81. K llensperger M, Krismer F, Pallua A, Stefanova N, Poewe W, Wenning GK. Erythropoiet in is neuroprotective in a transgenic mouse model of multiple system atrophy. Mov Disord 20 11; 26 : 507 \200\2231 5 . 492 \200\2234 . 63. Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler C, et al. Consensus statemen t on the diagnosis of multiple system atrophy. American Autonomic Society and American Acad emy of Neurology. Clin Auton Res 1998; 8 : 359 \200\2236 2 . 82. Fowler CJ, O \200\231Malley KJ. Investigation and management of neurogenic bladder dysf unction. J Neurol Neurosurg Psychiatry 2003; 74 (Suppl 4): iv 27 \200\2233 1 . 64. Holmberg B, Johansson JO, Poewe W, et al. Safety and tolerability of growth hormone the rapy in multiple system atrophy: a double-blin d, placebo-controlle d study. Mov Disord 200 7; 22 : 1138 \200\2234 4 . 83. Halaska M, Ralph G, Wiedemann A, et al. Controlled, double-blin d, multicentre clinical trial to investigate long-ter m tolerability and effi cacy of trospium chloride in patient s with detrusor instability. World J Urol 2003 May; 20 : 392 \200\2239 . 65. Stefanova N, Reindl M, Neumann M, Kahle PJ, Poewe W, Wenning GK. Microglial activation mediates neurodegeneration related to oligoden- droglial alpha-synucleinopath y: implicatio ns for multiple system atro- phy. Mov Disord 2007; 22 : 2196 \200\22320 3 . 84. Sakakibara R, Hattori T, Uchiyama T, et al. Are alpha-blocker s involved in lower urina ry tract dysfunction in multiple system atrophy? A com- parison of prazosin and moxisylyte. J Auton Nerv Syst 2000; 79 : 191 \200\2235 . 85. Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ. Treatment of erectile dysfunction with sildenafi l citrate (Viagra) in parki nsonism due to Parkinson \200\231s disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001; 71 : 371 \200\2234 . 86. Papa tsoris AG, Papapetropoulos S, Singer C, Deliveliotis C. Urinary and erectile dysfunction in multiple system atrophy (MSA). Neurourol Urodyn 2008; 27 : 22 \200\2237 . 66. Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cyto- chrome c release an d delays progression of amyotrophic lateral sclerosis in mice. Nature 2002; 417 : 74 \200 \2238 . 67. Casarejos MJ, Menendez J, Solano RM, Rodriguez-Navarro JA, Garcia de Yebenes J, Mena MA . Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced b y minocycline. J Neurochem 2006; 97 : 934 \200\2234 6 . 68. Dodel R, Spottke A, Gerhard A, et al. Minocycline 1-yea r therapy in multiple-system-at roph y: eff ect on clinical symptoms and [ 11 C] (R)-PK11195 PET (MEMSA-tria l). Mov Disord 2010; 25 : 97 \200\22310 7 . 69. Lee PH, Kim JW, Bang OY, Ahn YH, Joo IS, Huh K. Autologou s mesen- chymal stem cell therapy delays the progression of neurological defi cits in patie nts with multiple system atrophy. Clin Pharmacol Th er 2008; 83 : 723 \200\2233 0 . 87. O \200\231Sullivan JD. Apomorphine as an alternative to sildenafi l in Parkinson \200 \231s disease. J Neurol Neurosurg Psychiatry 2002; 72 : 681 . 88. Colosimo C, Pezzella FR. Th e symptomatic treatment of multiple system atrophy. Eur J Neurol 2002; 9 : 195 \200\2239 . 89. Sakakibara R, Yamaguchi T, Uchiyama T, et al. Calcium polycarbophil improves constipati on in primary autonomic failure and multiple system atrophy subjects. Mov Disord 2007; 22 : 1672 \200\2233 . 70. Park HJ, Bang G, Lee BR, Kim HO, Lee PH. Neuroprotective eff ect of human mesenchymal s tem cells in an animal model of double toxin-induce d multiple system atrophy-parkinsonis m . Cell Transplant 2011; 20 : 827 \200\22335 . 90. Eichhorn TE, Oertel WH. Macrogol 3350/electrolyte improves consti- pation in Parkinson \200\231s disease and multiple system atrophy. Mov Disord 2001; 16 : 1176 \200\2237 . 71. Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypoten- sion: a double- blin d, placebo-controlle d study with midodrine. Am J Med 1993; 95 : 38 \200\2234 8 . 91. Iranzo A, Santamaria J, Tolosa E, et al. Long-ter m eff ect of CPAP in the treatment of nocturnal stridor in multiple system atrophy. Neurology 2004; 63 : 930 \200\2232 . 72. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Effi cacy of midodrine vs placeb o in neurogenic orthostatic hypotension: a rand- omized, double-blin d multicenter study. M idodrine Study Group. JAMA 1997; 277 : 1046 \200\2235 1 . 92. Geser F, Wenning GK, Seppi K, et al. Progression of multiple system atrophy (MSA): a pr ospective natural history study by the European MSA Study Group (EMSA SG). Mov Disord 2006; 21 : 179 \200\2238 6 . 93. Lees AJ, Banister R. Th e use of lisuride in the treatment of multiple system atrophy w ith autonomic failure (Shy \200\223Drage r syndrome). J Neurol Neurosurg Psychiatry 1981; 4 4 : 347 \200\2235 1 . 73. Singer W, Sandroni P, Opfer-Gehrking TL, et al. Pyridostigmine treat- ment trial in neu rogenic orthostatic hypotension. Arch Neurol 2006; 63 : 513 \200\22318 . 