symptoms,
with the patient then able to proceed with surgery. Furthermore, depression may
confound interpretation of motor symptoms in PD (Doshi et al., 2002).
Depression can also cause significant impairment of attention, memory, and
executive function, resulting in a neuropsychological evaluation consistent with
dementia. Such a “pseudo-dementia” disappears when the depression is controlled. Thus,
if mood is not assessed or improperly evaluated, it may result in the exclusion of a
candidate who might otherwise be appropriate. The Beck Depression Inventory (BDI) or
the Montgomery and Asberg Depression Rating Scale (MADRS) can be used to assess
depression. The CAPSIT-PD recommends a score ranging from 7 to 19 on the MADRS
as an exclusion criterion. Another reason to exclude unstable psychiatric patients is that
they may be unable to provide the feedback needed postoperatively in order achieve
optimal results (Defer et al., 1999).
Review of Literature 60
4. Areas of controversy
a) Previous surgery for Parkinson’s disease
In general, previous surgery does not exclude the possibility of additional surgical
intervention. In a patient with a previous unilateral pallidotomy who continues to
experience contralateral benefit but now requires treatment on the opposite side, pallidal
deep brain stimulation on the opposite side of the brain can be used. Alternatively, if the
benefits from the previous pallidotomy have waned, bilateral subthalamic nucleus deep
brain stimulation can be employed with excellent benefit. Patients with a previous
thalamotomy can also be successfully treated with bilateral subthalamic nucleus or
globus pallidus deep brain stimulation (Mogilner et al., 2002).
b) Upper age limit
Whether there is an upper age limit above which surgery should no longer be
offered is the topic of debate. While several findings support an age-based cutoff for
surgery, other studies have shown that there is no difference in postoperative outcomes in
patients with advanced age, providing these patients are carefully selected and exhibit a
robust response to a dopaminergic challenge. If older patients experience severe motor
fluctuation, dyskinesia, a good response to levodopa, no signs of dementia or major
psychiatric disturbance, and are in good general health, surgical treatment is offered.
Thus, it appears that a strict age requirement for surgery may exclude some good
candidates. At this point, potential surgical cases over the age of 70 should be evaluated
on an individual basis (Ostrem et al., 2004).
c) Earlier Intervention
The possibility of intervening earlier in the course of disease with surgical
treatments has been proposed. There is speculation that subthalamic nucleus deep brain
stimulation could potentially exert a neuroprotective effect. This hypothesis is based on
indirect evidence implicating glutamate toxicity in Parkinson’s disease and the possibility
that deep brain stimulation of the subthalamic nucleus, by reducing glutaminergic
outflow, could produce a neuroprotective effect. Others have suggested that reduction of
medication or potential avoidance of medication exposure, often possible following
surgery, could result in less neuronal toxicity, leading to a secondary neuroprotective
effect (Mesnage et al., 2002).
Review of Literature 61
Frame-based systems
In the most common approach to DBS surgery, stereotactic frames are placed
over the patient’s head and secured with pins. The frame becomes the fixed point of
reference for accurate stereotactic surgery and must remain in place for the duration of
the procedure. Computed tomography or MRI is then performed with the frame in place,
so that the images are co-registered with the fiducial points of the stereotactic frame. The
targets are then selected for surgery and trajectories are chosen based on anatomic
structures. The patient is positioned supine and the frame and head are secured to the
operating table. The coordinates calculated by the clinical workstations are then set to the
stereotactic frame and arc. The stereotactic arc is attached to the base of the frame and the
entry points of the leads—where the burr hole will be placed—are marked on the skin
and then on the skull. Once the burr hole and opening of the meninges are completed, the
targeting cannulae are inserted. The microelectrode system is then mounted for recording
of the target area and subsequently for final lead implantation. Physiologic verification of
anatomic targets identified by imaging can be accomplished with microelectrode
recording (MER). This technique involves placing fine, high-impedance electrodes
through the target area, so that anatomic structures can be recognized by characteristic
electrical activity of individual neurons or groups of neurons (Machado et al., 2012).
Frameless systems
The workflow and overall surgical procedure for implantation of DBS with
frameless systems are similar to those of the frame-based procedure. However, instead of
fixing the head to a rigid frame that prevents head motion, a lighter-weight, frameless
system is fixed to the head and moves with it. First, metal screws and fiducials are fixed
to the head under local anesthesia or sedation. Preoperative imaging is then acquired with
the fiducials in place and the surgical plans are completed in the same fashion as for
frame-based surgery. The patient is then placed supine on the operating table and the
frameless system is attached to the head with the aid of image guidance, in the location
determined by target and trajectory planning (Machado et al., 2012).
The key advantage of the frameless system over the frame-based system is greater
mobility of the head. Another important advantage is easier access to the airway, should
an emergency situation occur. The frameless system also has disadvantages, including
Review of Literature 63
less secure fixation of the head, which can add risk to the procedure. In addition, because
of its lightweight, plastic construction, it provides less robust support to the
instrumentation entering the brain than do metallic head frames and, in some cases, there
is less flexibility for adjusting targets if needed during surgery. In addition, frameless
systems are nonreusable and represent a substantial additional cost (Machado et al.,
2012).
Figure 9: Electrode Implantation for Deep-Brain Stimulation.The lead for deep-brain stimulation
is implanted in either the subthalamic nucleus or the internal segment of the globus pallidus. The
lead passes through a burr hole in the skull. Attached to the lead is a connecting wire, which is
tunneled under the skin of the scalp and neck to the anterior chest wall, where it is connected to
an impulse generator (Machado et al., 2012).
Review of Literature 64
Operation-Related Complications
1. Intracerebral hemorrhage
Intracerebral hemorrhage is caused by insertion of the cannula or microelectrode
into the brain. Intracerebral hemorrhage is one of the typical and serious surgery-related
complications that occur in stereotactic neurosurgery. The incidence of hemorrhagic
complications in the DBS procedure is lower than in radiofrequency lesioning, a
procedure that damages the vessel wall with heat. Reported rates of intracerebral
hemorrhage in DBS surgery range from 0.3% to 3.6% per electrode track. However, the
incidence of symptomatic hemorrhage with permanent neurological deficit seems to be
less frequent (Rosenow and Rezai, 2005).
There is some evidence indicating intraoperative hemorrhage: bleeding from the
cannula, unexpected electrical silence on microelectrode recording, displacement of the
DBS electrode as seen on fluoroscopy, and so on. In such cases, we should control the
patient’s blood pressure at a lower level and watch the patient carefully. If deterioration
of consciousness or a focal neurological deficit is found, the procedure should be
interrupted and emergency computed tomography should be performed. On that occasion,
leaving the stereotactic frame in place will be helpful for subsequent emergent
stereotactic aspiration of hematoma when the patient’s airway is secured (Rosenow and
Rezai, 2005).
Meticulous surgical planning would minimize the haemorrhagic risk. Direct
magnetic resonance imaging (MRI) or composite MRI targeting should be able to bring
the electrode tip to within 2 mm from the target. This would minimise the number of
passages. Modern stereotactic surgery planning systems are all powered to plan a “safe-
track” by avoiding cortical veins and major arteries. A microdriver can drive the
Review of Literature 65
electrode down the track steadily and slowly at a measured increment of 0.1 mm. All
these would minimise the risk of haemorrhage (Danny et al., 2009).
2. Venous infarction
Venous infarction is caused by coagulating a large draining vein that enters the
dura at the site of the burr hole. Avoid damage to or coagulation of venous structures.
