Progressive Supranuclear Palsy Postgrad Med J: First Published As 10.1136/Pmj.76.896.333 on 1 June 2000

Home , Abnormal posturing, Ideomotor apraxia, Lewy body dementias, Parkinsonism

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Progressive supranuclear palsy Postgrad Med J: first published as 10.1136/pmj.76.896.333 on 1 June 2000. Downloaded from

H U Rehman

Abstract reported over-representation of tau ô alpha 1 Progressive supranuclear palsy (PSP) or allele and the ôá1 á1 genotype in individuals Steele-Richardson-Olszewski syndrome is with PSP and the ô polymorphism to be in a neurodegenerative disease of middle and linkage disequilibrium with the PSP disease late age. It is under-diagnosed not only by locus when a recessive inheritance model was general physicians but also by neurolo- employed.12 gists. The cause of PSP is not known. The cause of PSP is not known. Exposure to Exposure to toxins and viruses has been toxins and viruses has been proposed in the proposed in the aetiology of PSP without aetiology of PSP without any concrete any concrete evidence. The features of evidence.13 14 Abnormalities of the gene leading PSP resemble those of Parkinson’s disease to the formation of abnormal proteins that in and the two diseases are often confused. turn favour the development of neurofibrillary Corticobasal degeneration and multisys- tangles are currently under investigation.15 tem atrophy are other diVerential diagnoses. Despite certain common features Clinical features with Parkinson’s disease, corticobasal de- The onset of symptoms in PSP is insidious. generation, and mutisystem atrophy, Age of onset is usually between 55 and 70 there are important diVerences that help years.16 Postural instability, supranuclear verti- to diVerentiate it from these disorders. cal gaze palsy, rigidity with abnormal posturing (Postgrad Med J 2000;76:333–336) of the neck (retrocollis), frontal lobe symptoms, and dementia are the main features of Keywords: progressive supranuclear palsy; Steele- PSP. Pyramidal and cerebellar signs are Richardson-Olszewski syndrome variable. Postural instability and falls are the most common presenting features and patients have a slow, unsteady gait. Bradykinesia is clas- Progressive supranuclear palsy (PSP) or sically symmetric and rigidity is axial, and both Steele-Richardson-Olszewski syndrome is a are usually unresponsive to levodopa therapy. neurodegenerative disease of middle and late Dysarthria and dysphagia due to pseudobulbar age. Steele et al published the first clinicopatho- 1 palsy are early symptoms. Frontal lobe symp- logical description of the disorder in 1964, toms also develop early in the course of the although there are several previous case reports 23 disease. Diplopia, blurred vision, burning eyes, in the literature. and light sensitivity are other visual symptoms, http://pmj.bmj.com/ The annual incidence of the disease is 5.3 new occurring early in the course of the disease.5 cases per 100 000 person years and the preva- Slowing of saccades and hypometric sac- lence of the disease is estimated at 1.39 per 4 cades may precede the supranuclear limitation 100 000 population in the US. It is likely that of vertical gaze.17 18 Supranuclear vertical gaze these figures are a considerable under-estimate, palsy may be followed by horizontal gaze as many patients with PSP are not diagnosed 5 abnormalities. Supranuclear vertical gaze palsy and die with other diagnoses. In the UK may occasionally be absent,19 20 but when Parkinson’s Disease Society Brain Bank, 6% of present aVects first vertical gaze and then hori- on September 30, 2021 by guest. Protected copyright. 100 prospectively followed up patients dying zontal gaze unlike most other disorders causing with a clinical diagnosis of Parkinson’s disease 6 a supranuclear gaze palsy (see box 1). These were found to have PSP at necropsy. The results include dementia with Lewy bodies, corticoba- of the first large scale population prevalence sal degeneration, vascular parkinsonism, study of PSP have recently been presented. A Creutzfeldt-Jakob disease, and Whipple’s population of 121 608 people was screened for disease.21–23 Because limitation of upward gaze all patients with a mention of “Parkinson’s is more common than limitation of downward disease”, “parkinsonism”, “tremor” (with onset gaze in neurodegenerative disorders, and be- after age 50), “Shy-Drager syndrome”, “parkin- cause there is also a certain degree of upward sonism with orthostatic hypotension”, and gaze restriction with aging, limitation of down- “other extrapyramidal disorders, not otherwise ward gaze is considered more specific for the specified”, or those who had ever received diagnosis of PSP.24 Dysfunction of voluntary antiparkinsonian medication. The prevalence rate for PSP was 4.9 per 100 000 in this study and the diagnosis of PSP was not previously Box 1: Causes of supranuclear gaze Hull Royal Infirmary, made in any of these patients.7 palsy Anlaby Road, Hull The incidence of PSP increases with age (1.7 x Steele-Richardson-Olszewski syndrome HU3 2JZ, UK at 50–59 years, 14.7 at 80–99 years).8 Males are x Lewy body dementia 9 Correspondence to: aVected more commonly than females. x Corticobasal degeneration Dr Rehman PSP is a sporadic disease, although recently a x Vascular parkinsonism few familial cases have been reported.10 11 All x Creutzfeldt-Jakob disease Submitted 20 April 1999 Accepted 22 September the familial cases except one had a recessive x Whipple’s disease 1999 mode of inheritance. Moreover Higgins et al 334 Rehman