94. Klos KJ, Bower JH, Josephs KA, Matsumoto JY, Ahlskog JE. Pathological hypersexuality pr edominantly linked to adjuvant dopamine agonist therapy in Parkinson \200\231s disease and multiple system atrophy. Parkinsonism Relat Disord 2005; 11 : 381 \200\2236 . 74. Kaufmann H. l -dihydroxyphenylserin e (droxidopa): a new therapy for neurogenic orthost atic hypotension: the US experience. Clin Auton Res 2008; 18 (Suppl 1): 19 \200\2232 4 . 75. Mathias CJ. l -dihydroxyphenylserin e (droxidopa) in the treatment of orthostatic hypot ension: the European experience. Clin Auton Res 2008; 18 (Suppl 1): 25 \200\2239 . 95. Colosimo C, Merello M, Pontieri FE. Amantadine in parkinsonian patients unresponsive to levodopa: a pilot study. J Neurol 1996; 243 : 422 \200\2235 . CHAPTER 13 Multiple System Atrophy (MSA) 137 102. Brooks DJ, Seppi K. Proposed neuroimaging criteria for the diagnosis of 96. Wenning GK. Placebo-controlle d trial of amantadine in multiple-syste m multiple system atrophy. Mov Disord 2009; 24 : 949 \200\2236 4 . atrophy. Clin Neuropharmacol 2005; 28 (5): 225 \200\2237 . 103. Stefanova N, Reindl M, Neumann M, et al. Oxidative stress in trans- genic mice with ol igodendroglial alpha-synuclei n overexpression repli- cates the characteristic neuropatholo gy of multiple system atrophy. Am J Pathol 2005; 166 : 869 \200\2237 6 . 97. Friess E, Kuempfel T, Modell S, et al. Paroxetine treatment improves motor symptoms in patients with multiple system atrophy. Parkinsonism Relat Disord 2006; 12 : 432 \200\2237 . 98. Muller J, Wenning GK, Wissel J, Seppi K, Poewe W. Botulinum toxin treatment in atypical parkinsonian disorders associated with disabling focal dystonia. J Neurol 2002; 249 : 300 \200\2234 . 104. Shults CW, Rockenstein E, Crews L, et al. Neurological and neuro- degenerative alterat ions in a transgenic mouse model expressing human alpha-synuclei n under oligodendrocyte pr omoter: implications for multiple system atrophy. J Neurosci 2005; 25 : 10 689 \200\2239 9 . 99. Th obois S, Broussolle E, Toureille L, Vial C. Severe dysphagia aft er botu- linum toxi n injection for cervical dystonia in multiple system atrophy. Mov Disord 2001; 16 : 764 \200\2235 . 105. Wenning GK, Krismer F, Poewe W. New insights into atypical parkin- sonism. Curr Opin Neurol 2011; 24 : 331 \200\2238 . 100. Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unifi ed Multip le System Atrophy Rating Scale (UMSARS). Mov Disord 2004; 19 : 1391 \200\22340 2 . 106. Wenning GK, Stefanova N. Recent developments in multiple system atrophy. J Neurol 2009; 256 : 1791 \200\22380 8 . 101. Schrag A, Selai C, Mathias C, et al. Measuring health-relate d quality of life in MSA: the MSA-Qo L. Mov Disord 2007; 22 : 2332 \200\2238 . This page intentionally left blank CHAPTER 14 Progressive Supranuclear Palsy and Corticobasal Degeneration David R. Williams Summary Progressive supranuclear palsy (PSP) is the second most com- mon form of neurodegen erative parkinsonism aft er idiopathic Parkinson \200\231s disease. Patients most oft en pr esent with an insidious change in balance, personality, or cognitive function which charac- teristically leads to severe postural instability, vertical supranuclear gaze palsy, and d eath within 7 \200\2238 years; this classic clinical presenta- tion is now know as Richards on syndrome (also Steele \200\223Richardson \200\223 Olszewski syndrome). Less commonly, pa tients present with bradykinesia and rigidity (PSP \200\223parkinsonism) which is only late r followed by the emergence of falls, eye movement abnormalities, and cognitive impairment; others may present with pure akinesia and gait freezing (PSP \200\223PAGF), corticobasal s yndrome (PSP \200\223CBS), or progressive non-fl uent aphasia (PSP \200\223PNFA). Th e char acteristic neuropathological fi ndings of abnormal accumulations of neurofi - brillary tau protein in the subthalamic nucleus and other brainstem regions defi ne the disease, and bec ause of these fi ndings PSP is included amongst the primary \200\230tauopathies \200\231 ( 1). Essential background Epidemiology Community-based prevalence studies using operational diag nos- tic criteria suggest crude prevalence rates of between 3.2 and 6.5 per 100 000 and an age-adjusted prevalence of between 4.6 and 5.0 per 100 000 (2 \200\2234) which is about a f actor of 25 less than the rates in PD (5). Estimating the true prevalence of PSP is problem atic because of the diffi culty in accurately diagnosing PSP and its diff erent clinical ph eno- types. Th e median age of onset for PSP is 65, and the median disease duration from di sease onset to death ranges between 5 and 8 years (1). Patients who have PSP \200\223parkin sonism (PSP \200\223P) and PSP \200\223PAGF appear to have a better prognosis, with median disease durations of between 8 and 11 years. Th e most common modes of death are aspiration pneu- monia, primary neurogenic respiratory failure, and pulmonary emboli, regardless of c linical