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9
A Feedback control
B Feedforward control
movements
MOTOR SYSTEMS I: DESCENDING PATHWAYS AND CEREBELLUM
Primary motor cortex
Corrective
feedback circuit
Spinocerebellum
Input about
actual
movement
Dorsal
spinocerebellar tract
Fig. 9.17 Cerebellar control of movement. The cerebellum can operate using (A) feedback or (B) feedforward circuits to correct errors or predict
movement respectively.
Ventrolateral
thalamic nucleus
Pontine nuclei
Reticular
formation
Medial and lateral
reticulospinal tracts
Smooth movements
Intended
movement
Red
nucleus
Rubrospinal
tract
Corticospinal
tract
Motor association cortex
(supplementary or premotor)
Cerebrocerebellum
Ventral anterior
thalamic nucleus
Primary motor
cortex
Corticospinal
tract
Lower
motor neurons
Rapid, predicted
preprogrammed
Table 9.6 Causes of cerebellar diseases
Genetic (e.g. Friedreich’s ataxia [autosomal recessive],
Stroke
Primary (e.g. medulloblastoma) or secondary tumours
Trauma
Degeneration
Toxicity and metabolic disturbances (e.g. alcoholism, anticonvulsant
Miscellaneous (e.g. hydrocephalus, multiple sclerosis)
Developmental (e.g. cerebral palsy, Dandy-Walker malformation)
lead to loss or disturbed migration of granule and Purkinje
cells in the cerebellum. Lesions of the cerebellum must be
quite large before obvious symptoms appear, as there is
much functional redundancy within the cerebellum due to
the multiple somatotopic maps present.
Damage to the cerebellum does not produce paralysis or
muscle weakness, or affect the ability to start or stop movements, but does affect the precision and coordination of
movements. This is termed ataxia. Focal lesions of the cerebellum produce deficits on the same side of the body as the
lesion. The signs of cerebellar damage are as follows:
• asynergia:lossordecompositionofcoordinated
spinocerebellar ataxia [autosomal dominant])
drugs, hypothyroidism, vitamin E deficiency)
movement
• dysarthriaanddysphonia:speechdeficitssuchas
• intentiontremor:swayingtoandfroofthelimb
• nystagmus:involuntaryoscillatingeyemovementsin
• dysmetria:alterationintherateandforceofmovement,
• dysdiadochokinesis:theinabilitytoperformrapid
• hypotonia:lossofmuscletoneduetodecreased
of the head in an up- and- down (‘yes- yes’) or side- toside (‘no- no’) motion. Pendular (slow) reflexes may also
occur, but they are of little use as localizing signs.
effects of alcohol. Drunkenness is associated with many
of the symptoms of mild cerebellar damage! For example, slurred or incoherent speech, incoordination, ataxic
gait, clumsiness and double vision are all signs of
slurring due to errors in the timing of impulses to the
muscles controlling speech; articulation problems:
words become broken down into individual syllables
and flow becomes ‘explosive’ or ‘scanning’
perpendicular to the direction of movement; this is
present only during reaching movements and not
at rest
horizontal, vertical or circular directions
for example, over- or under- reaching for an object
alternating movements such as pronation and
supination of the hand
activity in γ- motor neurons
Other signs may include titubation, a rhythmic tremor
The cerebellum is particularly susceptible to the
199THE NERVOUS SYSTEM
9
cerebellar damage. These disorders reflect the role of the
cerebellum in the coordination of skilled movements.
Lesions of the vermis lead to truncal ataxia. This is
most commonly seen in children and is due to a tumour
called a medulloblastoma, which grows from the granule cell layer to invade (and block) the fourth ventricle.
Morning headache, dizziness, vomiting (due to raised
intracranial pressure affecting cranial nerve function)
and lethargy are common symptoms, and on physical
examination, a dramatic feature is the inability to stand
upright without support. Attempts to walk result in a
wide- based gait with reeling and swaying from side to
side. Truncal ataxia reflects the involvement of the flocculonodular lobe, which regulates balance and the coordination of the para- axial muscles. Symptoms are often
absent when the child is lying down. These tumours are
highly malignant and can spread to other parts of the
nervous system. They are treated surgically, and adjuvant chemotherapy and radiotherapy (except when the
child is less than 5 years old because of adverse effects
on brain development) are used to prevent reoccurrence.
Survival rates are 60%–85% at 5 years after diagnosis,
depending on how aggressive the post- radiation chemotherapy is. Prognosis is poorer for surgery only, as the
tumour re- emerges.
