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An Atlas of
PARKINSON’S DISEASEAND RELATED DISORDERS
G. David Perkin, BA, FRCPRegional Neurosciences Centre, Charing Cross Hospital
London, UK
Foreword by
Anthony E. Lang, MD, FRCPC
Director, The Toronto HospitalMorton & Gloria Shulman Movement Disorders Centre
Library of Congress Cataloging-in-Publication DataPerkin, G. David (George David)
An atlas of Parkinson’s disease and related disorders / G. David Perkin ; foreword by Anthony E. Lang.
p. cm. -- (The Encyclopedia of visual medicine series)Includes bibliographical references and index.ISBN 1-85070-943-21. Extrapyramidal disorders--Atlases. 2. Parkinsonism--Atlases.
3. Movement disorders--Atlases. I. Title. II. Series.[DNLM: 1. Parkinson Disease--atlases. 2. Basal Ganglia Diseases--atlases.
3. Movement Disorders--atlases. WL 17 P447ac 1997]RC376.5.P475 1997616.8’33--dc21DNLM/DLCfor Library of Congress 97-37265
CIPBritish Library Cataloguing in Publication DataPerkin, G. David (George David)
An atlas of Parkinson’s disease and related disorders. -(The encyclopedia of visual medicine series)1. ParkinsonismI. Title616.8’33
ISBN 1-85070-943-2
Published in the USA byThe Parthenon Publishing Group Inc.One Blue Hill PlazaPO Box 1564, Pearl River New York 10965, USA
Published in the UK and Europe byThe Parthenon Publishing Group LimitedCasterton Hall, CarnforthLancs. LA6 2LA, UK
No part of this book may be reproduced in any form without permission from the publishers, except for the quotation of brief passages for the purposes of review.
Since the widespread use of videotape, the neuro-logical subspecialty of movement disorders hasestablished a wide appeal and following, as evi-denced by the avid atttendance of neurologists at‘unusual movement disorders’ videotape sessionsheld at international meetings and the establish-ment of an international journal, MovementDisorders, which is accompanied by a videotapesupplement.
In this era of multimedia, it is important thatthe illustrative power and specific advantagesprovided by still photography not be forgotten.There is a long and illustrious history of thedepiction of disorders of movement and posturethrough the use of drawings and still photo-graphs, as exemplified by the work of Charcotand his pupils at L’Hôpital de la Salpetrière inParis in the late 1800s.
It is in this tradition that Dr David Perkin hascompiled a modern series of still photos highlight-ing various aspects of Parkinson’s disease and
related motor disorders. This book provides auseful sample of clinical, investigative (CT, MRIand PET) and pathological images with a succinctdescriptive text of the disorders featured. AnAtlas of Parkinson’s Disease and Related Disordersis an excellent introduction to this fascinatingtopic, and should serve as a stimulus to medicalstudents and neurologists in training to pursuefurther studies in the field. This work will alsoserve as a useful adjunct to teaching videotapesof movement disorders which are capable of pre-senting the clinical features from a unique pers-pective, but are unable to demonstrate suchaspects as imaging and pathology, which are sowell represented in this atlas.
It is hoped that, stimulated by this book in com-bination with these other sources of informa-tion, a future generation of physicians will pursuestudies designed to unlock the ‘dark basements’ ofthe brain (the basal ganglia) which contribute tothese unusual and fascinating disorders of motorcontrol.
In writing An Atlas of Parkinson’s Disease andRelated Disorders, I have been conscious of theneed to find an appropriate match between thetext and the illustrative material. The text isdesigned to provide a basic overview of the condi-tions discussed, inevitably concentrating on thoseareas which lend themselves best to photographicillustration. Some movement disorders, by theirvery nature, do not lend themselves to stillphotography whereas others, characterized bysustained postures, are ideally suited to the tech-nique. Perhaps nowhere else in neurology is theresuch an opportunity to blend patient material,pathology and imagery in the discussion of theconstituent conditions.
The development of brain-bank facilities such asthe Parkinson’s Disease United Kingdom BrainBank has provided new insight into the spectrumof pathological entities underlying a particularclinical presentation while, at the same time,demonstrating that specific neuropathologicalentities may present with a considerable range ofclinical features.
Accordingly, approximately one-third of thematerial in this atlas is pathological, incorporatingboth macroscopic and microscopic sections. A
further quarter of the material is represented byimaging, principally magnetic resonance imaging(MRI) and positron emission tomography (PET)scanning. The area of movement disorders hasbeen particularly fruitful for PET scanning, whichpromises with the development of specific ligandsfor the various receptor sites, to further expandunderstanding of the pathophysiological mecha-nisms of the movement disorders.
It is expected that this atlas will provide a stimu-lating insight into the various aspects of the move-ment disorders for neurologists in training, but itsapproach to the subject should make it equallyaccessible for the medical student with an interestin neurological disorders.
It is a great pleasure to record the generosity ofall the contributors who have provided me withmaterial. I am particularly indebted to Dr SusanDaniel, who has been largely responsible for thesuperb pathological material in this atlas. I wouldalso like to express a debt of gratitude to Dr M.Savoiardo who, not for the first time, has come tomy rescue by providing state-of-the-art imagingmaterial of many of the conditions discussed in thefollowing pages.
I would like to thank the following publishers andauthors, who have kindly allowed me to reproducethe following illustrations:
Figure 1, reproduced with permission ofHarcourt–Brace and Dr C.G. Gerfen, modifiedfrom Figure 1 in Gerfen & Engber, Molecularneuroanatomic mechanisms of Parkinson's disease:A proposed therapeutic approach. Neurol Clin1992;10:435–49
Figure 2, reproduced with permission ofLippincott–Raven and Dr C.G. Goetz, modifiedfrom a figure in Goetz et al., Neurosurgical horizonsin Parkinson's disease. Neurology 1993;43:1–7
Figure 19, reproduced with permission ofLippincott–Raven and Professor O. Lindvall, firstpublished as Figure 5 in Lindvall et al., Evidencefor long-term survival and function of dopamin-ergic grafts in progressive Parkinson's disease.Ann Neurol 1994;35:172–80
Figures 24 and 25, reproduced with permissionof Lippincott–Raven and Dr G. Fénelon, firstpublished as Figures 1A and 2A in Fénelon et al.,Parkinsonism and dilatation of the perivascularspaces (état criblé) of the striatum: A clinical,magnetic resonance imaging, and pathologicalstudy. Mov Disord 1995;10:754–60
Figure 42, reproduced with permission ofLippincott–Raven and Dr S. Gilman, first publishedin Gilman et al., Patterns of cerebral glucosemetabolism detected with positron emissiontomography differ in multiple system atrophy andolivopontocerebellar atrophy. Ann Neurol 1994;36:166–75
Figure 50, reproduced with permission ofLippincott–Raven and Dr E.R.P. Brunt, firstpublished as Figure 1b in Brunt et al., Myoclonusin corticobasal degeneration. Mov Disord 1995;10:132–42
Figure 55, reproduced with permission of RapidScience and Dr J. Jankovic, first published asFigure 1 in Jankovic, Botulinum toxin in movementdisorders. Curr Opin Neurol 1994;7:358–66
Figures 64 and 65, reproduced with permission ofLippincott–Raven and Dr A.E. Lang, first publishedas Figure 2 A and B in Jog & Lang, Chronic acquiredhepatocerebral degeneration: Case reports and newinsights. Mov Disord 1995;10:714–22
Figures 70 and 71, reproduced with permission ofthe American Roentgen Ray Society and Dr J.P.Comunale Jr, first published as Figure 1 B and C inComunale et al., Juvenile form of Huntington's dis-ease: MR imaging appearance. AJR 1995; 165:414–5
Figure 72, reproduced with permission of OxfordUniversity Press and Dr N. Turjanski, first pub-lished as Figure 2 in Turjanski et al., Striatal D1 andD2 receptor binding in patients with Huntington'sdisease and other choreas: A PET study. Brain1995;118:689–96
