CHAPTER 5 Electrophysiological Approaches to the Movement Disorder Patient 37 1 s/div 5 ms/div Fig. 5.5 Patient with myoclonus dystonia ( -sarcoglycan gene). is the trapezius or sternocleidomastoid (SCM). Subsequently, there is spread to cranial and caudal muscles with diff erent veloci- ties of propagation but with a constant pattern of muscle activa- tion. Myoclonic jerks may be associated with cortical spikes, but the lack o f correlation between the two suggests that spikes are projected to, but do not originate i n, the cortex. Evoked poten- tials are not increased in amplitude, but there may be an enha nced C-refl ex. Fig. 5.4 Giant evoked potential with P25/N35 of 53 V, C-re \202 ex at latency of 40 ms. refl ex myoclonus), its presence does not defi nitely indicate a corti- cal origin for the myoclonus (see Fig. 5.4). A C-refl ex is frequently found in corticobasal degeneration (CBD), a disease in which SEPs are not enlarged and EEG back-averaging fails to reveal a pre-myoclonus spike (28). In Creutzfeldt \200\223Jakob disease (CJD), myoclonus is not stimulus- sensitive and occurs continuously and quasi-periodically in the resting condition every 600 \200\2231500 ms. Th ere may be accompa- nying dystonic posturing. EMG bursts are similar to, or slightly longe r than, those of classical cortical myoclonus. Periodic sharp discharges (PSDs) are usually associated with muscle jerks, but can occur independently. EEG spike wave and EMG activity cor- relate loosely. On back-averaging, the negative spike wave is much smaller than the P SD recorded with the raw EEG. Th e time interval between EEG and jerks is 50 \200\22385 ms (much longer than required for conduction through the pyramidal tract). Typical cortical re fl ex myoclonus may be seen in the late stages of the disease. Th e normal human startle response consists of a brief fl exion response, most marked in th e upper half of the body, elicited by unexpected auditory, and sometimes somaesthetic, visu al or vestibular stimuli. Th e nucleus reticularis pontis caudalis seems to be particularly important. Conduction of eff erent impulses both upwards and downwards from the generator, possibly in the medial reticular formation, is slow. Th e shortest latencies are 20 \200 \22350 ms for the orbicularis oculi muscle, while in the quadriceps the latency of the resp onses reaches 100 \200\223150 ms. EMG responses in the intrinsic hand and foot muscles are particularly delayed. Auditory startle refl ex EMG latencies are rather variable. Th e con- stant refl ex EMG activity in orbicularis oculi is the most impor- tant event in the norma l auditory startle refl ex. Considering the auditory blink refl ex in orbicularis oculi as separated from the startle response, the earliest muscle recorded is the SCM with a latency of <100ms. Th e activity then spreads up the brainstem from cranial nerve XI to cranial ne rve V and down the spi- nal cord (refl ex brainstem myoclonus). In physiological startle th e stimulus-induced response tends to habituate, and disap- pears aft er four to six stimuli . Exaggerated startle responses are seen in hyperekplexia, neuropsychiatric startle syndrom e, and stimulus-induced epilepsy or other movement disorders such as stiff person syndrome or tics (30) (see Fig. 5.6). In subacute sclerosing panencephalitis (SSPE) sudden move- ments followed by a tonic phase ( \200\230hung-up jerks \200\231) can be related to periodic high amplitude EEG discharges occurring every 4 \200\22313 s. Myoclonus dystonia is a movement disorder characterized by a combination of rapid brief mus cle contraction (myoclonus) and/ or sustained twisting and repetitive movements that result in an abnormal posture (dystonia). Myoclonic jerks typically aff ect the neck, trunk, and upper limbs, with less common involvement of the legs (29). About 50% of patients have addi tional focal or seg- mental dystonia, presenting as cervical dystonia or writer \200\231s c ramp. Myoclonus dystonia is characterized by multifocal, focal, and gen- eralized jerks of brief and long duration, and spasms. Oft en they are stimulus-sensitive and may present a s tartle response. No cortical origin has been found for the absence of enlarged SEPs and pos itive cortical event on EEG back-averaging (see Fig. 5.5). Two diff erent patterns of spinal myoclonus are recognized: prop- riospinal myoclonus and s egmental myoclonus. In the latter, myo- clonus is limited to muscles innervated by one to t wo contiguous spinal segments. It is oft en caused by a structural lesion of the spi- nal c ord, although in some cases