Lesions of the anterior lobe result in gait ataxia. This
is commonly seen in chronic alcoholics, where alcohol abuse causes neuronal degeneration of granule and
Purkinje cells, resulting in cortical atrophy of the anterior lobe. This affects the coordination of the lower limbs,
MOTOR SYSTEMS I: DESCENDING PATHWAYS AND CEREBELLUM
resulting in a staggering, drunken gait, even when the
person is sober. As the degeneration progresses, loss of
control in trunk and arms and eventually speech may
ensue. The person also suffers from dysdiadochokinesis
and the heel- to- shin test is almost impossible to perform,
as the patient will have sensory ataxia (positive Romberg
sign) due to peripheral neuropathy.
Damage to the posterior lobe commonly results from
stroke, tumours, degenerative disease or traumas that
affect a cerebellar hemisphere, peduncle, midbrain or
pons. Symptoms manifest as incoordination of voluntary
movement and loss of muscle tone. The patient presents
with tremor of the limbs, dysmetria and dysdiadochokinesia, resulting in clumsiness of movements. There are
often speech impediments with regard to phonation and
articulation.
Self-assessment case study
Bryan, a 7-year-old boy, is brought to the GP by his mother
who is worried by his recent behaviour. For the last month he
has been suffering on and off from headaches, particularly in
the morning when he awakens. He has been resting a lot and
sleeps at least 9 hours a day. He also appears lethargic. In the
past week the pain of the headaches has been so severe he has
been sick several times and has been complaining of dizziness.
On examination, motor system testing shows him to sway from
side to side when standing. There is nystagmus and diplopia
and clumsiness of movement when asked to grab things. The
doctor suspects a brain tumour and sends him to the local hospital for a CT scan. The results confirm the suspicion. Bryan is
immediately admitted to hospital and scheduled for brain surgery the next day.
1. Explain the signs and symptoms
This case is an example of childhood medulloblastoma.
Medulloblastoma presents with the usual symptoms of a posterior fossa tumour. The symptoms are often absent when the
child is lying down. Morning headache and vomiting are due
to raised intracranial pressure affecting meningeal afferents.
Lethargy is also a common presentation. On physical examination, cerebellar signs dominate, e.g. truncal ataxia (reeling/
swaying, wide-based gait) and other signs of cerebellar dysfunction, e.g. loss of balance and clumsiness are common as
the tumour enlarges. Raised intracranial pressure may cause
hydrocephalus resulting in papilloedema and visual difficulties. Dizziness occurs as the flocculonodular lobe that is connected to the vestibular apparatus and is involved in balance is
affected, and nystagmus also indicates that the flocculonodular
lobe is affected.
2. Explain the pathophysiology of the brain tumour
Medulloblastomas are highly malignant and tend to
seed along the neuraxis following the CSF pathways.
They arise from the granular layer of cerebellar cortex and
invade the 4th ventricle. They can block CSF flow, yielding
hydrocephalus.
3. What treatment options are available and what is the
prognosis?
These tumours are treated surgically and, in most cases,
complete macroscopic removal is possible. Occasionally the
tumour is attached to the floor of the 4th ventricle, in which
case a sheet of tumour cells have to be left behind. In these
cases the tumour often returns. Adjuvant therapy is then essential. Chemotherapy and radiotherapy are used, as medulloblastomas are radiosensitive. Radiation of the entire neuraxis is
performed, as these are extremely malignant tumours that can
spread to secondary sites such as the spinal axis.
Current treatments result in a 60%–85% survival rate 5
years after diagnosis depending on how aggressive the postradiation chemotherapy is. Prognosis is poorer for surgery only
treatments as tumours often reappear elsewhere.
200 SYSTEMS OF THE BODY
MOTOR SYSTEMS II:
THE BASAL GANGLIA
Chapter summary
1. The basal ganglia are a group of subcortical structures that include
the striatum (caudate and putamen), globus pallidus (internal
and external), substantia nigra (SN) and subthalamic nucleus.
These structures have a role in the initiation and maintenance of
movement. The striatum receives major cortical glutamatergic input,
and its activity is modulated by dopaminergic input from the SN.
The output from the basal ganglia is directed towards the thalamus,
which sends projections to the cortex, thus closing the corticobasal
ganglia- thalamocortical loop.
2. Several pathways connect the cortex and the basal ganglia nuclei:
the direct, indirect and hyperdirect pathways. Neurodegenerative
processes in the basal ganglia lead to imbalance in the activity of
these pathways and emergence of hypokinetic disorders, such as
Parkinson’s disease, or hyperkinetic disorders, such as Huntington’s
disease.
10
3. Parkinson’s disease is characterized by rigidity, tremor and
bradykinesia, and a range of non-motor symptoms including
depression, cognitive dysfunction and autonomic nervous system
dysfunction. There is a marked loss of dopaminergic cells in the SN
and presence of widespread aggregates of the protein α- synuclein
in Lewy bodies and Lewy neurites. As the disease evolves, the
neurodegeneration progresses from the subcortical to the cortical
level and affects multiple cell types and neurotransmitter systems.
Pharmacological management is based on the principle of dopamine
replacement therapy using the precursor L- DOPA and dopaminergic
agonists. Treatment is symptomatic and associated with long- term
complications.
