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). (2) Focal or asymmetric atrophy on CT or MRI imaging (3) Focal or asymmetric hypoperfusion on SPECT or PET, typi- cally maximal in parietofronta l cortex with or without basal ganglia involvement Management Th ere are currently no treatments that substantially alter the course of PSP or CBD, so it is important that diagnoses are deliv- ered with compassion and reassurance. Pa tients and their carers should be informed that there are many options for optimizing indep endence, function, and care into the future. A management team which involves the primary c aregiver, the neurologist, the primary care physician, and an allied health care team inclu ding a physiotherapist, an occupational therapist, and a speech therapist is important. Distinction of PSP \200\223CBS from CBD \200\223CBS on clinical grounds is diffi cult. Whil e useful trends emerged from comparative stud- ies, no clinical features, including vertica l supranuclear gaze palsy, defi nitively distinguish PSP \200\223CBS from CBD \200\223CBS ( 16, 67, 75). Myoclonus seems to occur later and frontal release signs more fre- quently in PSP \200\223CBS, while cortical sensory loss occurs more com- monly in CBD \200\223CBS (67, 75). Central to the established criteria of Richardson \200\231s syndrome, the occurrence of early falls and vertical supranuclear gaze palsy may be useful as a clue to distinguishi ng PSP \200\223CBS from CBD \200\223CBS (67). Substantial impairment of episodic memory on neuropsychology testing is a good predictor of under- lying Alzheimer pathology in CBS (76) . Medications Dopaminergic medications Levodopa may help up to 40% of PSP patients by modestl y improv- ing gait, rigidity, and swallowing function. Ocular motor dysfunc- tion and dysar thria do not improve. Adverse eff ects are usually minimal. Patients with PSP \200\223P are more likely to respond than those with the classic Richardson syndrome variant. A sensible practice is to prescribe levodopa \200\223carbidopa for patients with PSP who have rigidit y or bradykinesia causing disability. Treatment can begin at levodopa 100 mg (with peripher al decarboxylase inhibitor) once daily, increasing on a bid or tid schedule until effi cacy , toxicity, or 1200 mg/day. If no benefi t is seen aft er a month, the drug can be quickly tapered and discontinued. Th e diagnosis of CBS should be considered in any patient who presents with progressive asy mmetric apraxia, dystonia, and rigid- ity (see Box 14.5). However, predicting underlying pa thology continues to be challenging (7). Th e terminology of \200\230corticobasal syndrome \200\231 is preferred to encompass all of these clinicopathologi- cal entities. Diagnosis Both PSP and CBD defy categorization as singular clinicopatho- logical entities b ecause of the substantially diff erent modes of presentation seen in these conditions. Over the past two decades it has become increasingly apparent that pathological diagnoses are r equired to reach absolute diagnostic accuracy in these condi- tions. Ante-mortem diagnosis relies fi rst upon the consideration of a clinical syndrome as being related to PSP-tau or CBD-tau pathol- ogy. Examination and observation of the patient over time is most helpful i n establishing a diagnosis in patients with unclassifi able parkinsonism. Dopamine receptor agonists are only mildly benefi cial in less than a fourth of patients. A mantadine has anticholinergic, antiglutama- tergic, and modest dopaminergic properties and may help patients with PSP and CBD. In some patients (probably less than 10%) there may be a marked benefi t in gait freezing, apraxia, speech, or swal- lowing. For that reason it sh ould probably be tried in all patients with PSP, except those with severe constipation or d ementia. If there is no benefi t at 200 \200\223300 mg aft er four weeks, it should be tape red and discontinued. Clinical guidance is given by operational diagnostic criteria for PSP, which have been vali dated in a small selected group of Oxford Textbook of Movement Disorders 146 (a) (b) Fig. 14.4 MRI scan showing atrophy of the superior cerebral peduncles (arrow heads): (a) ax ial image; (b) coronal image. (Reprinted from Paviour DC, Price SL, Stevens JM, Lees AJ, Fo x NC. Quantitative MRI measurement of superior cerebellar peduncle in progressive supranucl ear palsy. Neurology 2005; 64: 675 \200\2239) Antidepressants Amitriptyline 10 \200\22350 mg may be of modest benefi t, particularly for muscle pain, hypophonia, and dysphagia. Selective serotonin-reuptake inhibitors are commonl y used for the depression and pseudobulbar aff ect of PSP, with very little literature to g uide this choice. solids. Th e evaluation should usually