Parkinsonian Syndromes.8

ParkinsonianSyndromesDavid R. Williams, MD, MBBS, PhD, FRACP; Irene Litvan, MD, FAAN

ABSTRACTPurpose of Review: The different parkinsonian conditions can be challenging toseparate clinically. This review highlights the important clinical features that guidethe diagnosis of Parkinson disease (PD), progressive supranuclear palsy (PSP),multiple system atrophy (MSA), and corticobasal degeneration (CBD). Strategies fortreatment and disease management are also discussed.Recent Findings: Over the past decade there has been an increasing recognition ofthe broad clinical presentations of the neurodegenerative forms of parkinsonism.Nonmotor symptoms in these diseases, including psychiatric, cognitive, autonomic,and gastrointestinal dysfunction, appear to have a major impact on quality of lifeand disability. PSP and CBD are now considered pathologic diagnoses, with severaldifferent and varied clinical phenotypes, that overlap and share features withPD and frontotemporal dementia syndromes. PD is distinguished by its excellentresponse to dopaminergic medications that is maintained over many years, incontrast to the response seen in patients with MSA and PSP. New diagnostic criteriahave been proposed for CBD. No new therapeutic interventions have emerged forPSP, MSA, or CBD. Infusional therapies and deep brain stimulation surgery areestablished therapies for advanced PD.Summary: The ‘‘parkinsonian syndromes’’ encompass a number of nosologicentities that are grouped together on the basis of their shared clinical features butare separated on the basis of their different pathologies. Overall, the considerationof clinical signs, mode of disease onset, and nature of disease progression are allimportant to make a timely and definitive diagnosis.

Continuum (Minneap Minn) 2013;19(5):1189–1212.

INTRODUCTIONThe parkinsonian syndromes includeidiopathic Parkinson disease (PD), pro-gressive supranuclear palsy (PSP), multi-ple system atrophy (MSA), corticobasaldegeneration (CBD), and vascular Par-kinsonism (VaP), among other rarercauses of parkinsonism.

Bradykinesia is the most significantand indeed the essential clinical signthat leads to a diagnosis of parkinson-ism. Bradykinesia implies abnormalfunction of the basal gangliaYcorticalneuronal circuits that lead to a dis-order of motor function manifest asslowed, small-amplitude movements.The clinical recognition of bradykinesiarequires the identification of small-

amplitude movements that may affectlimb control (eg, reduced arm swing,micrographia, lack of dexterity), speech(eg, hypophonia), swallowing (eg, dys-phagia for liquids), gait (eg, shortenedstride length), facial expressivity (eg,hypomimia), or posture (eg, stoopingor leaning). In addition, parkinsonismtypically includes extrapyramidal rigid-ity, rest tremor, and postural instability,which are also considered features ofbasal ganglia dysfunction.

Parkinsonism is generally regardedin purely motor terms, but a morehelpful approach is to broaden this viewto incorporate the nonmotor featuresthat evolve coincident with the progres-sive motor disability of these diseases.1

Address correspondence toDr Irene Litvan, Universityof California, San Diego,Department of Neurosciences8950 Villa La Jolla Drive, SuiteC112, La Jolla, CA 92037,[email protected].

Relationship Disclosure:

Dr Williams serves on thescientific advisory board ofIpsen and receives researchsupport from the NationalHealth and Medical ResearchCouncil. Dr Litvan hasserved as a member of theAbbot/Abbvie, Biogen,Bristol-Myers-Squibb, andPfizer scientific advisoryboards and was a consultantfor Novartis. Dr Litvanreceives grant support fromthe NIH (R01AG024040)and CurePSP.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:

Drs Williams and Litvan reportno disclosures.

* 2013, American Academyof Neurology.

Supplemental digital content:Videos accompanying this ar-ticle are cited in the text asSupplemental Digital Content.Videos may be accessed byclicking on links provided inthe HTML, PDF, and iPadversions of this article; theURLs are provided in the printversion. Video legends beginon page 1209.

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These symptoms may be caused bybasal ganglia dysfunction or other sys-tem degeneration, leading to psychiat-ric, cognitive, autonomic, cerebellar, orpyramidal dysfunction.

THE CLINICAL EXAMINATIONBradykinesiaPatients with parkinsonian syndromesmay report that they have ‘‘sloweddown’’ or become clumsier, and fam-ily members may report an impressionof rapid aging or increased frailty.These observations often relate tothe emergence of bradykinesia, whichis defined as ‘‘slowness of initiationwith progressive reduction in speedand amplitude of repetitive action’’and which must be present in order tomake a diagnosis of parkinsonism. Inthe office, this clinical sign may betested in a number of ways, includingrepetitive finger tapping (index fingeron thumb for 15 seconds), sequentialfinger tapping (all fingers on thumb),rapid alternating movements (at thewrist), repetitive hand opening, andfoot or toe tapping. During these tasks,progressive diminution of the ampli-tude of movements is seen but mayrequire more than 15 seconds of obser-vation.2 In more severe cases, motorblocking (causing pauses or freezing ofmovement) may occur. Evaluation ofthe handwriting or drawing of anArchimedes spiral may reveal micro-graphia with characteristic reduction inamplitude with ongoing actions. Spon-taneous movements are often reduced,including muscles of facial expression(hypomimia) and noticeably reducedgesticulation. Patients will appear tomove stiffly and lack fluidity (en bloc)when standing from a seated positionor when sitting, which can often be thefirst sign when bringing a patient infrom the waiting room.

Although decrement in movementis required for the classification of

bradykinesia according to QueenSquare Brain Bank criteria, slowedmovements without decrement (hypo-kinesia) may be the only sign of basalganglia dysfunction in PSP.2 This mayreflect more widespread pathologicinvolvement in these patients com-pared to PD and could also be seenin patients with VaP.

Extrapyramidal RigidityPatients rarely report rigidity or mus-cle stiffness as a primary symptom, butit is an important clinical clue whendiagnosing parkinsonism. In the earlystages of disease, rigidity may manifestas pain, which can obscure the diag-nosis of a CNS problemVfor example,in the case of frozen shoulder and lowback pain.3

In the office, rigidity is tested bypassively moving the wrists, elbows,neck, knees, and ankles through theircomplete range of movement, withthe patient at rest. Extrapyramidalrigidity is defined by abnormally in-creased resistance to movement thatis independent of the velocity of themovement. This increase in tone canhave a ‘‘lead pipe’’ quality (ie, consis-tent throughout the movement) or‘‘cogwheel’’ quality (ie, jerky, inconsis-tent resistance). In contrast, pyramidaltone (spasticity) is dependent on thevelocity of passive movement and isdescribed as ‘‘clasp knife’’ in qualitybecause of the higher resistance duringearly acceleration of the passive move-ment followed by giving way, such as isseen when opening lock-blade knives.

TremorThe rest tremor of PD is one of themost characteristic signs in clinicalmedicine. It is differentiated fromother forms of tremor by its asym-metry, speed (4 to 6 Hz), the predom-inance of the tremor at rest (andattenuation or cessation during action),

KEY POINTS

h Bradykinesia is theclinical sign that mustbe invariably presentfor the diagnosis ofparkinsonism as asyndrome.

h Progressive decrementin movement amplitudeor speed is required forclassifying bradykinesia.However, slowedmovements withoutdecrement (hypokinesia)may be the only signof basal gangliadysfunction inprogressivesupranuclear palsy.

h Rigidity applies to thevelocity-independentabnormal increase inresistance to passivemovements, yieldinga ‘‘lead-pipe’’ or‘‘cogwheel’’ quality.Conversely, spasticity isrecognized by thevelocity-dependentabnormal increase inresistance to passivemovements, yielding a‘‘clasp-knife’’ quality.

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Parkinsonian Syndromes


the re-emergence of tremor whenmaintaining a posture, and its increasein amplitude during tasks that requiremental concentration.4

The tremor is evaluated in the officewith the patient seated and the fore-arms supported on the arms of thechair, on a pillow, or resting in the lap.The patient is advised to keep the armsand hands at rest, and a period ofobservation of up to 60 seconds maybe required to allow the tremor toemerge. Asking the patient to performcognitive tasks (eg, serial subtraction)may rouse the tremor. The patient’sarms are then examined outstretched,with particular attention paid to abnor-mal, dystonic posturing; action myoclo-nus; stimulus-sensitive myoclonus; orpostural tremor. A re-emergent tremorcan be seen in PD, often between 5 and10 seconds after adopting a new pos-ture. Slow pronation and supination ofthe forearms would often reduce thetremor in PD, but may accentuate adystonic tremor. Rest tremor in thehand can also be evaluated with thepatient walking. PD tremor in the legs ismost visible with the patient seated onthe edge of an examination couch, withthe legs hanging and feet unsupported.Rest tremor of the jaw can also be seen,particularly when the patient isperforming an activity with another partof the body.

Gait DisturbancePostural instability and gait distur-bance are universal features of ad-vanced disease in PD but may be animportant early sign in patients withPSP or MSA.5 Even before falls de-velop, patients often describe a loss ofconfidence on their feet, a feeling ofimbalance or reduced ability to nego-tiate uneven terrain or stairs. Speed ofwalking is slowed, and this may beone of the first signs of parkinsonismnoticeable to others.

