Cortex Glu Glu Striatum Striatum Glu Glu MSN-D2 MSN-D1 MSN-D1 MSN-D2 y a w h t a p y a w h t a p y a w h t a p y a w h t a p l l a d a d SNc SNc l l a d a d i l l i l l i l l i l l a p o t a i r t s a p o t a i r t s a p o t a i r t s a p o t a i r t s GPe Th Th GPe c i g r e A B A G t c e r i d n c i g r e A B A G t c e r i d n c i g r e A B A G t c e r i D c i g r e A B A G t c e r i D GABA GABA GABA GABA Glu Glu I I STN GPi STN GPi Fig. 8.1 (a) Basal ganglia motor loops with direct and indirect pathways. Black arrows indi cate inhibition; white arrows indicate activation. SNc, substantia nigra pars compacta; GPe , globus pallidus externus; STN, subthalamic nucleus; GPi, globus pallidus internus; SNr, s ubstantia nigra pars reticulata; Th , thalamus; Glu, glutamate; Enk, encephalin; SP, substa nce P; MSN, medium spiny neurons. (b) Impaired basal ganglia motor loops in patients with P arkinson \200\231s disease. Owing to neurodegeneration in the SNc, dopaminergic input into the striatum is reduced, resulting in a loss of excitatory dopaminergic drive on D1 recepto rs and inhibitory dopaminergic input on D2 receptors. Th e net result is increased GPi acti vity via direct and indirect pathways, leading to inhibition of Th and cortex. increased inhibitory input into the motor thalamus, thus reducing thalamocortical motor dri ve with underactivity of the motor parts of the prefrontal cortex leading to impaired movem ent initiation, speed, and amplitude (see Fig. 8.1b). Similar eff ects may also be due to d ownstream events at the level of the pallidum, motor thalamus, or thalamocortical projectio ns, as is the case in diff erent types of secondary parkinsonism. the single most disabling motor feature of PD, impacting on virtu- ally every aspect of act ivities of daily living, including handwrit- ing, getting dressed, handling feeding utensil s, hygiene, speech, and communication, as well as general mobility. Hypomimia with decrease d blink rate, micrographia with decrementing script size within a sentence or even a word ( see Fig. 8.2), or hypophonia with reduced volume of speech are clinical terms frequently us ed to describe isolated features of parkinsonian bradykinesia. Common early complaints of p atients related to bradykinesia include hand- writing diffi culties, buttoning up a shirt, turning keys, or brushing their teeth, while relatives, colleagues, or friends may note cha nges in facial expression, a soft er voice, or reduced arm swing or drag- ging of one leg w hile the patient is walking. With more advanced disease, getting up from an armchair or out of a car seat or turn- ing around in bed, as well as problems with walking become more pro minent among the symptoms reported in the patient interview. A peculiar and severely disabl ing feature of parkinsonian motor impairment, which is more aptly covered under the term of aki- nesia rather than bradykinesia, comprises diffi culties of movement initiation, and m aintenance of a fl ow of sequential or repetitive movements. Th is commonly manifests as he sitation when a patient is about to start walking or as sudden stops in a sequence of fi ng er Clinical presentation Cardinal features of parkinsonian syndromes A parkinsonian syndrome i s defi ned by the presence of bradyki- nesia in combination with at least one of the follow ing signs: rest- ing tremor, rigidity, and impaired postural refl exes, with the last of th ese not being the result of sensory, proprioceptive, or cerebellar dysfunction (10). Accord ing to the UK Parkinson \200\231s Disease Society Brain Bank criteria (QSBB criteria) brady kinesia is the anchor fea- ture for parkinsonism and is used as an umbrella term including reduced movement speed (bradykinesia in the strict sense) and amplitude (hypokinesia), as w ell as slowness of movement initiation, and decrementing speed and amplitude with or withou t interrup- tions (akinesia) of sequential repetitive movements. Bradykinesia is Fig. 8.2 Micrographia with decrementing script size in a patient with idiopathic PD. Oxford Textbook of Movement Disorders 64 tapping as well as during walking. Th e prototypical example of such motor blocks is freezi ng of gait (FoG), where the patient \200\231s feet appear to be glued to the ground while t he trunk is moving forward. FoG is a major cause of falls in people with parkinsonian disor ders and is commonly induced by changes in gait rhythmicity, such as turn- ing, as well as by environmental stimuli such as narrow passages or people approaching in the opposite dire ction. An extreme form of start hesitation with freezing, where patients are unable to init iate walking but once under way may almost walk normally, has been described as \200\230ga it ignition failure \200\231 (11). (also to avoid aspiration pneumonia) within the fi