35232ournal ofNeurology, Neurosurgery, and Psychiatry 1997;62:352-256

Dystonia in progressive supranuclear palsy J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.352 on 1 April 1997. Downloaded from

C L Barclay, A E Lang

Abstract recognised in this setting, whereas limb dysto- Objectives-To document the nature, dis- nia, oromandibular , and treatment tribution, and frequency of dystonic induced dystonia have all but been ignored. In symptoms in progressive supranuclear reviewing a large series of patients with PSP, palsy (PSP). we were impressed with the frequency of dys- Methods-Charts and videotapes of all tonia and report our findings below. clinically diagnosed patients with PSP seen between 1983 and 1993 were reviewed and the occurrence, nature, and distribu- Methods tion of all dystonic symptoms were The charts of all patients with a diagnosis of recorded. PSP who were seen in the Toronto Hospital Results-Of 83 identified cases 38 had movement disorders clinic between January some dystonic features. Twenty (24%) 1983 and February 1993 were reviewed. All had blepharospasm (one was induced by videotaped examinations available on these levodopa), 22 (27%) had limb dystonia patients were reviewed. The clinical diagnosis (one was induced by electroconvulsive was considered correct if the patient had a therapy and another by levodopa), 14 progressive, non-familial neurodegenerative (17%) had axial dystonia in extension, one disorder with onset after the age of 40 which had oromandibular dystonia induced by included supranuclear ophthalmoplegia with levodopa, and two had other cranial dys- downgaze abnormalities and at least two of the tonias. Six patients had limb dystonia as following features: postural instability with an early or presenting feature, sometimes backward falls, , bradyki- leading to misdiagnosis of cortical-basal nesia and rigidity, frontal lobe signs, or axial ganglionic degeneration. All three dystonia and rigidity (Lees' criteria).9 Any patients who had postmortem confirma- patient with limb apraxia, cortical sensory loss, tion ofthe diagnosis had other concurrent or dysphasia was excluded. All patients satisfy- disease. One patient with bilateral limb ing the criteria were reviewed for the presence dystonia and blepharospasm had evi- of dystonia. This was defined as a syndrome of dence of previous and involuntary movement dominated by sus-

severe arteriosclerotic changes. One with tained muscle contractions causing twisting http://jnnp.bmj.com/ arm dystonia also had cerebrovascular and repetitive movements or abnormal pos- disease and one with hemidystonia also tures.'0 Clinical aspects of the dystonic mani- had rare swollen chromatolytic neurons festations were reviewed including the in the frontotemporal cortex. location, nature, accompanying clinical fea- Conclusions-Dystonia is a common tures, and the time of onset. Accurate infor- manifestation of PSP. Limb dystonia is mation on the time of onset in relation to particularly common and may indicate onset of disease was not always available. the presence of concurrent disease. When on September 26, 2021 by guest. Protected copyright. dystonia occurs in PSP, dopaminergic medication should be cautiously reduced Results or discontinued to rule out the possibility Eighty three patients met the diagnostic criteria University of Ottawa, oftreatment induced symptoms. for PSP; 45 were men and 37 were women Division ofNeurology, (1 2:1). Twenty seven had at least one video- Ottawa Civic Hospital, ( Neurol Neurosurg Psychiatry 1997;62:352-356) taped examination. The age at onset of PSP 1053 Carling Avenue, 47 to 81 Ottawa, Ontario symptomatology ranged from years of K1H 4Y9, Canada age with a mean of 62-9 years. Duration of C L Barclay Keywords: progressive supranuclear palsy; dystonia; PSP symptoms to last follow up visit or death University ofToronto, was 4-7 (range 1-20) years. Thirty eight Toronto Hospital, (46%) had at least one dystonic feature at Western Division, MP 1lth Floor, Room 306, Since progressive supranuclear palsy (PSP) some point in their illness. Twenty had ble- 399 Bathurst Street, was first characterised in 1964,1 dystonic man- pharospasm (24%), 22 had limb dystonia Toronto, Ontorio ifestations have been reported only sporadi- (27%), 14 were noted to have so called axial M5T 2S8, Canada cally.2-7 "Axial dystonia in extension" is the "dystonia" in extension (17%), and three had A E Lang In three the Correspondence to: only such manifestation which has been other cranial . patients, Dr C L Barclay. emphasised; however, the pathogenesis of this dystonia was clearly induced by treatment Received 4 August 1995 tonic, rigid extended posture is probably dis- (one with oromandibular dystonia and ble- and in final revised form 14 November 1996 tinct from other forms of dystonia. pharospasm and two with limb dystonia). Accepted 14 November 1996 Blepharospasm has also been reasonably well Blepharospasm occurred either sponta- Dystonia in progressive supranuclear palsy 353