The office examination of gait re-quires a space 10 meters in length sothat the gait can be fully assessed. Thepatient is asked to stand out of the chairwithout support (when safe) and walk10 meters, then turn and walk back tosit down. To assess for gait freezing, thepatient is asked to stop and turn 360-and then repeat the turn in the oppositedirection. The Parkinsonian gait is nar-row based, with shortened stride lengththat may become shorter over distance,as well as reduced arm swing.6 Patientswill often take several steps to turn.The patient may show hesitancy at theinitiation of gait, or freezing of gait,which is often most prominent whenturning or walking through doorwaysor over verges. In most patients withMSA and PSP, tandem gait is impaired.7

Often in these patients, the gait be-comes broad based and unsteady,resembling an ataxic gait. In PSP, alurching gait with spontaneous falls ischaracteristic, so careful monitoring ofthe patient throughout the examina-tion is important.

THE PURPOSE OF CLINICALDIAGNOSISThe diagnosis of the parkinsoniansyndromes is entirely clinical, as atthe present time no imaging, bio-chemical, or genetic tests definitivelydiagnose or separate the differentdiseases.8 Diagnosis relies on taking acomplete medical history that in-cludes timeline of symptoms, recogni-tion of the important clinical signs,and consideration of the differentialdiagnoses. Individuals’ diagnostic acu-men is substantially influenced byclinical experience, and even amongmovement disorder specialists, theclinical diagnosis can change over timebecause of emerging clinical signs.9,10

While the identification of parkin-sonism is an important first step for theconsideration of therapeutic options,

KEY POINTS

h Slow pronation andsupination of theforearms often reducethe tremor in Parkinsondisease but accentuatea dystonic tremor.

h Start hesitation orfreezing of gait inParkinson disease aremost prominent whenturning or walkingthrough narrow spaces,such as doorways.



the differential diagnosis between PD,PSP, MSA, CBD, and VaP does not oftenprovide for further specific disease-modifying therapy. However, a defini-tive diagnosis serves to inform patients,caregivers, family, and the broadermultidisciplinary care team about prog-nosis, expected clinical progression,disease course, and potentially usefultherapeutic modalities. Furthermore, adefinitive clinical diagnosis gives a namefor the disease, which is regarded bypatients as very important and helpfulwhen coming to terms with a chronicdisease.11 Where possible, it is notrecommended to diagnose ‘‘atypicalparkinsonism’’ or a ‘‘parkinsonian syn-drome,’’ as these terms are meaning-less for patients and their care teamand provide no further informationabout management or prognosis. If adefinitive diagnosis cannot be reached,then a hierarchical list of diagnosticpossibilities should be discussed. Inthe case of PSP, CBD, and MSA, diag-nostic criteria allow for possible andprobable diagnostic categories, accord-ing to levels of diagnostic certainty.

PARKINSON DISEASEClinical Confirmation ofParkinson DiseaseThe diagnosis of PD is guided by theQueen Square Brain Bank diagnosticcriteria,12 which require two steps.Step one focuses on the definition ofparkinsonism and requires the pres-ence of bradykinesia and of either (1)typical rest tremor, (2) extrapyramidalrigidity, or (3) postural instability(Case 1-1). However, postural insta-bility is not an early PD feature andshould alert the clinician of an atypicalparkinsonian disorder. Step two focuseson features typical of the parkinsonismof PD, such as unilateral onset, excellentresponse to levodopa therapy, and de-velopment of dyskinesia. Exclusioncriteria include pyramidal signs, stepwise

deterioration of parkinsonism (implyingstroke), repeated head injury, history ofencephalitis or oculogyric crisis, neuro-leptic treatment at the onset of symp-toms, strictly unilateral features after 3years, supranuclear gaze palsy, cerebellarsigns, early severe autonomic dysfunc-tion, early severe cognitive dysfunction,negative response to levodopa, andimaging evidence of communicatinghydrocephalus.

Natural HistoryThe progression of disease and accu-mulation of disability in PD is variable,and to some extent depends on patientfactors, in particular age. Data from theQueen Square Brain Bank suggest thatthe mean time from diagnosis to deathis around 14 years; however, for pa-tients diagnosed in their forties it is24 years, and for patients in theirseventies it is 9.7 years.13 The meanage of disease onset is 61 years old.

While the cardinal motor signs ofPD commonly bring the diagnosis tomedical attention, early disease mayalso include symptoms of depression,fatigue, REM sleep behavior disorder,anosmia, or constipation that requiretreatment in their own right.14 CognitivedysfunctionVin particular, mild cogni-tive impairment with executive dys-function characterized by difficulties inmultitasking, planning, retrieval, concen-tration, and attentionVand visuospatialdysfunction are being recognized atearlier stages.15

Throughout the disease course, allpatients experience deterioration intheir clinical signs, and an associatedincrease in impairment and disability,with subsequent decline in quality oflife. The later stages of disease arecharacterized by reduced duration ofeffect of oral medications, increasedmedication-related side effects, dys-phagia, cognitive dysfunction (even-tual conversion of PDYmild cognitive

KEY POINTS

h Postural instability is notan early feature inParkinson disease andshould alert theclinician of an atypicalparkinsonian disorder.

h Younger age at onsetin Parkinson disease isassociated with longersurvival and sloweraccrual of disability.




impairment to dementia), reducedmobility with increased tendency tofall, and, in many, dependence onothers for activities of daily living. Themode of death is most often related torespiratory compromise in the settingof bronchopneumonia or aspiration.

Treatment ParadigmThe active treatment of PD begins atthe time of diagnosis but does notnecessarily require medical therapies

immediately. Much of the early treat-ment focus should be on informationdelivery, support, and counseling tofacilitate a realistic view of PD, prog-nosis, and management outcomes.These discussions usually take placeover a number of office visits and shouldinclude a discussion about the medicaltherapies that are available for PD(Table 1-1).

The timing of initiation of dopaminer-gic therapies is dependent on patient

Case 1-1A 52-year-old salesman presented with a 2-year history of left handtremor. He had noted the insidious development of left thumb tremor atrest over the course of 2 years that had lately spread to involve his lefthand. The tremor was also present when he held a newspaper and couldbe so intense that it affected his writing and impaired his functioning atwork. Over the previous year, he also developed mild pain in the leftshoulder. He had a long-standing history of REM sleep-behavior disorderand anosmia but no other neurologic disturbances or family history ofneurodegenerative disorders. On examination, he had a normal mentalstatus examination, mood, cranial nerves, and strength. He demonstratedmild hypomimia, a rest tremor in the left hand, and re-emergent posturaltremor (ie, it re-emerged with the same frequency it had at rest a fewseconds after he extended his arms, as shown in Supplemental DigitalContent 1-1, links.lww.com/CONT/A53). Significant bradykinesia waspresent on the left with finger tapping, hand movements, and foottapping with moderate cogwheel rigidity. His gait was normal butlacked associated movement of the left arm, and he displayed a resthand tremor when walking. Postural reflexes were normal.

He was clinically diagnosed with idiopathic Parkinson disease.Treatment options were discussed, and because his symptoms affected hisjob performance, medical therapy was recommended and he was startedon pramipexole, a dopamine agonist. His bradykinesia improved, buthe developed impulse control disorder characterized by gambling andcraving food, gaining 3.6 kg in 2 months. These symptoms subsided withthe discontinuation of pramipexole. Treatment with levodopa-carbidopaimproved the bradykinesia but did not improve the tremor. Benztropineand amantadine induced memory disturbances and had to bediscontinued. After deep brain stimulation of the subthalamic nucleus,his symptom control allowed him to resume work.

Comment. This is a typical presentation of Parkinson disease, withclassic resting tremor. A tremulous asymmetric parkinsonism phenotypepreceded by REM behavior disorder is the most characteristic presentationof Parkinson disease. The case highlights the challenges of therapy,including the development of an impulse control disorder (with adopamine agonist) and cognitive impairment induced by drugs withanticholinergic properties (amantadine and benztropine).



links.lww.com/CONT/A53

TABLE 1-1 Medications Used in Parkinson Disease

Class MedicationsTypical InitialDose

MaximalRecommendedDoses

ImportantSide Effects

Levodopapreparations

Carbidopa/levodopa

Benserazide/levodopaa

Carbidopa/levodopa/entacapone

25 mg/100 mg3 times/d

25 mg/100 mg3 times/d

25 mg/100 mg/200 mg 3 times/d

~1200 mglevodopa/d(selected casesmay require upto 2500 mg/ddivided in 5 or6 doses)

Short-term:nausea, vomiting,lightheadedness,orthostasis

Long-term: dyskinesia,motor fluctuations,hallucinations

Catechol-O-methyltransferaseinhibitorsb

Entacapone

Tolcapone

200 mg 3 times/d

100 mg 3 times/d

200 mg with eachdose of levodopa

200 mg 3 times/d

Same as for levodopapreparations (maximizelevodopa effects)

Entacapone: diarrhea,brownish-orangediscoloration of urine

Tolcapone: risk ofpotentially fatal fulminanthepatic toxicity, whichrequires close monitoringof liver function tests;diarrhea; brownish-orange discolorationof urine

Dopamine agonists Pramipexole IR: 0.125 mg3 times/d

XR: 0.375 mg/d

IR: 1.5 mg 3 times/d

XR: 4.5 mg/d

Excessive sleepiness,impulse control disorders,leg edema, hallucinations,orthostasis