subtype (6). Th ere are no reported gender diff er- ences. Th e epidemiology of CBD is more diffi cult to establish because of its rarity and diffi culties in confi rming the clinical diagnosis. It is probably about 10 times as rare as PSP, and appears to aff ect p eople at around the same age as PSP (7). Corticobasal degeneration (CBD) is another, rarer tauopathy characterized by the accumulati on of neurofi brillary and oligoden- droglial tau in the cortex and basal ganglia. Th e cla ssic \200\230motor \200\231 presentation of CBD is known as \200\230corticobasal syndrome \200\231: a com- bination of limb apraxia, cortical sensory loss, alien limb, focal myoclo nus, limb dystonia, as well as rigidity and bradykinesia that do not respond to dopaminergi c medications. Corticobasal syn- drome is not specifi c to CBD and is also known to occur i n other diseases such as PSP, Alzheimer \200\231s disease, and the frontotemporal dementias . Th e \200\230cognitive \200\231 presentation of CBD typically includes behavioral distur bance, including personality change and execu- tive dysfunction, and progressive non-fl uen t aphasia. Etiology and genetics PSP and CBD are considered amongst the many diff erent neuro- degener ative diseases that are characterized and classifi ed by depo- sition of insoluble proteins in the central nervous system (8). Th us both these diseases are defi ned by the character istic post-mortem fi ndings of accumulations of insoluble microtubule associated pro- tein tau (MAPT, tau protein), hence their designation as \200\230tauopa- thies \200\231. Tau pr otein is ubiquitous in the adult brain and its normal function is to assemble and stabilize microtubules, which are important structural elements in neuronal cells. Normal tau pro- t ein binds to microtubules in axons, but in PSP and CBD it is redis- tributed to the cell bo dy where it accumulates to form insoluble fi brillary deposits (9). Th ere is some clinical and pathological overlap between these two conditions, and in both progressive decline over 6 \200\22312 years is usual. Th ere are no disease-modifying thera pies for PSP or CBD, and treatment is focused on optimizing independence, minimizing the co mplications of the advancing parkinsonism and supporting caregivers. Tau protein is the most abundant microtubule-associated pro- tein in the brain. It was desi gnated by the Greek letter T ( \204 , tau) Oxford Textbook of Movement Disorders 140 because of its ability to induce tubule formation through assembly of tubulin (8). It exist s in six isoforms, diff ering by the presence or absence of 29- or 59-amino-acid inserts lo cated in the amino ter- minal end and a 31-amino-acid repeat in the microtubule-binding dom ain (Fig. 14.1). Depending on the presence or absence of the latter, the domain harbors eit her 3-repeat or 4-repeat sequences that are essential for microtubule binding. In normal ad ult brain there are similar levels of 3-repeat tau (3R) and 4-repeat tau (4R), but in neuro degeneration this ratio is oft en altered. patients with PSP and CBD develop. To some extent this is inde- pendent of the nature of th e tauopathy, and so there is variability and substantial overlap between the clinical \200 \230expression \200\231 of PSP and CBD pathologies (1, 16, 17). Th e substantia nigra pars compacta and ventrotegmental areas are aff ected more severely i n Richardson \200\231s disease than in Parkinson \200\231s disease. Th ese dopamine cell gr oups innervate motor and limbic cortical and thalamic regions, infl uencing motor, executiv e, and other cognitive and behavioral features, and their destruction is likely to contribu te to the relative lack of levodopa responsiveness and frontostriatal cognitive dysfunction in PSP (18, 19). Th e gene encoding tau is on chromosome 17, and comprises 13 exons (Fig. 14.1). Exon 10 cod es for the alternatively spliced amino acid repeat sequence in the binding domain, and muta tions here cause disease by altering the ratio of 3R and 4R tau (10). Diff erent mutations reduce the ability of tau to interact with microtubules (11), and others promote the assemb ly of tau into fi laments associ- ated with disease (Fig. 14.1) (10). A number of commonly occurring haplotypes of the MAPT gene are associated with the development of PSP and CBD, a nd although the precise mechanisms are yet to be determined the central importance of tau f or these diseases is beyond doubt (12). Patients with PSP \200\223P have less severe tau pathology than patients with Richardson \200\231s syndrome, although the pattern of distribution appears to be constant between the two, with the subthalamic nucleus and substantia nigra always the most severely aff ected regions (Fig. 14.3) (20, 21). Th e regions where the diff erences in pathological tau are g reatest between Richardson \200\231s syndrome and PSP \200\223P are the cerebral cortex, po ns, caudate, cerebellar