no lesion is found. Th e myoclonus is oft en rhythmic and may p ersist during sleep. Stimulus sensitivity is unusual. Reticular myoclonus (brainstem myoclonus) is characterized by generalized jerks with promin ent involvement of proximal and fl exor muscles. Jerks may be spontaneous or stimulus-induc ed, particularly with respect to sound (30). Th e jerks originate from the brainstem reticu lar formation. Th e fi rst muscle to be activated When segmental myoclonus is suspected a multichannel EMG recording should be performed in d istant muscles belonging to the Oxford Textbook of Movement Disorders 38 (a) (b) 200 ms/div 100 ms/div Fig. 5.6 (a) Acoustic stimulation. (b) Tapping on the nose. same myotome, and it is useful to study at least two myotomes. Th e frequency of the jerks is highly variable, and EMG burst can have a duration of up to 1000 ms (31). Propriospinal myoclonus is characterized by axial muscle con- tractions usually causing fl exion of the trunk and typically induced by lying down. Rhythmicity is not common in propri ospinal myo- clonus, although \200\230runs \200\231 or clusters of jerks are seen. It is h ypoth- esized that propriospinal myoclonus arises from a spinal myoclonic generator recruit ing axial muscles up and down the spinal cord via long propriospinal pathways (31, 32). Th e propagation of the myo- clonic discharge within the spinal cord can be studied by recordi ng proximal upper limb, trunk (cervical, thoracic paraspinal, and rec- tus abdominis), and lower limb muscles. is characterized by arrhythmic sequences or runs of axial jerks producing fl exion or exten sion of the trunk. Bursts of muscle activity vary from 50 ms to 4 s. EMG jerks arise from a bdominal or cervical spinal segments and slowly spread rostrally and caudally at <10 m/s. C ranial muscles are not involved, with the exception of the neck. Th is form of myoclonus ca n be stimulus-sensitive (see Fig. 5.7). Propriospinal myoclonus Fig. 5.7 Multichannel EMG recording in propriospinal myoclonus. 2 s and the latter 400 ms before the jerk onset. Both the components have a cortical genera tor: the early BP originates from the supple- mentary motor area (SMA) and the late BP from the primary motor cortex (M1). Cervical trauma, albeit mild, is reported in some idiopathic cases, and some have viral mye litis. Most cases are labeled as idiopathic as no structural lesion is found. As the \200 \230typical \200\231 clinical and electrophysiological features of propriospinal myoclonus can be voluntarily mimicked, and in some cases an immediate response to a placebo dose of b otulinum toxin has been reported, a psycho- genic etiology should be considered in idiopath ic cases (33, 34). Interestingly, however, ultrastructural lesions in the spinal tracts hav e recently been reported using diff usion tensor magnetic reso- nance imaging (35). BPs can be recorded prior to self-paced voluntary movements. A \200\230typical \200\231 BP has never been recorded prior to proven organic myoclonus. Its presence in patients with j erks or other intermit- tent movements indicates that there is a (conscious or unconscious) volition component in the origin of these jerks. Th e BP is obtained by back-averaging epochs of EEG preceding the muscle jerks. As this tes t requires a low/high-pass fi lter (0.05 Hz) the patient has to be very quiet between the j erks as the EEG recording is less stable and more sensitive to artifact. Th e eyes should b e covered with cotton-wool pads to avoid blink artifact. Th is technique is not useful when the jerks are too frequent (with inter-jerk interval <2 s) or too few (poor signal-to-nois e ratio requires at least 40 jerks). As this test involves the average of many jerks it is always possible that some organic jerks are averaged with jerks where a minor voluntary com ponent is included. Th e con- verse situation may also occur (in particular in patients wit h axial jerks). Th erefore a cautious interpretation of these features is neces- sary in su ch cases. Psychogenic myoclonus Jerking of the limbs that superfi cially resembles spinal segmental m yoclonus may also be seen in patients where either the clini- cal course or investigations reveal the cause to be psychogenic (34, 36). In psychogenic movement disorders, multichanne l sur- face EMG recording of the jerks may show an inconsistent pat- tern of muscle activat ion, variable intermuscular latencies, and distractibility. A useful tool that can distinguish between organic and psy- chogenic jerks is the detection of a Bereitschaft spotential (BP) via jerk-locked back-averaging