Ropinirole IR: 0.25 mg3 times/d

XR: 2 mg/d

IR: 8 mg 3 times/d

XR: 24 mg/d

Cabergoline isassociated withpulmonary fibrosis andcardiac valvulopathy

Rotigotine patch 2 mg/24hrs 8 mg/24hrs Apomorphine isassociated withorthostatic hypotension,nausea, lightheadedness,sedation

Cabergolinea 1 mg/d 6 mg/d

Apomorphine 0.2 mL (2 mg) 0.6 mL (6 mg)

Monoamineoxidase-Binhibitors

Rasagiline

Selegiline

1 mg/d

5 mg/d

1 mg/d

5 mg 2 times/d

Nausea, lightheadedness,dyskinesia, hallucinations

Selegiline orallydisintegrating

1.25 mg everymorning

2.5 mg everymorning

Others Amantadine 100 mg/d 100 mg 3 times/d Cognitive impairment,hallucinations, drymouth,myoclonus, livedoreticularis, leg edema

IR = immediate release; XR = extended release.a Formulation not available in the United States.b Catechol-O-methyltransferase inhibitors are used as adjunct to carbidopa/levodopa therapy.




preference, degree of disability, andpotential side effects of therapy. Ingeneral, early treatment with dopami-nergic therapies is recommended, andthe choice, depending on age andoverall cognition, is between levodopapreparations, dopamine agonists, andmonoamine oxidase inhibitors. Mono-amine oxidase inhibitors and dopamineagonists are longer-acting medicationsand therefore require only one dose perday. Levodopa (in combination with adopa decarboxylase inhibitor) is moreefficacious but requires dosing intervalsof 3 times per day initially.16

The dose adjustments of dopamineagonists and levodopa preparations aremade in response to clinical effect,emerging symptoms, and side effects.The risk of psychiatric side effects anddyskinesias is greater at higher doses, soa rule of thumb is to treat with thelowest dose possible to achieve benefitsfor the patient in terms of function andquality of life. Furthermore, patientsbelow 50 years of age who take dosesof greater than 600 mg of levodopa aremore likely to experience dyskinesia.17

As the disease progresses, motorfluctuations with end-of-dose wearing-off symptoms or peak-dose dyskinesiasare inevitable. Initially, the fluctuationswill respond well to medication ma-nipulation. Wearing-off symptomscan be alleviated by the addition ofmonoamine oxidase inhibitors,catechol-O-methyltransferase (COMT)inhibitors, or dopamine agonists, orwith increased levodopa dosing fre-quency. COMT inhibitors (entacaponeand tolcapone) can only be used inconjunction with levodopa to in-crease the ‘‘on’’ time, as they yield nointrinsic antiparkinsonian efficacy ontheir own.

Dyskinesias develop in about 50% ofpatients with PD, including patientstreated with dopamine agonists, levo-dopa preparations, or monoamine oxi-

dase inhibitors. They are more likely todevelop in patients using higher dosesof levodopa preparations, in men, andin younger patients. Often, when mild,they do not need any specific treatment.Where possible, doses of dopaminergicmedications should be minimized, andin some patients the addition of aman-tadine can reduce the dyskinesias.

Treatment of depression will oftenrequire the addition of tricyclic antide-pressants, selective serotonin reuptakeinhibitors, or serotonin-norepinephrinereuptake inhibitors. Constipation mayrespond to dietary adjustment, butpatients often require laxatives.

Advanced TreatmentsAs PD progresses, the development ofwearing-off symptoms and dyskinesiascan produce severe, disabling motorfluctuations that are not controllableusing oral medications. At this point inthe disease, advanced therapies areconsidered, which include deep brainstimulation (DBS) surgery or infusionaltherapies such as subcutaneous apo-morphine or intraduodenal levodopagel infusions. These therapies are gen-erally reserved for patients who havefailed to substantially improve on all ofthe available oral and transdermal ther-apies and who do not have symptomaticcognitive or psychiatric effects of PD.18

These advanced therapies are bestoffered by teams that include specialistnurse support and are experienced intheir use. DBS, apomorphine, andintraduodenal levodopa can substan-tially improve motor fluctuations bydecreasing both daily off-time anddyskinesias. The benefits of these ther-apies are known to continue manyyears after their initiation, but at thesame time the underlying pathologyprogresses. Even in patients who ex-perience an excellent response, ad-vancing disease can lead to theemergence of postural instability and

KEY POINT

h Although seen moreoften with levodopa,dyskinesias may developin Parkinson diseasepatients with dopamineagonists or monoamineoxidase inhibitors, in adose-dependentfashion.



falls, cognitive disturbance, autonomicdysfunction, and swallowing andspeech disturbance.

Postural hypotension may respondto a high-salt diet but may also requirethe addition of mineralocorticoids ormidodrine. Visual hallucinations requiremedication adjustment and may needspecific therapies if they are trouble-some, threatening, or associated withbehavioral change. Medications shouldbe reduced or stopped in order ofdecreasing hallucinogenic potential: an-ticholinergic medications, amantadine,dopamine agonists, monoamine oxi-dase inhibitors, and lastly levodopa.However, levodopa dose can only bereduced at the expense of motor dete-rioration, in which case clozapine is themost effective antipsychotic strategy.Although quetiapine is of lower efficacy,it may be preferred as initial therapybecause of its better side-effect profile.While other atypical antipsychoticmedications can reduce acute agita-tion, they often lead to deterioration inthe motor parkinsonism. Cholinester-ase inhibitors may improve concentra-tion and reduce the occurrence ofhallucinations in PD patients with cog-nitive dysfunction. Cognitive impair-ment, autonomic dysfunction, and fallsare all features of severe PD that sub-stantially affect function and quality oflife and incompletely respond to med-ication manipulation.19

PROGRESSIVE SUPRANUCLEARPALSYClinical Confirmation ofProgressive Supranuclear PalsyThe clinical manifestations of PSP-taupathology are variable, and diagnosiscan be difficult at times because of thesubtle early signs that may be difficultto discern from other physical orpsychological symptoms. The diagno-sis of PSP should be considered in allpatients presenting with parkinsonism

not responding to levodopa therapy;postural instability with falls; executivedysfunction; slowing of vertical saccades/supranuclear vertical gaze palsy; ordysarthria/dysphagia (Case 1-2).20

PSP can be divided into severalclinical subtypes, and this separationprovides some guidance on prognosisand natural history. Furthermore, the10% to 30% of patients with PSP-taupathology who do not present withthe classic clinical form of the diseaseare not diagnosable using the currentresearch diagnostic criteria.21 Theclassic form of PSP is referred to asRichardson syndrome (also known asSteele-Richardson-Olszewski syn-drome), and other variants includePSP-parkinsonism, PSPYpure akinesiawith gait freezing, and PSP-corticobasalsyndrome (PSP-CBS).22 (Table 1-2)

Richardson syndrome. Patientswith PSP-Richardson syndrome mostoften report early difficulties withbalance, personality changes, visual dis-turbances, or a combination of thesesymptoms. The mean age of onset isaround 65 years. Medical attention isfirst sought when patients experiencesevere postural instability with tendencyto fall, the family notices personalitychanges (apathy), colleagues reportunderperformance at work, or the pa-tient reports ‘‘slowing down.’’

The characteristic eye-movementabnormalities that help confirm thediagnosis of PSP-Richardson syndromedevelop over many months, often ini-tially as slowing of vertical saccadesand gradually evolve into hypometricsaccades, square-wave jerks (fixationinstability), and eventually supranuclearvertical gaze palsy.23,24 Development ofthese eye-movement abnormalities isassociated with midbrain atrophy, acharacteristic imaging finding in PSP-Richardson syndrome (Figure 1-125).Testing of saccadic eye movements isperformed by asking the patient to

KEY POINTS

h Threatening visualhallucinations require asequential reduction ordiscontinuation inmedications accordingto their decreasinghallucinogenicpotential: anticholinergicmedications,amantadine, dopamineagonists, monoamineoxidase inhibitors, andlastly levodopa.

h The diagnosis ofprogressivesupranuclear palsy isconsidered in casesof poor levodoparesponsiveness, earlypostural instability withfalls, early executivedysfunction, slowing ofvertical saccades, andsupranuclear verticalgaze palsy or earlydysarthria/dysphagia.

h Early eye-movementabnormalities inprogressivesupranuclear palsyYRichardson syndromeinclude slowing ofvertical saccades,square-wave jerks(fixation instability), andeventually supranuclearvertical gaze palsy.




generate rapid eye movements be-tween two targets, one in the neutralposition (0-) and the other at between30- and 40- from neutral. This isrepeated in four directions (up, down,left, and right), usually asking thepatient to make several attempts so

that careful judgment of speed ofmovement can be made. Over timethe speed and range of spontaneousand target-directed eye movementsbecomes reduced, first in the verticalplane, and eventually the eyes becomefixed.

TABLE 1-2 Subtypes of Progressive Supranuclear Palsy Pathology

Main Phenotype Designation

Classic phenotype Progressive supranuclear palsy(PSP)YRichardson syndrome (sometimesknown as Steele-Richardson-Olszewskisyndrome)

Parkinson diseaseYlike PSP-parkinsonism

Pure akinesia (no appendicularrigidity)

PSPYpure akinesia with gait freezing

Asymmetric parkinsonism PSPYcorticobasal syndrome

Frontal-predominant dementia PSPYfrontotemporal dementia

Case 1-2A 59-year-old right-handed man presented with a 3-year progressivehistory of problems with gait, falls, and speech and visual difficulties. Hereported changes in his gait, including slowing and increased difficulty inturning. He developed increasing falls that had become more frequent,particularly when turning and without any clear precipitant. He developeddysarthria and, later, drooling. He had become slower in performingactivities of daily living. Over the previous year, he developed photopho-bia and eye tearing and had recently noted difficulty reading, specificallyfollowing lines on a page. He denied symptoms of autonomic dysfunctionbut had recently noted urinary urgency.