10
4. Huntington’s disease is an inherited autosomal dominant disease
associated with a mutation in the gene encoding the protein
huntingtin. The neurotoxic consequences of this mutation lead to
loss of cells in the cortex and striatum and loss of striatal efferents.
The disease is characterised by involuntary choreic movements and
cognitive and psychiatric symptoms. Treatment is symptomatic and
based on the principle of reducing dopaminergic signalling.
5. Neuromodulatory techniques, such as deep brain stimulation, can
be used to address the complications of treatment in Parkinson’s
disease. Stimulation of the subthalamic nucleus leads to alleviation
of dyskinesias induced by dopaminergic stimulation and allows a
marked reduction in drug dosage.
6. Non-pharmacological treatments currently being explored for
neurodegenerative diseases of the basal ganglia include the use of graft
MOTOR SYSTEMS II: THE BASAL GANGLIA
cells that could replace the degenerating circuits, and blockade of the
effect of mutated genes, for example, using antisense- based therapies.
Introduction
The smooth execution of movements involving the trunk
and the limbs, and the maintenance of posture, balance
and normal gait, would not be possible without the coordinated activity of supraspinal centres, in particular,
the upper motor neurons (UMNs) of the corticospinal
pathway, the lower motor neurons (LMNs) of the spinal
cord ventral horn and an intact neuromuscular junction
and muscle. Disturbances in the function of the major
descending motor pathways are associated with paresis,
paralysis or spasticity. In parallel, several other structures provide the irreplaceable central input required for
normal motor activity and are involved in its continuous
control and coordination. The basal ganglia and cerebellum are the main structures fulfilling these roles. They
are at the interface between the intention and execution
of movement. Neuronal activity in these structures is
correlated temporally with motor activity in a complex
manner. This chapter is dedicated to the basal ganglia
and illustrates how their dysfunction leads to specific
alterations in motor performance, which can be severely
debilitating (Box 10.1). Disorders of the basal ganglia can
lead to either hyperkinetic or hypokinetic manifestations.
execution of movement. They comprise the caudate
nucleus, putamen and globus pallidus (in the telencephalon), subthalamic nucleus (in the diencephalon) and
substantia nigra (SN; in the mesencephalon). The relative
locations of these structures are described in Chapter 1.
The caudate nucleus and the putamen are two nuclei
that are interconnected and form the striatum. The globus pallidus has an internal (or medial) and an external
(or lateral) division (termed GPi and GPe, respectively).
The striatum receives afferents from the neocortex, thalamus and SN. The globus pallidus receives projections
from the striatum and subthalamic nucleus. The major
output of the basal ganglia, which represents mainly
projections from the GPi and SN, is directed to thalamic
nuclei (in particular, the ventral anterior, ventral lateral
and centromedian nuclei), which project to motor and
prefrontal cortical areas. A smaller contingent of efferent fibres project to the pedunculopontine nucleus in the
brainstem tegmentum and to the superior colliculus. The
SN can be subdivided into substantia nigra pars compacta (SNpc) and substantia nigra pars reticulata (SNpr).
The pars compacta contains neurons that project to the
striatum, whereas the pars reticulata receives striatal
input and provides the nigral output.
Circuits and neurotransmitters
202
Basal ganglia: structure and organization
General organization
The basal ganglia consist of several subcortical interconnected nuclei that are involved in the initiation and
SYSTEMS OF THE BODY
The basal ganglia form a network of parallel loops and
circuits that integrate the neuronal activity in various
cerebral regions (motor, oculomotor, limbic and associative), the basal ganglia nuclei and the thalamic nuclei.
Lesion or degeneration in the basal ganglia leads to diseases that present with a range of characteristic motor
10
A
B
C
Box
10.1
Gavin Porter, a 57- year- old recently retired businessman,
came to the doctor with his wife because of ‘trembling’ that
affected his hands, in particular the right hand. Over the last
year, the trembling had become worse, and he sometimes felt
that his legs trembled very slightly too. He had also become
rather slow in his movements, and sometimes sat for hours
in an armchair with a rather expressionless face. His wife
found this irritating; she thought that his general mood had
changed and he had become more withdrawn. He was finding it increasingly difficult to button and unbutton his shirt
and tie his shoelaces. He had recently suffered two falls, one
of which had resulted in a serious skin laceration on his head.
When asked, he could not pinpoint a specific cause for these
falls. He was otherwise in good health. He had taken early
retirement in order to enjoy other activities, such as gardening and voluntary work. Gavin seemed to be deeply worried
about his progressive physical incapacity. In his moments of
anxiety about the future, the trembling was much worse.