analysis (34, 36). Th e B P consists of an early (early BP) and a late (late BP) component, the former starting It is also important to note that healthy people do not have a pre-movement potential when jerks occur in response to external CHAPTER 5 Electrophysiological Approaches to the Movement Disorder Patient 39 1 s/div Fig. 5.8 Filters 0.05 \200\22310 Hz: amplitude axis in V; 3 s pre- and post-trigger. Back -averaging for detection of BP. stimuli, while patients with tics and myoclonus dystonia may have an abbreviated pre-moveme nt potential (see Fig 5.8). splenius capitus, levator scapulae, and trapezius) is useful to iden- tify \200\230leading \200\231 overactive neck muscles which are active at the onset of dystonic spasms and thos e muscles that show paradoxical activity, leading to restriction of head movements. For thi s reason, patients need to be studied at rest and during rotation and tilt of the neck. Dystonia Dystonia is characterized by co-contraction of agonist and antago- nist muscles an d overfl ow of muscle contraction, which refers to activation of muscles not required to pe rform the desired action. Th is may be due to impaired inhibition at multiple levels in the cen- tral nervous system. In dystonia, there is reduced reciprocal inhibi- tion in the spi nal cord, abnormal inhibitory function localized in the brainstem (enhanced blink refl ex), and reduced inhibition in the cortex, measured by transcranial magnetic stimulation (TMS) (37). TMS has provided useful information on pathophysiology of dystonia, but the technique is of limited help for diagnostic pur- poses in individual patients. Th e triple stimulati on test (TST) has proved to be a useful screening tool in patients with prolonged central m otor conduction times and mutations in the PARK2 gene, particularly because such mutations are a relatively common cause of young-onset PD. Th e selection of incorrect muscles for injection of botulinum toxin may explain why some p atients have a suboptimal response (Fig. 5.9). More sophisticated analyzes of EMG discharges consider EMG \200\223 EMG coherence. Th is ma y disclose the character of the descending discharges responsible for the abnormal muscle a ctivity in dysto- nia (38). An abnormal 4 \200\2237 Hz drive is seen in dystonic muscles in patients with the DYT1 gene mutation, idiopathic torticollis, and myoclonus dystonia. In the arms there is evidence of an abnormal corticomuscular drive in the 15 \200\22330 Hz band leading to co-contraction between antagonistic muscles, with the exception of writer \200\231s cramp where a discrete peak in EMG \200\223EMG coherence may be seen at 11 \200 \22312 Hz. Psychogenic dystonia A clinical distinction between organic and psychogenic dystonia can be extremely challenging. Most electrophysiological studies so far have focused on patients w ith a fi xed dystonia syndrome Patients with dystonia caused by mutations in TOR1A gene display abnormalities on some TMS measures (e.g. intra-cortical inhibition and silent period). Unaff ected carriers of the mu tation appear to have similar abnormalities and this may be used to iden- tify asymptomatic carriers (15). In patients with primary dystonia, including those with DYT1 mutations, there is an enhance d response to non-invasive brain stimulation protocols which can induce plastic changes in the motor system. Th us, PAS and repetitive transcranial magnetic stim- ulation (rTMS) prot ocols all produce larger and more long-lasting eff ects in patients with dystonia compared with healthy controls . Interestingly, non-manifesting carriers of the DYT1 mutation show a subnormal response to such protocols, indicating that abnormali- ties in the control of pl astic changes in the brain may be a primary driving force behind the development of dystoni a. 1 s/div Video multichannel EMG recording for cervical dystonia is a useful tool to identify the dys tonic neck muscles to be treated with botulinum toxin in cases where the clinical examinati on alone fails to determine which muscles contribute to the dystonic movement. Multichannel EMG recording of bilateral neck muscles (SCM, Fig. 5.9 Overactivity of left splenius capitus and levator scapulae at rest. Oxford Textbook of Movement Disorders 40 or psychogenic dystonia aff ecting limb, trunk, and neck muscles. While these patients show the same abnormalities of short- and long-interval intracortical inhibition, cortical sile nt period, and spinal reciprocal inhibition as patients with primary dystonia, the response to a plasticity protocol (paired associative stimulation) is abnormal only in primary dyst onia. However, these similarities and diff erences between psychogenic and primary dystonia have only been reported at a group level, hence their usefulness as a discrimi- nating too l for individuals remains to be proved. 