On examination, he was oriented to person, place, and time. Evidenceof executive dysfunction and motor perseveration was present. His visualpursuit movements were full, and he demonstrated slowing of verticalsaccadic eye movements and significantly decreased vertical optokineticnystagmus (Supplemental Digital Content 1-2, links.lww.com/CONT/A108).Square-wave jerks and decreased blink rate were noted. He had moderatehypomimia and mild frontalis overactivity. He displayed increased tone inthe neck but normal tone in the limbs, with mild bilateral bradykinesia(finger tapping and toe tapping). He had a slow and wide-based gait andturned en bloc, with diminished postural reflexes. He was unable totandem walk.

Comment. This patient presented with classic progressive supranuclearpalsy or Richardson syndrome with early falls in the context of saccadicabnormalities and a symmetric parkinsonism with axial-predominantrigidity.




The cognitive abnormalities thataccompany PSP-Richardson syndrometypically affect processing speed andcan be tested at the bedside using afrontal assessment battery.26,27 Mem-ory impairment and severe visuo-spatial dysfunction are unusual andcan be assessed using Addenbrooke’sCognitive Examination, which has char-acteristic findings in PSP-Richardsonsyndrome.28 Ideomotor apraxia andlimb dystonia may contribute to im-paired limb function in the CBS pre-sentation, also observed in PSP.

Postural instability is usually quiteabnormal in PSP-Richardson syn-drome, particularly in relation to therelatively mild bradykinesia. It is testedin the office using the pull test, inwhich the patient stands with feetcomfortably apart and is pulled back-ward by the shoulders sufficiently sothat the center of gravity is displaced.29

This is only performed after the test isexplained to the patient, including theinstruction that they may take a stepbackward to steady themselves if re-quired. The examiner will stand lessthan an arm’s length behind thepatient and ideally should have a wallless than an arm’s length behind theexaminer, in case the patient fallsbackward heavily.

In contrast to PD, dementia withLewy bodies, and MSA, patients withPSP-Richardson syndrome only rarelydevelop severe autonomic dysfunc-tion. Cerebellar ataxia, as distinct togait unsteadiness, is also unusual andis more common in MSA. Patientsusually become dependent on othersfor care 3 to 4 years after disease onsetas a result of increasing motor andcognitive slowing.30 Speech oftenbecomes unintelligible, and recurrentchoking can lead to frequent aspira-tion pneumonia. The mean diseaseduration from onset to death is about7 years.31

Progressive supranuclear palsy–parkinsonism. In contrast to patientswith PSP-Richardson syndrome, PSP-parkinsonism patients develop brady-kinesia and limb rigidity at diseaseonset, which can be asymmetric and, insome cases, associated with a jerkyaction or rest tremor.32 Axial rigidity isoften a striking early feature, and limbrigidity is more common and severethan in PSP-Richardson syndrome.Parkinsonism in this setting usuallyimproves to some extent after the in-troduction of dopaminergic therapies,although secondary unresponsivenessoccurring over a few years is usual(Case 1-3).33

Although patients with PSP-parkinsonism appear different frompatients with PSP-Richardson syn-drome in the first couple of years,over time most will develop severepostural instability, frontal cognitive

KEY POINTS

h Patients withprogressivesupranuclearpalsyYRichardsonsyndrome do notdevelop severeautonomic dysfunction,unlike Parkinsondisease, dementiawith Lewy bodies, andmultiple system atrophy.

h Response to levodopais a feature of earlyprogressivesupranuclear palsyYparkinsonism at astage when posturalinstability, frontalcognitive impairment,and verticalsupranuclear gazepalsy are uncommon.

FIGURE 1-1 Sagittal T2-weighted brain MRI of a patientwith progressive supranuclear palsyYRichardsonsyndrome demonstrating substantial atrophy

of the midbrain, yielding the ‘‘hummingbird sign’’ (arrow).Associated frontal-predominant atrophy, as demonstrated bythinning of the anterior portion of the corpus callosum and exvacuo hydrocephalus is also present.

Reprinted with permission from Biller J, Espay A, Lippincott Williams &Wilkins.25 B 2013, Wolters Kluwer Health.




decline, and vertical supranuclear gazepalsy as the disease progresses.32

These markers of disease severityemerge later in PSP-parkinsonism thanin PSP-Richardson syndrome, and dis-ease duration to death is about 3 yearslonger in PSP-parkinsonism. PSP-parkinsonism is difficult to differenti-ate from PD in the earliest stages, buthelpful pointers for PSP-parkinsonismmay include rapid progression, prom-inent axial symptomatology, andsuboptimal response to levodopa de-spite typical clinical features of PD.33

Drug-induced dyskinesias are ex-tremely unusual in PSP-parkinsonism.

Progressive supranuclear palsy–pure akinesia with gait freezing. Inthis small group of patients, isolatedbradykinesia, predominantly affectinggait and leading to gait freezing, is theonly initial manifestation of underlyingPSP-tau pathology.34 Patients presentto medical attention following theslow emergence of gait difficultiesand unsteadiness that may developfor up to 2 years after the freezing ofgait and gait-initiation failure develop.Characteristically, these patients alsodevelop early hypophonia, hypomimia,

and micrographia. Axial rigidity withincreasing neck stiffness in the absenceof limb rigidity is a distinctive feature.35

A supranuclear vertical gaze paresisand blepharospasm develop late inthe majority, and in contrast to PSP-Richardson syndrome, cognitive defi-cits and bradyphrenia are not promi-nent, although they may occur late inthe disease, which has a median dura-tion of more than 10 years.34,36

Progressive supranuclear palsy–corticobasal syndrome. CBS has typ-ically been associated with CBD buthas been increasingly recognized withseveral underlying pathologies, includ-ing PSP. CBS is characterized by lat-eralized motor (unilateral ideomotorapraxia, nonlevodopa-responsive par-kinsonism, myoclonus, dystonia) andnonmotor features (aphasia, corticalsensory and/or visuospatial deficits).Patients with PSP-CBS are at presentalmost undistinguishable from thosewith other underlying pathologies, in-cluding corticobasal degeneration.

Progressive supranuclear palsy–frontotemporal dementia. A smallnumber of patients with PSP-tau pa-thology develop behavioral variant

KEY POINT

h Absence of limb rigidityis a hallmark ofprogressivesupranuclear palsyYpureakinesia with gaitfreezing.

Case 1-3A 58-year-old woman was evaluated 6 years after onset of an asymmetric,levodopa-responsive tremor. Video was taken in the ‘‘on’’ state(Supplemental Digital Content 1-3, links.lww.com/CONT/A54). She showedreduced facial expression, axial-predominant rigidity, and unsteady gaitwith reduced arm swing and gait freezing during turning. Mild hypometricvertical saccades were present. Eight years after disease onset, shedemonstrated mild hypometric saccades on right gaze and moderatehypometric saccadic eye movements in the vertical plane. She had apositive glabellar sign and severe blepharospasm with eyelid-openingapraxia. Her gait had deteriorated with worse postural reflexes, greaterdifficulty turning, and some mild motor recklessness.

Comment. Progressive supranuclear palsyYparkinsonism is a variant ofprogressive supranuclear palsy that can be indistinguishable fromParkinson disease at the outset. Early response to levodopa can be robustbut wanes over time. Later development of oculomotor dysfunction andblepharospasm are clues that assisted the diagnostic revision in this case.




frontotemporal dementia (progressivepersonality change including disinhibi-tion, loss of empathy, change in eatingpatterns, ritualized or stereotypical be-havior, and apathy) or progressive non-fluent aphasia (predominant apraxia ofspeech), which are both consideredamong the frontotemporal dementia(FTD) syndromes.37,38 These patientsusually develop typical motor symp-toms of PSP (ophthalmoplegia, postur-al instability, rigidity, hypokinesia),although typically more than 5 yearsafter presentation.

Natural History of ProgressiveSupranuclear PalsyThe progression of disease and accu-mulation of disability in PSP is morerapid and severe than in PD, evengiven the variability described amongthe different clinical subtypes. Themean age at diagnosis is 65 years.32

Frequent falls, causing fractures andhead injuries, contribute substantiallyto morbidity and may be minimizedby physical therapy, use of a weightedwalker, and eventually wheelchair use.The terminal stages of disease arecharacterized by severe communica-tion difficulties, immobility, severeaxial rigidity, severe dysphagia andcomplete ophthalmoplegia (particu-larly in PSP-Richardson syndrome). Asin PD, the mode of death is most oftenrelated to respiratory compromise inthe setting of bronchopneumonia.