I am also indebted to the following colleagues,who have generously provided me with theirunpublished material:
Figures 3–5, 26, 27, 32, 33, 36–39, 43, 45, 46, 61–63,67 and 68, from Dr Susan E. Daniel, SeniorLecturer in Neuropathology and Head ofNeuropathological Research, The Parkinson'sDisease Society Brain Research Centre, Institute ofNeurology, London, WC1N 1PJ;
Figures 30, 35, 40, 41, 49 and 73, from Dr M.Savoiardo, Consultant Neuroradiologist, Depart-ment of Neuroradiology, Istituto NazionaleNeurologico "C. Besta", Milan, Italy
Figures 13, 74 and 75, from Dr P. Bain, SeniorLecturer in Clinical Neurology, The West LondonNeurosciences Centre, Charing Cross Hospital,London, W6 8RF
Figures 66 and 69, from Dr N. Wood, SeniorLecturer in Clinical Neurology, The Institute ofNeurology, Queen Square, London, WC1N 3BG
Figures 21 and 22, from Dr D. Miller, AssociateProfessor of Neuropathology and Neurosurgery,NYU Medical Center, New York, and ProfessorM.H. Mark, The University of Medicine andDentistry of New Jersey, New Jersey
Figures 20 and 34, from Dr D. Miller, AssociateProfessor of Neuropathology and Neurosurgery,NYU Medical Center, New York
Figure 6, from Dr W.R.G. Gibb, ConsultantNeurologist, Institute of Psychiatry, London SE58AF
The neurons of the corpus striatum receive anexcitatory input from the cerebral cortex andthalamus. The major outputs project to the ento-peduncular / substantia nigra (EP / SNr) nuclearcomplex and the globus pallidus. Neurons from theEP / SNr complex project to the ventral tier andintralaminar thalamic nuclei and to the superiorcolliculus and the pedunculopontine nucleus.Feedback to the striatum occurs through thedopaminergic nigrostriatal pathway (Figure 1). Theinhibitory output of nigral neurons is phasicallyinhibited in turn by cortical activity expressedthrough the striatonigral pathway. Striatal out-puts use gamma-aminobutyric acid (GABA) as atransmitter and comprise a direct striatonigralpathway together with an indirect pathway via theglobus pallidus and the subthalamic nucleus. Thedirect pathway is inhibitory, and the indirect
pathway modifies the excitatory input from thesubthalamic nucleus to the substantia nigra.
These separate pathways use different neuro-peptides and dopamine receptors. The directstriatonigral neurons express substance P anddynorphin, and use D1 dopamine receptors. Thestriatopallidal neurons express enkephalin and useD2 receptors. (Some neurons express both recep-tors.) Depletion of dopamine in the striatum resultsin increased activity of the striatopallidal pathwayand decreased activity in the striatonigral pathway.These effects (the former leading to disinhibition ofthe subthalamic nucleus) lead to increased activityof the GABAergic neurons of the output nuclei ofthe basal ganglia. Increased inhibitory output fromthese nuclei may be responsible for the bradykinesiaseen in patients with Parkinson's disease (Figure 2).
rate-limiting enzyme in the biosynthetic pathwayfor catecholamines. (Figures 4 and 5). A character-istic, indeed inevitable, finding is the presence ofLewy bodies in some of the remaining nerve cells(Figure 6).
Together with Lewy body formation, degenerativechanges occur at other sites, including the locusceruleus, the dorsal motor nucleus of the vagus, thehypothalamus, the nucleus basalis of Meynert andthe sympathetic ganglia. Cortical Lewy bodies areprobably present in all patients with idiopathicParkinson's disease, although not with the fre-quency that would permit a diagnosis of corticalLewy body disease (vide infra).
In Parkinsonian patients with cortical dementia,the pathological changes are either those of corticalLewy body disease, or those associated withAlzheimer's disease, including senile plaques,neurofibrillary tangles, granulovacuolar degenera-tion, and nerve cell loss in the neocortex and hippo-campus.
Epidemiology
The prevalence of Parkinson's disease has beenreported to lie between 30 and 300 / 100 000,producing approximately 60 to 80 000 cases in theUnited Kingdom. Prevalence increases with age
Any discussion of the clinical characteristics ofParkinson's disease must take into account theinaccuracies of clinical diagnosis. In a successiveseries of 100 patients with a clinical diagnosis ofParkinson's disease, only 76 fulfilled the criteria fordiagnosis at post-mortem examination (Table 1).Attempts to tighten the diagnostic criteria lead toincreased specificity but with reduced sensitivity.
Neuropathology
Typically, there is loss of at least 50% of the melanin-containing nerve cells of the substantia nigra, thechanges concentrating in the central part of thezona compacta (Figure 3). Accompanying thesechanges is depletion of tyrosine hydroxylase, the
Parkinson’s disease
Table 1 Pathological findings in 100 successiveParkinsonian patients
Idiopathic Parkinson's disease 76Progressive supranuclear palsy 6Multiple system atrophy 5Alzheimer's disease 3Alzheimer-type pathology with striatal involvement 3Lacunar state 3Nigral atrophy 2Postencephalitic Parkinsonism 1Normal (?essential tremor) 1
from Hughes et al., 1992
and the disease is slightly more common in men(Figure 7). Cigarette-smoking provides some protec-tive effect, whereas the risk is increased in thosewith a history of herbicide or pesticide exposure.
Clinical features
Typically, the condition produces bradykinesia,tremor, rigidity and impairment of posturalreflexes. An asymmetrical onset is characteristic.
Bradykinesia
Paucity of movement can affect any activity and isbest measured by assessing aspects of daily living.The problem tends to involve one upper limbinitially, leading to difficulty with fine tasks, suchas manipulating a knife or fork, dressing or shaving.The patient’s handwriting typically becomesreduced in size if the dominant hand is affected(Figure 8). Associates are likely to comment on areduction of arm swing when walking. Facialimmobility is evident, with a lack of animationand immediate emotional response (Figure 9). Theposture is stooped, and becomes more so as thecondition progresses (Figures 10 and 11). Walkingbecomes slowed, with a tendency to reduce stridelength and an increased number of steps beingtaken when turning. The problem can be assessedby asking the patient to repetitively tap with thehand or foot, or to mimic a polishing motion withthe hand, or to rhythmically clench and unclenchthe fingers (Figure 12). Even if the amplitude ofsuch movements is initially retained, it soondiminishes and may even cease.
Rigidity
The rigidity associated with Parkinson's disease isalso often asymmetrical at onset. It tends to bediffusely distributed throughout the limb although,initially, it may be more confined. It persiststhroughout the range of motion of any affected
joint. A characteristic judder (cogwheeling) occursat a frequency similar to that of the postural tremorseen in Parkinson's disease rather than at the rate ofthe resting tremor. If the rigidity is equivocal, it canbe activated by contracting the contralateral limb.
Tremor
The classical Parkinsonian tremor occurs at rest, ata frequency of around 3–4 Hz (Figure 13). Thetremor briefly inhibits during a skilled activity.A faster, postural tremor of around 6–8 Hz issometimes evident initially at a time when the resttremor is absent. The rest tremor most commonlyinvolves the upper limb, producing either flex-ion / extension movements or pronation / supina-tion, or a combination of these.
Postural reflexes
In addition to abnormalities of posture, the patienthas difficulty maintaining posture when suddenlypushed forwards or backwards. Other features ofParkinson's disease include dementia (perhaps inaround 15–20% of patients), autonomic dysfunction(principally in the form of urinary urgency andoccasional incontinence) and a variety of eye signs,including broken pursuit movements and somelimitation of upward gaze and convergence. Apositive glabellar tap (producing repetitive blinkingduring tapping over the glabella) occurs in themajority, but is also seen in Alzheimer's disease(Figure 14).