200 mS/div An enhanced R2 blink refl ex recovery curve in patients with blepharospasm is useful in dis tinguishing an organic from a psychogenic origin. In this protocol, surface EMG is recorded from the orbicularis oculi muscles. Electrical stimulation is applied to the supraorbital nerve in the supraorbital notch while the patient is at rest with eyes gently closed. Blink refl ex in response to paired stimulation is assessed at interstimulus inter- vals of 200, 300, 500, and 1000 ms. R2 is usually completely abol- ished at interstimulus intervals <20 0 ms; it then slowly recovers, reaching about 40 \200\22350% at the 500 ms interval and 70 \200\22390% at the 1500 ms interval (39). Fig. 5.10 Continuous motor activity in the legs and exteroceptive re \202 ex. of the tremors in the intermediate frequency range, as the clinical features oft en guide t he interpretation of the neurophysiological fi ndings. Studies involving a larger number of patients may help in validating the techniques. Unfortunately, many techniques are not wid ely available in the clinical setting and have limited clinical application as they are not particularly user-friendly (e.g. TMS and coherence studies). Dystonia of psychogenic origi n and organic movement disorders continue to present diagnostic challenges which may be hel ped by further studies. In the fi eld of myoclonus, neurophysiology provides better support even when the EEG fails to show abnormalities. In such cases, polygraphic recording is nec essary to demonstrate the origin of the myoclonus. Startle responses may be a guide in the diagnosis of brainstem pathology and in exaggerated startle responses. Th is test shows that the recovery curve is normal in patients with atypical (presumed psyc hogenic) blepharospasm, while in patients with organically determined blepharospasm the rec overy of R2 response is in an interstimulus interval <200 ms. Patients with solely involunt ary levator palpebrae inhibition exhibit a normal R2 recovery cycle. Rigidity Sti \200 person syndrome Th is syndrome is characterized by axial rigidity at rest, involv ing mainly trunk and proximal lower limb muscles. Exteroceptive stimuli may evoke a sudden exacerbation of rigidity (refl ex spasm) (40). A crucial fi nding is the presence of contin uous motor unit activity in the paraspinal muscles that persists even when trying to relax. EMG electrical silence cannot be obtained. Th e rigidity and continuous motor unit activit y lessen or even disappear during sleep and aft er spinal or general anesthesia, indicating a central source (41). Acknowledgements I would like to express special thanks to Mr Nathan Toms for the excellent technical support he has provided for many years. References 1. Jankovic J, Fahn S. Physiologic and pathologic tremors. Diagnosis, mechanism, and management. Ann Intern Med 1980; 93 : 460 \200\2235 . 2. Deuschl G. Neurophysiological tests for the assessment of tremors. Adv Exteroceptive or cutaneomuscular refl exes are enhanced, habitu- ate poorly, and spread as refl ex spasms into muscles normally not involved in the refl ex. Th ese fi ndings point to enhanced spi- nal interneuronal excitability due to defects within either spinal interneur onal networks at a segmental level or their descending control. Polysynaptic refl exes are characteristically exaggerated in both upper and lower limbs as well as the axial (paraspin al) mus- cles. Th ese responses begin with one or several myoclonic jerks at short interval s (50 \200\22370 ms) that are synchronous in antagonistic muscle pairs and are followed by prolonged tonic muscle activa- tion (observed clinically as spasm) (42). Th is pattern appe ars to be characteristic of stiff person syndrome. Neurol 1999; 80 : 57 \200\2236 5 . 3. McManis PG, Sharbrough FW. Orthostatic tremor: clinical and electro- physiologic characteristics. Muscle Nerve 1993; 16 : 1254 \200\2236 0 . 4. Ikeda A, Kakigi R, Funai N, Neshige R, Kuroda Y, Shibasaki H. Cortical tremor: a variant of cortical refl ex myoclonus. Neurology 1990; 40 (10): 1561 \200\2236 5 . 5. Toro C, Pascual-Leone A, Deuschl G, Tate E, Pranzatelli MR, Hallett M. Cortical tremor. A common manifestation of cortical myoclonus. Neurology 1993; 43 : 2346 \200\2235 3 . 6. Elia M, Musumeci SA, Ferri R, et al. Familial cortical tremor, epilepsy, and mental reta rdation: a distinct clinical entity? Arch Neurol 1998; 55 : 1569 \200\2237 3 . 