eyelid movements is a characteristic feature of In multiple system atrophy autonomic signs Postgrad Med J: first published as 10.1136/pmj.76.896.333 on 1 June 2000. Downloaded from PSP and includes reduced blinking, voluntary are prominent and cerebellar disturbances are eyelid motility impairment, and even full blown common while cognition is preserved. blepharospasm. Slowing of eye opening or eye PSP is occasionally confused with Pick’s dis- closure are late signs. The patients may fail to ease or Alzheimer’s disease. However cortical suppress their vestibuloocular reflex and may dementia is uncommon in PSP.32 have abnormalities of convergence.25 A visual glabellar reflex (inability to suppress a blink to Neuropathology a bright light) may become positive.18 The principal macroscopic abnormality is Motor diYculty particularly involves axial severe pigment depletion in the substantia more than limb muscles. In the axial muscula- nigra, which is orange discoloured and ture, neck muscles are more aVected than shrunken. Pigment is also reduced in the locus trunk muscles.26 Dysarthria is an early feature coeruleus.19 and is of mixed type with a combination of On light microscopy the substantia nigra, spastic, hypokinetic, and ataxic components.27 subthalamus, and pallidum are degenerate. Pyramidal signs develop in one third of Neurofibrillary tangles occur in a widespread patients. distribution including hippocampus, parahip- Disturbances of thought, perseveration, dif- pocampus, caudate, putamen, pallidum, sub- ficulty with planning and problem solving, and thalamus, substantia nigra, frontal cortex, behavioural disturbances including apathy, dis- insular region, colliculi, periaqueductal grey, inhibition, depression, and anxiety are the red nucleus, nucleus basis pontis, inferior olive usual frontal lobe symptoms.28–30 As a result of and dentate.19 The National Institute of the frontal lobe disturbance the PSP patient Neurological Disorders and Stroke (NINDS) may jump to his or her feet from a sitting posi- criteria for PSP require a high density of tion without thinking only to topple backwards neurofibrillary tangles and neuropil threads in into the chair because of postural instability. at least three of the following sites: pallidum, This is known as the “rocket sign”. subthalamic nucleus, substantia nigra or pons, The symptoms and signs progress steadily and a low to high density in at least three of the and most patients eventually are wheelchair following sites: striatum, oculomotor complex, bound and may require a feeding tube. medulla, or dentate nucleus. Neuronal loss and 33 Median survival time from symptom onset is gliosis are variable. Amyloid deposits and 5.6 years (range 2–16.6 years).8 Falls during neuritic plaques are notably absent. the first year, early dysphagia, and incontinence The major neurotransmitter systems aVected are poor prognostic signs.5 Pneumonia is the in PSP are the dopaminergic nigrostriatal path- most common cause of death. way, the GABAergic and cholinoceptive striatal neurones and the cholinergic brainstem and 34–36 DiVerential diagnosis (see box 2) basal forebrain nuclei. Marked degeneration PSP should be diVerentiated from Parkinson’s of several cholinergic nuclei has been found. disease. This can prove diYcult at an early Nearly 80% of the cholinergic neurones are lost http://pmj.bmj.com/ stage if the ophthalmoplegia and postural in the interstitial nucleus of Cajal. Loss of instability only develop late in the disease as cholinergic cells in the nucleus pontis centralis can happen with some PSP patients. Parkinso- caudalis may be related to the disturbances of nian signs are usually asymmetric in patients horizontal saccades. Choline acetyltransferase with Parkinson’s disease. Early falls and a lim- activity is also reduced in many brain regions, ited response to L-dopa treatment will point to including striatum, cerebral cortex, and substan- 37 a diagnosis of PSP. Dysphagia generally occurs tia innominata. early in the course of PSP in contrast to Although there is degeneration of the on September 30, 2021 by guest. Protected copyright. Parkinson’s disease in which it appears only in nigrostriatal dopaminergic system, the meso- middle to advanced stages. PSP progresses limbic and mesocortical dopaminergic projec- 38 much faster than Parkinson’s disease. tion systems seem to be relatively spared. D2 In addition to its asymmetric onset other dopamine receptor binding sites are decreased features of corticobasal degeneration which in the caudate nucleus and putamen in PSP 39 diVerentiate it from PSP include unilateral patients. Dopamine and homovanillic acid ideomotor apraxia, unilateral cortical sensory contents are markedly reduced in the caudate signs, unilateral visual neglect, unilateral dysto- nucleus and putamen, but normal in the 37 40 nia, and segmental myoclonus. PSP patients nucleus accumbens and cerebral cortex. may also exhibit ideomotor apraxia, but this is The density of the GABAergic neurones has usually mild and bilateral.31 also been found to be significantly lower in the caudate nucleus, the ventral striatum, the internal pallidum, and the external pallidum in patients with PSP.41 Box 2: DiVerential diagnosis of Serotonin-S2 receptors are decreased in the progressive supranuclear palsy temporal cortex of patients with Parkinson’s x Parkinson’s disease disease and PSP.42 Caudate and putamen x Corticobasal degeneration opioid receptor binding is also significantly x Multiple system atrophy reduced in PSP patients compared to normal x Pick’s disease controls and Parkinson’s disease patients.43 x Alzheimer’s disease Other neurotransmitter abnormalities found in x Postencephalitic parkinsonism patients with PSP are raised glutamate content in the nucleus accumbens, raised taurine Progressive supranuclear palsy 335