Imaging
Although imaging techniques, particularly positronemission tomography (PET) scanning, are notrelevant to the diagnosis of most patients withParkinson's disease, they do provide insight intothe pathophysiology of the disease and can assumeclinical relevance where the clinical presentation isatypical. PET scans using 6-[18F]-fluorodopa show
therefore be enhanced by providing more precur-sor (dopa; Figure 16), stimulating dopamine release(amantadine), using an agonist to act on thedopamine-receptor site (bromocriptine, lysuride,pergolide, ropinirole and cabergoline) or inhibitingdopamine breaknown through inhibition of eithermonoamine oxidase (selegiline) or of COMT(tolcapone).
Dopa, combined with a dopa-decarboxylase inhib-itor, remains the cornerstone of treatment. Theuse of subcutaneous apomorphine as a diagnostictest for idiopathic Parkinson’s disease has beenadvocated, but both false-positive and false-negative results occur. There is no consensus asto whether agonist therapy should be introducedearlier or later. After 5–10 years, major therapeuticproblems arise, with loss of efficacy, fluctuationsin response and the emergence of increasinglyuncontrollable dyskinesias or dystonic posturing(Figures 17 and 18). These problems havestimulated consideration of other therapeuticapproaches, including thalamic (Figure 19) andpallidal surgery, and transplantation of dopamin-ergic grafts. Such grafts, derived from humanembryonic mesencephalic tissue, have been shownto have a functional effect for at least 3 years aftertransplantation, as substantiated by evidence ofenhanced putaminal fluorodopa uptake over thesame period (Figure 20).
reduced uptake of the isotope, particularly in theputamen and mainly contralateral to the clinicallymore affected side (Figure 15).
Drug intervention
There are potentially several stages during thesynthesis, release and metabolism of dopaminewithin the central nervous system at whichintervention, by enhancing dopamine levels, mayinfluence the clinical manifestations of Parkinson’sdisease.
Dopa is converted to dopamine within the dopa-minergic neuron by the action of L-aromatic-amino-acid decarboxylase (dopa decarboxylase).The dopamine is then transported into storagevesicles before being released, through depolar-ization and entry of calcium ions, to act on thepostsynaptic dopamine-receptor site. Some of thedopamine is taken up again in the dopaminergicneuron while another part is converted, withinglial cells, to 3-methoxytyramine by the action ofcatechol O-methyltransferase (COMT). The 3-methoxytyramine is then metabolized by mono-amine oxidase-B to homovanillic acid (HVA).Some of the dopamine that is taken up again intothe neuron is transported back into storagevesicles, whereas the remainder is metabolized bymonoamine oxidase-B to 3,4-dihydroxyphenyl-acetic acid (DOPAC). Dopaminergic activity can
A vast number of disorders can produce a clinicalpicture which closely resembles Parkinson's disease(Table 2).
Postencephalitic Parkinsonism
Cases of postencephalitic Parkinsonism still occursporadically. Besides the Parkinsonism, clinicalfeatures include oculogyric crises, behavioraldisorders, pyramidal tract signs and variousmovement abnormalities. Depigmentation of thesubstantia nigra is evident, along with the presence
of neurofibrillary tangles. Although inflammatorycells are conspicuous in the acute stage, they maystill be present years later.
Drug-induced Parkinsonism
Any drug affecting the synthesis, storage orrelease of dopamine, or interfering with dopaminereceptor sites, is capable of causing an akinetic rigidsyndrome which may closely resemble idiopathicParkinson's disease. The most well-recognizeddrugs in this category are the phenothiazines but, inaddition, a calcium-blocking vasodilator such asflunarizine or the antihistamine cinnarizine caninduce Parkinsonism, possibly through a presyn-aptic effect on dopaminergic and serotonergicneurons.
The condition tends to be symmetrical and to lacktremor. If a tremor is present, it tends to be posturaland of a higher frequency than the classical restingtremor of idiopathic Parkinson’s disease. Most casesare evident within 3 months of starting therapy.
The problem is more likely to affect the elderly andwomen, and may take several months to subsideafter drug withdrawal. If the symptoms are dis-abling and the drug therapy is still required, eitheramantadine or an anticholinergic agent has beensuggested as appropriate treatment.
Parkinsonian syndromes
Table 2 Disorders with clinical presentations similar toParkinson’s disease
Parkinsonian features are sometimes part of theclinical spectrum associated with diffuse cerebro-vascular disease. In the original description, certainclinical features were held to distinguish arterio-sclerotic Parkinsonism from idiopathic Parkinson'sdisease, including the lack of tremor, a predomi-nance of gait involvement over upper limb disorderand the presence of signs in other systems, forexample, bilateral extensor plantar responses. Insuch patients, particularly those with a history ofhypertension or stroke-like events, the possibility ofa Binswanger-type encephalopathy as the under-lying mechanism is considerable (Figure 21).
Microscopy reveals sharply defined zones ofmyelin loss (Figure 22), with or without coexistentareas of lacunar infarction (Figure 23). Eitherpathology is usually demonstrable with appropriateimaging (Figure 24).
Some patients with a Parkinsonian state due tovascular disease have rest tremor whereas othersshow dopa responsiveness. Whether expandedperivascular spaces alone (état criblé) within thestriatum can be responsible for a Parkinsonianstate is still under debate. If this is the case, theclinical picture is then atypical for idiopathicParkinson’s disease with the presence of predom-inant axial involvement (Figures 25 and 26).
Cortical Lewy body disease
The prevalence of a cortical-type dementia inParkinson's disease has long been debated. Most of
the recent surveys give a figure between 15–20%of the population.
Risk factors for dementia in Parkinsonian patientsinclude age and duration of the disease. In someParkinsonian patients with dementia, post-mortemexamination establishes the presence of neurofib-rillary tangles, granulovacuolar degeneration, andnerve cell loss in the hippocampus and neocortex ofa nature consistent with a diagnosis of Alzheimer'sdisease. In other patients, the major cortical pathol-ogy is the presence of Lewy bodies (Figure 27).
Occasional cortical Lewy bodies can probably befound in all Parkinsonian patients but, where thebodies are profuse and widely scattered in theneocortex, a differing clinical pattern emerges,described as diffuse Lewy body disease or Lewybody dementia. Additional pathological featuresinclude spongiform degeneration and ubiquitousimmunoreactive neurites in parts of the hippo-campus. To further complicate the classification ofthis entity, perhaps as many as half the patients withcortical Lewy body disease have concomitantAlzheimer pathology.
In patients with Lewy body dementia, the dementiamay precede, coincide with or follow the extra-pyramidal features. Early onset of paranoidideation accompanied by visual hallucinations in aParkinsonian patient is suggestive of the diagnosis.Falls are commonplace. The Parkinsonian featuresmay or may not be responsive to dopa therapy.
For many, or perhaps even all, extrapyramidalsyndromes, a classical picture is described whichis anticipated to predict a particular pathologicalentity at post-mortem examination. As knowledgeof the disease grows, however, it soon becomesapparent that the same disease process – as definedpathologically – has a much broader clinical spec-trum than was appreciated in the original descrip-tion. The converse also applies: patients with aclassical clinical syndrome may prove to have otherpathological entities.
Nowhere are these discrepancies more evidentthan in cases of progressive supranuclear palsy(PSP). One of the problems in establishingclinicopathological correlations in PSP is the lack ofconsensus as to the pathological criteria for thediagnosis. Certain features, however, are predic-table. The substantia nigra shows severe pigmentdepletion as does the locus ceruleus. Neuronal lossis found in the substantia nigra, subthalamus andglobus pallidus. Neurofibrillary tangles can beidentified in the cerebral cortex, caudate, putamen,globus pallidus, subthalamus and brain stem(Figure 28). Accompanying the neurofibrillary
tangles are neuropil threads (silver- and tau-positive). Typically, changes are found in theregions associated with vertical gaze, including therostral interstitial nucleus of the medial longitudinalfasciculus and the interstitial nucleus of Cajal.