dentate nucleus, and cerebellar white matter (Fig. 14.3) (20 \200 \22323). Atrophy of the pallidum, amygdala, thalamus, and frontal lobe (frontal pole, infer ior gyrus) is also more severe in Richardson \200\231s syndrome than in PSP \200\223P (23, 24). Th e tremor and moderate levodopa responsiveness that characterize PSP \200\223P may b e due to this less severe extra-nigral midbrain dopamine depletion (20, 21, 25). Pathophysiology Th e neuronal degeneration and gliosis that occurs in these diseases is alm ost always most severe in regions of the basal ganglia, includ- ing the subthalamic nucleus and nigra (for PSP and CBD) and the striatum (for PSP), and, for patients with CBD, cortic al atrophy centered on the peri-Rolandic posterior frontal and parietal cortex is conspicuo us (13). Patients who present with PSP \200\223PAGF have severe atrophy, neu- ronal loss, and gliosi s in the globus pallidus, substantia nigra, and subthalamic nucleus, with less severe tau p athology in the motor cortex, striatum, pontine nuclei, and cerebellum (26, 27). Functional imaging studies refl ect these pathological observa- tions, with decreased glucose metabol ism restricted to the mid- brain in patients with PAGF and relative preservation of frontal metabolism (28). Th e pathological diagnosis of PSP relies on the identifi cation of tau-positive neurofi br illary tangles and neuropil threads at high density in the pallidum, subthalamic nucleus, s ubstantia nigra, or pons, and at a lower density in other subcortical structures (13). Th e pathological signature of PSP is the tuft ed astrocyte, which is rare in other tauopathies (Fig. 14.2) (14). CBD is defi ned pathologi- cally by the presence of achromatic balloon-s haped neurons and prominent diff use cortical glial tau pathology, including neuropil threa ds, coiled bodies, and astrocytic plaques (Fig. 14.2) (15). Patients with PSP-tau pathology who present with progressive non-fl uent aphasia have more severe pathology in the temporal cortex and superior frontal gyrus than patients with other subtypes of PSP, but less severe pathology in the brainstem and subcortical gray regions ( 29). Patients with PSP-tau pathology who present with corticobasal syndrome have a greater severity of tau pathol- ogy in the mid-frontal and inferior parietal cortices, but not the motor cortex, than patients with Richardson \200\231s syndrome (16). Th e Th e anatomical distribution of pathological changes, which include tau accumulation, neuro nal loss, gliosis, and atrophy, is the most important factor that determines the clinical f eatures that MAPT genomic structure KNOWN MUTATIONS \200\2231 1 2 3 4 4A 5 6 7 8 9 10 11 12 13/14 alternatively spliced alternatively spliced Tau isoforms Recombinant Tau PSP N1 N2 R1 2N, 4R R4 R2 R3 R4 2N, 3R R3 R1 N1 N2 R4 1N, 4R R3 R1 R2 N2 Fig. 14.1 MAPT genomic structure. (Reprinted with permission from Williams DR. Tauopathies: classi \201 cation and clinical update on neurodegenerative diseases associated with micr otubule-associated protein tau. Intern Med J 2006; 36: 652 \200\22360. John Wiley & Sons Inc., 2006) N2 R4 1N, 3R R3 R1 R4 0N, 4R R3 R1 R2 R4 0N, 3R R3 R1 CHAPTER 14 Progressive Supranuclear Palsy and Corticobasal Degeneration 141 (a) (b) (c) (d) Fig. 14.2 Pathological characteristics of PSP-tau and CBD-tau pathology (AT8 anti-tau antib ody): (a) tufted astrocyte (arrow head); (b) neuro \201 brillary tangle (arrow head); (c) glial pathology, coiled body (arrow head); (d) astrocytic plaque. (a) (b) Frontal lobe Parietal lobe Caudate GPe GPi STN Putamen Substantia nigra Griseum pontis Dentate nucleus Cerebellar white matter (c) (d) (e) (f) Fig. 14.3 Th e severity of PSP glial tau pathology varies according to distribution: gray, mild severity; light green, moderate severity; medium green, severe; dark green, very sever e. PSP, progressive supranuclear palsy; PSP \200\223P, PSP \200\223parkinsonism; PAGF, pure akinesia with gait freezing; STN, subthalamic nucleus; GPi, globus pallidus internus; GPe, globus pallidus externus. (Reprinted from Williams DR, Holton J, Strand C, et al. Patholog ical tau burden and distribution distinguishes progressive supranuclear palsy \200\223parki nsonism from Richardson \200\231s syndrome. Brain 2007; 130: 1566 \200\22376. Oxford Uni versity Press, 2007) Oxford Textbook of Movement Disorders 142 distribution of the tau pathology in those patients is similar to that seen in CBD patients with corticobasal syndrome, suggesting that the topography and not the type of tau patholo gy infl uences the clinical picture (16). Patients oft en report insomnia and frequent nocturnal awakening, but REM behavior disorder in not common. In distinction to PD, dementia with Lewy bodies, and multiple system atroph y, patients with Richardson \200\231s syndrome only rarely develop severe autonomic dysfunc tion (31). Cerebellar ataxia, as distinct from gait unsteadi- ness, is