rst six to eight years of disease. Postural deformities are also common to many types of parkinson- ism. A stooped posture wit h fl exion of the trunk is a hallmark of PD, while in MSA parkinsonism antecollis or mixed anterolat erocollis deviations are oft en seen in the absence of signifi cant trunk fl ex- ion (13). However, patients with PSP typically show some degree of hyperextension of the ne ck and trunk, while severe degrees of trunk fl exion, termed camptocormia, occur in PD and occasion- ally in MSA (14). Th e stooped posture of PD as well as hyperexten- sion of the n eck in PSP have been related to muscular rigidity, but there is ongoing controversy as to w hat extent antecollis posturing in MSA or camptocormia in PD might also be the result of dy stonic muscle contractions or myopathy of extensor muscles (15, 16). Most patients presenting with bradykinetic parkinsonism also exhibit muscular rigidity , ch aracterized by a steady resistance to passive movement which is independent of velocity and may include cogwheel-like rhythmic oscillations. Rigidity in parkin- sonism is oft en desc ribed as lead-pipe rigidity since it is present to the same extent over the whole range of movement. It tends to aggravate when patients are asked to perform active movements of the opposite limb during rigidity testing. Parkinsonian rigidity can aff ect both limb and axia l muscles, with somewhat diff erent distri- butions in the diff erent forms of parkinsonism . Dystonia is a rare presenting feature of idiopathic PD (17), but is not uncommon in autosom al recessive froms with young-onset disease like Parkin, Pink-1, and DJ-1 where focal limb dystonia has been reported in up to 40% of cases (18). Focal limb dystonia with strictly as ymmetrical parkinsonism should raise suspicions of CBS; further examples of dystonia \200 \223parkinsonism syndromes include rare genetic disorders such as X-linked rapid-onset dyst onia \200\223par- kinsonism (Lubag), PARK 9 (Kufor \200\223Rakeb disease), PARK 16 or neuro degeneration with brain iron accumulation (NBIA), Wilson disease or secondary parkinsonian syndromes in manganese, car- bon monoxide, or cyanide poisoning, basal ganglia infarcts, or drug-induced parkinsonism (see Table 8.2). Tremor (involuntary rhythmical sinusoidal oscillation of a body part) is the third cardinal motor feature of parkinsonism. Th e prototypical parkinsonian tremor is a 4 \200\2236 Hz r esting tremor, which decreases or diminishes upon voluntary movements to revert aft er a ne w position is obtained (re-emergent tremor). It may be aggravated by fatigue, stress, or em otions. Unilateral onset and persistent asymmetry defi ne the classical rest tremor of PD, with a subgroup of patients also showing additional pos- tural tremor of higher frequency ( 12). In PD, rest tremor usually involves the limbs in isolation; head, chin, and voice trem or are uncommon. Similarly, classical 5 Hz rest tremor is uncommon in atypical degenerative parkinsonian disorders such as MSA or PSP, where irregular and jerky types of postural or kinetic tremor prevail. Myoclonus may rarely be observed as part of the spectrum of levodopa-induced involuntary mo vements in PD, but is otherwise incompatible with a diagnosis of idiopathic PD. Focal myocl onus of a dystonic limb is classically seen in CBS, and myoclonic jerking also causes the \200\230irregular \200\231 tremor commonly seen in patients with MSA. Oculomotor disorders are usually inconspicuous in PD, where they may include slightly broken pursuit and some sa ccadic hypometria, but are defi ning features of some of the atypical parkinsonian dis- ord ers, including vertical gaze palsy in classical PSP or oculomotor dysmetria and gaze-evoked nystagmus in MSA. Th e fourth cardinal feature of parkinsonism is postural instability and loss of postural r efl exes, resulting in frequent falls. While pos- tural instability and falls are frequent problems in advanced stages of PD, their early appearance is a hallmark in atypical parkins onian disorders such as PSP, MSA, or CBS. Ataxia is a disease-defi ning accompaniment of parkinsonism in MSA, and some of the heredit ary ataxias (spinocerebellar ataxias (SCAs)) may also cause a parkinsonian phenotype, in pa rticular SCA3. Additional clinical features Apart from the defi ning cardinal motor features, patients wit h parkinsonian syndromes commonly show additional motor and non-motor signs that may oft en be helpful clinical clues to diff eren- tial diagnosis depending on their type, severity, and time of presen- tation in the course of disease. Apraxia is one of the focal cortical signs constituting a clinical hallmark of CBS, but an exclusion criterion for PD. Dementia is a common late feature of idiopathic PD, aff ecting 70 \200\22380% of patients a ft er prolonged