Treatment ParadigmThe active treatment of PSP is directedat optimizing function and alleviatingsuffering. Supportive therapy usingpharmacologic approaches and reha-bilitation by a multidisciplinary team isusual. Information delivery, support,and counseling are particularly impor-tant in PSP because of the expectationof deterioration and increase in careneeds over a short period of time.39

The specialist neurologist has a roleto help coordinate the multidis-ciplinary team, educate the patientand caregiver, and clarify the role ofmedications and interventions in man-agement of the disease. This will in-clude the trial of different medicationsto improve parkinsonism, affective oradjustment disorders, pain, and sleepdisturbance. Physical, occupational, andspeech therapy have a crucial role inmanaging the various progressivesymptoms by instituting strategies toovercome impairment and optimizefunction. Decisions whether to proceedwith interventions such as gastrostomytube insertion to manage dysphagia aremade in consultation with the neurolo-gist and speech therapist.

The multidisciplinary team shouldinclude the following:

1. PhysiotherapistVto assessmobility,with a view to prescribing gait aideswhen necessary, and instruct ontechniques for safe transfers

2. Occupational therapistVtoperform an environmentalassessment, including the needfor lifting devices or wheeledmobility aides, and optimizeupper limb function

3. Speech pathologistVto treatdifficulties with communication(eg, speech amplifiers orcommunication boards) andmonitor swallowing (modifiedbarium swallow test), with a view toprescribing increased consistenciesof food when required

4. Nurse or social workerVtoprovide support and liaison forstrategies to manage medicationdelivery and coordinate theprovision of home care andsupport as required

Other aspects of care that should beconsidered include counseling (to assistin coming to terms with the diagnosis

KEY POINT

h The phenotype ofprogressivesupranuclear palsymay occur as partof the spectrum offrontotemporal lobardegeneration due to taudeposition. This can besuspected in the settingof marked personalitychanges and/orlanguage abnormalities(usually, nonfluentaphasia).




of a neurodegenerative condition andend-of-life decision making) and pallia-tive care (for appropriate nursing nearthe end of disease).

Medical intervention has a limitedrole in alleviating symptoms. Unfortu-nately, the dopaminergic medicationsdo not improve symptoms in PSP tothe same extent as in PD, except inPSP-parkinsonism, where the effectoften diminishes over months oryears. Levodopa responsiveness canbe tested by administering escalatingdoses (with a peripheral decarboxyl-ase inhibitor) up to 1200 mg/d for atleast 1 month (if necessary and iftolerated). Dopamine agonists are lesseffective than levodopa and are notoften used in PSP because of their sideeffects. Amantadine is occasionallyhelpful in improving motor symp-toms, including gait freezing and dys-phagia, and may be helpful whensialorrhea is severe. Anticholinergicsshould be avoided as they may worsencognition. Antispasmodics for thetreatment of the overactive bladder(eg, solifenacin)Videally those thatcross the blood-brain barrier lessVmay improve the neurogenic bladdersymptomatology (urgent micturition).Botulinum neurotoxin is used for treat-ment of blepharospasm and apraxiaof eyelid opening, painful dystonicpostures that can affect the neck orlimbs, and, more recently, neurogenicbladder.

MULTIPLE SYSTEM ATROPHYClinical Confirmation ofMultiple System AtrophyIn patients with MSA-parkinsonism, theslow evolution of apparently unrelatedsymptoms often leads to early mis-diagnosis. It is not unusual for a gas-troenterologist, cardiologist, sleepmedicine physician, and urologist to beinvolved in the care of patients by thetime the neurologic diagnosis is made.

The classic and striking clinicalcharacteristic of MSA is the progres-sive autonomic dysfunction that oftendominates the early clinical pictureand precedes the evolution of motorsymptoms by up to several years. Thediagnosis of MSA is usually consideredin patients who develop parkinsonismin the presence of increasing urinaryurgency, constipation, postural hypo-tension, and erectile dysfunction inmen.40 A neuroimaging feature sup-portive of MSA-parkinsonism is thesubtle slitlike signal abnormality ofthe posterolateral putamen, bilaterallyor only contralateral to the more af-fected side, due to atrophy and exces-sive iron deposition at the putamen(Figure 1-225). A proportion of patientswith MSA develop a predominantly cer-ebellar phenotype with no or only verysubtle parkinsonism (MSA-cerebellar),

KEY POINT

h Multiple system atrophyis invariably associatedwith progressive andsevere autonomicdysfunction that oftendominates the earlyclinical picture andprecedes the evolutionof motor symptoms byup to several years.

FIGURE 1-2 Axial T2-weighted brain MRI of a patientwith multiple system atrophyYparkinsonismdemonstrating a slitlike area of hyperintensity

bordered by hypointensity (from iron deposition) in theputamen, worse on the right (arrows). The putaminal atrophyis always greater on the opposite side of the more affectedhemibody.




usually in association with autonomicdysfunction.40

The parkinsonism of MSA is usuallysymmetrical and classically respondspoorly to dopaminergic therapies(although in approximately 30% ofpatients the response is good), anddrug-induced dyskinesias can develop,particularly axially. Bradykinesia andrigidity progress somewhat faster thanin PD, and as a consequence, posturalinstability and falls usually emergewithin the first 3 years of diseaseonset. Rest tremor can be present,but stimulus-sensitive myoclonus ismore frequent. The gait disturbanceof MSA may be purely parkinsonian,purely cerebellar (broad based, un-steady, with truncal and upper limbataxia giving an appearance of flailing),or a combination of both.

To aid in the clinical diagnosis, inaddition to the bedside assessment ofparkinsonism, postural blood pressurerecordings should be taken. The patientshould be assessed after lying supine forseveral minutes. The blood pressureand pulse rate should be taken, afterwhich the patient stands and bloodpressure and pulse is recorded after 2to 3 minutes of standing. When auto-nomic failure is present, the bloodpressure will fall by more than 20 mmHg systolic and/or 10 mm Hg diastolicon standing, with no reactive increase inpulse rate (Case 1-4).40

Natural HistoryThe median survival of patients withMSA with either the parkinsonism orcerebellar phenotype is approximately8 years, but the range is large.31 Motorand autonomic features lead to majordisability. Early autonomic failure;older age of onset; short interval fromdisease onset to frequent falling, cog-nitive disability, unintelligible speech,severe dysphagia, dependence onwheelchair for mobility, and urinary

catheter use; and lack of admission toa nursing home facility independentlypredict short disease survival.31

Treatment ParadigmThe appropriate management of pa-tients with MSA requires a multidisci-plinary team approach, as for patientswith PSP.

Dopaminergic medications. Ap-proximately one-third of patients withMSA-parkinsonism benefit from dopa-minergic medication, and 10% mayimprove more than 50% of their motorsymptoms after levodopa therapy.However, in general, the benefits oflevodopa in MSA are less gratifying thanin PD because they are not as significantand long-lasting. Despite this, an ade-quate trial of levodopa should beattempted in MSA patients who exhibitparkinsonism. The treatment shouldbe initiated with carbidopa/levodopa25/100 and could be started at a lowerdose than usual (eg, one-half tablet withan increase in dose every other day astolerated to 3 times a day, and there-after a weekly increase of one-halftablet per dose to a total dose of up to1200 mg/d, according to best responseor emergent side effects. The use ofdopaminergic medications requirescaution, as it may worsen orthostatichypotension and REM sleep behaviordisorder.

Autonomic dysfunction. Monitor-ing and management of comorbid or-thostatic hypotension is critical in MSA.It is important to reduce or discontinueany concurrent antihypertensive medi-cations. Other strategies are increasingdietary salt and noncaffeinated fluids,getting up slowly, and wearing thigh-high compression stockings.

Pharmacologic strategies are neces-sary when the abovemeasures fail. Theseinclude increasing the patient’s bloodvolume through the use of fludro-cortisone or increasing the peripheral

KEY POINTS

h Action spontaneous andstimulus-sensitive distalmyoclonus is morecommon than resttremor in multiplesystem atrophyYparkinsonism.

h Early autonomic failure,older age of onset, andshort interval fromdisease onset to motormilestones (particularly,frequent falling,unintelligible speech,and severe dysphagia)are predictors of a moreaggressive disease ofmultiple system atrophy.




vascular resistance via midodrine or, ifmidodrine is ineffective, indomethacinor pyridostigmine.

Urologic symptoms. Urinary incon-tinence or retention are usually pres-ent early in MSA. Urodynamic studiesare helpful to determine the type ofneurogenic bladder. The principalproblem is often bladder spasticity,which responds to peripherally actinganticholinergic agents or botulinumtoxin. Occasionally, intermittent cathe-terization or transcutaneous suprapubiccatheterization may be required.

Supportive therapy including al-lied health care team. Consideringthe limited pharmacologic benefit, it iscrucial that MSA patients be treated by a

multidisciplinary team as describedabove for PSP. Because of the occur-rence of cervical, laryngeal, and pharyn-geal dystonia that can cause upperairway obstruction, tracheostomy andgastrostomy tube may be considered inselected patients. The advisability ofeither gastrostomy or tracheostomyshould be approached on an individualbasis with a realistic appraisal of thepatient’s general quality of life.

CORTICOBASAL DEGENERATIONClinical ConfirmationCBD usually develops in the fifth toseventh decades of life and presents withvarious phenotypes that include CBS,FTD, progressive nonfluent aphasia, and

KEY POINT

h Pharmacologicstrategies to treatorthostatic hypotensioninclude increasingthe blood volume(fludrocortisone) orincreasing theperipheral vascularresistance (midodrineor, if midodrineis ineffective,indomethacin orpyridostigmine).

Case 1-4A 50-year-old man presented with a 2-year progressive history of gaitslowness and instability. He reported frequent falls, was slow inperforming activities of daily living, and had noted some jerkiness in hisupper limbs as well as progressive dysarthria and lately dysphagia forliquids. Levodopa was started, and the patient showed a moderateimprovement in bradykinesia and rigidity but soon developed dyskinesia.