also unusual and is more common in MSA (31, 42, 43). Patients with PD are more likely to have severe hyposmia a nd visual hallucinations (44, 45). Rarely, patients with CBD-tau pathology present with Ric hardson \200\231s syndrome (CBD \200\223RS), with early falls and vertical supranuclear gaz e abnormalities (46). Patients with CBD \200\223RS appear to have more frontal-type behavio ral changes than patients with PSP \200\223RS. Clinical features Th e clinical manifestations of PSP-tau and CBD-tau pathology can be cons idered according to their syndromal associations. In this context the classic form of PSP i s referred to as Richardson \200\231s syn- drome (also known as Steele \200\223Richardson \200\223Olszewski syndrome) to diff erentiate it from the other clinical variants of PSP. T h ey all share some clinical features and are linked by similar natural histo- ries that le ad to death usually within 6 \200\22312 years of diagnosis. Th e other variants include PSP \200\223P (25), PSP \200\223PAGF (27), PSP \200\223CBS, and PSP \200\223PNFA (16, 29). Patients usually become dependent on others for care 3 \200\2234 years aft er disease onset because of increasing motor and cognitive slow- ing (34, 47). Speech oft en becomes uninte lligible and recurrent choking can lead to frequent episodes of aspiration pneumonia (34, 4 8). Th e early features of all these clinical syndromes can be non-specifi c, and many PSP pati ents remain undiagnosed for up to 3 years (30). Nevertheless, symptom progression within th ese fi rst few years of disease is most informative when it comes to prognosis and clinical characterization. Clinical diagnostic criteria Th e National Institute of Neurological Disorders and Stroke a nd Society for Progressive Supranuclear Palsy (NINDS \200\223SPSP) clinical diagnostic crit eria (see Box 14.1) were developed to optimize diag- nostic specifi city and were developed aft er reviewing previously proposed criteria (49 \200\22352). Th ese criteria allow a dia gnosis of prob- able PSP in patients (1) older than 40 years of age, (2) with severe postur al instability and falls within the fi rst 12 months of disease, and (3) with vertical supr anuclear gaze palsy or slowed vertical sac- cades. Th ey were developed with research goals in mind, and may not be sensitive enough to defi ne patients in routine clinical prac- tic e (32, 49, 50). Clinical diagnosis of Richardson \200\231s syndrome Th e earliest clinical features of Rich ardson \200\231s syndrome are oft en subtle, may be diffi cult to discern from other physic al or psycho- logical complaints, and oft en do not satisfy the operational clinical diagno stic criteria (see below) (31, 32). However, in most cases as the disease progresses the cl inical diagnosis of Richardson \200\231s syn- drome is evident within the fi rst 2 years (2 5, 32, 33). An unsteady gait and sudden unexplained falls is the most com- mon presentation of PSP. Cog nitive slowing occurs in the majority of patients within the fi rst 2 years and may precede gait disturbance by many months (25, 34 \200\22336). PSP is the prototypic form of \200 \230subcortical dementia \200\231, with reduced processing speed that can be demonstrated e arly at the bedside by testing verbal fl uency, digit span, and alternating hand sequences, as well as demonstrating the applause sign. Subsequent amendments propose a 2-year window for the emer- gence of postural instability a nd the recognition of subcortical cognitive decline common in Richardson \200\231s syndrome . Th e NINDS \200\223 SPSP diagnostic criteria exclude patients with clinical signs sug- ge stive of Alzheimer \200\231s disease, frontotemporal dementia, vascular parkinsonism, prion disease, Niemann \200\223Pick type C, dementia with Lewy bodies, Parkinson \200\231s disea se, and multiple system atrophy. Aft er exclusion of these conditions, the diagnosis of Ric hardson \200\231s syndrome should be considered in all patients presenting with spontaneous falls, subcortical cognitive dysfunction, personality change, or vertical supranuclear oph thalmoplegia. Th e characteristic eye movement abnormality seen in patients with Richardson \200\231s syn drome develops over some time, oft en pre- senting initially as subtle diplopia. Th e fi rs t signs that emerge are failure of convergence and a slowing of vertical saccadic eye move- ments with hypometria (25, 35, 37 \200\22339). Increased frequency of macro-square wave je rks in the primary position of gaze is typical (40). Patients oft en report irritated redde ned dry eyes with excessive tearing due to the reduced spontaneous blink rate. Eyelid abnor - malities are common, and include spontaneous involuntary eyelid closure or apraxia of eye lid opening. Over time the range of spon- taneous and target-directed eye movements becomes restricted, fi rst in the vertical plane, and eventually the eyes become fi xed. Character