disease of more than 10 years (19), while onset of dementia within 12 month s of the fi rst appear- ance of parkinsonism defi nes DLB. Parkinsonism \200\223dementia co m- binations are also characteristic of several tauopathies, including frontotemporal demen tia with parkinsonism linked to chromosome 17 (FTDP-17), CBS, and PSP, and may also occur i n Alzheimer \200\231s disease. Dysarthria is common in all types of parkinsonism, but clinical presentation and severity d iff er. While some loss of volume and prosody is almost universal in PD speech, this does n ot signifi cantly impair intelligibility until late in the disease course. Severe dysar- th ria with marked loss of volume and occasionally a high-pitched quavering voice with early l oss of intelligibility are typical of MSA. Likewise, marked dysarthria is also an early fea ture of PSP. Depending on the cause, dysarthria may also be associated with early loss of i ntelligibility in some forms of symptomatic parkin- sonism such as those seen in chronic ma nganese poisoning. Hallucinosis is a characteristic feature in both PD and DLB, where it includes minor forms with sensations of presence or passage in addition to well-formed visual hallucinations and , less commonly, auditory or tactile sensations. A recent study found that the occur- rence of visual hallucinations had high specifi city for the distinc- tion between PD and DLB an d other parkinsonian disorders like PSP, MSA, or vascular parkinsonism (20). Dysphagia is also a late feature of PD, but is present earlier and to a more severe degree in PSP and MSA, where nasogastric or per- cutaneous gastrostomy tube feeding regularly beco mes necessary Autonomic failure, including orthostatic hypotension, male erec- tile dysfunction, and neur ogenic bladder dysfunction, is a defi ning CHAPTER 8 Overview of parkinsonism and approach to differential diagnosis 65 post-mortem confi rmed PD occurred in about a third of cases, while this percentage was eve n higher in those with post-mortem confi rmed diagnoses of one of the atypical disorders (2 2). Clinical misclassifi cation rates are likely to be higher in a non-specialist setting, as exemplifi ed by a large series of post-mortem confi rmed PSP cases, of which a fourth ha d initially been referred as PD and only about 60% had received the correct diagnosis (23). While there are clinical pointers to aid diff erential diagnosis between PD and other neur odegenerative types of parkinsonism (see Table 8.3), ancillary tests are oft en needed to e nhance diagnostic accu- racy. Th ese include drug challenge tests to assess dopaminergic re sponsiveness, neuroimaging to evaluate nigrostriatal presynaptic dopaminergic function or e vidence for structural abnormalities as seen in many of the atypical or secondary parkinson ian disorders, or, still somewhat limited regarding use in clinical routine, genetic testin g to identify the more common genetic subtypes of PD such as Parkin or LRRK2 parkinsonism. Table 8.2 Conditions causing dystonia \200\223parkinsonism Sporadic Parkinson \200\231s disease Progressive supranuclear palsy Multiple system atrophy Corticobasal syndrome Hemiatrophy \200\223hemiparkinson syndrome Toxic Carbon monoxide/cyanide Neuroleptics Manganese MPTP Basal ganglia infarction Inherited X-linked dystonia \200\223parkinsonism (Lubag, DYT3) Dopa-responsive dystonia (DYT 5) Drug challenge testing Th e responsiveness of motor symptoms to levodopa is a key fea- ture of PD, and the sustained effi cacy of levodopa even aft er years of treatment remains one of the major diff erences between PD and other forms of parkinsonism. Acute single-dose dop aminer- gic drug challenges using levodopa or the equipotent dopamine agonist apomorphine h ave been suggested as a useful tool in the diff erential diagnosis of PD (24). A positive r esponse is usually defi ned as an improvement of more than 30% in the UPDRS motor section f ollowing acute challenges with 100 \200\223200 mg of lev- odopa or 2 \200\2233 mg of subcut aneous apomorphine (pre-treatment with oral domperidone 24 hours prior to testing is recomm ended to block the emetic eff ects of apomorphine). Unfortunately, the sensitivity and spec ifi city of these acute drug-challenge tests in diff erentiating levodopa-responsive PD fro m poorly responsive atypical or secondary forms of parkinsonism are limited. Th e posi- tiv e predictive values for the long-term response to levodopa were only 67% for apomorphine an d 80% for levodopa, meaning that at least 20% of patients with levodopa-responsive parkinso nism during long-term treatment respond poorly to acute drug chal- lenges (25). Also, patie nts with atypical parkinsonian disorders, such as MSA, PSP, or vascular parkinsonism, may s how initial levodopa responsiveness in up to 50% of cases (26 \200\22328). In clinical prac tice, a negative outcome of acute dopaminergic testing should never discourage a trial of s ustained treatment with levodopa at a suffi cient dose (300 \200\223600 mg/day for at least 2 months, and even higher doses can be tried for clinically typical PD). In view of this, acute drug challenge testing is of limited use in clinical practice. In addition, it should be noted that, although similar diagnostic accuracies have been reported for single-dose d rug challenges and chronic dopaminergic therapy (29), some guidelines discour- age its use in the diff erential diagnosis of parkinsonian disorders (www.nice.org.uk). Rapid-onset dystonia \200\223parkinsonism (DYT 12) PARK 2 PARK 6 PARK 7 PARK 9 (Kufor \200\223Rakeb disease) PARK 16 NBIA 1 (Hallervorden \200\223Spatz syndrome) NBIA 2/PARK 14 (PLA2G6-related neurodegeneration) Wilson disease Huntington \200\231s disease Neuroacanthocytosis Spinocerebellar ataxia (SCA3) GM 1 gangliosidosis Rett syndrome feature of MSA (21), but is also common in PD, where it occurs later in the disease course and is usually of lesser severity than in MSA. Approach to di \200 erential diagnosis Parkinsonism may be the clinical manifestation of a plethora of neurodegenerative, structural, toxic, metabolic, infectious, and vascular diso rders (see Table 8.1). As prognosis and therapy dif- fer considerably among parkinsonian sy ndromes, an early correct diagnosis is of great clinical signifi cance. In patients present ing with the classical motor signs, including asymmetric rest tremor responding to levodopa and without atypical features, the diagnosis of PD is usually straightforward without the need for further tests. However, in the early stages of the disease, clinical overlap betwe en PD and other neurodegenerative diseases, such as MSA, CBS, or PSP, can cause diagnostic diffi culties. In a recent clinicopathologi- cal study of more than 100 cases of parkinsoni sm diagnosed and followed by experienced neurologists or geriatricians, specifi city and po sitive predictive value for a post-mortem diagnosis of PD was above 90% aft er long-term cl inical follow-up in a specialist setting. However, even in a movement disorder specialist s et- ting, diagnostic reclassifi cation during follow-up of patients with Genetic testing An increasing number of genetic loci, currently listed as PARK1 \200\22318, have been linked to PD, and mutations within six of these loci cause familial parkinsonism in a Mendelian fashion (SNCA, LRRK2, PARKIN, DJ1, PINK1, and ATP13A2), all but ATP13A2 cli nically closely resembling idiopathic PD (30). Furthermore, polymorphic variations within t wo of these loci (SNCA, LRRK2) have been Oxford Textbook of Movement Disorders 66 Table 8.3 Di \200 erential diagnosis of parkinsonian syndromes PD MSA PSP CBS Vascular parkinsonism Negative Drug-induce d parkinsonism Negative Family history Occasionally positive Rarely positive Rarely positive Rarely positive Symmetry Asymmetric Asymmetric Symmetric Asymmetric Asymmetric or symmetric Asymmetric or symmetric Akinesia + + + + + + Classical resting tremor + \200\223 +/ \200\223 \200\223 + + Rigidity + + Axial > limb Axial < limb + + Early postural instability \200\223 + + + +/ \200\223 +/ \200\223 Early falls \200\223 + + + \200\223 \200\223 Supranuclear gaze palsy \200\223 \200\223 + + \200\223 \200\223 Early autonomic failure \200\223 + +/ \200\223 +/ \200\223 \200\223 \200\223 Apraxia \200\223 \200\223 + + \200\223 \200\223 Levodopa response Excellent and sustained response Transient and poor response Transient and poor response Poor response Inconsistent response Inconsistent response validated as genetic risk factors for PD (31 \200\22333). In the absence of implications of a positive or negative test on patient manage- ment against a background of cost and unres olved ethical issues, genetic testing is currently not part of clinical routine in the diag - nostic work-up of PD. Th is may well change for the more common mutations once selective and disease-modifying therapies begin to emerge. Th e chance of detecting a Parkin gene mut ation in a subject with young-onset parkinsonism is less than 5% in sporadic cases, and the chance of identifying a mutation of LRRK2 in European patients with typical late-onset PD and a positive family history is about 7% (18, 34). comprises subtests for olfactory discrimination, identifi cation, and odor threshold, and h as been successfully applied to PD patient cohorts (38). Cardiovascular re \202 ex testing Since the presence of autonomic failure is a key feature of MSA, car- diovascular refl ex testing, especially the verifi cation of ortho static hyp otension in head-up tilt-table testing, has been put forward for the diff erentiation betwe en PD and MSA. Indeed, orthostatic