neously or reflexively in response to facial left leg during a course of electroconvulsive J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.352 on 1 April 1997. Downloaded from stimuli or voluntary facial movements (reflex therapy.'5 Within one month of cessation of blepharospasm). Because of incomplete that treatment, this symptom resolved. It reporting, it was not possible to discern how spontaneously recurred and gradually wors- many patients had isolated spontaneous ble- ened over the subsequent 18 months of follow pharospasm, reflex blepharospasm only, or a up. One patient developed right arm dystonia combination of the two. Ten of the 20 patients with associated choreic movements while with blepharospasm also had "apraxia of eye- receiving levodopa/carbidopa. All involuntary lid opening" (referred to elsewhere as levator movements ceased on discontinuation of the inhibition or eyelid freezing). Reflex ble- drug. pharospasm was a common accompaniment of In two other cases, arm dystonia was the this disorder. Two patients had ble- initial manifestation of disease. One of these, pharospasm with apraxia of eyelid closure. In with right arm involvement, died after an eight nearly all those affected, blepharospasm year history of gradually progressive neurologi- occurred as a late manifestation of their dis- cal dysfunction compatible with a clinical ease, with only one patient reporting difficulty diagnosis of PSP. Postmortem examination, in with eyelid opening within one year of onset of addition to the typical pathological changes of symptoms. One patient with blepharospasm PSP, showed severe arteriosclerosis with and other dystonic features had a postmortem microinfarcts in the left caudate, left lateral performed and the results are reported below. thalamus, right dorsomedial thalamus, and One patient developed blepharospasm and multiple neocortical regions. oromandibular dystonia while receiving lev- The one patient with dystonic posturing in odopa/carbidopa 100/25 thrice daily. On with- all four limbs late in the course of his illness drawal of the drugs, the blepharospasm also had PSP confirmed at necropsy. This resolved but apraxia of eyelid opening patient is reported elsewhere.'6 He presented remained. The oromandibular dystonia also at age 69 with incontinence, gait impairment, resolved on stopping levodopa. No other falls, and cognitive dysfunction. Brain CT sug- patient had oromandibular dystonia although gested normal pressure hydrocephalus and one had a dystonic grin with repetitive lower ventricular shunting was performed. His facial grimacing and one had sustained invol- symptoms improved greatly for a few months; untary smiling. however, his gait then worsened, dysphagia Limb involvement was the most common and dysarthria occurred, and he developed a dystonic manifestation in our PSP population vertical supranuclear gaze palsy, ble- (22 patients, 27%) and hemidystonia the most pharospasm, and mild bilateral limb dystonia. frequent distribution (nine patients (11%)). He died aged 75 and in addition to the typical Although in many instances the precise limb findings of PSP, his postmortem examination posture was not recorded, a "pointing gun" showed evidence of previous hydrocephalus posture, with extension of the index finger and and severe arteriosclerotic changes in the thumb, was often noted. In four patients, white matter and deep grey structures with hemidystonia was a very early or presenting numerous small infarcts (1-8 mm in diameter) feature of their disease. Two were initially bilaterally in the centrum semiovale and basal

diagnosed elsewhere as having cortical-. http://jnnp.bmj.com/ ganglionic degeneration because of the pro- Whereas we do not consider the neck pos- nounced unilateral (left sided) dystonia. ture typically seen in PSP to be dystonic in However, these patients had a vertical nature, as some authors consider it such, we supranuclear gaze palsy at presentation and no recorded the frequency of this feature. cortical sensory loss or stimulus sensitive Fourteen patients (17%) were documented as . Significant limb apraxia was also having "axial dystonia in extension". This was absent but was difficult to assess due to the characterised by constant extensor posturing pronounced disability caused by their dysto- of the neck with severe nuchal rigidity. No on September 26, 2021 by guest. Protected copyright. nia, bradykinesia, and rigidity. One patient, patient had phasic or intermittent dystonic last seen six years after symptom onset, neck movements, improvement with antago- remains free of manifestations of cortical-basal nistic gestures, "morning benefit", or other ganglionic degeneration. The other died five clinical features characteristic of classic cervi- years after onset of symptoms. Postmortem cal dystonia. examination disclosed the typical pathological With the retrospective nature of this review, abnormalities of PSP. In addition, rare swollen the lack of a consistent approach to treatment, chromatolytic neurons were noted in the fron- and the complex symptomatology that our totemporal cortex and there was neuronal loss patients experienced, an accurate assessment and gliosis in the left motor cortex and right of the response of the patients' dystonia to posterior middle frontal gyrus. These findings, medical management could not be obtained. although suggestive of cortical-basal gan- None of the patients receiving levodopa or glionic degeneration, have been described in dopamine agonists were reported to experi- PSP"I-"3 and due to the overwhelming predom- ence a lessening of their dystonic symptoms. inance of the findings of this disorder, the final Rarely, patients with limb dystonia or ble- neuropathological diagnosis was that of "atyp- pharospasm were noted to have some benefi- ical PSP".'4 cial response to tricyclic agents whereas only Single limb involvement occurred in eight those who received injections patients (10%). In seven, an arm was involved. for blepharospasm clearly experienced a good In one the patient developed dystonia in his response to therapy. No patient in this series 354 Barclay, Lang