include a modifi ed barium swallow and may result in recommendations to alter feeding hab- its or food texture. Th ickeners for thin fl uids ar e available. Th e issue of tube feeding is oft en diffi cult to discuss with patients and c aregivers, and it is important to guide the patient and family according to their cultural beliefs. Tube feeding can be helpful in maintaining weight when oral intake is poor, but ma y not neces- sarily improve quality of life. Potential abdominal complications should be co nsidered. Dysarthrophonia is a common problem that may require use of communication aids. Benzodiazepines and related drugs Bedtime sedatives can be used for the sleep disturbances that are common in PSP. Clonazepam may be helpful for persistent and intru- sive myoclonus in CBD. Zolpidem is also useful in many patients for sleep and may occasionally improve the motor features of PSP. Gaze paresis in PSP Prisms for the downgaze palsy are rarely successful. However, a single lens prism may help the dysconjugate gaze that is common in PSP. Practical measures to comp ensate for gaze paresis include elevating reading material and placing food more horizontal to the eye level. Others Th e mitochondrial defect in PSP has prompted a trial of co-enzym e Q-1 0 for neurop rotection in PSP. Th ere is some emerging evidence of improvement compared with placebo and possibly of sympto- matic benefi t of doses up to 1200 mg/day (83). Botulinum toxin inject ions for disabling blepharospasm, painful cervical dystonia, or limb dystonia, when skin in tegrity and hygiene are compromised, are oft en helpful in well-selected patients with CBD or PSP. Care must be taken not to exacerbate dysphagia when injecting even small doses in t he neck muscles. Other physical therapies Acupuncture, massage, and gentle passive stretching exercises can be applied to alleviate symptoms of discomfort throughout the dis- ease. Enrolment with a s upport group can be helpful for patients and their caregivers, and information booklets pub lished for care-givers provide helpful advice for home care. Occupational therapy helps to limit the handicap resulting from the patient \200\231s disabilities and should include a h ome visit. Provision of a wheelchair is usually dictated by the likelihood of falls because of postural instability and gait ataxia, but not by akinesia and rigidity per se . Psychol ogical support for patients and partners is also of great importance. Surgical approaches Th ere are no established targets for deep brain stimulation or lesiona l therapy in PSP. Pedunculopontine nucleus stimulation may improve gait freezing in patient s with pure akinesia. Physical therapies and strategies Postural instability/physical therapy Th e frontal disinh ibition in PSP causes many patients to suddenly rise from a chair, only to fall on attempti ng to walk. Strategy train- ing may be of benefi t for some patients, and ongoing physiothe rapy is important to maintain range of motion and ensure that optimal gait aids are prescri bed. Key advances Th e increasing recognition and clarifi cation of clinical variants asso- ciat ed with PSP-tau and CBD-tau pathology have been important in understanding these broader cl inicopathological entities. Th is is most likely to impact on the diagnosis of patients wit h \200\230unclassifi a- ble parkinsonism \200\231 (84) and will lead to patients and their care-givers having a clearer understanding of the disease and prognosis when Dysphagia and dysarthrophonia A swallowing evaluation should be performed in response to th e fi rst evidence of dysphagia, which usually aff ects fl uids before CHAPTER 14 Progressive Supranuclear Palsy and Corticobasal Degeneration 147 Conclusion PSP and CBD are tauopathies that are related by their clinical and pathological overlap. Both conditions rely on refi ned clinical skills and consideration of a broad rang e of clinical features for diagnosis and categorization. Th e inevitable progression of the se forms of neurodegenerative parkinsonism challenges the scien- tist and physician to deve lop strategies that decrease or cure the cell loss that is so prominent at post-mortem. Whi le the future holds hope for compounds that directly reduce tau-protein toxic- ity, there a re a number of current strategies that can be employed to reduce suff ering and improve sym ptoms in patients with these conditions. faced with the rarer presentations of these diseases (1). It has become clear that experime nts involving patients with PSP and CBD need to address the clinical presentation of those studied, as the severity and distribution of tau-pathology varies and is likely to aff ect the interpretation of results of clinical and pathological studies as well