hypotension with a drop of blood pressure of more than 3 0 mmHg systolic or more than 15 mmHg diastolic in head-up tilt has been found in about 50% of patients with MSA but in only about 20% of PD patients (39). In addition, orthostatic dr ops in blood pressure are signifi cantly higher in patients with MSA. Nevertheless, because of the overlap between the two entities, cardiovascular refl ex test- ing is not conclusiv e in individual cases even at the earliest stages of disease. On the other hand, molecular genetic testing is an essential part of the diagnostic process in a variety of conditions present- ing as \200\230parkinsonism-plus \200\231 disorders f eaturing various combina- tions of parkinsonism with dystonia, ataxia, pyramidal signs, and cognitive dysfunction including Wilson disease, SCA2 or SCA3, dopa-responsive dystonia (DY T3 and DYT5) or DYT12, NBIAs, or fragile X-associated tremor \200\223ataxia syndrome (FXTAS ) (see Table 8.4). Urodynamic assessment Analogous to orthostatic hypotension, other features of autonomic fai lure, such as urodynamic and erectile dysfunctions, are much more common in MSA than in PD and PSP. Th erefore character- istic patterns of abnormality, such as detrusor hyperrefl ex ia and abnormal urethral sphincter function, have been assessed for dif- ferential diagnosi s. Similarly, the use of sphincter electromyogra- phy, exhibiting denervation in MSA due to degeneration of Onuf \200\231s nucleus in the spinal cord (40), has been tested regarding its role in diff erential diagnosis. None of these parameters was able to reli- ably discr iminate between MSA and PD in clinical trials (41). Olfactory testing Hyposmia, referred to as diffi culties in the detection, discrimina- tion , and identifi cation of odors, is a prominent and early symp- tom in PD and is found in up to 90% of patients (35). Notably, olfactory dysfunction seems to be unrelated to disease d uration or the manifestation of motor symptoms of PD, and is not infl uenced by antiparkins onian drugs. In contrast, olfactory function is nor- mal in PSP, CBS, vascular parkinsonism , and essential tremor, and the defi cit seems to be mild in MSA (36). A recent study has a lso shown that hyposmia discriminates between patients with par- kinsonism who have abnorma l nigrostriatal function as assessed by dopamine transporter (DAT) imaging and those who do not (scans without evidence of dopaminergic defi cit (SWEDDs)) (37). Th erefore olfactory testing may be useful in the diff erential diagno- sis of parkinsonian syndromes. Th e most widely used test world- wide to date is the University of Pennsylvania Smell Identifi cati on Test (UPSIT) which contains some odors culture-specifi c for the North American populati on, while the test battery called Sniffi n Sticks has been validated for the European popul ation. It Brain imaging Neuroimaging techniques are the single most informative group of ancillary in vestigations in the diagnostic work-up of parkinsonism in clinical practice. While their us e may seem unnecessary in patients with the classical clinical presentation of levodopa-res ponsive PD, they may yield important clues in many instances of clinical uncer- tainty; fun ctional radiotracer imaging may distinguish between parkinsonian and non-parkinsoniam tremo r syndromes, and structural imaging may reveal causes of secondary parkinsonism or give ind ications for MSA, PSP, or CBS. CHAPTER 8 Overview of parkinsonism and approach to differential diagnosis 67 Table 8.4 Rare hereditary neurodegenerative disorders causing symptomatic parkinsonism Diso rder Frontotemporal dementia with parkinsonism linked to chromosome 17 (FDTP-17) Genes (loci) Microtubule-associated protein tau-gene (17q21.1) Clinical features Parkinsonism, vertical gaze palsy, dystonia, executive dysfunction, behav ioral changes, language impairment, progressive dementia Huntington \200\231s disease Huntingtin gene (4p16.3) Akinetic \200\223rigid syndrome, often associated with early disease onset (Westphal varian t) SCA mutations SCA2 Ataxin-2 (12q24) Ataxia, dystonia, pyramidal signs, neuropathy, myoclonus, tremor, parkinsonism (rarely resp onsive to levodopa) SCA3 (Machado \200\223Joseph disease) Ataxin-3 (14q24.3-q31) Ataxia, dystonia, chorea, spasticity, parkinsonism (rarely responsive to levodopa) Wilson disease ATP7B gene (13q14.3-q21.1) Neurological presentation with tremor, dystonia, parkinsonism, cerebellar signs, gait distu rbance and psychiatric disturbance, Kayser \200\223Fleischer rings, hepatic manifestation, osteoporosis, haemolytic anemia, skin hyperpigmentation Fragile X-associated tremor \200\223ataxia syndrome FMR1 gene (Xq27.3) Tremor, parkinsonism, ataxia Dystonia-plus syndromes DYT3 (X-linked dystonia parkinsonism, Lubag) TAF1-gene (Xq13) Progressive generalized