istically, activation of the vestibulo-ocular refl ex over- comes these limitations, indica ting the \200\230supranuclear \200\231 lesion in PSP (38). However, in advanced disease th is vestibulo-ocular refl ex is diminished (39). Hypophonia may occasionally be prominent ea rly but, typically, slow slurred growling speech and swallowing diffi cul- ties are common (25, 34, 35). Overactivity of the frontalis muscles with eyelid retraction and a staring ga ze contribute to the charac- teristic surprised worried facial appearance (41). Clinical diagnosis of PSP \200\223parkinsonism Up to a third of patients with PSP-tau patho logy do not develop the postural instability, gaze palsy, and cognitive changes of Richards on \200\231s syndrome within the fi rst 2 years of disease. Th ese patients may have bradyk inesia and limb rigidity at disease onset, which can be asymmetric and in some cases associ ated with a jerky action or rest tremor. Th is is referred to as PSP \200\223parkinsonism ( PSP \200\223P) (25, 35, 53). Axial rigidity is oft en a striking early feature, and limb ri gid- ity is more common and severe than in Richardson \200\231s syndrome. Parkinsonism in t his setting will oft en show a modest improvement with dopaminergic therapies, although the response is rarely \200\230excel- lent \200\231 and secondary unresponsiveness occurring over a few years is usual (25, 53 \200\22356). PSP \200\223P is separated from Richardson \200\231s syndrome on the basis of the clinical picture over the fi rst 2 years of disease, but clinical overlap occurs and over 6 years of disease progression the clin- ical phenomenology may become similar (25, 53). Falls and co g- nitive dysfunction do eventually occur, but later in PSP \200\223P than Bradykinesia and extrapyramidal limb rigidity are oft en absent early, but may emerge as th e disease advances (38). Axial (neck) rigidity is oft en most prominent. Ideomotor apraxia and limb dys- tonia contribute to impaired limb function in advanced disease. CHAPTER 14 Progressive Supranuclear Palsy and Corticobasal Degeneration 143 Box 14.1 Diagnosing Richardson \200\231s syndrome Box 14.2 Diagnosing PSP \200\223parkinsonism Within 2 years of presentation, patients over 40 develop two of: Within two years of presentation, patients over 40 develop: (1) Progressive gait disturbance and spontaneous falls (1) Progressive parkinsonism, extrapyramidal rigidity: including bradykinesia and (2) Loss of ocular vergence and hypometric vertical saccades (eventually leading to progres sive vertical supranuclear ophthalmoplegia) (a) Parkinsonism will oft en have an axial predominance (b) Tremor is not an essential component, but may be present (3) Subcortical cognitive decline, including reduced verbal fl uency (c) Signs may initially be bilateral or unilateral (2) At best a modest or good response to levodopa, with dimin- AND do not develop: ishing eff ect over time (4) Levodopa-responsive parkinsonism or rest tremor AND do not have: (5) Cerebellar dysfunction (3) Richardson \200\231s syndrome (by defi nition within the fi rst 2 years (6) More than one of: of disease) (a) REM behavior disorder (4) An excellent sustained response to levodopa (b) Severe hyposmia (5) Evolving drug-induced dyskinesias (c) Visual hallucinations (6) Pyramidal signs (d) Symptoms of generalized autonomic dysfunction (two of): (7) Cerebellar signs (i) (ii) Urinary urgency (iii) Postural hypotension Chronic constipation (8) More than one of: (a) REM behavior disorder (7) Clinical features suggestive of: (b) Severe hyposmia (a) Niemann \200\223Pick type C (c) Visual hallucinations (b) Prion disease (d) Symptoms of generalized autonomic dysfunction: (c) Alzheimer \200\231s disease (i) (ii) Urinary urgency (iii) Postural hypotension Chronic constipation (8) MRI changes suggestive of: (a) Vascular parkinsonism (9) Radiological evidence of vascular disease aff ecting the basal (b) Frontotemporal lobar dementia ganglia Richardson \200\231s syndrome and, perhaps as a consequence, disease duration to death is a bout 3 years longer in PSP \200\223P (35, 53, 57). PSP \200\223P is diffi cult to diff eren tiate from PD in the earliest stages, but helpful pointers for PSP \200\223P may include ra pid progression, prominent axial symptomatology, and relatively poor response to levodopa d espite typical clinical features of PD (25, 54, 56). Unlike in PD and multiple system atrop hy, drug-induced dyskinesias are extremely unusual in PSP \200\223P and autonomic dysfuncti on is not severe or widespread (54). Th e diagnosis of PSP \200\223P is supported by development of the fol- lowing, aft er two years of disease: (1) Severe postural instability and falls (2) Loss of ocular vergence and hypometric vertical saccades (eventually leading to progres sive vertical supranuclear ophthalmoplegia) months before they seek medical attention. Th is experience of unsteadiness may develop for up