as the analysis of environmental and genetic risk factors. Th e improved understanding of regional vulnerability to tau-pathology in this context has led to interesting hypotheses about the \200\230cause \200\231 of this tau-neurodegenerati on. Chen and col- leagues suggest that the distribution of PSP-tau pathology may be related to neural systems that have evolved to promote erect bipedal locomotion in Homo sapiens an d the visual needs conse- quent on freedom to independently use the upper limbs (39). Th e suggestion that this recently evolved neural system is vulnerable to PSP-tau neurodegenerat ion has resonance with other tauopathies (Alzheimer \200\231s disease and CBD-tau pathology ) and their regions of selective vulnerability that aff ect cognition, language and the abi lity to learn motor tasks which all involve functions characteristic of human evolution. Key points PSP and CBD are related, but distinct, forms of neurodegenera- tive parkinsonism associated with the accumulation of hyper- phosphorylated tau protein in the basal ganglia and cortex . Th ey are considered amongst the \200\230tauopathies \200\231. \227\206 One of the enduring challenges in treating patients with these diseases is providing accura te early diagnosis. Th is will be most important when disease-modifying therapies become av ailable. Th ere are no radiological features that absolutely separate these pathological en tities from other causes of progressive parkinson- ism, but taken in the context of the cli nical presentation a number of imaging techniques show some promise. Using MRI measures of midbrain and pons areas, as well as superior and middle cerebel- lar peduncle widths, it ma y be possible to separate patients with PSP-tau pathology from PD (85). Th e clinical presentation of these conditions can be variable, and it is best to consider a number of diff erent clinical variants of both PSP and CBD. \227\206 PSP-tau pathology most commonly causes progressive pos- tural instability, falls, subcortic al cognitive slowing, and vertical supranuclear gaze palsy (Richardson \200\231s syndrome). Other variants include progressive parkinsonism with diminishing response to levodopa (PSP \200\223P), gait disturbance with micrographia, hypo- phonia, and eventually gait freezing (PSP \200\223PAGF), corticobasal syndrome (PSP \200\223CBS), and progressive non-fl uent a phasia char- acterized by apraxia of speech (PSP \200\223PNFA). \227\206 Th e understanding and identifi cation of genetic factors involved in PSP and CBD have open ed up new lines of investigation in the aetiopathogenesis of these disorders. It is of grea t interest that a genetic variation of a Mendelian gene ( MAPT ) predisposes patients to a sporadic disease, and identifi cation of the risk allele is a key advance in our understand ing of this process (12, 86). Th e recent identifi cation of families with \200\230inherit ed PSP \200\231 has confi rmed the genetic link to this classically sporadic disorder, and provides fur- ther lines of enquiry aimed at understanding the biology of this disorder (10 ). CBD-tau pathology classically presents with a corticobasal syn- drome (CBD \200\223CBS), bu t may also present with a behavioral var- iant of frontotemporal dementia, progressive non- fl uent aphasia, or rarely Richardson \200\231s syndrome. \227\206 Brain imaging is not suffi ciently sensitive or specifi c to be use- ful in diagnosing thes e conditions, but the presence of the \200\230hum- mingbird \200\231 sign and atrophy of t he superior cerebellar peduncle are suggestive of underlying PSP-tau pathology. Asymmetric frontal (>temporal) atrophy is more suggestive of underlying CBD-tau pathology. \227\206 Future developments Future developments in the understanding and treatment of PSP- and CBD- tau pathology are likely to follow several paths. Treatment strategies that include optimization of function and support for caregivers are a n important aspect of managing these diseases. Involvement of a multidisciplinary care team is essential for achieving these goals. \227\206 Molecular studies of these tauopathies will continue to unravel the nature of the pathologi cal lesion and the relationship between tau-protein accumulation and neuronal and glial dys function. Th is will further inform strategies for combating cell death. A number of clinic al trials using diff erent compounds with the puta- tive action of reducing the accumulatio n of hyperphosphorylated tau in viv o have already started. 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Trans Am Neurol Assoc 1967; 92 : 23 \200\2236 . This page intentionally left blank CHAPTER 15 Primary Dementia Syndromes and Parkinsonism A.W. Lemstra , H. Seelaar , and J.C. van Swieten