Surgical planning with gadolinium-enhanced magnetic resonance (MR) image clearly
identifies cortical veins. This method is quite useful for avoiding the cortical vein at the
entry point and for preventing hemorrhagic complications and venous infarction. In
addition to detailed surgical planning with gadolinium-enhanced MR image, it is
recommended to place the burr hole anterior to the coronal suture. In the case of a venous
infarct, it will be more likely to be asymptomatic from this position (Danny et al., 2009).
3. Postoperative seizures
The reported incidence of postoperative seizures related to the DBS procedure is
3.1%. However, prophylactic use of anticonvulsant agents in DBS surgery may increase
the risk of medication-related complications and drug interaction in this mostly elderly
population and may not be necessary. When seizure occurs postoperatively, antiepileptic
medication should be administered for a certain period (Hamani et al., 2005).
4. Pulmonary embolism
Pulmonary embolism is a prominent source of mortality and morbidity in
neurosurgical patients. The reported incidence of postoperative pulmonary embolism
ranges from 0.4% to 4.9%; in those cases, the mortality rate ranges from 8.6% to 59.4%.
Despite standard prophylaxis with pneumatic compression boots, fatal deep vein
thrombosis can still occur. Patients at high risk include those with heart disease, obesity,
and polycythemia. Hence, early rehabilitation is important, especially for patients with
PD (Inci et al., 1995).
5. Perioperative confusion
Perioperative confusion is a common adverse effect after STN DBS surgery,
especially in older patients. Perioperative confusion is usually transient and several
factors may contribute to its pathogenesis, including penetration of the bilateral frontal
lobe, long duration of brain surgery, and the withdrawal of dopaminergic medication
(Hamani et al., 2005).
Review of Literature 66
Hardware-Related Complications
Skin erosion is a common problem in DBS series and has been reported to range
between 0.4% and 6%. If the subcutaneous pocket receiving the pulse generator at the
time of the initial implantation is too small for the device, undue tension on the overlying
skin may cause gradual erosion. Erosion of the skin may also occur over the connector
site or in the scalp incision when bulky hardware is implanted. There is now a new
connector (model 7482, Medtronic), with a lower profile that may help to reduce skin
erosions. If erosion has just occurred, transposition without device removal may be
attempted, but the most definitive treatment is to remove the part of the device that has
eroded and replace it later after the skin has completely healed. If an erosion of a pulse
generator occurs in a very thin individual, we replace the IPG in the abdomen rather than
the chest (Oh et al., 2002).
2. Sterile Fluid Collections
Patients may present within 1 month post-surgery with tense swellings around the
IPG, which were fluctuant but painless and without redness or warmth. Surgical
exploration of one of these revealed a sterile clear fluid collection consistent with
cerebrospinal fluid (CSF). This appears to occur more frequently with burr hole-based
anchoring methods that are not watertight (such as the Medtronic Stim-lock system), as
CSF can “wick” along the hardware to accumulate in the pectoral cavity. If a swelling
around an IPG is not red, tender, or warm, and the incision is healing well, it is
recommended to observe it. Sterile fluid collections typically resolve spontaneously, or
with application of a pressure dressing to the chest (Blomstedt and Hariz, 2005).
3. Misplaced electrodes
At this time, there are no clear guidelines for what constitutes acceptable lead
locations for movement disorders, other than that the electrode should be in a position to
affect the motor territories of the relevant nuclei: the dorsolateral STN or posterolateral
internal pallidum. Radiographically, an electrode is considered malpositioned if it is more
than 2 mm from the intended location in the relevant axial plane on postoperative
imaging. Clinically, an electrode may be considered malpositioned if it is
radiographically well positioned, but fails to provide the expected clinical benefit despite
multiple programming attempts, and/or produces simulation-induced side effects at
thresholds low enough to interfere with clinical use. If an electrode is malpositioned on
Review of Literature 68
clinical grounds, stereotactic insertion of a new lead is performed, using the initial
malpositioned lead as an internal reference marker. MER is not used in this setting. MER
is very difficult to interpret if a nearby lead has just been removed, because the resulting
tissue edema alters neuronal discharge characteristics (Okun et al., 2005).
4. Lead Migration
Lead migration seems to occur when fixation of the lead to the skull is
insufficient. If the lead does not remain correctly positioned, it will result in clinical
failure. Downward dislocation of the connector, extension cable, or IPG is responsible for
upward migration of the lead. In early series, electrode migration occurred in up to 14%
of cases. More recent series have quoted an incidence of electrode dislodgement from
0% to 5.1% (Oh et al., 2002).
Various methods have been developed to secure the DBS electrodes to the
calvaria. Some centers use the silicone burr hole ring and cap, which is supplied by the
electrode manufacturer (Medtronic). Other centers use bone cement or miniplates to
secure the lead electrode. Normally, a lead migration will require a new stereotactic
procedure to re-insert the lead (Favre et al., 1996).
5. Lead Fractures
Electrode fracture or malfunction may occur if the connector screws are
overtightened or if the connection between electrode and cable is subjected to excessive
movement such as in the neck below the mastoid (Schwalb et al., 2001).
The wires in the electrode are made of platinum and can easily be crushed by the
screws. Any point of the electrode subjected to stretching or crushing is susceptible to
these complications, but most fractures occur in the lead near the connection between the
lead and extension. A fracture is suspected when a patient realizes that the stimulation is
not working properly and the benefits of the surgery disappear suddenly. The electrical
examination of the system reveals elevated electrode impedance (>2000 Ohms) with low
system current (<7 µAmp). The diagnosis can be confirmed by radiography. Some
authors have reported that dynamic radiography (with the head turned) may be needed to
demonstrate the disrupted electrodes (Mohit et al., 2004).
The incidence of electrode fracture or malfunction ranges from 0% to 13.3% per
patient among the reported series (Joint et al., 2002). It is recommended to place the
Review of Literature 69
vulnerable connection between lead and extension under the parietal scalp, as this
location prevents the connection from moving. The mobility of the neck may be better
tolerated by the extension because its wires are made of steel. Medtronic has recently
included a torque wrench with its extension kit to prevent over tightening at the lead-
extension connection (Blomstedt and Hariz, 2005).
6. Inadvertant Thermal Lesioning
Inadvertent thermal lesioning around a DBS electrode has been reported
following cardioversion, diathermy, and MRI using a body transmit coil. Diathermy is a
treatment of undocumented utility that involves the application of rapidly alternating
electromagnetic current to produce “deep tissue heating.” When applied near a DBS
device, large radiofrequency lesions around the DBS contacts in the brain may occur
which produce permanent brain damage. Exposure to diathermy is absolutely
contraindicated in patients with deep brain electrodes. MRI must be used with caution,
following the manufacturer’s guidelines, in the setting of implanted DBS devices. One
permanent thermal brain injury due to MRI in a patient with deep brain stimulators has
been reported. This occurred during a lumbar spine MRI in a 1.0 Tesla unit, using a body
transmit coil, in a patient with a pulse generator in the abdomen and a long lead extender
(Henderson et al., 2005).
7. Electrolysis and Gas Production
Normally the current transmitted through a DBS contact is alternating current so
that there is no net charge build-up on a contact. Malfunction of a pulse generator so as to
produce a net direct current may result in electrolysis and the production of an
intraparenchymal gas bubble presenting as an expanding mass lesion. This has been
reported in the context of a malfunction of an external pulse generator that was used for
several days of testing through an externalized lead (Radbauer et al., 2000). The authors
recommended that the duration of external test stimulation, if done at all, should be kept
to a minimum. Acute battery failure may cause a parkinsonian crisis. Therefore,
replacement of the IPG should be considered before complete depletion of the battery
(Chou et al., 2004).