1. What is the cause of the symptoms (i.e. tremor, rigidity,
2. Would confirmation of the diagnosis require additional
3. Are there any risk factors for developing this disease?
Case history
This case gives rise to the following questions:
slow movements, altered gait and balance)?
tests?
symptoms. Fig. 10.1 summarizes the functional organization of the basal ganglia and shows the major neurotransmitters present in afferent and efferent pathways.
The striatum is a heterogeneous structure consisting of two main compartments: the matrix and the
striosomes. These compartments can be identified by
the differential distribution of various neurochemical
markers such as the various subtypes of opioid receptors (mu [μ], delta [δ] and kappa [κ]) or the enzyme acetylcholinesterase. The majority of neurons in the matrix
and striosomes are medium- sized projection neurons,
which have highly collateralized axons and dendrites
endowed with dense spines. These cells are the medium
spiny neurons.
The cortex provides glutamatergic excitatory input to
all striatal projection neurons. The cortical projections are
organized somatotopically, innervating both the matrix
and the striosomes. The cortex is connected with the globus pallidus and the SN through several distinct pathways: direct, indirect and hyperdirect (see Fig. 10.1A).
1. The projection of the striatal medium spiny neurons
to the GPi and SNpr is known as the direct pathway.
The main neurotransmitter in this projection is γ-
aminobutyric acid (GABA), which is colocalized
with peptides such as substance P and dynorphins.
GPi and SNpr neurons project to the thalamus
and are also GABAergic. Thalamic neurons, which
contain glutamate, project to the cortex, thus closing
the loop.
MOTOR SYSTEMS II: THE BASAL GANGLIA
Cortex
Glutamate
Striatum
GABA
Glutamate
Fig. 10.1 Functional organization of the basal ganglia. The diagrams illustrate the functional organization of the basal ganglia circuits (A) under
normal conditions, (B) in Parkinson’s disease and (C) in Huntington’s disease. Thin and broken lines indicate pathways that are hypoactive, and
thick lines indicate pathways that are hyperactive. DYN, Dynorphin; ENK, enkephalin; GABA, γ-aminobutyric acid; GPe, external globus pallidus;
GPi, internal globus pallidus; SNc, substantia nigra compacta; SNr, substantia nigra reticulata; SNpc, substantia nigra pars compacta; SNpr,
substantia nigra pars reticulata; S P, substance P; STN, subthalamic nucleus.
ENK
Dopamine
GABA GABA
SNpc
GPe
GABA GABA GABAGlutamate Glutamate Glutamate
STN
GABA
SP and
DYN
Glutamate
GPi/
SNpr
Thalamus
GABA
Glutamate
GABA GABA
Glutamate
GPe
Striatum
GABA
ENK
Dopamine
SNpc
Cortex
STN
GABA
SP and
DYN
SNpr
Glutamate
GPi/
Thalamus
GABA
Glutamate
GABA
Glutamate
GPe
Striatum
GABA
ENK
Dopamine
SNpc
Cortex
STN
GABA
SP and
DYN
SNpr
Glutamate
GABA
GPi/
Thalamus
GABA
THE NERVOUS SYSTEM
203
10
2. In the indirect pathway, striatal GABAergic medium
spiny neurons (which also contain enkephalins)
project to the GPe. These pallidal neurons are
GABAergic and project to the subthalamic nucleus
(STN). The STN has glutamatergic neurons that
project to the GPi and SNpr. The circuit is ultimately
completed through the GABAergic nigrothalamic
projection and the glutamatergic thalamocortical
projections, as in the case of the direct pathway.
Another link between the direct and indirect
pathways is provided by neurons of the GPe, which
establish contact with the GPi and SNpr through axon
collaterals.
3. The third projection, the hyperdirect pathway, is
monosynaptic and glutamatergic. It links the frontal
cortex to the STN bypassing the striatum, thereby
facilitating faster stopping behaviours. In a similar
way to the indirect pathway, it has a net inhibitory
action on the thalamus and cortex.
MOTOR SYSTEMS II: THE BASAL GANGLIA
Through these three pathways the cortex modulates,
for example, increases (direct pathway) or decreases
(indirect and hyperdirect pathway) the excitatory thalamocortical projections. The presence of GABA as a main
transmitter in the striatal efferents indicates that the striatal projection neurons will have an inhibitory effect on
target cells in the SN and globus pallidus. In contrast,
the STN is a source of excitation through glutamatergic
transmission. Thus through parallel loops and the balance between excitation and inhibition, the basal ganglia
are involved in the transfer of information from the neocortex to the motor areas, in particular the premotor and
supplementary motor areas. This results in facilitation or
inhibition of the major descending motor pathways (e.g.
corticospinal projection).
The SNpc contains neurons that produce dopamine
and project to the striatum, exerting a modulatory influence on the activity of striatal projection neurons that
are involved in both the direct and indirect pathways.