7. Okuma Y, Shimo Y, Hatori K, Hattori T, Tanaka S, Mizuno Y. Familial cortical tremor with epilepsy. Parkinsonism Relat Disord 1997; 3 : 83 \200\2237 . Patients with stiff limb syndrome present continuous motor units at rest at least in one li mb. Spasms tend to involve repetitive grouped discharges of motor units (see Fig. 5.10). 8. Striano P, Robbiano A, Zara F, Striano S. Familial cortical tremor and epilepsy: a well- defi ne d syndrome with genetic heterogeneity waiting for nosological placement in the ILAE classifi cation. Epilepsy Behav 2010; 19 : 669 . Conclusion Th e pathophysiology of movement disorders is an active research fi eld. Neuroph ysiological diagnostic support is still limited in most 9. van Rootselaar AF, van Schaik IN, van den Maagdenberg AM, Koelman JH, Callenbach PM, Tij ssen MA. Familial cortical myoclonic tremor with epilepsy: a single syndromic classifi cati on for a group of pedigrees bearing common features. Mov Disord 2005; 20 (6): 665 \200\2237 3 . CHAPTER 5 Electrophysiological Approaches to the Movement Disorder Patient 41 myoclonic activity and its relevance to epilepsy. Brain 1991; 114 : 2333 \200\2235 1 . 10. Shibasaki H, Hallett M. Electrophysiological studies of myoclonus. Muscle Nerve 2005; 31 (2): 157 \200\2237 4 . 27. van Rootselaar AF, Maurits NM, Koelman JH, et al. Coherence analysis diff erentiates be tween cortical myoclonic tremor and essential tremor. Mov Disord 2006; 21 : 215 \200\2232 2 . 11. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Trem or. Ad Hoc Scientifi c Committee . Mov Disord 1998; 13 (Suppl 3): 2 \200\2232 3 . 28. 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Distinguishing SWEDDs patients with asymme tric resting tremor from Parkinson \200\231s disease: a clinical and electrophysiological s tudy. Mov Disord 2010; 25 : 560 \200\2239 . 31. Brown P, Rothwell JC, Th ompson PD, Marsden CD. Propriospinal myo- clonus: evidence for spinal \200\230pattern \200\231 generators in humans. Mov Disord 1994; 9 : 571 \200\2236 . 15. Edwards MJ, Talelli P, Rothwell JC. Clinical applications of transcra- nial magnetic st imulation in patients with movement disorders. Lancet Neurol 2008; 7 : 827 \200\2234 0 . 32. Brown P, Th ompson PD, Rothwell JC, Day BL, Marsden CD. Axial myo- 16. Deuschl G, Koster B, Lucking CH, Scheidt C. Diagnostic and pathophysi- ological aspects of psychogenic tremors. Mov Disord 1998; 13 : 294 \200\22330 2 . clonus of propriospinal origin. Brain 1991; 114 : 197 \200\22321 4 . 33. Kang SY, Sohn YH. Electromyography patterns of propriospinal myo- clonus can be mimicke d voluntarily . Mov Disord 2006; 21 : 1241 \200\2234 . 34. 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Aramideh M, Ongerboer de Visser BW. Brainstem refl exes: electrodiag- nostic techniques , physiology, normative data, and clinical applications. Muscle Nerve 2002; 26 : 14 \200 \2233 0 . 23. Caviness JN, Brown P. Myoclonus: current concepts and recent advances. 40. Hadavi S, Noyce AJ, Leslie RD, Giovannoni G. Stiff person syndrome. Lancet Neurol 2004; 3 : 598 \200\22360 7 . Pract Neurol 2011; 11 : 272 \200\2238 2 . 24. Shibasaki H. Neurophysiological classifi cation of myoclonus. Neuro- 41. Lorish TR, Th orsteinsson G, Howard FM Jr. Stiff -ma n syndrome updated. physiol Clin 2006; 36 ( 5 \200\2236 ): 267 \200\223 9 . Mayo Clin Proc 1989; 64 : 629 \200\2233 6 . 25. Cassim F, Houdayer E. Neurophysiology of myoclonus. Neurophysiol 42. Armon C, McEvoy KM, Westmoreland BF, McManis PG. Clinical neu- rophysiologic studies in stiff -ma n syndrome: use of simultanous video- electroencephalographic-surfac e electromy ographic recording. Mayo Clin Proc 1990; 65 : 960 \200\2237 . Clin 2006; 36 : 281 \200\2239 1 . 26. Brown P, Day BL, Rothwell JC, Thompson PD, Marsden CD. Intra- interhemispheric spread o f cerebral cortical hemispheric and This page intentionally left blank CHAPTER 6 Movement Disorders: Structural and Functional Imaging David J. Brooks Structural imaging in Parkinsonian disorders Parkinsonism (a combination of bradykinesia, r igidity, tremor) can result when the nigrostriatal dopaminergic projections or the outfl ow tracts from the striatum and pallidum are interrupted. In Parkinson \200\231s disease (PD) the neurons of the substantia nigra com- pacta (SNc) are targeted by Lewy body inclusions. In multiple system atrophy (MSA), an atypical form of degenerative parkin- sonism associat ed with autonomic failure and ataxia, argyrophilic inclusions are additionally found in the striatum, while