to 2 years before the emergence of freezing of gait and gait initiation failure (27). P honation diffi - culties with hypophonia and slurred speech, facial immobility, and microgr aphia are additional early signs. Axial rigidity with marked neck stiff ness in the absence of limb rigidity is a distinctive feature (27, 59). Th is clinical syndrome is highly sugg estive of PSP-tau pathology (27, 60). PSP \200\223P should be considered in any patient over the age of 40 pre- senting with prog ressive parkinsonism, including those with rest tremor, bradykinesia, and extrapyramidal ri gidity (see Box 14.2). Establishing the degree of response to dopaminergic medications and progression of disease over time are important elements in clar- ifying the diagnosis of PS P \200\223P. Th e predominant diff erential diagno- sis in this scenario will be PD, and it is likely that the fi nal clinical designation can only be reached aft er a period of obse rvation. A supranuclear vertical gaze paresis and blepharospasm develop late in the majority, althou gh careful evaluation of eye movements may reveal slow hypometric saccadic eye movements ea rlier in the disease (27, 39, 60). In contrast with Richardson \200\231s syndrome, cog- nit ive defi cits and bradyphrenia are not prominent, although they may occur late in the disea se which has a median duration of more than 10 years (26, 27). Clinical diagnosis of PSP \200\223pure akinesia with gait freezing In some patients with PS P-tau pathology the clinical presentation is almost entirely limited to bradykinesia predom inantly aff ect- ing gait, and is referred to as PSP \200\223pure akinesia with gait freez- ing (PSP \200\223PAGF) (58). Patients report insidious gait diffi culties and mild postura l instability that may have been developing for Oxford Textbook of Movement Disorders 144 is the most likely underlying pathology (PSP \200\223PNFA), although CBD-tau pathology or P ick disease may also present in the same way (66). Patients who present in this way have a similar age of onset and disease duration as patients with Richardson syndrome (29, 66). Box 14.3 Diagnosing PSP \200\223PAGF Patients over 40 develop: (1) Progressive onset of gait disturbance, with start hesitation and subsequent freezing of gait PSP-tau and CBD-tau pathology should be considered along with other primary tauopathies as a cause of isolated disturbances of language or bvFTD with associated motor disturbances. T h e clin- ical diagnosis of CBD-tau pathology in this setting is diffi cult and diagnostic accuracy is notoriously diffi cult, although radiological markers may be helpful (62, 67). In contrast, the rare presentation of patients with apraxia of speech appears to be highly suggestive of underlying PSP-tau pathology (66). A designation of PSP \200\223PNFA should b e reserved for patients who present with prominent (iso- lated) apraxia of speech that prog resses slowly (see Box 14.4). (2) Rapid micrographia or rapid hypophonia AND do not have: (3) Any measurable improvement following treatment with levodopa (4) Limb rigidity (5) Rest tremor (6) Within the fi rst fi ve years of disease: Clinical diagnosis of corticobasal syndrome Corticobasal syndrome (CBS) is characterized by progressive asymmetric dyspraxia, cortical sensory loss including alien limb and jerky dys tonia of the limb, and rigidity and bradykinesia that is unresponsive to levodopa (68). It was fi rst described in patients with corticobasal degeneration (CBD); however, pathologica l series have indicated that only 50% of cases with CBS have CBD pathol- ogy (69). PSP, cer ebrovascular disease, and Alzheimer \200\231s disease account for the majority of other cas es (16, 70 \200\22373). (a) Cognitive dysfunction (b) Supranuclear gaze palsy (7) Clinical or radiological evidence of lacunar infarcts and dif- fuse deep white matter ischaemia Th e syndrome of PAGF should not be confused with isolated gait freezing where the associat ed neurological signs are not seen (27). Isolated gait freezing can be caused by a number o f diseases, includ- ing subcortical white matter ischaemia (Binswanger leukoaraiosis). PD a nd dementia with Lewy bodies can also present in this way (61). Th e clinical syndrome of P AGF should be considered in any patient who presents with progressive gait disturbance, par ticularly if other signs of bradykinesia are present without limb rigidity (see Box 14.3). Establishing the degree of response to dopaminergic medications and progression of disease over time are important elements in clarifying the diagnosis of PAGF. Approximately 25 \200\22350% of patients with post-mortem confi rmed CBD-tau pathology deve lop CBS during life, and it appears to be an uncommon presentation of PSP-tau pathology, ac counting for less than 5% of all pathologically diagnosed cases of PSP (67). PSP \200\223CB S appears to run a less aggressive disease course, with a mean dis- ease