dystonia and parkinsonism, occasionally responsive to levodopa DYT5 (Segawa syndrome, dopa-responsive dystonia) GTP cyclohydrolase 1-gene (14q22.1-q22.2) Young-onset dystonia parkinsonism, responsive to levodopa DYT12 (rapid-onset dystonia parkinsonism) ATP1A3 (19q12-q13.2) Rapid onset of dystonia and parkinsonism in young adults Neuronal brain iron accumulation syndromes NBIA type 1 (Hallervorden \200\223Spatz disease, pantothenate kinase-associated neurodegene ration) PANK 2 (20p13-p12.3) Onset in the \201 rst decade, progressive generalized dystonia, dysarthria, spasticity, m ental retardation; rarely presenting as rapidly progressive parkinsonism NBIA type 2/PARK 14 PLA2G6 (22q13.1) Infantile neuroaxonal dystrophy; may present as dopa-responsive parkinsonism with dystonia Neuroferritinopathy FTL 1 (19q13.3-q13.4) Dystonia, chorea, occasionally parkinsonism Parkinsonism \200\223amyotrophic lateral sclerosis dementia complex of Guam TRPM7 gene (15q21) Parkinsonism, ALS, dementia Fahr \200\231s syndrome (familial basal ganglia calci \201 cation) IBGC1 ( 14q) VPS13A gene (9q21) Progressive parkinsonism, dystonia, tremor, dementia Neuroacanthocytosis Orofacial chorea, dystonia, tics, parkinsonism, axonal neuropathy, cognitive decline, cardi ac manifestations (arrhythmias and cardiomyopathies) ALS, amyotrophic lateral sclerosis. Role of structural brain imaging Although usually normal in classical PD, cranial computed tomog- raphy (cCT) should probably be performed as part of the routine diagnostic work-up i n every patient presenting with parkinsonism to rule out secondary forms such as vascular p arkinsonism, nor- mal pressure hydrocephalus, structural basal ganglia pathology, or (rarel y) frontal meningioma. Even in otherwise typical PD, vascu- lar or other concomitant brain pathology revealed by structural imaging is of potential clinical relevance regarding drug treatment and prognosis. Furthermore, advanced MRI techniques, such as diff usion- weighted imaging (DWI) and diff u sion tensor imaging (DTI), are sensitive to changes in the integrity of neuronal tissue tha t are not associated with signal changes or atrophy on conventional MRI. Diff usivity chang es have been described in the putamen in MSA and PSP patients, and increased diff usivity i n the middle cerebellar peduncle has been proposed as a diff erential diagnostic MRI sign s eparating MSA from PSP (42). Single photon emission computed tomography (SPECT) Radiotracer imaging is able to provide i nformation on func- tional changes of the nigrostriatal dopaminergic projection, as fi rst shown with positron emission tomography (PET) using 18 F-fl uorodopa as a tracer molecule i n patients with PD (43). In contrast with PET, which has developed into a powerful research tool in parkinsonian disorders, SPECT is widely clinically avail- able and, although it ha s lower spatial resolution and poorer signal-to-noise-ratio, it can also detect pre- and po st-synaptic functional changes in the nigrostriatal dopaminergic system and elsewhere, depe nding on the tracers used. Currently, only Wherever possible, however, magnetic resonance imaging (MRI) should be the preferred imagin g modality because of its superior solution and higher diagnostic sensitivity. In particula r, MRI has far greater sensitivity for detecting basal ganglia pathology in con- ditions su ch as Wilson disease, NBIA, or manganism. ln addition, only MRI has suffi cient sensitivity to detect structural abnormali- ties suggesting atypical parkinsonism, such as midbrain at rophy and the \200\230penguin \200\231 or \200\230colibri \200\231 sign in PSP, putaminal and/or cerebel- lar and pontine atrophy in MSA, or asymmetrical parietal cortical atrophy in CBS (see Table 8.5 and Fig. 8.3). Oxford Textbook of Movement Disorders 68 Table 8.5 Role of cCT and MRI in the di \200 erential diagnosis of parkinsonism Imaging te chnique cCT Findings Structural lesions Diagnostic relevance Discrimination of secondary causes of parkinsonism Sensitivity Moderate \200\223high Speci \201 city Moderate \200\223high Cerebral micro/macroangiopathy Discrimination of VP Moderate \200\223high Low Dilated ventricles Discrimination of NPH High High Cortical atrophy Discrimination of DLB, CBS, FTDP-17 Moderate Moderate Subcortical/infratentorial atrophy Discrimination of MSA, PSP Low Moderate Structural MRI Structural lesions Discrimination of secondary causes of parkinsonism High Moderate \200\223high Cerebral micro/macroangiopathy Discrimination of VP High Moderate \200\223high Dilated ventricles Discrimination of NPH High High Cortical atrophy Discrimination of DLB, CBS, FTDP-17 Moderate \200\223high High Subcortical/infratentorial atrophy Discrimination of MSA, PSP Moderate \200\223high Moderate \200\223high Subcortical signal alterations