A disturbance of gait is common and manypatients are liable to falls. The body tends to remainextended rather than taking on the stooped postureof Parkinson's disease. Pseudobulbar features areprominent, with dysphagia, dysarthria and emo-tional incontinence. The supranuclear palsy firstaffects down gaze, and particularly downwardsaccades (Figure 29). Some patients complain ofblurred vision or frank diplopia. Later, vertical, thenhorizontal, saccades become compromised followedby impairment of pursuit movement. Reflex eyemovements, elicited by the doll's-head maneuver,are spared initially (Figure 30), but are later lostso that a total ophthalmoplegia becomes evident.In well-documented cases, despite the appropriatepathological changes found post-mortem, thepatient may have had no disturbances of eyemovements in life. Limb rigidity is less prominentthan axial rigidity. Bradykinesia is present to avarying degree with some patients presenting as apure akinetic syndrome. Tremor occurs in around12–16% of cases. A subcortical, rather than cortical,dementia is characteristic.
Related disorders
In most cases, dopa therapy is ineffective andalmost never influences the ophthalmoplegia.
Imaging changes include both generalized andselective brain stem atrophy (Figure 31). Singlephoton emission computed tomography (SPECT)can demonstrate impairment of frontal perfusionwith an intact cortical rim. PET scanning showsdecreased metabolic activity in the frontal cortex,caudate and putamen (Figure 32).
Striatonigral degeneration
This condition is frequently confused withParkinson's disease in life. At post-mortem, thereis atrophy and discoloration of the putamina(Figure 33) accompanied, in almost half the cases,with atrophy of the caudate nuclei. The changesin the putamen begin dorsally in the posteriortwo-thirds, then spread ventrally and anteriorly.On microscopy, the putamen shows intracellularpigmentation, gliosis and loss of myelinated fibers(Figure 34). Neuronal depletion, gliosis and loss ofmyelinated fibers are seen in the globus palliduswhereas both the substantia nigra and locusceruleus show pallor with microscopic evidenceof neuronal loss and gliosis (Figure 35). Lewybodies are seldom found. In some cases, evenwithout clinical features in life, there is involvementof the olivopontocerebellar system.
Striatonigral degeneration has considerable clinicaloverlap with Parkinson's disease, but sufficientdifferences to suggest the diagnosis in life. Resttremor in the early stages of the disease isdistinctly uncommon, although it appears in halfof the cases during the later stages of the disease.The condition is equally likely as Parkinson'sdisease to be asymmetrical at onset. Falls early inthe course of the disease are a recognized feature.Some patients show a response to dopa. Otherfeatures which should suggest the diagnosisinclude severe dysphonia and dysphagia, and the
development of autonomic symptoms or cerebellarsigns, indicating the development of multiplesystem atrophy (vide infra).
On T2-weighted magnetic resonance imaging (MRI),low signal intensity is seen in the putamen, some-times bordered by a thin rim of hyperintensity(Figure 36). PET scanning can demonstrate reducedstriatal and frontal lobe metabolism.
Multiple system atrophy
Autonomic features may accompany a Parkinsoniansyndrome without evidence of other systeminvolvement. In such patients, the autonomicfailure is due to intermediolateral column degen-eration in the spinal cord whereas the Parkinsoniansyndrome reflects the classical features of idio-pathic Parkinson's disease, including typicalchanges in the substantia nigra and locus ceruleus,with Lewy body formation. In other patients,described as having multiple system atrophy, theautonomic failure is due to the same pathologicalprocess in the spinal cord, but the other clinicalfeatures represent a combination, in varyingdegrees, of striatonigral degeneration and olivo-pontocerebellar atrophy (OPCA).
In OPCA, there is macroscopic evidence ofatrophy of the pons, middle cerebellar peduncle,parts of the cerebellum and the olives (Figure 37).Microscopically the pontine tegmentum is virtuallyspared, but there is pallor of the transverse fibersin the basis pontis together with neuronal loss(Figure 38). Depletion of both granules andPurkinje cells is seen in the cerebellum. Where thelatter has occurred, empty ‘baskets’ with hyper-trophied fibers are seen associated with the form-ation of axon ‘torpedoes’ in the molecular layer(Figure 39). Oligodendroglial cycloplasmic inclu-sions are seen in probably all sporadic cases ofmultiple system atrophy, but have not beenidentified in other neurological diseases nor in
cases of dominantly inherited multiple systematrophy (Figure 40).
Clinical criteria have been suggested for thediagnosis of multiple system atrophy (Table 3).Diagnostic problems arise as the result of somepatients who present with Parkinsonism, otherswho have a cerebellar syndrome, and a third groupwho manifest autonomic failure, without clearevidence in all three instances of other systeminvolvement. Sporadic cases are not seen in thoseunder 30 years of age. Dementia is not a feature ofmultiple system atrophy, nor is there an ophthalmo-plegia (although this is recorded in both sporadicand familial forms of OPCA). Although poor orabsent dopa responsiveness is the norm, some cases– confirmed at post-mortem examination – may
show a response comparable to that seen in idio-pathic Parkinson's disease.
Multiple system atrophy usually presents in thesixth decade of life. The median survival is of theorder of 7–8 years. Men are slightly more oftenaffected than women. The most common combina-tion of clinical features is autonomic impairmentwith Parkinsonism. Autonomic symptoms includepostural hypotension, urinary urgency with inconti-nence and erectile failure in male patients. Fecalincontinence is uncommon and syncopal attacks area feature in only a minority of cases. Speech impair-ment is almost inevitable, with a combination ofdysarthria and dysphonia producing a variety ofspeech disorders. Overall, cerebellar signs arerecorded in nearly half the cases, and pyramidal
Table 3 Multiple system atrophy: Proposed clinical diagnostic criteria
Striatonigral type Olivopontocerebellar type (predominantly Parkinsonism) (predominantly cerebellar)
Possible Sporadic, adult-onset, non- or poorly Sporadic adult-onset cerebellar syndrome levodopa-responsive Parkinsonism with Parkinsonism
Adult-onset; ≥30 years of age; Sporadic; no multiple system atrophy in first- or second-degree relatives;Autonomic failure; postural syncope and / or urinary incontinence or retention not due to other causes;Levodopa-responsive; moderate or good levodopa-response accepted if waning and multiple atypical features present;Parkinsonism; no dementia, areflexia or supranuclear down-gaze palsy
signs in almost two-thirds. Both bradykinesia andrigidity are likely, but a classical resting tremoris unusual. Even when the condition has presentedin a pure cerebellar, Parkinsonian or autonomicformat, it is never the case that that picture remainsunaltered until death, except in the small percen-tage of cases with isolated Parkinsonism.
The good response to dopa, seen in a minority ofcases, is seldom sustained. In such cases, substitu-tion of a dopaminergic agonist is usually unhelpful.Drug-induced movements in these patients usuallytakes the form of dystonia rather than chorea.Certain other clinical features are suggestive ofthe disease and are notoriously difficult to manage.These include postural instability with falls, exces-sive snoring associated with vocal cord abductorpalsy and anterocollis.
Imaging
Magnetic resonance imaging
MRI identifies sites of maximum atrophy in thebrain stem and cerebellum. The middle cerebellarpeduncle shows the most marked reduction insize, but other affected structures include thecerebellar vermis, the cerebellar hemispheres, thepons and the lower brain stem (Figure 41). Signalhyperintensities can be identified within the ponsand middle cerebellar peduncles (Figure 42).Additional MRI findings include putaminalhypointensities. The relative distribution of thechanges seen on MRI correlates, to a limited degree,with the clinical characteristics.