Cortical input to medium spiny neurons is controlled by
dopaminergic fibres at the level of their dendrites and
the dendritic spines. Dopamine appears to facilitate the
activity of medium spiny neurons involved in the direct
pathway and to inhibit the activity of the medium spiny
neurons involved in the indirect pathway. The striatum
also contains several types of interneurons, for example,
cholinergic neurons. Nigral dopaminergic cells provide
inhibitory input to striatal cholinergic interneurons.
Although the latter represent less than 10% of striatal
cells, they exert important integrative functions in the
striatum.
Parkinson’s disease
Symptoms
Parkinson’s disease (PD) was first described in 1817 by
James Parkinson, a doctor with encyclopaedic interests,
who was practising in the East End of London (Box 10.2).
He based his monograph, ‘An Essay on the Shaking
Palsy’, on the analysis of six cases. The cardinal features
of this disease are motor: tremor (unilateral or bilateral),
bradykinesia and rigidity. They may occur in isolation or
in any combination (Box 10.3).
Tremor
The most prominent symptom is resting tremor of the
extremities and usually accompanies the disease. The
tremor has a characteristic frequency of 4–6 Hz and may
begin in only one extremity and spread to others. The
distal joints of the limbs are preferentially affected. In the
hand, the tremor is characteristic and involves the thumb
and fingers rolling together. This is called a ‘pill-rolling’
tremor. The tremor occurs at rest and disappears during
intentional movement and sleep. However, in the late
stages of the disease, an ‘active’ tremor may emerge with
a frequency of 6–8 Hz. Tremor is exacerbated by anxiety;
it primarily affects the hands but can also affect the lower
limbs, jaw and lips.
Box
10.2
James Parkinson was a general practitioner, whose medical writings attest to his busy medical career. However, his
intellectual interests were much wider. He was a respected
palaeontologist, and his two books ‘Organic Remains of a
Former World’ and ‘Outlines of Oryctology’ were considered reference works by his contemporaries. He also had an
interest in politics and social issues, as a member of several
‘reform societies’ and ‘revolutionary clubs’.
short definition of the disease, for which he also provides
a Latin synonym, ‘paralysis agitans’: ‘Involuntary tremulous motion, with lessened muscular power, in parts not
in action and even when supported; with a propensity to
bend the trunk forwards, and to pass from a walking to a
running pace: the senses and intellect being uninjured.’ He
believed that the disease had ‘escaped particular notice’,
and he hoped that other colleagues in the medical community would ‘extend their searches’ so that in the end they
could ‘point out the most appropriate means of relieving a
tedious and most distressing malady’. Parkinson provided a
graphic depiction of most of the symptoms of the disease
but apparently failed to appreciate features such as the significant muscular rigidity and bradykinesia.
description of this disease were made by the French neurologists Armand Trousseau and Jean-Martin Charcot and
their pupils. In recognition of James Parkinson’s first incisive insight into this pathology, it is the eminent neurologist Jean- Martin Charcot who gave the disease the name of
‘Parkinson’s disease’.
James Parkinson (1755–1824): a
physician and a radical thinker
In ‘An Essay on the Shaking Palsy’, Parkinson gives a
In the 19th century, other important contributions to the
204 SYSTEMS OF THE BODY
Box
10.3
Gavin had a full neurological examination. He was alert
and oriented for time and place. Memory and general
knowledge were appropriate for his age, but his speech
was slow and quiet, rather monotonous and almost devoid
of natural voice inflexions. His face was impassive, and he
rarely blinked. A mild resting tremor was present in the
orofacial musculature, which diminished on speaking or
swallowing.
normal. There was cogwheel rigidity upon passive movement of the limbs. The ‘pill- rolling’ 4–6 Hz tremor of the
right thumb and index fingers was abolished by volitional
movement. Gavin’s gait was rather slow. If given an abrupt
push, he could not quickly restore his posture, and was at
risk of falling. Cutaneous sensation and proprioception
were intact.
prescribed L- dihydroxyphenylalanine (L- DOPA) with carbidopa. The doctor discussed the prognosis with Gavin and
his wife.
1. Why was Gavin given L- DOPA with carbidopa and are
2. What is the long- term prognosis for this patient?
Case history (continued)
His strength was intact and deep tendon reflexes were
Gavin was diagnosed with Parkinson’s disease and was
This case gives rise to the following questions:
there any therapeutic alternatives?
Bradykinesia/akinesia
Bradykinesia is a slowing of normal movement. In the
advanced stages of the disease, the patient becomes
akinetic and shows almost no motor initiative. There is
reduced arm- swing when walking and reduced blinking,
and various simple or complex daily tasks (e.g. washing,
brushing the teeth, dressing and writing) can be affected.
There is a gradual loss of normal facial movement and
expression (Fig. 10.2). Speech is poorly articulated, and
the voice is quiet and monotonous. Eating and swallowing become increasingly difficult. This may result in
a tendency to drool (sialorrhoea). It is estimated that up
to 70% of patients ultimately experience drooling, which
may lead to dermatitis and aspiration.