duration of 11 yea rs compared with 6.9 years in PSP \200\223RS (16). Patients with PSP \200\223CBS develop po stural instability or falls within the fi rst year of disease; most eventually develop thes e features at a later stage (16, 71). Dysarthria, dysphagia, and axial rigidity are also ab sent in the early stages of PSP \200\223CBS (16, 67, 71). Th e most common eye movement abn ormality in PSP \200\223CBS is an increase in latency to initiate saccadic eye movements, e ventually with com- pensatory head tilts, and typically it is more marked on the side where apraxia predominates (67, 74). Clinical diagnosis of PSP and CBD with features of frontotemporal dementia Th e behavioral variant of frontotemporal dementia (bvFTD) encompasses the clinical problem of progressive personality change including disinhibition, loss of empathy, change in eating patterns, rit ualized or stereotypical behavior, and apathy. Th ese features may be the earliest signs of frontotemporal lobar degeneration due to CBD-tau or, more rarely, PSP-tau pathology (62, 6 3). In these cases clinical progression usually includes the emergence of motor symp- toms of apraxia, dystonia, and parkinsonism (63). Pick disease and TDP-43 pathology are the most common causes of isolated bvFTD without parkinsonism or motor disturbances (62, 63). Box 14.4 Diagnosing PSP \200\223PNFA Patients over 40 develop: (1) A progressive language disorder characterized by early iso- lated apraxia of speech Progressive non-fl uent aphasia (PNFA) is a disorder of language characterized by non-fl ue nt spontaneous speech, with hesitancy, agrammatism, and phonemic errors. Patients oft en re quire signifi - cant eff ort in speech production (64). It fi ts within the spectrum of a f rontotemporal dementia syndrome and is most likely due to underlying Pick disease or CBD-ta u neurodegeneration aff ecting the frontal lobes. It may be seen in association with CBS (6 3). AND do not have: (2) Richardson \200\231s syndrome (3) Corticobasal syndrome Th e diagnosis of PSP \200\223PNFA is supported by: (1) Ideomotor limb apraxia (2) Aft er 2 years, the development of \200\230Apraxia of speech \200\231 is one of several components of speech and language dis turbance that make up PNFA, and it describes errors in timing, coordination, and initiation of speech secondary to disor- ders of motor command (65). Clinically this is evident when patients perform serial repetition and it usually accompanies agrammatism (29). When seen a s an early and isolated feature, PSP-tau pathology (a) Loss of ocular vergence and hypometric vertical saccades (eventually leading to progres sive vertical supranuclear ophthalmoplegia) (b) Postural instability and falls CHAPTER 14 Progressive Supranuclear Palsy and Corticobasal Degeneration 145 patients with pathological diagnosis (50) and CBD on the basis of clinical observation and small clinicopathological cases series (7). Th e diagnosis of these conditions remains a cl inical one, so guide- lines such as those outlined in the previous section serve as a use- ful starting point. Box 14.5 Diagnosing corticobasal syndrome Patients over 40 develop both: (1) Progressive asymmetric onset of cortical dysfunction charac- terized by at least one of: Imaging modalities do not provide much useful diagnostic evi- dence early in the course of either PSP or CBD. In some cases the diff erential diagnosis includes vascular aetiologies which require MRI brain scanning for exclusion (77). Ventriculomegaly on imaging can lead t o the radiological diagnosis of \200\230normal pres- sure hydrocephalus \200\231, but this does not exclude the possibility of an underlying tauopathy (78, 79). In the setting of an emerging behav- ioural variant of FTD, a relatively symmetric and predominantly extratempo ral (frontal) pattern of atrophy is more suggestive of CBD pathology than of Pick \200\231s disease or TDP-43 pathology (62). In established disease, thinning of the superior cerebel lar peduncle and midbrain atrophy are helpful diagnostic clues for a diagnosis of PSP (Fig. 14.4). (a) Apraxia (b) Cortical sensory loss (c) Alien limb (2) Progressive asymmetric onset of at least one of: (a) Akinetic rigid syndrome that is levodopa resistant (b) Limb dystonia (c) Refl ex or spontaneous positive myoclonus Supportive investigations: (1) Variable degrees of focal or lateralized cognitive dysfunction, with relative preservat ion of learning and memory on neu- ropsychometric testing Biomarker studies, in particular cerebrospinal fl uid (CSF) anal- ysis of proteins related to the underlying neuropathology (80), hold some hope of improving clinical diagnostic accu racy. Direct measurement of CSF-tau levels has not proved suffi ciently accurate in diagnos tic studies, but exclusion of other pathologies, such as Parkinson \200\231s disease or Alz heimer \200\231s disease, using other biomarkers appears to be achievable (81, 82).