SPECT / PET
With the use of 123I-iodobenzamide (IBZM)–SPECT,dopamine D2 receptors can be imaged and shown tobe significantly depleted in the striatum in patientswith multiple system atrophy. PET using [18F]-fluorodeoxyglucose has been used to measure local
cerebral metabolic rates for glucose in bothmultiple system atrophy, and sporadic and familialforms of OPCA. In the former two, reduced meta-bolic activity, albeit to differing degrees, is found inthe brain stem, cerebellum, putamen, thalamusand cerebral cortex. In familial OPCA, changesare confined to the brain stem and cerebellum(Figure 43).
Corticobasal degeneration
This disorder bears some superficial resemblance toPSP, but has distinctive clinical and pathologicalfeatures which distinguish it. The gross pathologicalfindings include a marked asymmetrical fronto-parietal atrophy with relative sparing of thetemporal cortex (Figure 44). Both gray and whitematter show gliosis and cell loss. Subcortical nucleiare also affected, with the most prominent changesbeing found in the substantia nigra. Other affectedareas include the lateral thalamic nuclei, globuspallidus, subthalamic nuclei, locus ceruleus andred nucleus. A characteristic, but non-specific,finding is the presence of swollen achromaticneurons (balloon cells) in the affected cortical areas(Figures 45 and 46). A number of inclusion bodieshave been found: those with a weakly basophilicbody, called the corticobasal inclusion body; andsmall, more basophilic, bodies, which may repre-sent a variant of the former rather than a distinctentity (Figure 47).
Typically, the condition begins insidiously andasymmetrically with a variety of motor deficits,including dystonia (Figure 48), an akinetic–rigidsyndrome or the alien limb phenomenon. Theaffected upper limb takes on characteristicabnormal postures, particularly when the patient'sattention is diverted or their eyes are closed. Attimes, the hand carries out relatively complex taskswhen the patient is concentrating on other activities.In addition, the patient often shows features of anideomotor or ideational apraxia (Figure 49). Other
Table 4 Classification of dystonia according to distribution
A. Generalized dystonia
B. Multifocal dystonia: affects two or more non-contiguous parts
C. Hemidystonia: Involvement of one arm and the ipsilateral leg
D. Segmental dystonia: either cranial (two or more parts of cranial and neck musculature), axial (neck and trunk), brachial (arm and axial or both arms ±neck ± trunk) or crural (one leg and trunk or both legs ± trunk)
E. Focal dystonia: affecting a single site such as eyelids (blepharospasm), mouth (oromandibular dystonia), larynx (spastic dysphonia), neck (torticollis) or arm(writer's cramp)
Fahn, Marsden & Calne, 1987
limb abnormalities include focal reflex myoclonus,other involuntary movements and grasp reflexes. Asupranuclear eye-movement disorder similar to thatseen in PSP may be present, or an apraxia of eyemovement or eyelid opening. Postural instability iscommon, whereas falls and cortical sensory lossare found in around three-quarters of patients.
Computed tomography (CT) or MRI may demon-strate asymmetrical cortical atrophy (Figure 50).[18F]-Fluorodopa–PET scanning shows striatal andcortical dopamine depletion. [18F]-Fluorodeoxy-glucose–PET scanning demonstrates regionalreduction in glucose metabolism (Figure 51). Acomparison has been made between corticobasaldegeneration and Pick's disease but, in most cases,there are sufficient clinical and pathological differ-ences to establish the conditions as separate entities.
Dystonia
Torsion dystonia is a condition in which sustainedmuscle contraction leads to altered postures of thelimb and trunk. The condition may be associatedwith other movement disorders, and is classifiedinto a primary (idiopathic) form and varioussecondary (symptomatic) forms.
Idiopathic torsion dystonia may occur sporadicallyor in a genetically determined form, when it usuallydemonstrates autosomal-dominant transmission.The hereditary forms tend to present in childrentypically with involvement of one leg beforeprogressing to the other limbs and the trunk.Dystonias can also be classified according to theirdistribution (Table 4).
Idiopathic dystonia usually starts in one leg, lesscommonly in the arm and least often in the trunk,particularly in cases presenting in the first decadeof life. With a late presentation, initial involvementof the arm is more likely. With time, the conditionspreads and accentuates.
Typically, the foot tends to invert and plantar flexwhile involvement of the trunk produces a varietyof abnormal body postures (Figures 52 and 53).Muscle tone is normal apart from the presence ofactive muscle contraction. Other clinical abnormal-ities are absent. No clear pathological substratefor idiopathic torsion dystonia has been found.Treatment for the condition is often disappointing,although anticholinergic therapy, in large doses, issometimes beneficial. An occasional response isseen to dopaminergic agonists and antagonists,and benzodiazepines.
Focal dystonia
A variety of focal dystonias has been described.These tend to present in adult life and principallyaffect the muscles of the arm or neck, or thoseinnervated by the cranial nerves. As with idiopathictorsion dystonia, focal pathological abnormalitieshave not been demonstrated post mortem.
This involves an increased blinking frequencywhich may culminate in the eyes becoming almostpermanently closed (Figure 54). Sometimes a lighttouch to the eyelid may relieve the spasm, as mayvarious diversionary physical actions on the part ofthe patient.
Oromandibular dystonia
This describes an abnormal movement of the jaw,mouth and tongue associated with dysphagia anddysarthria. The symptoms are typically triggeredby attempts to speak or eat. Trauma to the tongueand buccal mucosa is a common occurrence.
Spasmodic dysphonia
Dystonia of the laryngeal muscles produces anabnormal voice pattern. Adduction of the vocalcords is seen more often than is abduction, andimparts a strained and harsh quality to the speech.
Spasmodic torticollis
Abnormal neck postures result from contraction ofthe sternocleidomastoid, splenius capitis, or both.There may be predominant rotation, or lateralflexion or extension. The condition may resolve,only to return later (Figure 55). A tremulousmovement is often superimposed on a more sus-tained posture. Neck discomfort is common, andsome patients develop degenerative disease of thecervical spine.
Writer’s cramp
This is one of a number of occupational cramps inwhich dystonic posturing, frequently of a painfulnature, develops in patients who use their handshabitually in performing a skilled task. Otheractivities associated with this condition include
typing, playing the violin and cutting hair. Themovements typically are generated only when aspecific task is attempted. Other skilled activities ofthe hand are spared. Typically, excessive force isused, and the pen is held in an abnormal posture.The movement is often accompanied by inappro-priate movement and posturing of the proximalarm muscles. Occasionally, the problem remits.Eventually, some patients learn to write with theother hand, although at the risk of then developingthe problem in that hand as well.
Treatment
Treatment of the focal dystonias has been largelyineffective in the past, although certain dystonias(particularly blepharospasm and spasmodic torti-collis) have shown a gratifying response toinjections of botulinum toxin. There are severalimmunologically distinct forms of the toxin, ofwhich type A is the most widely researched.Type A inhibits acetylcholine release from thepresynaptic neuromuscular terminal by clearingsynaptosomal-associated protein (SNAP-25;Figure 56). The consequent chemodenervationproduces muscle paralysis and atrophy. Nervesprouting and reinnervation occur over the follow-ing 2–4 months.
Secondary (symptomatic) dystonia
A vast array of conditions has been described aspotential causes of secondary or symptomaticdystonia. These perhaps account for one-third ofall cases. Although some patients present with puredystonia, the majority have additional neurologicalabnormalities.