concentrations in the nucleus accumbens, glo- Postgrad Med J: first published as 10.1136/pmj.76.896.333 on 1 June 2000. Downloaded from bus pallidus, and substantia nigra, and in- Box 4: Mandatory exclusion criteria creased contents of glycerophosphoeth- for the diagnosis of progressive anolamine in most brain regions.44 supranuclear palsy x History compatible with encephalitis Clinical diagnostic criteria lethargica. Several criteria for the diagnosis of PSP have x Alien hand syndrome, cortical sensory. been proposed. To improve diagnostic accu- deficits, focal frontal, or temporoparietal racy and standardisation, the NINDS and the atrophy. Society for Progressive Supranuclear Palsy x Hallucinations or delusions unrelated to have proposed the following criteria.18 dopaminergic therapy. For possible PSP, onset at age 40 or later, x Cortical dementia of Alzheimer type. gradual progression, and either vertical supra- x Prominent cerebellar symptomatology or nuclear palsy, or slowing of vertical saccades unexplained dysautonomia. and prominent postural instability with falls in x Severe asymmetry of parkinsonian signs. the first year after disease onset, are mandatory x Neuroradiological evidence of relevant inclusion criteria (see box 3). When both structural abnormality. supranuclear vertical palsy and prominent pos- x Whipple’s disease confirmed by tural instability with falls in the first year of dis- polymerase chain reaction, if indicated. ease onset are present, the diagnosis becomes probable. Mandatory exclusion criteria include recent history of encephalitis, alien limb Absent orbicularis oculi responses to median syndrome, cortical sensory deficits, focal fron- nerve electrical stimuli and severely reduced tal or temporoparietal atrophy, hallucinations orbicularis oculi responses to acoustic startling or delusions unrelated to dopaminergic stimuli have been shown, reflecting the impair- therapy, cortical dementia of Alzheimer’s type, ment of reflex brainstem function.45 46 Absent prominent early cerebellar symptoms, unex- orbicularis oculi response on median nerve plained dysautonomia, severe asymmetric par- stimulation is specific for PSP and does not kinsonian signs (that is, bradykinesia), neurora- occur in other parkinsonian syndromes. diological evidence of relevant structural Magnetic resonance imaging (MRI) may abnormality and Whipple’s disease confirmed show thinning of the quadrigeminal plate and by polymerase chain reaction, if indicated (see atrophy of the midbrain and the region around box 4). Supportive features are symmetric aki- the third ventricle, supporting a diagnosis of nesia or rigidity, proximal more than distal, ret- PSP.47 Atrophy of the corpus callosum with rocollis, poor or absent response to levodopa anterior predominance has been shown to be therapy, early dysarthria or dysphagia and early associated with cognitive impairment in PSP.48 cognitive impairment including at least two of The main value of computed tomography and the following: apathy, impaired abstract MRI is to exclude other diagnoses such as cor-