He had a 5-year history of progressive erectile dysfunction and urgentmicturition, with occasional episodes of incontinence. He also reportedsevere constipation.

On examination, his blood pressure was 150/70 lying down, 90/50standing immediately, and 89/60 at 3 minutes. He denied symptoms oflightheadedness. He had hypermetric saccades, but otherwise his cranialnerves, strength, and sensation were normal. Moderate bradykinesia waspresent in the upper and lower extremities, with moderately severe axialrigidity and moderate rigidity in the limbs (Supplemental Digital Content1-4, links.lww.com/CONT/A55). He showed no tremor at rest, but distalpostural and stimulus-sensitive myoclonus was present in the upperextremities, as was minimal dysmetria. His gait was slow and slightlywide-based, and he demonstrated freezing and postural instability,particularly when turning. He progressed significantly, developed stridor,and required a tracheostomy 1 year later.

Comment. This case illustrates a number of key features pointing tomultiple system atrophyYparkinsonism despite a falsely reassuring earlyresponse to levodopa. Importantly, myoclonus should not be part ofthe phenomenology of Parkinson disease and was a red flag againstthis diagnosis. The prominent dysautonomiaVincluding neurogenicbladder, orthostatic hypotension, and the almost-diagnostic inspiratorystridorVwere also critical elements supporting the diagnosis of multiplesystem atrophyYparkinsonism.




Richardson syndrome, which make it avery challenging disorder to diagnose(Table 1-3). None of these phenotypesis sufficiently specific to unequivocallydiagnose CBD. New diagnostic criteriahave been recently developed thatinclude all these phenotypes.41 Thesecriteria are a step forward regardingidentification of possible CBD, butthey will need to be validated andmay require further refinement. De-finite diagnosis of CBD requires au-topsy confirmation.

Corticobasal degenerat ion–corticobasal syndrome. CBS is theclassical presentation of CBD; how-ever, CBS can be due to PSP (as de-scribed above), a focal form ofAlzheimer disease, or FTD.42 TheCBS usually presents with an asym-metric progressive ideomotor apraxiathat frequently affects the hand and isassociated with rigidity, myoclonus,and dystonia (Case 1-5). These symp-toms spread to the lower extremityand eventually affect all four extremi-ties but remain asymmetric. The my-oclonus is frequently stimulus sensitive

but not always present. Dystonia andmyoclonus are less frequent than theakinetic-rigid syndrome and apraxia.43

Alien-limb phenomenon is seen insome patients and identified by invol-untary grasping, purposeless move-ments, or levitation in an apraxic limb.When CBS affects the right extremities, itis more likely to be associated with anonfluent aphasia, whereas, when affect-ing left extremities, it may associate atonset with visuospatial and visuocons-tructive deficits. Eventually, patients maydevelop both language and visuospatialdeficits, as well as a cortical sensorysyndrome and an alien limb. CBS lessfrequently affects lower extremities first.

Patients with CBS can also manifestoculomotor disturbances. They maypresent with oculomotor apraxia(delayed latency of saccades with normaloptokinetic nystagmus) that frequentlywould affect horizontal and vertical gaze.However, they can also develop, usuallylater, vertical supranuclear gaze palsy.

Newly proposed diagnostic crite-ria for CBD-CBS include two levelsof clinical confidence, possible and

KEY POINT

h Corticobasal syndromeapplies to an asymmetricprogressive parkinsonismwith ideomotor apraxia,rigidity, myoclonus,and dystonia, oftenassociated with an alienlimb phenomenon. Thepathology can be diverse,including corticobasaldegeneration,progressive supranuclearpalsy, Alzheimer disease,and frontotemporal lobardegeneration.

TABLE 1-3 Phenotypes Associated With Pathology-Proven CorticobasalDegeneration

Main Phenotype Key Features

Asymmetric parkinsonism, ideomotor apraxia,dystonia, myoclonus (classic phenotype)

CBD-CBS: 50% of all pathologic diagnosesof CBS

Symmetric parkinsonism, posturalinstability, oculomotor disturbances(PSP-like)

CBD-PSP: More executive and behavioralabnormalities than in pathology-provenPSP patients

Posterior cortical atrophy (PCA) syndrome(visuospatial disturbances, apraxia,myoclonus)

CBD-PCA: More frequent myoclonus thanin other CBS phenotypes (more commonAlzheimer disease pathology)

Frontotemporal dementia (FTD) (behavioral,visuospatial, and language disturbances)

CBD-FTLD: Sporadic and familial FTLD-Tauand FTLD-TDP pathologies (see Figure 1-5)

Progressive nonfluent agrammatic aphasia(PNFA)

CBD-PNFA: most common aphasia subtypein CBD, but other pathologies are alsofound in PNFA

CBD = corticobasal degeneration; CBS = corticobasal syndrome; PSP = progressive supranuclear palsy; FTLD =frontotemporal lobar degeneration; TDP = TAR DNA-binding protein (TARDBP) coding for TDP-43.




probable (Table 1-4).41 Imaging stud-ies often demonstrate asymmetric pa-rietal or frontoparieto-occipital atrophy(Figure 1-325).

Corticobasal degeneration–progressive supranuclear palsy. Infre-quently, CBD can present with a PSP

phenotype that is hard to differentiatefrom PSP-Richardson syndrome, butin CBD usually there are more cogni-tive and behavioral frontal distur-bances.44 CBD-PSP patients tend to bemore disinhibited than PSP-Richardsonsyndrome patients.

TABLE 1-4 Clinical Criteria for the Diagnosis of Corticobasal Syndromea

Category of Certainty Features Required Besides Asymmetric Onset

Probable Two of these three:1. Limb rigidity or akinesia2. Limb dystonia3. Limb myoclonus

Plus two of these three:1. Orobuccal or limb apraxia2. Cortical sensory deficit3. Alien limb phenomena

Possible At least one of these three:1. Limb rigidity or akinesia2. Limb dystonia3. Limb myoclonus

Plus at least one of these three:1. Orobuccal or limb apraxia2. Cortical sensory deficit3. Alien limb phenomena

a Adapted with permission from Armstrong MJ, et al, Neurology.41 B 2013 American Academy of Neurology.www.neurology.org/content/80/5/496.abstract?sid=44cb8cff-d094-4df2-9de1-29b9ebcd2ba3.

KEY POINT

h Criteria for probablecorticobasaldegeneration requiresan asymmetricpresentation of two ofthe following threesymptoms: (1) limbrigidity or akinesia, (2)limb dystonia, (3) limbmyoclonus, plus twoof the following: (1)orobuccal or limbapraxia, (2) corticalsensory deficit, (3) alienlimb phenomena.

Case 1-5A 75-year-old woman presented with a 3-year history of progressive loss ofcontrol of her right hand. Initially, she noted difficulties with writing,which evolved to a more pervasive loss of dexterity. Performing activitieswith her right arm became difficult, and she felt that the right arm became‘‘useless.’’ She developed myoclonic jerks and progressive dystonicposturing of the hand and arm. She reported her arm as ‘‘having a mindof its own,’’ exhibiting levitation. She also became slower, particularlywhen getting out of a car and performing activities of daily living. Herspeech became slow and dysarthric but without language difficulties. Onexamination, she was found to have ideomotor apraxia and sensoryneglect in the right upper extremity. She exhibited a dystonic rightarm and hand myoclonus, with greater bradykinesia and rigidity in theright compared to the left limbs (Supplemental Digital Content 1-5,links.lww.com/CONT/A56).

Comments. This example of markedly asymmetric parkinsonism with a‘‘useless’’ dystonic and apraxic limb, exhibiting alien-limb phenomena andmyoclonus, is the classic presentation of corticobasal syndrome.



www.neurology.org/content/80/5/496.abstract?sid=44cb8cff-d094-4df2-9de1-29b9ebcd2ba3


Natural HistoryPatients with CBD may exhibit morethan one phenotype during life. Symp-toms are relentless and survival isusually 7 to 8 years.

Treatment ParadigmPharmacologic therapies are usually ofno benefit. The parkinsonism usuallydoes not benefit from dopaminergictherapy, although it is always useful toattempt treatment with levodopa for atleast 1 month with the maximum toler-ated dose (900 to 1200 mg/d). The mostuseful symptomatic therapies are thosetargeting myoclonus (eg, valproic acid,clonazepam, levetiracetam, and pirace-tam) and dystonia (eg, botulinum toxin)when they affect the patient’s quality oflife. Treatment of dystonia is indicated

when the contractures cause pain orimpede hygiene.

Supportive therapy including an al-lied health care team is important andshould follow the principles describedabove. Patients with CBD benefit fromrehabilitation services more than phar-macologic approaches.

IMPORTANT DIFFERENTIALDIAGNOSESVascular Parkinsonism VersusPrimary NeurodegenerationVaP is suspected in the setting of alower bodyYpredominant parkinsonismand a brain MRI showing exten-sive subcortical white matter lesions(Figure 1-425) (Case 1-6).45 Onlyaround half of patients with VaPdevelop pyramidal signs, but whenpresent, according to diagnosticcriteria, they exclude PD. In a minorityof cases, a history of stepwise deteri-oration will be present, which sug-gests a large-vessel infarct, and inthese patients MRI should demon-strate a vascular lesion involving theglobus pallidus externa, substantianigra, ventrolateral nucleus of thethalamus, or frontal lobe contralateralto the side of parkinsonian symptoms.