progressive supranuclear palsy (PSP) is associated with neurofi brillary t angles in the SNc, basal ganglia, and oculomotor nuclei. cerebellar and pontine atrophy becomes visually obvious, and increased signal can be detect ed in the middle cerebellar peduncles. PSP patients do not show the putamen signal changes characteristic of MSA but develop third-ventricular widening and midbrain atro- phy \200 \224the humming bird sign on sagittal views. Superior cerebellar peduncle atrophy diff eren tiates PSP patients from other parkinso- nian conditions. Corticobasal degeneration (CBD) is a tauopathy characterized by swollen achromatic neurons in the inferior parietal and premotor cortex, striatum, SNc, and dentate nuclei. MRI charac teristically shows asymmetric hemispheric atrophy in established cases. While the above MRI changes can all be found in atypical parkinsonian syndromes, they are not sensitive marker s of these disorders, being generally only seen in more advanced cases. Diff usion-weighted MRI provides a more sensitive modality for discriminating atypi- cal from typical parkinso nian disorders. Most cases of probable MSA and PSP diagnosed on clinical criteria both show increased putamen water diff usivity, whereas this is absent in typical PD (5). However, M SA and PSP can be discriminated from each other by the presence of altered signal in the mi ddle cerebellar peduncles in the former and the superior cerebellar peduncles in the latter (6). Magnetic resonance imaging Conventional magnetic resonance imaging (MRI) weighted to detect T 1 - and T 2 -relaxation times of water protons can sensitively exclude structural causes of parkinsonism, such as basal ganglia tumors, toxic necrosis such as aft er methcathinone (ephedrone) ingestion, small vessel ischaemic disease, and calcifi cation, and can detect cortical atrophy and hydrocephalus (1). Volumetric MRI has so far failed to demonstrate a r eduction in SNc volume in PD, prob- ably because of the diffi culty in defi ning the border s of this struc- ture owing to its high iron content. Diff usion tensor imaging (DTI) uses fi eld gradient sequences which allow MRI to detect the direc- tionality (anisotropy) and a mplitude of water movement along fi bre tracts. In a recent series, DTI was reported to det ect reduced anisot- ropy of SNc water diff usion in 100% of de novo PD cases, changes being greatest in the lateral nigra where pathology is known to be most severe (see Fig. 6.1) (2 ). Transcranial sonography Transcranial sonography (TCS) reveals structural midbrain and stria tal changes in parkinsonian disorders as hyperechogenic signals (Fig. 6.3). Over 90% of cas es with clinically established PD show increased midbrain echogenicity with TCS, but this c an also be seen in 10% of elderly normals and 15% of essential tremor cases, so the specifi city of this fi nding is suboptimal (7). Th e intensity of midbrain hyperechogenicity dete cted with TCS does not correlate with disability in PD and remains static over fi ve years despite clinical progression (8). It has been suggested that its presence is a marker of su sceptibility to PD rather than a state marker, and may be refl ecting the presence of midbr ain iron deposition rather than dopamine cell loss. In support of this, abnormal nigral hyp erechogenicity can be detected in subjects at risk for PD, such as carriers of alpha synucl ein, LRRK2 , parkin , and While the striatum is pathologically spared in PD, the putamen in patients with MSA shows r educed signal on T 2 -weighted MRI when cell loss and iron deposition are present (Fig. 6.2 a). Th is is oft en accompanied by a lateral rim of increased signal due to glio- sis. If d egeneration of the pons has occurred, the lateral as well as longitudinal pontine fi bres b ecome evident as high signal manifest- ing as the \200\230hot cross bun \200\231 sign (Fig . 6.2b) (3,4). In advanced MSA Oxford Textbook of Movement Disorders 44 (a) (b) 0.8 Control PD 0.6 y p o r t o s i n a l a n o i t c a r F 0.4 0.2 Fig. 6.1 Fractional anisotropy (FA) of the midbrain. Nigral FA is reduced in a rostral caud al gradient in PD. (Picture from Vaillancourt et al. 2009) 0.0 Rostral Middle Caudal (b) (a) Fig. 6.2 T 2 -weighted MRI showing (a) low lateral putamen signal at the same level as the pallidum in MSA and (b) the pontine \200\230hot cross bun sign \200\231 in MSA. DJ1 gene mutations (9) or subjects with late-onset hyposmia (10). Nigral hyperechogenicity is not seen in atypical parkinsonian dis- orders despite the presence of dopamine cell loss at post-mortem. Hyperechogenic