Review of Literature 70
symptom of untreated PD and only the temporal association with STN stimulation may
suggest a pathogenetic correlation. The pathogenesis of dysphagia after STN DBS may
be similar to dysarthria. Swallowing abnormalities may result from unwanted
interference with corticobulbar fibers to the swallowing muscles. Significant
improvement of dysphagia is observed after applying the same approach described for
speech abnormalities, i.e., lowering stimulation amplitude, switching to more dorsal
contacts and/or switching to a bipolar configuration (Krack et al., 2002).
Activation of the corticobulbar and corticospinal tracts coursing in the internal
capsule can produce tonic muscle contractions of the contralateral face, hand, and more
rarely arm and leg. The internal capsule borders the STN laterally, anteriorly, and
medially. It can be determined if the electrode has been placed too anteriorly, laterally, or
ventrally by the threshold voltage necessary to produce tonic contractions using different
active contacts in monopolar configuration. The threshold to tonic contraction through
the ventral contact will be very low for an STN DBS lead placed too ventrally and
laterally. In fact, tonic contractions time-locked with the activation of DBS contacts
suggest current diffusion to corticospinal fibers, which run anterior and lateral to the
STN. Reduction of amplitude and switching to another clinically effective contact are
usually effective in preventing the unwanted activation of the pyramidal system. If these
adjustments provide little relief, lead revision should be considered (Krack et al., 2002).
Diplopia, blurred vision, and abnormal eye movements may occur in patients with
STN DBS. These are not symptoms usually seen in PD and clearly suggest current
diffusion beyond the therapeutic target toward the fibers of the oculomotor nerve, which
sweeps medially, ventrally and posteriorly to the STN. When stimulation affects the
oculomotor nerve, adduction or downward movement of the ipsilateral eye can be seen.
Deviation of the eyes is less common and is usually transient. It is possible that the
electrical field of a DBS lead placed too laterally could activate the fronto-pontine tract in
the internal capsule en route to brainstem nuclei to result in conjugate horizontal eye
movements. However, the exact mechanism for conjugate deviation is not known. In
these cases, it is imperative to switch to a more dorsal contact and eventually lower the
amplitude or change the configuration to bipolar (field shaping). If abnormal eye
Review of Literature 72
movements are observed at unusually low voltages, lead revision should be considered
(Limousin et al., 1998).
Postural instability is another symptom frequently encountered in patients with
PD that may occasionally worsen or present for the first time after STN DBS. Preexisting
postural instability is generally improved by STN DBS, unless it had not responded to
levodopa therapy before surgery. In some cases, postural instability may derive from
hypotonia caused by the additive effects of successful stimulation. Successful resolution
of rigidity can predispose to rapid loss of tone of the antigravity muscles of the lower
limbs, with resulting impairment of gait and postural instability. A complaint of “jelly
legs” or falls that were not experienced before the surgery is not uncommon in the first
few weeks of DBS therapy. Usually, these symptoms are exacerbated by levodopa and
should be managed with a reduction in either levodopa dose or stimulation voltage. In
addition, we find that specific gait rehabilitation with strengthening of antigravity
muscles can further stabilize these symptoms (Bronte-Stewart et al., 2002).
In other cases, the patient complains of a more distinct truncal ataxia, with feeling
of retropulsion and near falling. In these instances, the current is likely spreading to the
cerebellorubro-thalamic fibers medial to the STN or to the red nucleus positioned
medially and ventrally. Decreasing amplitude and pulse width, moving to more dorsal
contacts and/or to a bipolar configuration may improve balance (Krack et al., 2002).
Transient contralateral “tingling” or sensation of “electrical current” are usually
predictive of good location and positive stimulation outcome. However, if medial
lemniscus fibers are activated, the patient will report persistent paresthesia. In most cases,
programming adjustments like decreasing the amplitude and focusing the field with
bipolar stimulation will relieve sensory symptoms. If the patient reports persistent
dysesthesias at unusually low voltages, lead revision should be considered (Pollak et al.,
2002).
A wide range of neuropsychiatric complications of STN DBS has been reported,
including acute transient depressive and euphoric mood states, as well as the subacute
onset of major depression, mania, anxiety, and substance abuse (Houeto et al., 2002).
Mania is usually transient in the immediate postoperative period. Depression
occurring several months after surgery often coincides with a significant reduction of
Review of Literature 73
Weight gain may appear with variable incidence and has been up to 96% in some
series. This weight gain occurs in the first three months and continues to increase slowly
beyond one year. However, its cause remains unclear. This unintended effect of STN
DBS may not be a direct effect of stimulation but may be at least partially related to
reduction of energy expenditure related to the control of dyskinesia, rigidity, and tremor.
Alternative hypotheses include an unproven regional effect of STN DBS on the satiety
hypothalamic centers, and the possible effect of dopaminergic drug dosage reduction
following STN DBS on hypothalamic homeostasis in PD. Therefore, candidates for STN
DBS should be given nutritional counseling to prevent rapid and excessive weight gain
(Macia et al., 2004).
Apraxia of eyelid opening (AEO) is an infrequent side effect of STN DBS. Its
incidence is approximately 5%. ALO is more frequently seen in patients who obtain a
good anti-PD effect of STN DBS. Apraxia of eyelid opening (AEO) is a condition in
which patients have difficulty opening their eyelids. Originally, this symptom was
observed in idiopathic PD and other degenerative diseases involving the basal ganglia
(Boghen, 1997).
The specific cause or control center for AEO is poorly understood, as is the
mechanism by which DBS causes or aggravates this problem. The fact that AEO is
generally associated with good motor responses has led some authors to think that it may
be a direct consequence of STN stimulation, possibly secondary to the involvement of the
oculomotor loop. When functionally disabling, AEO can be treated either using more
dorsal contacts or with pretarsal botulinum toxin injections (Krack et al., 2002).
adverse events are observed at low voltages, further increases in pulse width should be
tested in order to increase current density without further spread of the electrical field.
Finally, bipolar or tripolar settings can be used (Kumar, 2002).
Impairment of axial symptoms such as freezing, transient impairment of balance,
falling, and persistent gait akinesia have been also reported as a specific adverse effect of
GPi stimulation, but the responsible lead location in these cases is uncertain. On average
however, most studies report that axial symptoms improve following GPi DBS compared
to the preoperative state (Volkmann et al., 2001).
Similar to STN DBS, the majority of studies addressing neuropsychological
changes following GPi DBS have failed to reveal significant cognitive decline. Mild
declines in semantic word fluency and visuoconstruction scores have been reported,
while significant, but partially reversible, executive dysfunction was described in one
report following bilateral pallidal stimulation. Whether GPi stimulation is cognitively
safer than STN stimulation is currently debated (Okun and Foote, 2005).
Aim of the Work 76
A im of w ork
The aim of this study is to review and evaluate the different modalities of
stereotactic techniques, and their efficacy in the management of idiopathic Parkinson’s
disease.
Patients and Methods 77
3. Clinically significant medical disease that would increase the risk of developing
complications (for example; cardiac or pulmonary disease, or uncontrolled hypertension).
Application of the aforementioned criteria was considered in light of each patient’s
condition, including quality of life issues, before making a final decision concerning their
candidacy for surgery.
►Preoperative protocol
Clinical aspect
1. All patients were preoperatively evaluated including detailed history taking, general
examination and neurological examination.
2. All patients were assessed on the clinical rating scales. The guidelines of the Core
Assessment Program for Surgical Interventional Therapies in Parkinson's disease
(CAPSIT) were followed. CAPSIT recommended the use of Unified Parkinson’s Disease
Rating Scale (UPDRS) in off and on phases. The UPDRS has four primary sections to
assess clinical problems associated with PD:
• Part I: Behavior, cognition, mood, psychosis, and motivation scores (score 0-16);
• Part II: Activities of daily living (score 0-52);
• Part III: Motor examination (score 0-108);
• Part IV: Additional complications of disease or therapy including dystonia,
dyskinesia, and motor fluctuation estimates (score 0-23) (Fahn et al., 1987).