If a VaP-suggestive history is notassociated with a brain MRI demonstrat-ing leukoencephalopathic changes, adiagnosis of primary neurodegeneration(eg, PD, PSP, MSA, or CBD) should bepreferred.

Dystonia Versus ParkinsonDiseasePatients with segmental dystonia candevelop asymmetric slow movementsand rest tremor in the absence of PDneurodegeneration. In these patients,the clinical signs do not progress, orprogress extremely slowly, and medi-cations are often not required becauseof the mild symptoms. Other clinicalsigns that might suggest dystonic

FIGURE 1-3 Axial fluid-attenuated inversion recovery(FLAIR) brain MRI showing asymmetrichemispheric atrophy, predominantly right

parietal, in a patient with corticobasal syndrome due toAlzheimer disease pathology.


KEY POINT

h The presence ofpyramidal signssupports the diagnosisof vascular parkinsonismand excludes Parkinsondisease.




tremor over PD in this scenario in-clude the presence of hypokinesia(rather than bradykinesia with decre-ment of movement), position-specifictremor, and the co-occurrence ofdystonia in the affected limb.46

Frontotemporal DementiaSyndromesPatients with FTD can develop parkin-sonism before, during, or after the

development of the frontal cognitive orbehavioral disturbances. The spectrumof FTD includes the behavioral variantFTD, primary progressive aphasia, andFTD with ALS. These phenotypes canpresent as sporadic (tauopathies: PSPand CBD; TAR DNA-binding protein-43[TDP-43] proteinopathies with or with-out ALS) or familial diseases (FTD withparkinsonism linked to chromosome17; TDP-43 proteinopathies due to

Case 1-6A 75-year-old woman had an 11-year history of gradually progressiveslowness in walking and spontaneous falls, with poor responsiveness tolevodopa (less than 30% improvement). Brain MRI showed ‘‘age-relatedvascular changes.’’ Muscle stretch reflexes were not exaggerated, and tonewas mildly increased, but no clonus was evident. She showed difficultystanding from a chair, start hesitation, and an unsteady short- andwide-stepped gait requiring the use of a four-wheeled walker(Supplemental Digital Content 1-6, links.lww.com/CONT/A57). Pathologicfindings at autopsy confirmed vascular changes within the basalganglia and no other pathologic abnormalities to account for herclinical signs.

Comment. Patients with vascular parkinsonism most often present withan insidious onset of bilateral parkinsonism with rigidity and bradykinesia,often with an early onset of gait disorder.

FIGURE 1-4 Axial fluid-attenuated inversion recovery (FLAIR) brain MRI of a patient with vascular parkinsonismdemonstrating moderate confluent periventricular and cotton-shaped deep white matter hyperintensities,with associated enlargement of the lateral ventricles and moderate cortical atrophy.

Reprinted with permission from Biller J, Espay A, Lippincott Williams & Wilkins.25 B 2013, Wolters Kluwer Health.




progranulin or C9ORF72 mutations)(Figure 1-547).

Niemann-Pick DiseasePatients with Niemann-Pick type C mayoccasionally present with an akinetic-rigid syndrome, tremor or ataxia, andsupranuclear gaze palsy, usually withouthepatosplenomegaly. One should sus-pect this disorder in young patients,

usually also when in the presence ofseizures and dementia.

Prion DiseasePatients with prion disease can de-velop a clinical picture that resemblesRichardson syndrome or corticobasalsyndrome.48 In general, the progres-sion of disease is fast (months ratherthan years). Diagnostic MRI, EEG, or

FIGURE 1-5 The pathologic (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD],frontotemporal lobar degeneration [FTLD]Ytau, FTLDYTAR DNA-binding protein [TDP],and Alzheimer disease [AD]), genetic (frontotemporal dementia with parkinsonism-17

[FTDP-17]/FTLD with progranulin mutations [FTLD-PGRN], FTDP-17T/FTLD with microtubule-associated proteintau mutations [FTLD-MAPT]), clinical (bottom), and neuroimaging (top) overlap between motor and cognitivedisorders. Classic PSP (green) is predicted by the presence of symmetric parkinsonism and brainstempredominant atrophy, among other features (left end of the diagram; relatively few pathology-provenCBD cases). Conversely, classic CBD (red) can be predicted by a markedly asymmetric parkinsonism withcortical-predominant atrophy (right end of the diagram; relatively few pathology-proven PSP cases). Lesscharacteristic presentations with co-occurrence of behavioral or personality changes or bulbar/pseudobulbarfeatures fall within the spectrum of FTLD (purple)Vmost often FTLD-tau when PSP-like features areassociated, or FTLD-TDP when corticobasal syndrome (CBS)Ylike or language abnormalities are associated.AD is the most common non-CBD etiology in the CBS spectrum (also right end of the diagram).

Modified from Espay AJ,Litvan I, J Mol Neurosci.47 B 2013 with permission from Springer Science + Business Media. link.springer.com/article/10.1007%2Fs12031-011-9632-1.




link.springer.com/article/10.1007%2Fs12031-011-9632-1

link.springer.com/article/10.1007%2Fs12031-011-9632-1

CSF findings are supportive, but defin-itive diagnosis remains pathologic(Case 1-7).

SUMMARYThe different parkinsonian syndromesare separated by subtle but definitesigns and symptoms that can berecognized through careful evaluation.Consideration of the differences, par-ticularly in the mode of presentationand disease progression, may lead toan earlier diagnosis and more certaintreatment and greater understandingof the disease for patients, theircaregivers, and other health care pro-fessionals. Recognition of these dif-ferent syndromes wil l becomeincreasingly important in the era whendisease-specific treatments emerge.

VIDEO LEGENDSSupplemental Digital Content 1-1

Idiopathic Parkinson disease. Video showsthe patient with clinical diagnosis of idiopathicParkinson disease described in Case 1-1. Heshows left hand resting tremor with reemergenceon posture and exacerbation during walking. Dec-rement of amplitude and speed can be seen dur-ing performance of rapid alternating movements.


B 2013 American Academy of Neurology.

Supplemental Digital Content 1-2

Progressive supranuclear palsy. Video showsthe patient clinically diagnosed with progres-sive supranuclear palsy described in Case 1-2.

The oculomotor examination shows preservedhorizontal pursuit. Vertical pursuit is inter-rupted by square-wave intrusions. Convergenceis absent. Square-wave jerks are present inprimary gaze. Optokinetic nystagmus is hori-zontally preserved and vertical optokineticnystagmus is reduced, with observation ofsquare-wave jerks. He also shows poor blink rate.




Progressive supranuclear palsyYparkinsonism.Video shows the patient with early clinical diag-nosis of Parkinson disease described in Case 1-3,who progressed to a progressive supranuclear palsyphenotype between 6 and 8 years after symptomonset (both time points shown in the video). Laterdevelopment of oculomotor impairment andblepharospasm with apraxia of eyelid openingwere clues regarding the revised diagnosis.




Multiple system atrophy, parkinsonian type.Video shows the patient in Case 1-4 who hasbeen clinically diagnosed with multiple systematrophy, parkinsonian type. He is shown tohave a tremorless parkinsonism with axial-greater-than-appendicular rigidity, distal-armpostural and stimulus-sensitive myoclonus,and slow, slightly wide-based gait with freezingand postural instability when turning.




Corticobasal syndrome. Video shows the pa-tient clinically diagnosed with corticobasal

Case 1-7A 74-year-old woman was seen 2 months after the onset of clumsiness ofthe left hand. She was observed to have left-sided dystonia, apraxia, andmyoclonus (action and stimulus sensitive) (Supplemental Digital Content1-7, links.lww.com/CONT/A58). She also had alien limb phenomenon,rigidity, and cortical sensory loss. She died 3 months later, and a pathologicand immunohistologic diagnosis of prion disease (Creutzfeldt-Jakobdisease) was made.

Comment. In patients in whom the clinical syndrome is rapidlyprogressive, primary neurodegeneration must not be assumed. Priondisease should be suspected in very rapidly progressive Richardsonsyndrome or corticobasal syndrome.








syndrome described in Case 1-5. Among otherfeatures, she illustrates an asymmetric parkin-sonism with a markedly dystonic right arm,myoclonus, ideomotor apraxia, and corticalsensory loss.




Vascular parkinsonism. Video shows the pa-tient with a pathologic diagnosis of vascularparkinsonism described in Case 1-6. Thepatient demonstrates severe gait impairmentwith start hesitation, short- and wide-steppedgait, and reliance on a walker for ambulation.




Creutzfeldt-Jakob disease. Video shows theexamination of the patient in Case 1-7 whoshows left-sided dystonia, rigidity, apraxia, my-oclonus, and cortical sensory loss. Pathologicdiagnosis confirmed Creutzfeldt-Jakob disease.



REFERENCES1. Lim SY, Lang AE. The nonmotor symptoms

of Parkinson’s diseaseVan overview. MovDisord 2010;(25 suppl 1):S123YS130.

2. Ling H, Massey LA, Lees AJ, et al.Hypokinesia without decrementdistinguishes progressive supranuclear palsyfrom Parkinson’s disease. Brain 2012;135(pt 4):1141Y1153.

3. Williams DR, Lees AJ. How do patients withparkinsonism present? A clinicopathologicalstudy. Intern Med J 2009;31(1):7Y12.