Certain characteristics point to the symptomaticforms of dystonia. Hemidystonia usually implies astructural lesion in the contralateral putamen orits connections. Perinatal hypoxia can lead to anumber of movement disorders, including chorea,
athetosis and dystonic posturing (Figures 57 and58). In cases with a global failure of cerebralperfusion, pathological consequences include bor-der-zone infarction together with ischemic changesin the putamen, thalamus and cerebellum. A morefocal cerebral insult in the perinatal period mayalso be associated with focal dystonia and corres-ponding imaging abnormalities (Figures 59 and60). Adult-onset ischemia is equally capable ofproducing a hemidystonic phenomenon that oftenappears following resolution of an initial hemi-paresis (Figure 61).
Aspects of the clinical course also help to differ-entiate between the idiopathic and symptomaticforms of dystonia. Idiopathic forms tend to developinsidiously, are more or less progressive and onlyeventually lead to sustained dystonic postures.Symptomatic dystonias tend to develop moreabruptly with sustained postures at an earlier age.
Wilson’s disease
Wilson's disease is inherited as an autosomal-recessive trait. The prevalence of the condition isestimated to be 30 / 1 000 000 with the carrier stateestimated to be 1% of the population. The diseaseis associated with a deficiency of serum cerulo-plasmin. Impaired hepatic excretion of copper intobile leads to an abnormal accumulation of copper,initially in the liver and later in other organs. Insome patients, the changes in the liver are non-specific in the form of a toxic hepatitis whereas,in others, a macro- and micronodular cirrhosisevolves, sometimes with no previous clinicalevidence of liver disease.
Changes found in the brain include atrophy,softening and contraction of the basal ganglia,especially in the putamen. Changes are also foundin cortical white matter, the cerebellar folia and thepons. Microscopically the putamen is atrophiedand rarefied (Figure 62). The white matter shows
spongy degeneration with loss of myelin fibers.Accumulation of type 1 and type 2 astrocytes(Figure 63) and Opalski cells is seen (Figure 64).The latter are of unknown origin. There is asurprisingly poor correlation between the degreeof hepatic and cerebral damage and the clinicalcondition of the patient.
Neurological manifestations of the disease, whichmay be the presenting feature in nearly half thecases, appear from the second decade of ageonwards, but rarely after the age of 40 years.The major declaration of the disease is in theform of involuntary movements coupled withprominent involvement of the facial and bulbarmuscles. Abnormal movements principally consistof various forms of dystonic posturing. Chorea orchoreoathetosis is uncommon. Dysarthria, whichmay partly be due to dystonia of the face andbulbar muscles, is prominent. Dysphagia is presentand is accompanied by incessant drooling ofsaliva. A particular facial expression is describedwith retraction of the upper lip (risus sardonicus).On occasions, a more Parkinsonian pictureemerges, with rigidity and tremor. The tremor issometimes resting, at other times postural and,occasionally, of the so-called wing-beating type,describing a large-amplitude, violent, upper-limb tremor capable of causing trauma to thepatient's own body. Cerebellar findings have alsobeen identified, including limb and gait ataxias.A variety of eye-movement disorders has beendescribed, but seldom proves to be symptomatic.Deposition of copper in Descemet's membraneof the cornea is probably inevitable in patientswith neurological manifestations of Wilson'sdisease, but may require slit-lamp microscopyfor identification.
Psychiatric manifestations are virtually ubiquitous,and may antedate other features of the disease.A profound psychotic state that is indistinguish-able from schizophrenia is recognized, as are
depressive states and severe behavioral disorders.Other organs that may be affected include theskin, the kidney and the skeleton.
The diagnosis can be confidently made if Kayser–Fleischer rings are identified. The vast majority ofpatients have a serum ceruloplasmin concentration< 20 mg / dl. Urinary copper levels are usuallyhigh. Measurement of serum copper is unhelpful.On occasions, a liver biopsy with estimation ofcopper content is needed to establish the diagnosis.
Imaging is of value in demonstrating the partic-ular changes occurring in the brain. CT candemonstrate ventricular dilatation and corticalatrophy as well as hypodensities in the basalganglia. MRI is more sensitive in detecting bothlesions within the basal ganglia and in thethalamus.
A chronic non-familial form of hepatic cerebraldegeneration has been described. The clinicalfeatures are similar to those of Wilson's disease,but there are no Kayser–Fleischer rings, and noevidence of abnormal copper accumulation. Theclinical features are variable and include anencephalopathic syndrome, various movementdisorders and a myelopathy. The underlyinghepatic disease may be silent. The condition islikely to coexist with episodes of acute hepaticencephalopathy, but its severity does not correlatewith the frequency of such episodes. Indeed, insome cases, episodes of hepatic encephalopathyhave not been reported. The initial presentationmay be with either the hepatic or neurologicalfeatures. As regards the movement disorder,dystonia is uncommon whereas chorea, andpostural and action tremors, are often prominent.A variety of hepatic diseases appear capable oftriggering acquired hepatocerebral degeneration,including chronic active hepatitis, primary biliarycirrhosis and other forms of intra- or extrahepaticportal–systemic shunt.
Both cerebral and cerebellar cortical atrophy canbe demonstrated by CT scanning. MRI changesinclude hyperintense signals on T1-weightedimages in the globus pallidus, putamen andmesencephalon in the region of the substantianigra (Figures 65 and 66).
The etiology of the brain lesions has not yet beenestablished, although abnormal accumulation ofmanganese has been proposed as a possible factor.Some of the movement disorders may respond todopa treatment.
Huntington’s disease
The reported prevalence rates for this disease fromthe UK and USA have been 5–9 / 100 000. Althoughthe disease most often appears in subjects in theirlate 30s and early 40s, onset in adolescence andover the age of 50 years is well recognized. Apreponderance of juvenile-onset cases show maletransmission. The Huntington gene has beenlocalized to the short arm of chromosome 4.The gene displays an expanded and unstabletrinucleotide repetition (37–86 repeat units in oneseries) compared with 11–34 copies in the normalchromosome. The age of onset of the disease isinversely correlated with the repeat length(Figure 67).
In terms of pathology, there is severe neuronal lossin the caudate and putamen and, to a lesser extent,in the globus pallidus and cerebral cortex. Macro-scopically the brain is shrunken with widening ofthe cortical sulci and dilatation of the lateralventricles (Figure 68). On microscopy, there is amarked depletion of striatal neurons whichdisproportionally affects small cells. Glial cell lossis less intense (Figure 69). The changes in the cortexare less substantial and are predominant in thethird and fifth layers. A number of neurotrans-mitter systems is affected with particular depletionof GABA and acetylcholine.
Characteristic clinical features of the conditioninclude chorea with intellectual decline andbehavioral disorders. The onset is insidious. Thechorea is often initially very subtle and may presentin the limbs, axial muscles or muscles innervatedby the cranial nerves. With time, dysarthria anddysphagia emerge together with an alteration ofgait. Various eye movement changes are described,including abnormalities of pursuit and saccades.Intellectual changes affect the ability to planand carry out sequential processes coupled withdefects of memory and the ability to acquire newinformation. Behavioral abnormalities includelability, withdrawal and substantial changes inpersonality.
Juvenile cases (defined as onset before the age of20 years) account for approximately 5% of casesand usually inherit the disease from affectedfathers. In these cases, an akinetic–rigid syndromeis more likely than the classical presentation. Atthe other end of the age spectrum, Huntington'sdisease may also present atypically. Families aredescribed in whom the disease usually presentsafter the age of 50 years and then in the form ofchorea, with little or no evidence of dementia.Typically, these patients survive for much longerthan classical cases. Furthermore, imaging failsto reveal evidence of disproportionate caudate orputaminal atrophy.