The UPDRS, especially the UPDRS motor subscale, is a reliable and valid assessment
of global PD severity as well as distinct multiple areas of physical disability. Patients
were divided into two groups according to their predominant symptoms: patients with
the strongest impairments due to tremor were assigned to the tremor-dominant group;
those with the strongest deficits concerning akinesia and rigidity were assigned to the
akinetic-rigid group [calculation of scores: tremor (UPDRS item 20 + 21), akinesia-
rigidity (UPDRS item 22-26)].
The off phase was defined as the condition of the patient after withholding
antiparkinson medication for 12 hours and being awake for at least 1 hour. The on phase
was the condition 1 hour after taking the usual first morning dose.
Patients and Methods 79
Investigative aspect
1. The routine laboratory workup.
2. Preoperative video recording (only after obtaining written informed consent) was done
in off and on phases to analyze the movement disorder pattern and as well as a
documentation.
3. Preoperative MRI on the brain.
►Operative procedure
Deep brain stimulation (DBS) was the preferred option for all patients. Each
procedure was based on the stereotactic method for targeting the chosen neural structure.
The targeting process was refined using intraoperative macroelectrode stimulation or
macrostimulation based on microelectrode recording (MER). The subthalamic nucleus
(STN) was the preferred target for all patients to control all the three cardinal symptoms
of Parkinson’s disease.
Clinical aspect
Postoperative clinical assessment was done, by a team consisting of: a
neurosurgeon and a neurologist, every three months in standardized off and on phases as
recommended by the Core Assessment Program for Surgical Interventional Therapies in
Parkinson's disease (CAPSIT). Outcome measures included:
1. The UPDRS, especially the UPDRS motor subscale. The total off UPDRS III score
was considered the primary outcome measurement. Based on the degree of improvement
in the total off UPDRS III score, a four graded system was used as the following:
• Excellent: >75% improvement in the total off UPDRS III score
• Good: 51- 75% improvement in the total off UPDRS III score
• Fair: 25-50% improvement in the total off UPDRS III score
• Poor: <25% improvement in the total off UPDRS III score
2. Changes in the medications measured by L-Dopa equivalent dose (LED). To compare
the effects of changes in antiparkinsonian medications, we calculated that a 100-mg daily
dose of standard levodopa was equivalent to the following doses of other medications:
Patients and Methods 80
Investigative aspect
1. Immediate postoperative CT imaging for early detection of eventual complications and
to estimate the accuracy for electrode placement. Subsequent postoperative CT imaging
will be obtained in cases in which new neurological symptoms appeared.
2. Postoperative video recording (only after obtaining written informed consent) was
done in off and on phases.
►Statistical analysis
Statistical analysis was performed with the SPSS Statistical Package for the
Social Sciences (SPSS Inc., Chicago, IL, USA).
Operative details
►Preoperative Preparation
All patients were admitted the day before surgery. All dopaminergic medications
were stopped the night before or the morning of surgery, depending on the severity and
quality of the patient’s symptoms, to achieve a "practical off state" for intraoperative
neurological testing. Patients with hypertension should take their antihypertensive
medications on the morning of surgery because elevated blood pressure may increase the
risk of perioperative hemorrhage, and withholding dopaminergic medications for the
surgery often results in rebound hypertension. Patients are instructed to discontinue
aspirin and vitamin E for at least 2 weeks prior to surgery because these agents may
increase the risk of intracerebral hemorrhage.
Nonstereotactic MR imaging was performed 2 to 3 days before surgery. Thin-
slice axial (T1- and T2-weighted) and coronal images (T2-weighted, from in front of the
Patients and Methods 81
anterior commissure to behind the posterior commissure) were obtained using a 1.5-tesla
scanner. Data acquisition was achieved without interslice spacing (2-mm slice thickness).
The pins were tightened in opposing pairs to evenly distribute pressure on the
skull. Pins were hand tightened and should not be over tightened. Over-tightening can
result in frame distortion, which can create a source of targeting error. If the pins are set
appropriately, it should be possible to gently shake the patient’s head, gripping the frame,
without causing pain. Pain results from pin slippage. If performed carefully, this
maneuver provided added assurance against intraoperative displacement. In addition,
since the pins create significant artifactual distortion of computed tomography (CT)
imaging, they were placed such that they do not distort the anterior commissure, the
posterior commissure, or the STN. Moreover, pin lengths were chosen so that the frame
Patients and Methods 82
and its posts did not contact the patient’s nose, scalp, neck, or shoulders to avoid the risk
of developing a pressure sore.
After intravenous injection of iodine containing contrast medium (e.g. 1.5 g
iopamidol/kg) stereotactic cranial CT scanning was performed using 2-mm slice
thickness and no inter- slice spacing. The gantry angle must be kept at 0 degree in order
to allow most planning software to construct a volumetric cranial model. The field of
view is enlarged so that all of the fiducial rods are visible. The CT data were transferred
through the hospital’s data network (in the German group) or from an optical disk (in the
Egyptian group) to a workstation located in the OR. Multiplanar reconstruction software,
Praezis plus 3 (Inomed Company, Germany) was used in every patient for planning. The
stereotactic coordinate system was then established by registering the fiducial rods. Once
the rods were identified, the computer could then assign a triplanar set of Cartesian
coordinates to any intracranial structure. The posterior portion of the anterior commissure
(AC), the anterior portion of the posterior commissure (PC) and at least one midline point
are then identified and stored (Fig. 12). The data obtained from nonstereotactic MR
images were integrated into the 3D stereotactic coordinate system by using landmark-
based image fusion. Briefly, a set of corresponding anatomical landmarks, which were
clearly visible on both CT and MR images, was manually defined by the neurosurgeon on
the computer screen. For each pair of points an algorithm, which is part of the treatment-
planning software, was used to calculate particular correlation accuracy. Points with a
difference exceeding 2 mm were rejected before image fusion. Superimposing the 3D net
of correlation points, the software integrated the MR images into the stereotactic CT
scan–based coordinate system. The fusion was accepted by the neurosurgeon if the mean
deviation was below 1.2 mm. The course of characteristic anatomical contours (large
intracranial vessels, ventricular walls, gyri, and/or sulci) at the CT/MR–image interfaces
provided additional visual control for the validity of the fusion process (Fig. 11).
Patients and Methods 83
Figure 12: T1-weighted MRI on the surgical planning station with the AC and PC marked.
The technique for target selection has three options: direct, indirect, or both.
Direct targeting relies on visualization of the surgical target. Toward this end, coronal
and axial T2-weighted images have proven most successful for imaging the STN. Indirect
targeting methods rely on the visualization of the commissures and the known
relationship of these structures to commonly described surgical targets.