Discrimination of MSA, PSP Putaminal hypointensity in combination with a hyperintense putaminal rim Discrimination of MSA Hot cross bun sign Discrimination of MSA \200\230Penguin \200\231 sign Discrimination of PSP DWI/DTI ADC putamen Discrimination of MSA, PSP High High FA putamen Discrimination of MSA High High ADC pons Discrimination of MSA Moderate Moderate ADC superior cerebellar peduncle Discrimination of PSP High High ADC middle cerebellar peduncle Discrimination of MSA Moderate \200\223high High Planimetry Reduced AP midbrain diameter Discrimination of PSP Moderate Moderate \200\223high Reduction of midbrain-to-pontine area ratio Discrimination of MSA High High Volumetry Volume loss putamen Discrimination of MSA Moderate Moderate \200\223high Volume loss midbrain Discrimination of PSP Moderate \200\223high moderate \200\223high VP, vascular parkinsonism; NPH, normal pressure hydrocephalus; DLB, dementia with Lewy bodi es; CBS, corticobasal syndrome; FTDP-17, frontotemporal dementia with parkinsonism linked t o chromosome 17; MSA, multiple system atrophy; PSP, progressive supranuclear palsy; ADC, ap parent di \200 usion coe \203 cient; FA, fractional anisotropy; DWI, di \200 usion-weigh ted imaging; DTI, di \200 usion tensor imaging. dopamine transporter SPECT imaging using the commercially available tracer FP-CIT is licens ed as a routine procedure for dif- ferential diagnosis in parkinsonian disorders. tremor. SWEDDs can be taken as a fi rm exclusion of PD according to long-term follow-up dat a of a series of cases with this constel- lation. In contrast, DAT-SPECT is not able to dis tinguish reliably between patients with diff erent types of degenerative parkinson- ism, su ch as PD, MSA, PSP, or CBS, although novel image analysis techniques may improve this in fu ture (48). Distinction between PD and vascular parkinsonism when using DAT-SPECT also seems imperfect (49). FP-CIT SPECT Th e SPECT technique most widely used in the diff e rential diagnosis of parki nsonism is dopamine transporter (DAT) imaging. Th e commercially avail able tracer 123 I-FP -CIT ( 123 I-2-carbomethoxy-3-(4-iodophenyl)- N -(3-fluoropropyl) -nortropane) (DAT-Scan) b inds specifi cally to presynaptic dopamine transporters of nigrostriatal nerve endings, and semiquantitative region of interest (ROI) based analysis of DAT-SPECT is able to identify reduced striatal tracer binding in PD and other parkinso- nian syndromes associated with de generation of the nigrostriatal projections (44). In PD, these changes are typically asymme trical and correlate with disease duration and severity of motor symp- toms (45, 46). DAT-S PECT is useful to distinguish PD from other tremor disorders without nigrostriatal neurodeg eneration, such as essential or dystonic tremor, as well as from drug-induced parkin- sonis m, psychogenic parkinsonism, and levodopa-responsive dys- tonia presenting with parkinsonis m (47). Th is imaging modality is also helpful in rejecting or confi rming a possible diagn osis of neu- rodegenerative parkinsonism in subjects with equivocal or vague symptoms or at ypical tremor presentations like unilateral postural IBZM \200\223SPECT IBZM ( 12 3 I-3-iodo-6-methoxy benzamine) is a ligand which specifi call y binds to D2-receptors, enabling visu- alization of postsynaptic dopamine receptors within the striatum. Based on the sparing of striatal neurons in the pathology of PD and their in volvement in other types of degenerative parkinsonism, such as MSA and PSP, postsynaptic do pamine receptor imaging has been proposed as a diff erential diagnostic tool (50). In early untreated PD patients, IBZM-SPECT studies revealed a relative increase in D2-binding, espe cially in the putamen contralateral to the more aff ected body side (51). In contrast, trac er uptake seems to be reduced even in the earliest stages of atypical parkinsonian conditio ns such as MSA and PSP (52). However, there is consider- able overlap, particularly in earl y disease stages, where clinical dif- ferentiation is the most diffi cult, such that postsy naptic dopamine CHAPTER 8 Overview of parkinsonism and approach to differential diagnosis 69 (a) (b) (c) (d) (e) (f) Fig. 8.3 (a) Normal MRI in a patient with idiopathic PD; (b) putaminal atrophy and putamina l hypointensity in a patient with MSA; (c) vascular lesions in a patient with vascular park insonism; (d) mid-sagittal T 1 -weighted MRI in a patient with idiopathic PD; (e) mid-sagit tal T 1 -weighted MRI in a PSP patient, exhibiting marked midbrain atrophy without signi \201 cant pontine atrophy (divided by white line) forming the silhouette of a penguin or co libri; (f) asymmetric parietal atrophy in a patient with CBS. D2 receptor SPECT imaging has limited value in clinical practice, although high predictive values have been reported for the