Imaging
CT reveals evidence of cortical and basal gangliaatrophy. A measure of caudate nuclear size (thebicaudate diameter) shows significant differencescompared with a control population (Figure 70).The caudate and putaminal atrophy are betterdefined by MRI. In the classical form of the disease,abnormal signals from these nuclei are unusual.In the akinetic–rigid form, however, T2-weightedimages demonstrate increased signal intensity inboth the caudate and the putamen (Figures 71
and 72). SPECT can demonstrate reduced striatalblood flow compared with controls. Post-mortemstudies have established a reduction of both D1and D2 receptors in the putamen. The radioactivetracer 11C-raclopride is a selective reversible D2-receptor antagonist whereas 11C-SCH 23390 is aselective D1-receptor antagonist. Using these tracers,Huntington's disease patients can be shown tohave significant reductions in striatal D1 and D2receptor density. The abnormalities apply both tothe choreic and akinetic–rigid forms of the disease,but are greater in the latter group (Figure 73).
The condition is untreatable, although the move-ment disorder can be controlled, to some extent,by dopaminergic blockade. Isolation of the respon-sible gene has allowed accurate genetic counseling.
Hallervorden–Spatz disease
This rare disorder is usually familial with anautosomal-recessive inheritance. Onset is withinthe first two decades of life with disturbances ofspeech and gait. Extrapyramidal features predomi-nate on examination, but with the addition ofspasticity. Iron accumulates particularly in thesubstantia nigra and globus pallidus. MRI findingsare characteristic, with diffuse low signal intensityon T2-weighted images in the globus pallidus,accompanied by an anteromedial area of highsignal intensity (eye-of-the-tiger sign; Figure 74).
Sydenham’s chorea
This disease is one of the recognized manifestationsof acute rheumatic fever. The chorea is accompaniedby dystonia and often psychological symptoms, ofwhich emotional lability is the most prominent.The psychological manifestations usually antedatethe chorea. The condition usually presents ataround 8–9 years of age and lasts for an averageof 6 months. In some cases, the chorea is confinedto one side of the body. Most children with
Sydenham's chorea have other manifestations ofrheumatic fever, usually either arteritis or carditis.Chorea is estimated to occur in around 10–20% ofpatients with acute rheumatic fever. The conditionis explicable on the basis of an antibody, triggeredby group A beta-hemolytic streptococcal infection,which crossreacts with an unidentified antigenon neurons within the basal ganglia. The severityof the chorea can be correlated with the presenceand titer of the antibody. Plasmapheresis orimmunoglobulin therapy probably shortens theduration, and lessens the severity, of the illness.
Tremor
Tremor has been classified according to its etiologyand to the circumstances in which the tremor occurs(Table 5). The tremor of Parkinson's disease hasbeen discussed on page 16. Essential tremortypically affects the upper limbs, but may spread toinvolve the legs, head, facial muscles, voice andtongue. The tremor is sometimes asymmetrical.The condition is inherited through an autosomal-dominant gene, but also occurs sporadically. Thereis a bimodal age distribution with a median age ofaround 15 years. Alcohol relieves the tremor inapproximately 50% of cases. In some patients,cogwheeling rigidity can be detected at the wrists.The tremor can readily be demonstrated byasking the patient to draw a spiral or crossed lines.Serial drawings allow an objective evaluation ofdrug therapy (Figure 75). The tremor sometimesresponds to propranolol, phenobarbitone orprimidone.
Orthostatic tremor appears on standing and affectsthe legs and trunk. Various tremor frequencies havebeen recorded in such patients, some at 6–7 Hz andothers at around 16 Hz (Figure 76). Some patientsdisplay an upper-limb tremor suggestive of anessential tremor but, despite this, orthostatic tremoris more likely to respond to clonazepam than eitherpropranolol or primidone.
Tremor is observed in a number of other situations.The tremor of cerebellar disease is typically inten-tional in quality, but postural elements have beendescribed, affecting the arms at the shoulders, thelegs at the hips, and the head and trunk on standing.Tremor is a recognized feature of certain neurop-athies and is usually action-related. Rubral tremoris a coarse resting tremor exacerbated by postureand more so by action, and usually secondary tobrain stem vascular disease or multiple sclerosis.In some dystonic syndromes, tremor appearsalongside the dystonic features.
Myoclonus
This condition consists of sudden short-lived shock-like contractions of muscle. The movement variesgreatly in both amplitude and frequency. Perhapsthe most useful classification is anatomical,categorizing the movement as focal, segmental(two or more contiguous regions), multifocal orgeneralized. Although myoclonus is usually erratic
in time and rhythm, it sometimes appears to berhythmical. Some episodes of myoclonus appearspontaneously; the others appear either with startleor in response to the initiation of muscle activity.
Essential myoclonus appears in the first twodecades of life and is inherited as an autosomal-dominant trait with variable penetrance. Sporadiccases are common. Postanoxic myoclonus appearsafter a period of coma triggered by cardiac orrespiratory arrest. Muscles of the limbs, face,pharynx or trunk may be affected. Seizures arethe norm, and many patients have particularproblems with gait control. Drugs that enhanceserotonin activity improve the condition.
Segmental myoclonus originates from a brain stemor spinal level. The movements are more or lesscontinuous, usually at around 1–3 Hz, and explic-able by discharges from contiguous anatomicallevels (Figure 77). Palatal myoclonus is a rhythmiccontraction of the soft palate, frequently accom-panied by contraction of other muscles of thepharynx and larynx, sometimes extending to the
face and even the diaphragm. Typically, it followspontine infarction, often after a latent period ofseveral weeks or months.
Tardive dyskinesia
Although tardive dyskinesia is typically associ-ated with previous exposure to dopaminergicantagonists, the condition may also arise sponta-neously. The movements predominate around themouth and tongue, with lip-smacking, sucking,pursing and tongue protrusion. In some cases,involuntary movements affect the limbs or thetrunk. A repetitive quality is characteristic. Thecondition may persist despite withdrawal of thecausative agent and, indeed, may be temporarilyworsened at such times. Tardive dystonia consistsof focal dystonic movement particularly affectingthe neck or trunk, which are also liable to persistafter neuroleptic withdrawal. Both tardivedyskinesia and tardive dystonia may sometimesrespond to presynaptic dopaminergic blockadewith reserpine or tetrabenazine.