We preferred combining both direct and indirect targeting to give a far better feel
for the target location. The STN was targeted on the basis of Schaltenbrand–Wahren
Patients and Methods 84
atlas (SWA; Schaltenbrand & Wahren, 1977) coordinates, using stereotactic cranial
computed tomography and stereotactic high resolution magnetic resonance imaging
(MRI; T1- and T2-weighted) fusioned images, and also by determination of STN on T2-
weighted MRI series. Our standard coordinates for targeting the dorsolateral part of the
STN in patients with PD were 1.8 mm posterior to the mid AC (commissura anterior)–PC
(commissura posterior) line (midcommissural point, MCP), 3.8 mm ventrally to MCP and
12 mm laterally to midline. In older patients with more generous ventricles, the lateral
coordinate needed to be shifted several millimeters laterally. The trajectory taken to the
target can be as important as the target itself. In the Schaltenbrand atlas on the sagittal
plane 12 mm lateral from the AC–PC line, the rostrocaudal angulation is approximately
70°. In the coronal section (3 mm posterior to the MCP) the lateromedial angulation is
approximately 65°. The entry points were defined according to these angulations 2.5 to 3
cm rostral to the coronal suture and approximately 3.5 cm lateral to the midline of the
skull in order to avoid the medial bridging veins and avoid the internal capsule. In
addition to the risk of damaging the internal capsule, lateral trajectories that do not pass
through the thalamus and zona incerta provide limited MER data. The precise entry point
was refined on the planning console such that the trajectory passed through the crown of
a gyrus rather than into a sulcus to avoid inadvertently damaging sulcal or pial vessels
which lie on the cortical surface. The approach then was traced at millimeter intervals to
ensure that no deep sulci or ventricular ependyma were transgressed.
Patients and Methods 85
Figure 13: Magnetic resonance images demonstrating intraoperative treatment planning. The
trajectories are displayed in coronal (upper left), sagittal (lower left), and axial (upper and lower
right) reconstructions with lines representing the projection of the trajectory onto the respective
plane.
Figure 14: The contour of the STN was outlined on the axial T2-weighted fast spin echo MR
images, in which the STN was visible as a hypointense ovoid structure located lateral to the red
nucleus. The STN, red nucleus (RN), putamen, globus pallidus pars internus (GPi) and pars
externus (GPe) are highlighted in white.
Patients and Methods 86
►Surgical technique
frame coordinates to the right side target and performing the entire procedure on that
side. Once the first electrode was implanted, the frame was once again set to the left side
target and microelectrode recording and lead placement was completed there. This served
the dual purpose of rapidly completing all the skull drilling (eliminating the need for
heavy sedation) and reducing the number of frame movements. The dura was coagulated
and then opened in a cruciate manner. The dural leaves were thoroughly coagulated to
prevent oozing of blood into the burr hole. The pia arachnoids were bipolar cauterized to
obtain absolute hemostasis. A generous opening in the pia was then created with a #11
blade to allow passage of the stimulating electrode. It was important not to make this
opening too small or the brain will be deformed as the stimulating electrode is passed,
risking hemorrhage from cortical vessels and bridging veins. The stimulating electrode
was inserted into the brain with a constant gentle rotating motion to gently push aside,
rather than tear, any small vessels it encounters. Fibrin glue was used to seal the hole
during each track to prevent the egress of the cerebrospinal fluid and the entry of air.
Intraoperative Examinations, Target Verification and Electrode implantation
The targeting process was refined using intraoperative macroelectrode stimulation
with or without microelectrode recording (MER). In the Egyptian group (20 patients),
microelectrode recording was done in 10 patients while MER was used only in 5 patients
of the German group (40 patients). MER was used when MRI scans were not of sufficient
quality to visualize the target because the nuclear boundaries were indistinct or when
MER was the preferred method of the neurosurgeon.
Microelectrode recording (MER)
Intraoperative recordings were performed, in the awake, non-sedated patients,
with 3–5 electrodes (central, anterior, posterior, lateral, medial) that were concentrically
configured with a distance of 2 mm from the central electrode. We used combined micro-
macroelectrodes (INOMED, no. 230767) that consist of a fine microelectrode tip (Ø 4
µm) and a macroelectrode ring 1 mm above the tip. The diameter of the macroelectrode
is 800 µm. The high impedance microelectrode (at about 1–2 MΩ) recorded single-unit
activity and was used to identify the border of the STN on the basis of the typical single-
cell activity. Intermittent impedance measurements ensured the correct functioning of the
microelectrodes. Only impedance values of about 1 MΩ were accepted. Data acquisition
Patients and Methods 88
was performed using the INOMED MER system (INOMED, Tenningen, Germany) with
ISIS MER -system software 2.4beta. Recordings were performed from 4 to 6 mm above
the planned target point (negative distance values), entering the nucleus in steps of 0.5–2
mm and ending 1–3 mm beyond the planned target. The optimal subthalamic nucleus
trajectory was the one traversing four major anatomical structures which are the anterior
thalamus, zona incerta (ZI), STN, and substantia nigra pars reticulata (SNr). Thalamic
neurons were usually encountered within the first several millimeters of recording,
followed by a relatively silent ZI. The clearest indicator that the electrode had breached
STN was the dramatic increase in signal background level followed by intense, irregular
neuronal activity. Frequently, a brief pause in STN activity was observed as the electrode
further passes between dorsal and ventral part of STN. On exiting STN, a sudden drop in
background activity was observed and was followed by a period of silence before the
electrode entered the SN. We further advanced the electrode through the STN to the
substantia nigra pars reticulata (SNr) in order to estimate the length of STN traversed by
each trajectory.
Micro-Recordings
Trajectory: Thalamus - Subthalamic Nucleus - Substantia Nigra
Thalamus (depth -9)
Thal
Lpo Cd
Rt
VimVopVoa
Zi
H2
STN Subthalamic Nucleus (depth -1,6)
Hy
SNi
10mm
Substantia Nigra, p. reticulata (depth+1,3)
Macroelectrode stimulation
Starting 6 to 10 mm above the intended target and extending up to 4 mm below,
intraoperative stepwise macrostimulation (in 1-mm steps, 130 Hz, 0.2-msec pulse width,
0-5 V; stimulator N50, Fischer-Leibinger, Freiburg, Germany) was performed through a
bipolar electrode (TCB 013, Fischer-Leibinger, outer diameter, 2 mm; distance between
the poles, 2 mm). The effects on contralateral bradykinesia and rigidity and side effects
were evaluated by a neurologist. When involuntary muscle contractions were
encountered, low-frequency stimulation (3 Hz, 0.2-msec pulse width, 0-5 V) was also
performed to distinguish stimulation-induced dystonia from capsular responses.
Teleradiographic x-ray controls were regularly performed to check whether the electrode
was following the calculated trajectory. Once the optimal target point resulting in best
clinical improvement at lowest stimulation intensities had been defined, the testing
electrode was replaced by the permanent quadripolar stimulating electrode (Model DBS
3389, Medtronic, Minneapolis, MN, 0.5-mm spacing between each of the four electrodes)
placing the most distal electrode pole (defined as pole 0 on a scale ranging from 0 to 3) at
the clinically defined optimum target point. The lead was affixed with a suture and
additionally stabilized by application of methyl methacrylate. The correct electrode
position was finally documented in the operative room (OR) by using teleradiography.
After both leads have been placed (the right non-dominant side was done first),
the anesthesiologists were informed that they may liberalize sedation to make the patient
comfortable. One lead was carefully tunneled so that its connector was brought out into
the contralateral incision. The residual lead length from the tunneled lead was coiled
around its ipsilateral burr hole cover to avoid having too much lead under the incision.
The incision on the tunneled side was then closed with meticulous attention to avoid
catching the traversing lead with a stitch. The second incision, with a short length of the
contralateral lead and the ipsilateral lead coiled around its own burr hole cover, was
temporarily closed. The head frame is removed in preparation for implantation of the
pulse generator (IPG).