Rigidity
Parkinsonian patients have increased muscle tone in
flexor and extensor muscles and typically present resistance to passive movement of the limbs. This rigidity is due to inappropriate sensitivity of the muscles to
stretching and an inability to obtain complete relaxation. The increased resistance to movement, combined
with tremor, leads to the ‘cogwheel’ phenomenon.
Manipulating the patient’s limbs feels like manipulating
a lead pipe; hence the term ‘lead pipe’ rigidity.
10
MOTOR SYSTEMS II: THE BASAL GANGLIA
A B
Fig. 10.2 (A) Rigid posture of a patient with Parkinson’s disease. (B)
Characteristic flexed posture of a patient with Parkinson’s disease.
(A, Drawn by Paul Richer, a former intern of Jean-Martin Charcot’s.
From Richer (1888). In Koller, WC, ed. Handbook of Parkinson’s
Disease. New York: Marcel Dekker Inc., 1987. B, From Hauser RA,
Zesiewicz TA. (1996) Parkinson’s Disease—Questions and Answers.
Merit Publishing International, Basingstoke.)
Other motor and non-motor manifestations of
Parkinson’s disease
Abnormalities of posture and gait are associated with
this disease and tend to appear at a later stage. The gait
of a parkinsonian patient becomes slow and shuffling,
and the posture is flexed (see Fig. 10.2). Patients have a
marked tendency to fall, which is partly due to the rigidity of limb and trunk muscles but also a consequence of
the failure of postural adjustment movements, such as
holding out the arms. As the disease progresses, ‘freezing’ also begins to appear. Patients become ‘frozen’ when
trying to initiate walking, when passing through narrow
spaces or when turning. This immobility can be overcome using sensory cues, such as drawing lines on the
floor, and asking the patient to step over them.
The patient’s handwriting is altered (Fig. 10.3), and as
the disease evolves, it becomes small and indecipherable
(micrographia). The skin may have a greasy appearance
(seborrhoea), and constipation is common. Other autonomic abnormalities, such as urinary dysfunction (in
particular, urinary incontinence due to bladder detrusor
hyperreflexia), increased sweating and sexual dysfunction, are also encountered in parkinsonian patients.
205THE NERVOUS SYSTEM
10
Fig. 10.3 A specimen of the handwriting of a patient with paralysis
agitans under the care of Professor Charcot at the Hôpital St Louis
in 1869. (From Charcot (1872). In Koller, WC, ed. Handbook of
Parkinson’s Disease. New York: Marcel Dekker Inc., 1987.)
Table 10.1 Classification of parkinsonian syndromes
Idiopathic Parkinson’s disease
Secondary parkinsonian syndromes
Infectious/post-infectious (e.g. linked to meningitis or HIV/AIDS)
Toxic (e.g. manganese or carbon monoxide poisoning)
Drug- induced (e.g. MPTP)
Metabolic (e.g. Wilson’s disease)
Posttraumatic (e.g. linked to brain injury)
Vascular (e.g. multiinfarct in cerebrovascular disease)
Tumour (e.g. meningioma)
Box
10.4
Gavin continued to take L- DOPA with carbidopa for 6 years.
MOTOR SYSTEMS II: THE BASAL GANGLIA
Initially, he complained of nausea and tiredness. The drug
improved his motor symptoms, especially during the first
year. However, the dose administered had to be increased
gradually, and during the last year, he had started suffering
from totally unpredictable complete immobility, although
he was taking his medication regularly. Sometimes, episodes of immobility alternate with abnormal violent
movement of his limbs, which he cannot control and finds
extremely embarrassing. His sleep is disturbed, and he complains of nightmares. He has frequent falls, and his wife
finds it very difficult to lift him. He has become very apathetic and withdrawn, and has lost interest in any activities
that he used to enjoy before he became ill.
following questions:
1. Was the prescription of L- DOPA with carbidopa the best
2. What could have been done to alleviate the additional
Case history (continued)
Gavin’s condition after 6 years of treatment raises the
choice when treatment was initiated?
problems that emerged in this case?
PD patients also present with sleep- wake cycle dysregulation, and, especially in the late stages of the disease, many patients present with memory impairment,
confusion and disorientation, and other features of
dementia. Cognitive deficits represent a significant clinical problem and may be compounded by the unwanted
effects of medication. It is estimated that dementia occurs
in approximately 30% of parkinsonian patients, especially when the disease is diagnosed after the age of 70
years. Depression is also very common at any stage of
the disease and may be reactive or part of the disease
process (Box 10.4). Interestingly, some of the non-motor
symptoms can predate the onset of the disease by years
or even decades. As the disease evolves, they become
increasingly prevalent and significantly affect the
patient’s quality of life.