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Cortical Lewy body disease
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Multiple system atrophy
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Section 2 Parkinson’s Disease and Related DisordersIllustrated
Figure 2 Connections of striataloutput neurons in controls (left)and in rats with 6-0H dopaminelesions of the nigrostriatal dopa-mine system (right). MC, motorcortex; SMA, supplementarymotor area; PMC, premotorcortex; D1 / D2, D1 / D2 dopa-mine receptor systems; SNc,substantia nigra pars compacta;SNr, substantia nigra pars retic-ulata; GPe / GPi, external / inter-nal portions of globus pallidus;STN, subthalamic nucleus; VLo,ventral lateral, pars oralis,nucleus of thalamus; VApc / mc,ventral anterior, pars parvo-cellularis / pars magnocellularis,nucleus of thalamus; CM, centro-median nucleus of thalamus
All areasof cerebral
cortex
Areas 4 and 6
Area 6supplementary
motor area
Afferent pathways
Intrinsic pathways
Efferent pathways
C,PGPe
GPi
Thalamus
VA
Sth
SC
SNcSNr
VL
I,CM
Figure 1 Major pathways of the basal ganglia (some pathways, including the subthalamonigral fibers,and afferents from the locus ceruleus and raphe nucleus, have been omitted for the sake of clarity.)C, P, caudate nucleus and putamen (striatum); GP, globus pallidus (e, externa; i, interna); SN, substantia nigra(c, compacta; r, reticulata); Sth, subthalamic nucleus; T, thalamus (nuclei: VA, ventral anterior; VL, ventro-lateral; CM, centromedian; I, other intralaminar); SC, superior colliculus. Modified from Riley and Lang, inBradley et al., Neurology in Clinical Practice, 1996 (see page 31)
Figure 4 Histology of normal substantia nigra, which is well-populated with nervecells immunoreactive for tyrosine hydroxylase (immunostained for tyrosine hydroxylase)
Figure 3 Horizontal sections of midbrain (upper)and pons (lower) in idiopathic Parkinson's diseaseof 10 years' duration show pallor in the substantianigra (arrowed) and locus ceruleus (arrowed),respectively
Figure 5 Histology of substantia nigra in idiopathic Parkinson's disease of 12 years'duration showing depletion of tyrosine hydroxylase-containing nerve cells (immuno-stained for tyrosine hydroxylase)
Figure 6 Histological views of a Lewy body in the substantia nigra pars compactastained with H & E (left) and with a modified Bielschowsky stain (right)
Figure 12 As this patient repetitively clenches and unclenches his fists, a paucity ofmovement is apparent in his left hand
Figure 13 Power-spectrum (upper) and accelerometer (lower) tracings taken froma patient with Parkinsonian tremor. The main tremor peak is at approximately 5 Hzwith a harmonic at 10 Hz
Figure 16 Synthesis and metabolism of dopamine within the central nervous system. Thegreen arrows indicate the sites at which various agents might enhance dopaminergic activity.COMT, catechol O-methyltransferase; +, by stimulation; –, by inhibition
Figure 22 Histology showing parietal white matter at the bottom of the cortex, arelatively preserved (but not quite normal) arcuate zone (white arrow), and rarefiedpale-staining deep white matter, containing thick-walled arteriosclerotic blood vesselslying in dilated and fibrotic perivascular spaces (black arrow)(Luxol fast blue–H & E)
Figure 21 Coronal brain section showing abnormal white matter (white arrow) abovethe ventricular roof with relative preservation of subcortical white matter (U fibers;black arrow)
Figure 24 CT of a patient with a Parkinsoniansyndrome shows multiple lacunar infarcts
Figure 23 Histology showing a lacunar infarct (pale area) with an irregular cavitylined by reactive cells (astrocytes and macrophages). Debris and a few vascular channelscan be seen (Luxol fast blue–H & E)
Figure 25 T1-weighted MRI showing multiplesmall hypointense foci in the putamen andcaudate nuclei bilaterally. The patient hadpresented with a Parkinsonian state with,eventually, predominant axial features
Figure 26 Coronal brain section (same patient as in Figure 25) showing numeroussmall lacunes in the heads of both caudate nuclei and in the anterior part of theputamen
Figure 33 Coronal section ofbrain from a patient with striato-nigral degeneration showing sym-metrical atrophy and discolorationof the putamen
Figure 32 11C-raclopride binding in a normal subject (left) compared with that in Parkinson's disease(middle) and in progressive supranuclear palsy (right). (11C-raclopride is a selective reversible antagonistof D2 receptors)
Figure 38 Histological sections of basis pontis (arrowed) show the normal comple-ment of pontine neurons in a control subject (left) compared with neuronal depletion(right) in multiple system atrophy (H & Es)
Figure 37 Coronal sections showing normal(upper) compared with atrophied (lower) basispontis secondary to olivopontocerebellar atrophyin multiple system atrophy
Figure 39 Multiple system atrophy with olivopontocerebellar atrophy. Histologyshows (left) depletion of Purkinje cells (only two can be seen; black arrows). Theremainder of the Purkinje cell layer (seen between the white arrows) consists only ofsmall astrocytic cells. Atrophy of the central white matter in the cerebellar folia isalso seen. Evidence of Purkinje cell degeneration (right) with formation of axon torpe-does (white arrow) is seen in the molecular layer (H & Es)
Figure 42 T2-weighted MRI (upper) shows hyperintensity of the middle cere-bellar peduncles and the cerebellum. The axial proton-density MRI (lower) showshyperintensity of the transverse pontine fibers, middle cerebellar peduncles andcerebellum in olivopontocerebellar atrophy
Figure 43 PET scans showing local cerebral metabolic rate for glucose in a normalcontrol compared with patients with multiple system atrophy (MSA), sporadic olivo-pontocerebellar atrophy (sOPCA) and dominantly-inherited olivopontocerebellaratrophy (dOPCA)
Figure 44 Macroscopic view of the brain in corticobasal degeneration. Theleptomeninges have been partially removed to show cortical atrophy involvingthe posterior frontal and anterior parietal regions
Figure 48 Dorsal (left) and palmar (right) views of dystonic posturing of the lefthand of a patient with corticobasal degeneration. In particular, note the ulnar deviationat the wrist and the abducted posture of the little finger
Figure 47 Histology ofcerebral cortex in cortico-basal degeneration shows aputaminal neuron (arrowed)containing a basophilic inclu-sion (H & E)
Figure 49 This patient with corticobasal degener-ation shows ideomotor apraxia of the left hand.When asked to copy three hand postures (A–C,lower), in each instance, the patient's version wasdefective (A–C, upper)
Figure 51 [18F]-fluorodeoxyglucose–PET scan shows reduced metabolism inthe left frontoparietal cortex and leftstriatum in a patient with corticobasaldegeneration
Figure 52 Scoliotic posture in a patientwith idiopathic torsion dystonia
Figure 57 Dystonic postur-ing of the hand consequentto perinatal hypoxia
Figure 58 Dystonic postur-ing of the foot consequentto perinatal hypoxia. There isinversion of the foot andrelative dorsiflexion of thebig toe of the patient’s leftfoot compared with the right
Figure 59 CTs showing focal ischemicchange (black arrows) in the right frontalregion with deep extension and dilatation ofthe right frontal horn (white arrow)
Figure 61 Dystonic postur-ing of the left big toe in apatient who had experiencedan ischemic event in the rightcerebral hemisphere follow-ing attempted removal of asphenoidal wing meningioma
Figure 60 Dystonic hand posture (same patient as in Figure 59)
Figure 62 Histology in Wilson's disease showsatrophy and rarefaction of the putamen (blackarrows). Loss of myelin bundles in the putamencontrasts with the more normal appearances inthe globus pallidus (white arrow; Luxol fast blue)
Figure 63 Histology of brainin Wilson's disease shows aBergmann type 2 astrocytewithin an atrophic putamen(H & E)
Figure 65 T1-weighted MRIshows the presence of high-signal areas (arrowed) in thesubstantia nigra in a patientwith chronic acquired hepato-cerebral degeneration
Figure 66 T1-weighted MRI shows the presence of high-signal areas(arrowed) in the pallidum in a patient with chronic acquired hepatocere-bral degeneration
Figure 67 Pedigree (upper) of a family withHuntington's disease is accompanied byDNA gels (lower) which indicate trinucleo-tide repeats of between 40 and 52
Figure 69 Histological section of brain inHuntington's disease shows atrophy with loss ofneurons and astrocytic gliosis (immunocytochem-istry preparation for glial fibrillary acidic protein)
Figure 68 Coronal section ofbrain in Huntington's diseaseshows symmetrical atrophy andbrown discoloration (arrowed) ofthe caudate and putamen togetherwith dilatation of the lateral vent-ricles
Figure 72 Coronal proton-density MRI in a patient withHuntington's disease showsfeatures similar to those inFigure 71
Figure 71 Axial proton-density MRI ina patient with Huntington's disease showsareas of increased signal in both the cau-date nucleus (white arrow) and putamen(black arrow)
Figure 73 PETscans showing integrated 11C-raclopride and 11C-SCH 23390 activityin a normal subject (left) and choreic patient (right) with Huntington's disease. BothD1 and D2 binding is reduced in the Huntington's patient in both the caudate andputamen
Figure 74 Axial T2-weighted MRI (upper)of a patient with Hallervorden–Spatz diseaseshows marked pallidal hypointensity (arrow-ed). The coronal proton-density MRI (lower)shows a similar picture together with ananteromedial zone of high intensity