Patients and Methods 90
Neurostimulator implantation
Implantation of the programmable pulse generator was done the same day as the
electrode placement. The procedure was performed under general anesthesia. Once again,
prophylactic antibiotics were administered 45 min prior to skin incision. The head was
thoroughly cleaned and prepped along with the neck and upper chest. An infraclavicular
subcutaneous pocket was then created over the pectoralis fascia. This should be sized so
as to hold the implanted pulse generator (IPG) without leaving significant excess space
that could become filled with seroma. The subcutaneous tunneling device was passed
from the cranial incision to the pocket incision. Once the tunnel was created, the proximal
extension connector was placed in its carrier and brought cranially through the tunnel
until it reached the cranial incision. The slim-line boot was placed on the electrode and
the lead and connector were attached. Excessive force on the screws should be avoided.
The current equipment includes a torque wrench that is designed to prevent this. The boot
was slid over the connector and secured with multiple ties. The other end of the extension
was placed into the generator and the screws were tightened. The generator was tacked
down to the pectoralis fascia with two silk sutures to prevent migration and rotation. Any
extra extension lead was coiled beneath the IPG. Gentle traction on the extension was
used to remove any significant kinks or bends in the lead. The connector should be seated
over the occipital region rather than in the neck, where the connector could become
subjected to excessive torque, risking lead fracture. A multilayer closure of all incisions
is performed.
►Postoperative Management
Postoperative care
After recovery from anesthesia the patients were monitored in the intensive care
unit overnight, restarted on all parkinsonian medications, and transferred to the
neurosurgical floor on the first postoperative day. Antibiotics were administered
intravenously for two days following the surgery. Patients were discharged from the
hospital on postoperative day two, or referred for rehabilitation as desired.
Patients and Methods 91
R esults
A series of 60 patients (20 Egyptians and 40 Germans) with idiopathic
Parkinson’s disease (PD) treated with subthalamic nucleus (STN) deep brain stimulation
(DBS) in The Department of Neurosurgery at Tanta University and The Centre for
Stereotactic and Functional Neurosurgery at The University of Cologne, Germany, over
more than five years from January 2007 to March 2012.
1) Sex distribution
In our series, 60 patients (42 males and 18 females) with idiopathic PD underwent
bilateral stereotactic guided STN implants and received continuous stimulation for the
subsequent years (Table 3, Figure 17).
Male 42 70
Female 18 30
Total 60 100
Patients had a mean age at PD onset of 48.5 years, a mean age at implant of 59.5
years with mean duration of symptoms of 10 years. Youngest age at STN DBS surgery
was 29 years while the oldest was 78 years. The shortest duration of symptoms was 4
years. The longest duration of symptoms was 25 years (Table 4).
3) Age groups
In the age group 61-70, we had 22 patients comprising 36.7%. We had 7 (11.7%)
patients above the age of 70 years and only 2 (3.3%) patients below 40 years (Table 5,
Figure 18).
<40y 2 3.3
40-50y 10 16.7
51-60y 19 31.7
61-70y 22 36.7
>70y 7 11.7
Total 60 100.0
Twenty six (43.33%) of patients had duration of symptoms of 6-10 years. Only 4
(6.66%) patients had duration of symptoms of more than 20 years (Table 6, Figure 19).
≤ 5 years 7 11.66
6-10 y 26 43.33
11-15 y 13 21.66
16-20 y 10 16.66
>20 4 6.66
5) Subtype of PD
Tremor-dominant PD 6 10
Akinetic-rigid PD 36 60
Equivalent-type PD 18 30
Total 60 100
Fourty three (71.7%) patients had moderate parkinson’s disease (H&Y Stage III)
while 17 (28.3%) patients had severe parkinson’s disease (H &Y Stage IV) (Table 8,
Figure 21).
Stage I 0 0
Stage II 0 0
Stage IV 17 28.3
Stage V 0 0
Total 60 100
Mean preoperative off medication total UPDRS III score was 50.89 while the
mean preoperative on medication total UPDRS III score was 21.74. Mean preoperative
off medication bradykinesia score was 10.84 while the mean preoperative on medication
bradykinesia score was 5.79. Mean preoperative off medication tremor score was 3.47
while the mean preoperative on medication tremor score was 1.66. Mean preoperative off
medication rigidity score was 5.18 while the mean preoperative on medication rigidity
score was 1.84. Mean preoperative off medication postural instability and gait score was
5.46 while the mean preoperative on medication postural instability and gait score was
1.68 (Table 9).
UPDRS-II was scored referring to the patient’s on and off conditions in the 4
weeks preceding the evaluation. The subscore for freezing of gait (item 14) was analyzed.
Mean preoperative off medication total UPDRS II score was 26.5 while the mean
preoperative on medication total UPDRS II score was 17.5. Mean preoperative off
medication freezing subscore was 2.1 while the mean preoperative on medication
freezing subscore was 1.4.
Mean current AC-PC-Line length measured was 25.76 mm while the mean
biparietal diameter measured was 131.67 mm (Table 12).
Table 12: AC-PC based localization of STN target in 60 patients with PD.
The functional coordinates for STN target are measured in millimeters and shown
in (Table 13). “X” represents medio-lateral coordinate, “Y” represents antero-posterior
coordinate (positive for anterior and negative for posterior) and “Z” represents vertical
coordinate (positive for superior and negative for inferior). All
Mean current amplitude used was 3.24 V (range 2-4.5 V). Mean current
frequency was 146.84 Hz (range 130-185 Hz). Mean pulse width was 68.79 µs (range 60-
90 µs) (Table 14).
Patients were followed up for a mean period of 32.4 months (Table 15).
Table 16: Overall change in H & Y scale among 60 patients with PD operated upon.
Results 102
The mean postoperative off UPDRS III score was 27.74 with the rate of
improvement in off UPDRS III score was 45.5%. The mean postoperative on UPDRS III
score was 7.84 with the rate of improvement in on UPDRS III score was 63.9%.
The mean postoperative off bradykinesia score was 4.82 with the rate of improvement in
off bradykinesia score was 55.5%. The mean postoperative on bradykinesia score was
2.15 with the rate of improvement in on bradykinesia score was 62.9%.
The mean postoperative off tremor score was 1.11 with the rate of improvement in off
tremor score was 68.01%. The mean postoperative on tremor score was 0.39 with the rate
of improvement in on tremor score was 76.5%.
The mean postoperative off rigidity score was 1.46 with the rate of improvement in off
rigidity score was 71.81%. The mean postoperative on rigidity score was 0.39 with the
rate of improvement in on rigidity score was 78.8%.
The mean postoperative off postural instability & gait score was 2.98 with the rate of
improvement in off postural instability & gait score was 45.42%. The mean postoperative
on postural instability & gait score was 0.64 with the rate of improvement in on postural
instability & gait score was 61.9% (Table 17).
Results 103
Bradykinesia
Off 8 13 10.84 3 8 4.82 55.5
score
(0-12)
On 3 9 5.79 2 5 2.15 62.9
Rigidity score
Off 3 8 5.18 1 3 1.46 71.81
(0-20)
Table 17: Overall change in severity of parkinsonian symptoms measured by UPDRS III in
60 patients with PD operated upon.
Results 104
Postoperative mean L- Dopa equivalent dose (LED) was 452.6 mg and thus
reduced by 64.4% postoperatively. The mean postoperative UPDRS IV total score was 2.8
with the mean rate of improvement was 65.9%. The mean postoperative L Dopa induced
dyskinesia score was 0.54 with the mean rate of improvement was 83.6%. The mean rate
of improvement of off duration subscore was 71.4% (Table 18).
The mean postoperative off UPDRS II score was 11.45 with the rate of
improvement in off UPDRS II score was 56.79%. The mean postoperative on UPDRS II
score was 6.8 with the rate of improvement in on UPDRS II score was 61.4%.
The mean postoperative off freezing subscore was 0.8 with the rate of improvement in off
freezing subscore was 61.9%. The mean postoperative on freezing subscore was 0.4 with
the rate of improvement in on freezing subscore was 71.42% (Table 19).