lentiform signals can be detected in MSA cases which, when combined with absent midbrain hyperechogenicity, can help discriminate them from PD (11). the coding region of the gene on chromosome 9q34 which codes for torsin A, an ATP-binding p rotein of unknown function. A sec- ond generalized dystonia locus has been mapped to chromo some 8p ( DYT6 ); aff ected individuals tend to have adult-onset dystonia presenting with c raniocervical or focal symptoms. Conventional MRI fi ndings in idiopathic and genetic dystonias are normal, although acquire d dystonia cases may show structural lesions in the lentiform nucleus or posterior thalamus (12). Wilson disease patients characteristically show cystic lesions in their basal gangli a. However, diff usion tensor imaging has revealed abnormal water diff usivity in the basal ganglia of cervical dystonia patients (13). As DTI detects the directionality of water fl ow, it allows bun- dles of nerve fi bres to be delineated \200\224a process known as tracto g- raphy. In dystonia associated with DYT1 gene mutations, abnormal Structural imaging in hyperkinetic disorders Dystonia Th e most common familial form of gen eralized dystonia is an auto- somal dominant disorder associated with a DYT1 gene mutation which has around 40% penetrance and is generally early onset start- ing in a lower limb. Th e DYT1 mutation is a GAG deletion within CHAPTER 6 Movement Disorders: Structural and Functional Imaging 45 (a) (b) Fig. 6.3 Transcranial sonography showing hyperechogenicity from the lateral midbrain (subst antia nigra) in PD. (Picture from Berg et al. 2001) Parkinson \200\231s disease Th e presynaptic dopaminergic system Dopamine terminal function in PD can be examined in vivo in three main ways: structural connectivity between the cerebellar nuclei and the thala- mus and between fronta l cortex and striatum can be demonstrated with tractography, although conventional MRI appe ars normal (14). Th ese fi ndings all support idiopathic and genetic dystonias arising from an abnormal structural development of subcortical \200\223 cortical connections. terminal dopa decarboxylase activity can be measured with 18 F-dopa positron emission tomog raphy (PET); \227\206 Huntington \200\231s disease Huntington \200\231s disease (HD) is an autosomal dominantly t rans- mitted disorder associated with an excess of CAG triplet repeats (>38) in the hunting tin ( HTT ) gene on chromosome 4. The function of this gene is still uncertain, but the pat hology of HD targets medium spiny projection neurons in the striatum, causing intranuclear and cytoplasmic inclusions to form. While altered striatal T 2 -weighted MRI signal and cau date atrophy are only visually evident in cases of established HD (15), MR volumetry reveal s subclinical caudate and putamen atrophy in pre-manifest gene carriers close to predicted symptom onset (16). Striatal atrophy becomes more marked as they become symptomatic and dev elop motor signs. Aylward and colleagues (17) were able to predict time of conversion from preclinical to clinical HD by measuring caudate volumes. These workers sug- gested that cau date volume may be a useful outcome measure for assessing treatment effectiveness in both p re-manifest and symptomatic subjects. the availability of dopamine transporters (DATs) can be assessed with 11 C-methylphenidate (MP) PET or tropane-based PET and single photon emission computed tomography (SPECT) mark- ers such as 11 C-2- -carbomethoxy-3- -(4-fl uorophenyl)tropane ( 11 C-CFT), 18 F-FP-C IT, 123 I-altropane, 123 I- -CIT, and 123 I-FP- CIT; \227\206 vesicle monoamine transporter density (VMAT2) can be studied with 11 C- or 18 F-dihydrotetr abenazine (DTBZ) PET (Fig. 6.4) (18). \227\206 In PD patients with early stage 1 disease aff ecting only one side bilaterally reduced puta men tracer uptake can be seen, activity being most depressed in the putamen contralateral t o the clinic- ally aff ected limbs. Head-of-caudate dopamine terminal function remains rela tively preserved until later in the condition. Onset of symptoms has been estimated to occu r aft er a 30 \200\22350% loss of putamen dopamine terminal function (19). Unlike nigral hy per- echogenicity, reductions in putamen dopamine terminal func- tion correlate well with s everity of limb rigidity and bradykinesia although, interestingly, they correlate poorly wi th severity of tremor (20). Functional imaging Th e changes in regional cerebral function that characterize dif- ferent movement disorders can be examined in two main ways: fi rst, focal changes in resting leve ls of regional