4. Deuschl G, Bain P, Brin M. Consensusstatement of the Movement DisorderSociety on Tremor. Ad Hoc ScientificCommittee. Mov Disord 1998;(13 suppl 3):2Y23.

5. Williams DR, Watt HC, Lees AJ. Predictorsof falls and fractures in bradykineticrigid syndromes: a retrospective study.J Neurol Neurosurg Psychiatry 2006;77(4):468Y473.

6. Iansek R, Huxham F, McGinley J. Thesequence effect and gait festination inParkinson disease: contributors to freezingof gait? Mov Disord 2006;21(9):1419Y1424.

7. Abdo WF, Borm GF, Munneke M, et al. Tensteps to identify atypical parkinsonism. J

Neurol Neurosurg Psychiatry 2006;77(12):1367Y1369.

8. Berardelli A, Wenning GK, Antonini A, et al.EFNS/MDS-ES recommendations for thediagnosis of Parkinson’s disease. Eur JNeurol 2013;20(1):16Y34.

9. Litvan I, MacIntyre A, Goetz CG, et al.Accuracy of the clinical diagnoses ofLewy body disease, Parkinson disease,and dementia with Lewy bodies: aclinicopathologic study. Arch Neurol 1998;55(7):969Y978.

10. Hughes AJ, Daniel SE, Ben-Shlomo Y,Lees AJ. The accuracy of diagnosis ofparkinsonian syndromes in a specialistmovement disorder service. Brain 2002;125(pt 4):861Y870.

11. Groves MS, Forrest DV. Parkinson’s diseaseas a model for psychosocial issues in chronicneurodegenerative disease. Adv Neurol2005;96:65Y83.

12. Gibb WR, Lees AJ. The relevance ofthe Lewy body to the pathogenesisof idiopathic Parkinson’s disease. J NeurolNeurosurg Psychiatry 1988;51(6):745Y752.

13. Selikhova M, Williams DR, Kempster PA,et al. A clinico-pathological study ofsubtypes in Parkinson’s disease. Brain 2009;132(pt 11):2947Y2957.

14. Chaudhuri KR, Schapira AH. Non-motorsymptoms of Parkinson’s disease:dopaminergic pathophysiology andtreatment. Lancet Neurol 2009;8(5):464Y474.

15. Litvan I, Goldman JG, Troster AI, SchmandBA, Weintraub D, et al. Diagnostic criteriafor mild cognitive impairment in Parkinson’sdisease: Movement Disorder Society TaskForce guidelines. Mov Disord. 2012;27:349Y356.

16. Fox SH, Katzenschlager R, Lim SY, et al.The Movement Disorder SocietyEvidence-Based Medicine Review Update:treatments for the motor symptoms ofParkinson’s disease. Mov Disord 2011;(26 suppl 3):S2YS41.

17. Cervantes-Arriaga A, Rodriguez-Violante M,Yescas P, et al. Incidence of motorfluctuations in a retrospective cohort ofMexican patients with Parkinson’s disease[in Spanish]. Rev Med Inst Mex SeguroSoc 2012;50(2):141Y146.

18. Ferreira JJ, Katzenschlager R, Bloem BR,et al. Summary of the recommendations ofthe EFNS/MDS-ES review on therapeuticmanagement of Parkinson’s disease. Eur JNeurol 2013;20(1):5Y15.







19. Seppi K, Weintraub D, Coelho M, et al. TheMovement Disorder Society Evidence-BasedMedicine Review Update: treatments forthe non-motor symptoms of Parkinson’sdisease. Mov Disord 2011;(26 suppl 3):S42YS80.

20. Gerstenecker A, Mast B, Duff K, et al.Executive dysfunction is the primarycognitive impairment in progressivesupranuclear palsy. Arch Clin Neuropsychol28(2):104Y113.

21. Litvan I, Agid Y, Jankovic J, et al. Accuracyof clinical criteria for the diagnosis ofprogressive supranuclear palsy(Steele-Richardson-Olszewski syndrome).Neurology 1996;46(4):922Y930.

22. Williams DR, Lees AJ. Progressivesupranuclear palsy: clinicopathologicalconcepts and diagnostic challenges. LancetNeurol 2009;8(3):270Y279.

23. Litvan I, Mangone CA, McKee A, et al.Natural history of progressive supranuclearpalsy (Steele-Richardson-Olszewskisyndrome) and clinical predictors of survival:a clinicopathological study. J NeurolNeurosurg Psychiatry 1996;60(6):615Y620.

24. Chen AL, Riley DE, King SA, et al. Thedisturbance of gaze in progressivesupranuclear palsy: implications forpathogenesis. Front Neurol 2010;1:1Y19.

25. Biller J, Espay A. Practical neurology visualreview. 2nd ed. Philadelphia, PA: LippincottWilliams & Wilkins, 2013.

26. Paviour DC, Lees AJ, Josephs KA, et al.Frontotemporal lobar degeneration withubiquitin-only-immunoreactive neuronalchanges: broadening the clinical picture toinclude progressive supranuclear palsy. Brain2004;127(pt 11):2441Y2451.

27. Dubois B, Slachevsky A, Litvan I, et al. TheFAB: a frontal assessment battery at bedside.Neurology 2000;55(11):1621Y1626.

28. Bak TH, Caine D, Hearn VC, Hodges JR.Visuospatial functions in atypicalparkinsonian syndromes. J Neurol NeurosurgPsychiatry 2006;77(4):454Y456.

29. Munhoz RP, Li JY, Kurtinecz M, et al.Evaluation of the pull test technique inassessing postural instability in Parkinson’sdisease. Neurology 2004;62(1):125Y127.

30. Nath U, Ben-Shlomo Y, Thomson RG, et al.Clinical features and natural historyof progressive supranuclear palsy: aclinical cohort study. Neurology 2003;60(6):910Y916.

31. O’Sullivan SS, Massey LA, Williams DR,et al. Clinical outcomes of progressive

supranuclear palsy and multiple systematrophy. Brain 2008;131(pt 5):1362Y1372.

32. Williams DR, de Silva R, Paviour DC, et al.Characteristics of two distinct clinicalphenotypes in pathologically provenprogressive supranuclear palsy: Richardson’ssyndrome and PSP-parkinsonism. Brain2005;128(pt 6):1247Y1258.

33. Williams DR, Lees AJ. What featuresimprove the accuracy of the clinicaldiagnosis of progressive supranuclearpalsy-parkinsonism (PSP-P)? Mov Disord2010;25(3):357Y362.

34. Williams DR, Holton JL, Strand K, et al.Pure akinesia with gait freezing: a thirdclinical phenotype of progressivesupranuclear palsy. Mov Disord 2007;22(15):2235Y2241.

35. Mizusawa H, Mochizuki A, Ohkoshi N, et al.Progressive supranuclear palsy presentingwith pure akinesia. Adv Neurol 1993;60:618Y621.

36. Imai H, Narabayashi H. AkinesiaVconcerning 2 cases of pure akinesia. AdvNeurol Sci (Tokyo) 1974;18:787Y794.

37. Hodges JR, Davies RR, Xuereb JH, et al.Clinicopathological correlates infrontotemporal dementia. Ann Neurol2004;56(3):399Y406.

38. Josephs KA, Duffy JR, Strand EA, et al.Clinicopathological and imagingcorrelates of progressive aphasia andapraxia of speech. Brain 2006;129(pt 6):1385Y1398.

39. Williams DR. Progressive supranuclearpalsy. In: Kompoliti K, Verhagen L, eds.Encyclopedia of movement disorders.Oxford: Academic Press, 2010:479Y485.

40. Gilman S, Wenning GK, Low PA, et al.Second consensus statement on thediagnosis of multiple system atrophy.Neurology 2008;71(9):670Y676.

41. Armstrong MJ, Litvan I, Lang AE, et al.Criteria for the diagnosis of corticobasaldegeneration. Neurology 2013;80(5):496Y503.

42. Ling H, O’Sullivan SS, Holton JL, et al.Does corticobasal degeneration exist? Aclinicopathological re-evaluation. Brain2010;133(pt 7):2045Y2057.

43. Stamelou M, Alonso-Canovas A, Bhatia KP.Dystonia in corticobasal degeneration:a review of the literature on 404pathologically proven cases. Mov Disord2013;27(6):696Y702.

44. Kouri N, Murray ME, Hassan A, et al.Neuropathological features of corticobasal



degeneration presenting as corticobasalsyndrome or Richardson syndrome. Brain2011;134(pt 11):3264Y3275.

45. Glass PG, Lees AJ, Bacellar A, et al. Theclinical features of pathologically confirmedvascular parkinsonism. J Neurol NeurosurgPsychiatry 2012;83(10):1027Y1029.

46. Schwingenschuh P, Ruge D, Edwards MJ,et al. Distinguishing SWEDDs patientswith asymmetric resting tremor fromParkinson’s disease: a clinical and

electrophysiological study. Mov Disord2010;25(5):560Y569.

47. Espay AJ, Litvan I. Parkinsonism andfrontotemporal dementia: the clinicaloverlap. J Mol Neurosci 2011;45(3):343Y349.

48. Lee W, Simpson M, Ling H, et al.Characterising the uncommon corticobasalsyndrome presentation of sporadicCreutzfeldt-Jakob disease. ParkinsonismRelat Disord 2013;19(1):81Y85.




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