Results 105
5) Overall outcome
Table 21 summarizes the surgery and device related adverse events reported for
the 60 patients operated upon in this study. Additionally, table 22 lists the stimulation
related adverse events noted in our study. Operative complications were noted in 18/60
patients (30%). They were transient in 14/18 patients (77.8%).
Two patients (3.3%) had transient postoperative confusion and hallucinations. There was
1 device-related infection (internal pulse generator removal was done and replaced after 6
months with new one). Lead displacement was detected in two patients (revision surgery
was done) while lead fracture occurred in only one patient (lead replacement was done).
Results 107
Seizures 0 0
Pulmonary embolism 0 0
Lead migration 0 0
Table 21: Surgery and device related Complications in 60 patients with PD operated upon.
Speech problems were seen in five patients and seemed to be caused by excessive
stimulation of the corticobulbospinal tract located laterally. These speech problems were
transit and required stimulation parameters adjustment.
Emotional lability problems including mania, depression, and other psychosis were seen in
three patients treated with STN DBS in our study. Mania was usually transient in the
immediate postoperative period. Depression was generally alleviated by increasing the
dose of the dopaminergic treatment.
Results 108
Paresis 0 0
Figure 23: Trajectory planning. In this axial T2-weighted scan, both trajectories to the
subthalamic nucleus are drawn in. The target points are marked by crosses.
Figure 24: The location of the active electrode in relation to the stereotactic frame was
determined from intraoperative stereotactic X-rays (anteroposterior and lateral) after final
implantation of the permanent stimulation electrode.
Discussion 110
D iscussion
Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for
Parkinson's disease (PD). It is considered a surgical treatment for patients with intractable
tremor or for those patients who are affected by long-term complications of levodopa
therapy such as motor fluctuations and severe dyskinesias. The DBS procedure contrary
to ablative surgery has the unique advantage of reversibility and adjustability over time.
Target selection
All our 60 patients in this study underwent bilateral STN DBS electrode
placement. Sub-thalamic nucleus deep brain stimulation is currently considered superior
to GPi-DBS because it has effectively provided significant improvement of the motor
conditions of patients with motor fluctuations and dyskinesias, and has allowed to reduce
antiparkinsonian medication. Moreover STN DBS has allowed the possibility to also
influence the subthalamic region (which contains pallidofugal fibres) and lower energy
consumption (Anderson et al. 2005; Limousin and Martinez-Torres 2008). Thalamic
stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of
contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease
(Volkmann 2004).
Patient selection
The most important step in successful DBS remains attention to selecting the
appropriate candidate. A multi-disciplinary approach (neurologist, neurosurgeon,
neuropsychologist, and psychiatrist) is the best and safest method for selecting DBS
patients. In our study, the assessments are performed by experienced DBS teams and the
results of individual evaluations are discussed in a multidisciplinary team meeting prior
to proceeding with surgery.
In our study, positive clinical outcome was not associated with age or gender. The
majority of centers have arbitrarily utilized an upper age limit of 75 years but there is no
consensus on what a safe upper age limit should be for DBS surgery. Russmann et al.
(2004) showed that patients over 70 years old had worsening of UPDRS motor score after
Discussion 111
STN-DBS. So it is possible that older patients benefit to a lesser extent than younger
ones. Moreover, older patients might also tolerate surgery less because of the co-
morbidities, and they might be at a higher risk for mental deterioration after STN-DBS
(Saint Cyr et al. 2000). We did not find our older STN-DBS patients did less well
although the mean age was 59.5 years. It is recommended that patients older than 75
should be evaluated on a case-by-case basis and consideration for the level of disability,
degree of expected improvement, presence of medical comorbidities, life expectancy,
cognition, and the ability to satisfactorily meet the operative and postoperative
requirement of surgery should all be weighed rather than age alone.
Timing of surgery has been a matter of debate since the efficacy of STN DBS is
widely recognized. The established approach is to offer surgery to patients only when
medical therapy has failed and all other options have been exhausted as the risk of
surgery may only be justified under such circumstances. Despite this prevailing view,
Kleiner-Fisman et al. (2006) has revealed that patients with milder disease (as
determined by lower baseline UPDRS III medication off scores) were increasingly being
operated upon in studies published after 2002. Charles et al. (2014) provide preliminary
evidence that DBS is well tolerated in early PD. The results of their trial provide the data
necessary to design a large, phase III, double-blind, multicenter trial investigating the
safety and efficacy of DBS in early PD. This trend suggests that DBS is becoming a more
accepted treatment modality and being considered earlier in the course of PD. The
possible merits of early surgery are to avoid disability and prevent loss of employment.
Discussion 112
Target localization
►Imaging
Some centers use a CT scan (Samuel et al. 1998), while others use a MRI (Vitek
et al. 1998) or a combination of both (Iacopinno et al. 2003). The potential benefits of
CT include faster scan times, less expensive equipment, and no distortion of images. Its
disadvantages are poorer anatomic detail including grey-white differentiation. The
potential benefits of MRI include enhanced anatomic detail, easier visualization of the
intercommissural line in the sagittal plane, and better grey-white matter differentiation. It
is possible to visualize and directly target the STN. However, it can be difficult to
differentiate the STN from the substantia nigra. The disadvantages of MRI include image
distortion, long scanning times, and the other standard contraindications for MRI (Giller
et al. 1998).
In our study, we used CT/MRI based indirect targeting. Regarding these points,
the fusion of preoperative MR images with stereotactic CT scans has some advantages: 1)
the stereotactic MR data set that is created by the fusion process, displays a high spatial
accuracy; 2) the patient/object–related distortion of MR imaging is nearly corrected; and
a more practical aspect is that 3) MR-based stereotaxy is possible, even at institutions in
which an MR unit is not located close to or inside the OR. Nonstereotactic MR imaging
was performed 2 to 3 days before surgery. The data obtained from MR images were
integrated into the 3D stereotactic coordinate system by using landmark-based image
fusion.
►Physiological Targeting
patients while MER was used only in 5 patients of the German group (40 patients). MER
was used when MRI scans were not of sufficient quality to visualize the target because
the nuclear boundaries were indistinct or when MER was the preferred method of the
neurosurgeon. MER appears to provide a patient-specific physiological map that may not
only be more anatomically accurate than image-based targeting, but that also may be
more functionally relevant for final target determination and provide better definition of
vital structures to be avoided. Most current literature supports the use of some form of
microelectrode refinement in targeting deep brain structures for movement disorder
surgery (Zonenshayn et al. 2000). Numerous other studies have reported that MER
changed the final target in most or all cases, regardless of choice of deep brain target and
regardless of whether lesioning or stimulation was employed (Forster et al. 1999;
Bejjani et al. 2000).
Stimulation parameters
The mean current amplitude used for therapeutic stimulation was 3.24 V (range 2-
4.5 V). Mean current frequency was 146.84 Hz (range 130-185 Hz). Mean pulse width
was 68.79 µs (range 60-90 µs).
In our study, the motor Unified Parkinson’s Disease Rating Scale (UPDRS III)
was used as a primary outcome measure for assessment of clinical improvement because
this measure is most commonly reported in the published literature pertaining to the
surgical treatment of PD. UPDRS Part III is based on a neurological examination, and
requires observation of the patient sitting quietly at rest, carrying out movements,
standing, walking and in response to challenged postural reflexes (Fahn et al., 1987).