The diagnosis of PD is made entirely on symptom
presentation and does not involve additional laboratory
Parkinsonian syndromes as part of other neurodegenerative
disorders
Multiple system atrophy
Progressive supranuclear palsy
Corticobasal ganglionic degeneration
Diffuse Lewy body disease
investigations or imaging procedures. PD is diagnosed
by: (1) finding at examination at least two out of several signs of a movement disorder (e.g. rigidity, resting
tremor, bradykinesia or problems with posture and gait)
and (2) a positive response to dopamine substitution
treatment. In the early phase of the disease, misdiagnosis
can be quite common. Imaging of the dopamine transporter using a single photon emissoin computed tomography (SPECT) ligand (DaTscan; see Chapter 2) can be
used to confirm the diagnosis: a decreased signal reflects
decreased dopaminergic innervation.
The presentation in the patient described in Boxes
10.1 and 10.4 is typical of PD. His muscle strength is not
affected, but his symptoms reflect difficulties in initiating
and coordinating simple motor acts, and impaired posture and gait. The patient has no gross sensory impairment. Furthermore, no muscle weakness, paralysis or
spasticity are detected, which rules out a lesion of the
UMNs or LMNs. The motor abnormalities have global
effects on his performance of motor acts that form part of
normal daily activities and also on also his posture. This
suggests an abnormality of motor systems that is not
strictly localized. The onset of this dysfunction in motor
performance is gradual, which rules out a vascular event
and is suggestive of a neurodegenerative process. There
is no pattern of relapse and remission, and the state of
the patient is constantly deteriorating. Thus, as the pathological process is likely to be progressive, it is important
to understand the rationale of any treatment attempted
and to establish whether therapeutic strategies can at
least slow down the neurodegenerative process and
improve the patient’s quality of life.
All parkinsonian syndromes (Table 10.1) are char-
acterized by akinesia, rigidity and tremor at rest. It is
important to differentiate between idiopathic PD (i.e.
206 SYSTEMS OF THE BODY
Table 10.2 Hoehn and Yahr staging of Parkinson’s disease
Stage 1
Signs and symptoms on one side only
Mild symptoms
Inconvenient but not disabling symptoms
Usually presents with tremor of one limb
Friends have noticed changes in posture, locomotion and facial
expression
Stage 2
Symptoms are bilateral
Minimal disability
Posture and gait affected
Stage 3
Significant slowing of body movements
Early impairment of equilibrium on walking or standing
Generalized dysfunction that is moderately severe
10
MOTOR SYSTEMS II: THE BASAL GANGLIA
Fig. 10.4 Neurodegeneration in Parkinson’s disease. Brain sections
from the midbrain of a normal patient (left) and a Parkinson’s disease
patient (right). The Parkinson’s disease hemisphere on the right shows
loss of melanized dopaminergic neurons in the substantia nigra. (From
Alexi T. et al. (2000). ‘Neuroprotective strategies for basal ganglia
degeneration: Parkinson’s and Huntington’s diseases’ Progress in
Neurobiology 60:409.)
Stage 4
Severe symptoms
Can still walk to a limited extent
Rigidity and bradykinesia
No longer able to live alone
Tremor may be less than in earlier stages
Stage 5
Cachectic stage
Invalidism complete
Cannot stand or walk
Requires constant nursing care
no detectable cause for the disease) and secondary parkinsonism, which may be due to other causes such as
vascular lesions in the basal ganglia, carbon monoxide
or manganese poisoning, repeated head trauma (‘boxer’s parkinsonism’) or chronic blockade of dopaminergic receptors in the basal ganglia (use of antipsychotic
drugs in schizophrenic patients). PD is an irreversible
neurodegenerative disease. In the final stages of the disease, patients become bedridden and death occurs due to
medical complications (Table 10.2).
Pathology of Parkinson’s disease
The pathological hallmark of PD is degeneration of the
nigrostriatal dopaminergic pathway. Postmortem analysis of specimens from patients with PD shows a striking reduction in dopaminergic cells in the SN (Fig. 10.4).
In vivo imaging of dopaminergic neurons, using, for
example, a labelled precursor of dopamine or markers of
the dopamine neuronal reuptake system, also confirms
the loss of striatal dopaminergic terminals (see below).
Unfortunately, when the diagnosis is made, it is likely
that more than 50%–60% of dopaminergic neurons in the
SN will have been already lost.
Nigrostriatal dopaminergic neurons are tonically active
and exert a modulatory influence on the striatum and striatonigral and striatopallidal efferent pathways through D1
and D2 receptors, respectively. According to the prevailing
model of basal ganglia circuitry, dopamine facilitates the
activity of striatal projection neurons in the direct pathway
through D1 receptors and inhibits the activity of striatal
projection neurons in the indirect pathway via D2 receptors. Under normal conditions, as a result of the activity
in the two pathways and the neuromodulatory effect of
dopamine, there is adequate thalamocortical excitatory
input (see Fig. 10.1A) and facilitation of movement.