cerebral metabo- lism, blood fl ow, and neuroreceptor availability can be me as- ured. Secondly, abnormal patterns of regional brain activation, evidenced as changes in blood fl ow or levels of neurotransmit- ter release, can be detected when patients with mo vement disor- ders perform motor and cognitive tasks or are exposed to drug challenges. PET and SPECT can diff erentiate clinically probable PD from normal subjects or benign esse ntial and dystonic tremor patients with a sensitivity and specifi city of around 90% (21). An abnor- mal PET or SPECT scan provides support for a diagnosis of a dopamine-defi cient p arkinsonian syndrome and a rationale for treating with dopaminergic agents, while a normal scan eff ectively excludes this diagnosis. Several studies have examined the utility of using DAT imaging to determine whether \200 \230gray \200\231 parkinsonian cases are associated with Oxford Textbook of Movement Disorders 46 18F-DTBZ VMAT2 11C-DTBZ VMAT2 18F-dopa DDC 123I-altropane DAT 123I-io \202upane DAT Healthy PD Fig. 6.4 SPECT and PET images of dopamine terminal function in normal subjects and early PD patients. striatal dopamine defi ciency. In the Query PD study the standard of truth (SOT) was the cl inical impression of two movement disorder experts aft er 6 months of clinical follow-up (2 2). While referring cli- nicians showed 92% sensitivity for diagnosing dopamine-defi cient parkinsonism, their baseline clinical specifi city was poor (30%) compared with the SOT, wh ile baseline imaging specifi city with 123 I- -CIT SPECT was 100%. Th ese fi ndings sugg est that clinicians tend to overdiagnose PD when uncertain. Th e Clinically Uncertain Parki nsonian Syndromes (CUPS) trial was designed to establish whether knowledge of baseline stri atal DAT binding infl uenced the diagnosis and subsequent management of patients with uncer tain PD (23). When FP-CIT SPECT fi ndings were revealed to clini- cians, the diagnosis of d opamine-defi cient parkinsonian syndrome was revised in 52% of the 118 cases and the manage ment strategy changed in 72% of cases. A two-year follow-up found that 90% of subjects stil l retained the diagnosis assigned aft er baseline FP-CIT SPECT fi ndings were released (24) . Th e CUPS study supports the view that including a measure of striatal dopaminergic funct ion in the work-up of uncertain parkinsonian cases infl uences their sub- sequent managemen t. diagnostic doubts led to DAT imaging with FP-CIT SPECT. Th is was negative, and subsequent withdrawal of antiparkinsonian ther- apy was achieved without clinical deterioration, sugge sting that dopaminergic imaging can be valuable where inappropriate use of antiparkinsonian medication is suspected. Postsynaptic dopaminergic receptor binding Th e striatum contains primarily dopamine D1 and D2 receptor subtypes which both play a role in modulating locomotor func- tion. 123 I-iodo benzamine ( 123 I-IBZM) SPECT studies have reported normal levels of striatal D2 binding in untreated PD (Fig. 6.5) while 11 C-raclopride PET detects a 10 \200\22320% increase in put amen D2 availability (18). As 11 C-raclopride competes with endogenous dopamine for D2 bind ing, this raised receptor availability probably refl ects dopamine depletion rather than an adaptive rise in recep- tor numbers. In chronically levodopa-exposed PD cases levels of pu tamen D2 binding normalize as synaptic levels of dopamine are restored. Measuring striatal dopamine As 11 C-raclopride competes with synaptic dopamine to bind to D 2 receptors its uptake is sensitive to changes in synaptic levels of striatal dopamine. PET can be used to detect changes in dopamine induced by drugs or behavior. Microdialysis stud ies in animals suggest that a 10% reduction in striatal 11 C-raclopride binding refl ects a fi vefold increase in synaptic dopamine levels (28). When Th ere was no non-imaged control group as a comparator in the CUPS study, so the prevalence of change in management plan with- out SPECT was not determined. Th e PDT409 study, which had a similar design but included a control arm, has recently reported (25). Th ere were ar ound 130 possible PD cases in each arm, and patients were assessed at baseline and assigned a diagnosis and management plan. Twelve weeks aft er FP-CIT SPECT or no imag- ing they wer e re-assessed and their diagnosis and management reviewed. Forty-four per cent who had SPEC T versus 12% who were not imaged had a change in their diagnosis aft er 12 weeks of follow- up, while 49% in the imaging arm versus 31% in the non-imaged arm had a change of managemen t plan.