►Bradykinesia
In our study, the rate of improvement in OFF bradykinesia score was 55.5% while the
rate of improvement in ON bradykinesia score was 62.9%. Limousin et al. (1998)
reported a 56% improvement in akinesia after STN DBS in response to stimulation alone,
but noted a 12% worsening in akinesia scores when patients were tested with both
stimulation and L-Dopa. Other reports documented improvements in akinesia that range
from 25% to 71% (Abosch et al. 2003; Rizzone et al. 2014).
►Tremor
In our study, the rate of improvement in OFF tremor score was approximately 68
% while the rate of improvement in ON tremor score was 76.5%. This is consistent with
other studies that reported 74-79% reduction in total tremor score (Rodriguez et al.
1998; Burchiel et al. 1999).
Discussion 115
We found 45.5% improvement in OFF postural instability & gait score while the
rate of improvement in ON postural instability & gait score was approximately 62%. In
agreement with our data, Fasano and colleagues (2010) found a lower rate of postural
instability at 5 and 8 years from surgery. The positive effects of subthalamic nucleus
DBS on balance and postural stability, which was reported by most authors, seem to be
mostly related to the improvement of rigidity and bradykinesia, rather than on a specific
effect on balance and gait. In comparison with our data, the results of a recent meta-
regression analysis (St George et al., 2010) showed that postural instability and gait
disability progress over time in patients treated with subthalamic nucleus DBS. Some
degree of variability might be observed in the results of long-term subthalamic nucleus
DBS clinical studies, likely reflecting a combination of factors, such as disease duration
at the time of subthalamic nucleus DBS and age at Parkinson’s disease onset. This may
be also due to different disease mechanisms with the involvement of non-dopaminergic
systems as well as other cerebral regions, for example, the pedunculopontine (Hamani et
al. 2004).
L Dopa induced dyskinesia score was 83.6% while the mean rate of improvement of off
duration subscore was 71.4%. This is consistent with other studies that reported
76.9±12.6% (range: 58–91%) reduction in ON medication-ON stimulation dyskinesia
severity for STN DBS (Krause et al. 2001; Vesper et al. 2002; Herzog et al. 2003).
Our study showed that the activities of daily living were also improved by STN
deep brain stimulation in the long-term follow-up. The rate of improvement in OFF
UPDRS II score was 56.79% while the rate of improvement in ON UPDRS II score was
61.4%. The rate of improvement in OFF freezing subscore was 61.9% while the rate of
improvement in ON freezing subscore was 71.42%.
This is consistent with other studies that reported 50% improvement in ADL
scores after surgery (Kleiner-Fisman et al. 2006). Zibetti et al. (2011) reported that
UPDRS-II OFF score improved 66% at 1 year and 47% at 5 years. OFF period freezing
of gait score improved at 1 year, but no longer at 5 years with respect to baseline.
UPDRS-II score in the ON condition, did not vary significantly 1 and 5 years after
surgery with respect to baseline. ON period freezing of gait score did not vary
significantly 1 and 5 year after surgery.
Overall outcome
Table 22 displays our results in comparison with the results of other centers as regarding
the change in UPDRS III, ADL, dyskinesia and medication.
Discussion 117
Thobois et al. 14 12 62 60 91 NA
2002 months
Kleiner-Fisman 25 12-52 41 24 82 36
et al. 2003 months
Visser- 20 4 years 43 59 74 47
Vandevalle et al.
2005
Table 22: Clinical studies on the treatment of advanced Parkinson disease with bilateral
STN stimulation. NA not addressed: UPDRS Unified Parkinson’s Disease Rating Scale;
ADL activities of daily living.
Discussion 118
Adverse effects
Most hardware problems, however, occurred in the first patients of a series and were less
frequent afterward. This sheds light on the sophisticated nature of the procedure, which
requires one to learn extensive neurosurgical skills before performing DBS surgery.
Possible therapeutic problems with the STN DBS result from the complex
interactions of medical therapy and electrical stimulation. One of the challenges in the
follow-up treatment is to distinguish between genuine stimulation-induced side effects
and preexisting symptoms of the disease that are uncovered by a combination of reduced
dopaminergic therapy and inadequate stimulation effects (Volkmann 2004).
Discussion 119
Speech problems were seen in five patients in our study. These speech problems
were transit and required stimulation parameters adjustment. Stimulation-induced
dysarthria is caused by excessive stimulation of the corticobulbospinal tract located
laterally to the STN. Therefore, dysarthria is inevitable with the increase of stimulation
power. In such cases, changing stimulation parameters is effective in most patients. As
the effect on cardinal PD symptoms may decrease with changing stimulation parameters,
a balance between the expected effect of DBS and the side effect of dysarthria should be
achieved by determining the patient's satisfaction level. Dysarthria in the early period
after surgery may be a problem of verbal fluency, which is a cognitive sequela, described
later. On the other hand, dysarthria in the later period may be caused by disease
progression (Umemura et al. 2011).
STN-DBS seems to be a relatively safe treatment option for medically refractory PD.
Serious complications with permanent sequelae are rare, but significant incidences of
adverse effects may occur. Surgery-related and device-related complications could be
reduced with increased surgical experience and the introduction of new surgical
equipment and technology. Treatment-related adverse events may be caused not only by
stimulation effect but also excessive reduction of dopaminergic medication after surgery
or progression of disease. Physicians engaged in this treatment should have a
comprehensive grasp of the probable complications and how to avoid them.
Summary and Conclusion 121
In the past years there has been an increasing interest in the surgical therapies for
Parkinson's disease. This renewed interest is related to different factors. First,
pharmacological treatments are still unable to alter substantially the progression of the
disease and after a few years they generally cause motor complications and dyskinesias.
Motor complications in Parkinson's disease (PD) result from the irregular plasma
fluctuations of oral levodopa. Secondly, the great advances in the surgical techniques,
especially with the improvement of stereotactic surgery, have decreased morbidity in
recent years. Finally, the introduction of deep brain stimulation, now allows surgical
treatment without damaging brain structures.
Both the GPi and STN targets for DBS in Parkinson's disease (PD) might offer
similar motor benefits. However, the STN has become the primary target in most DBS
centers because of a more profound anti-akinetic effect allowing the reduction of
medication by some 50–60%. Furthermore, long-term efficacy appears to be better for
neurostimulation of the subthalamic nucleus because several reports describe a delayed
decline of stimulation efficacy in GPi patients, which has not been observed after STN-
DBS.
The horizon for tailoring DBS for PD over the next 5 years will probably include
advances in clinical management and advances in research. Clinically, we anticipate that
more data will become available to help assist interdisciplinary teams in deciding: who
should get DBS; what brain target(s) should be implanted; whether patients should be
implanted unilaterally versus bilaterally; and what specific cognitive, mood and motor
profiles may sway a change in surgical target or surgical approach. In the research realm,
we anticipate greater clarity, especially in explaining the cognitive and neuropsychiatric
effects of DBS.
We also anticipate advances in imaging, targeting and DBS hardware. These advances
will aid in better predicting the benefits and the side effects of the therapy. Smart devices,
which provide physiological output, may become available and assist clinicians and
researchers in DBS placement, optimization and DBS programming.
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ا زء ا ث ن ا س ا و د رض ر ون ن دة )٪75-50 ا ر( -
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٪64.4د ا #ا را .و ن و ط دل ر ل-دو .5' -و د م '+ض ر
ن ن و ط دل ا ر ل-دو .٪83.6 ر ا ر D 5ر ن ا
18 ر ل-دو .٪71.4و د و ظت ' -ت د ا #ا را ا ت Dر
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ا ذ ن د ت م ' -ت(.
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& + ,د * & أ .د /
أﺴﺘﺎذ ﺠراﺤﺔ اﻝﻤﺦ و اﻷﻋﺼﺎب
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2014