As illustrated in Fig. 10.1B, the degeneration of dopaminergic nigrostriatal cells leads to an imbalance in striatal output pathways, and there is also evidence of early
dysfunction in the STN and an altered cortical drive of
the STN in the hyperdirect pathway. The loss of dopamine appears to lead to an increase in the activity of
GABAergic striatal neurons in the indirect circuit and a
decrease in the activity of GABAergic striatal neurons in
the direct circuit. Decreased inhibition in the direct pathway leads to increased activity of inhibitory GABAergic
nigrothalamic projections and diminished thalamocortical input, and therefore, less activation of the motor
cortex. The slowness of normal movement (bradykinesia) or lack of movement (akinesia) seen in parkinsonism is considered to be a consequence of this increased
inhibition of thalamic neurons that project to the cortex.
The increased activity in the indirect pathway leads ultimately to a similar consequence through disinhibition
of the STN, which provides an excitatory glutamatergic projection to the SN. Therefore, in PD, the excitatory input to cortical areas involved in motor control
is reduced. In other diseases of the basal ganglia, such
as Huntington’s disease, the opposite occurs, leading
207THE NERVOUS SYSTEM
10
Early subcortical Lewy bodies
to a hyperkinetic syndrome (see later in this chapter).
However, this is a simplified view of the functioning of
the basal ganglia, and the limitations of this functional
model become apparent as the disease evolves and as
complications of treatment emerge.
PD is characterized by the massive loss of nigrostriatal dopaminergic melanized cells, but the pathological
examination also reveals other abnormalities. For example, another characteristic finding in PD, although not
pathognomonic, is the presence of Lewy bodies in neuronal cells. These are concentric eosinophilic cytoplasmic inclusions with peripheral halos and dense cores,
containing aggregates of the proteins α- synuclein and
ubiquitin and also lipids and membranous organelles.
Lewy neurites are also detected in PD. Lewy bodies are
a frequent incidental finding at postmortem examination
in elderly patients. In PD, Lewy bodies and other signs
of neurodegeneration can be found in the SN and also
in other structures, such as the locus coeruleus, nucleus
MOTOR SYSTEMS II: THE BASAL GANGLIA
basalis of Meynert, pedunculopontine nucleus, dorsal
motor nucleus of the vagus, cerebral cortex and spinal
cord, as the disease evolves. It is important to note that
Lewy body pathology initially occurs in cholinergic
and monoaminergic brainstem neurons and in neurons
in the olfactory system, and ultimately is also found in
neocortical areas. Thus there is evidence that the neurodegenerative process in PD does not exclusively affect
dopaminergic systems; as the disease evolves, significant changes in noradrenergic, serotonergic and cholinergic neurons can be detected. Thus multiple cell types
in the central and peripheral autonomic nervous system are involved in the neurodegenerative processes. In
2003, Braak and colleagues formulated a hypothesis for
the spread of the pathology in PD. They proposed that
an unknown pathogen (virus or bacterium) could trigger
synuclein pathology in the gut, and that this would then
be transferred, via the vagus nerve, to the central nervous system, where the spread would gradually affect
higher structures in the neuraxis (Fig. 10.5). Synuclein
pathology in the gut may be exacerbated by changes
in the gut microbiome, which have been reported in
PD patients. Later on, Braak suggested an additional
point of entry of the pathology, through the olfactory
mucosa, and propagation through the olfactory tract.
Accumulating in vitro, in vivo and clinical evidence are
lending significant support to this hypothesis of a rapidly progressing pathology.
Genetics and pathophysiological processes in
Parkinson’s disease
PD is one of the most common neurological disorders
leading to major disability and ultimately death. It affects
1/1000 of the population and is increasing in both incidence and prevalence due to increased longevity and
improvements in treatment. It is at present the fastest
growing neurological disorder worldwide. It is more
common in men than in women in most populations,
and occurs in all races. It is the second most common
neurodegenerative disease, affecting 2%–3% of the population above the age of 65 years.
The cause of PD is unknown. There is evidence for
a role of both environmental and genetic factors. The
increased risk associated with exposure to certain toxic
agents, such as manganese or pesticides, and the association of parkinsonism with viral encephalitis lethargica
clearly show that external precipitating causes cannot
be ruled out. The risk of developing PD is heightened
by previous traumatic brain injury. The proportion of
risk associated with genetic factors is significant. The
progress in identifying genes associated with the disease is due to research on familial PD, which has an
Braak stage I and stage II
and severity of the disease presentation
Fig. 10.5 Progression of Lewy body pathology according to the Braak hypothesis. (adapted from Braak H. et al. (2003), Idiopathic Parkinson’s
disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. Journal of Neural
Transmission, 110:517.)
208 SYSTEMS OF THE BODY
Braak stage III and stage IV Braak stage V and stage VI
Progression of the pathology
Cortical spread of Lewy bodies