com- bined application of IBZM-SPECT and FP-CIT SPECT in the eval- uation of PD and MSA (53). hyperechogenicity in the substantia nigra (SN) region of the mid- brain with this technique (see Fig. 8.4), but this is not the case in patients with PSP and MSA who, unlike PD patie nts, have been reported to show increased areas of echogenicity in the lenticular nucleus ( 55). A recent study has proposed that hyperechogenicity of the SN in combination with norma l echogenicities in the len- ticular nucleus discriminates PD from PSP and MSA with a posi- tive predictive value of over 90% (56). In addition, another recent study has demonstrated that midbrain hyperechogenicity is able to distinguish between PD patients and SWEDD patie nts (57). While these observations are certainly of great interest, the precise role of TCS in the diagnostic work-up of parkinsonism in clinical practice still needs to be defi ned. MIBG-SPECT 123 I-MIBG (meta-iodobenzyl guanidine), an analog of norepinephrine, is a tracer used to assess sympa- thetic cardiac innervation, which is signifi cantly reduced even in early PD, while postganglionic sympathetic eff erents are spared in MSA. Th erefore MIBG-SP ECT is potentially useful in the diff erential diagnosis of these types of degenerative par - kinsonism, with reduced binding in PD versus normal cardiac uptake in MSA. However, there can be false-negative results in patients with PD without signifi cant autonomic nervous s ystem involvement (54). Principles of management Th e therapeutic management of parkinsonian disorders is complex a nd oft en involves multidisciplinary approaches combining medical therapies with non-pharma cological measures such as physiotherapy, speech therapy, or psychosocial counseling. In Transcranial sonography Transcranial sonography (TCS) can visualize the butterfl y-shaped s tructure of the midbrain using an acoustic temporal bone window. About 90% of patients with idiopathic PD show increased areas of Oxford Textbook of Movement Disorders 70 (a) (b) Fig. 8.4 (a) TCS visualization of the butter \202 y-shaped structure of the midbrain in a healthy subject; (b) hyperechogenicity of the substantia nigra in a patient with idiopathic PD. addition, deep brain surgery has become an important modal- ity for a subset of PD patients with drug-related complications. Details of these diff erent approaches and their indicati ons for the miscellaneous forms of degenerative and secondary parkinsonism can be found in the respective chapters of this volume. In princi- ple, all available therapies for degener ative parkinsonian disorders are symptomatic, and so far no approach has been proved to slo w or halt the underlying progression of disease. Th is can be diff er- ent for some seconda ry types of parkinsonism where removal of a causative drug or tumor or eradication of an un derlying infection (see Table 8.1) may even lead to complete remission. Despite all recent advances in the drug treatment of parkinsonism, levodopa substitution has remained the gold standard of symptomatic effi - cacy for PD, and is oft en at least partially eff ective in other types of degenerative or secondary parkinsonism. However, the magnitude of response is most pronounced in PD, such that levodopa respon- siveness is part of the clinical diagn ostic criteria of PD. Th erefore, depending on the results of the diagnostic work-up, a tri al of levo- dopa will be part of the treatment approach in most patients pre- senting with parkinsonism. clinically but with \200\230scans without evidence of dopaminergic defi - cit \200\231 (59 ). Perhaps even more importantly, advanced MRI has shown promise of diff erentiating betwee n the diff erent types of degen- erative parkinsonism early in the disease course, and tran scranial ultrasound has entered the stage as a potential novel diagnostic imaging tool. Future developments A key priority of clinical research in parkinsonian disorders is again driven by the PD field and is likely to lead to new concepts for early diagnosis and at-ris k definition, including \200\230pre- motor \200\231 signs of disease as well as molecular and imaging markers. Biomarkers for the different degenerative parkinsonian syn- dromes are also a major requirement for improved differential diagnosis, and studies of their progres sion include clinical trials of disease-modifying agents. Genetic and proteomic markers dis - tinguishing between the different neurodegenerative disorders associated with parkinsonis m are evolving, with some showing promising sensitivities and specificities (60, 61). High- field MR holds the promise of detecting early PD with high sensitivity and specificity (62) , and transcranial ultrasound is being sug- gested as a future tool for screening for PD ri sk in the general population (63).