thought, decreased verbal ﬂuency, imitation ticobasal degeneration (asymmetric atrophy in http://pmj.bmj.com/ behaviour, and frontal release signs. Deﬁnite the parietal area), multiple system atrophy PSP is a clinicopathological diagnosis. (atrophy of the pons, middle cerebellar pedun- cles and cerebellum), multi-infarct dementia, Investigations hydrocephalus, and tumours. PSP is a clinical diagnosis but some investiga- Evoked potentials, polysomnography, and tions may be helpful in supporting the diagno- positron emission tomography are research sis or excluding related disorders. Electro- tools and may prove helpful in the future to

oculographic recording can be useful in support an early diagnosis of PSP. on September 30, 2021 by guest. Protected copyright. diVerentiating PSP from related conditions.17 Patients with PSP have hypometric horizontal Treatment voluntary saccades of normal latency, while At present there is no eVective treatment of PSP. patients with corticobasal degeneration show Dopaminergic replacement therapy is only tran- opposite results. Patients with Parkinson’s dis- siently or mildly eVective in relieving some of the ease or striatonigral degeneration have sac- symptoms. It is however, worth trying because cades of normal latency and amplitude. sometimes useful benefit is obtained. In spite of the severe loss of cholinergic neurones in the brains of patients with PSP, marginal or no ben- Box 3: Mandatory inclusion criteria for efits are seen after administration of physostig- the diagnosis of progressive mine, a cholinesterase inhibitor, or of a choliner- supranuclear palsy gic agonist.49 Isolated reports of improvement in x Onset at age 40 or later. symptoms after treatment with trazodone,50 x Gradually progressive disorder. idazoxan,51 methysergide,52 L-threo-DOPS,53 x Vertical supranuclear gaze abnormalities. and amitriptyline54 are found in the literature. x Prominent postural instability with ten- However no persistent beneficial eVect has been dency to falls in the first year after symp- seen. More research is needed before any of tom onset Presence of both vertical these can be recommended for the treatment of supranuclear ophthalmoparesis and PSP. prominent postural instability with falls Blepharospasm and levator inhibition may within 1 year of symptom onset makes be treated with botulinum toxin injections, but the diagnosis of PSP probable. the success rate in the latter is only about 50%. Artificial tears may help to avoid exposure 336 Rehman

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