with any other form of dystonia received botu- of symptoms in only one patient. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.352 on 1 April 1997. Downloaded from linum toxin injections. One patient with blepharospasm in our series had postmortem confirmation of diag- nosis but he also had severe arteriosclerotic Discussion changes and normal pressure hydrocephalus Dystonia was first reported in association with which may have contributed to the develop- PSP with the initial description of the disorder ment of this symptom. The pathological distri- by Steele, Richardson, and Olszewski in bution of degenerative changes in classic PSP 1964.1 Whereas they emphasised "axial dysto- includes extensive involvement of the mid- nia in extension", one of their patients also brain and as midbrain lesions have been showed unilateral arm dystonia. known to result in blepharospasm,27 it is not Axial dystonia in extension is by far the surprising that this sign occurs so often in most commonly recognised and reported PSP. The more severe abnormalities of eye "dystonic" manifestation of PSP. De Bruin movement noted by Golbe et al would also be and Lees noted that 48-3% of all necropsied consistent with this.24 patients with PSP reported in the literature De Bruin and Lees recently reviewed had axial dystonia of some sort. 17 The posturing reports of patients with pathological changes seen in this condition, however, lacks the typi- of PSP and found 90 cases.'7 Only five (5 6%) cal features of dystonia and many authors had blepharospasm; however, only 68-5% of think that this term should be avoided.8 18 The their cases actually met clinical criteria for a neck positioning in PSP tends to be fixed and diagnosis of PSP. The patients who did not does not alter with posture or activity as idio- fulfill the criteria lacked the appropriate eye pathic dystonia does. Patients fail to show sen- findings, suggesting that they had less severe sory tricks for improving the posturing, diurnal pathological involvement of the midbrain, per- variation ("morning benefit") is absent, and haps explaining the low frequency of this sign. painful neck and hypertrophic muscles In addition, after the initial characterisation of are not seen. For these reasons, nuchal rigidity the disease, necropsied cases reported in the in extension would be a more appropriate literature are more likely to be atypical and so term. We would reserve the term "axial dysto- this series may have underestimated the true nia" for those rare cases reported in which tor- prevalence of this sign in PSP. ticollis was described.1' 20 In our series, no Oromandibular dystonia or other cranial patient had such neck movements. Fourteen dystonias are rare features of PSP. In 1968, (17%), however, were noted to have overt David et al described a patient with "dystonic nuchal rigidity in extension. This is likely an stiffness" of the face28 and Anzil reported underrepresentation of the true prevalence of another with "trismus".29 Although in both this sign as the position of the neck was not cases, the diagnosis was confirmed at necropsy always specified and so milder examples may it is not clear from the case summaries that have been overlooked or not documented. these signs were truly dystonic. A recent The most widely accepted dystonic mani- necropsy series of 12 patients with PSP festation of PSP is blepharospasm.2' In two reported one with dystonia of the face30 but the clinic based series, blepharospasm was noted necropsy series of 90 cases reported by De

in between 8% and 23% of cases.22 23 Golbe et Bruin and Lees does not comment on this sign http://jnnp.bmj.com/ al reported a community based series of 38 at all.'7 Details in clinical series are similarly patients with PSP in whom 10 (26%) had ble- lacking. Jankovic et al reported that 28 of 104 pharospasm, or "levator inhibition" ("apraxia patients had blepharospasm "or other facial of eyelid opening"), or both.24 It should be spasms".22 Elsewhere they noted that 24 of noted that "levator inhibition" is probably an these had blepharospasm but there is no men- uncommon cause of "apraxia of eyelid open- tion of the nature of the "facial spasms" in the ing". Recent studies have emphasised the other four or whether any of the patients with presence of isolated contraction of the pre- blepharospasm had other associated facial on September 26, 2021 by guest. Protected copyright. tarsal component of the orbicularis oculi mus- movements. Hayashi et al described a case of cle in a high proportion of cases, making this a otherwise typical PSP in which the patient subtype of dystonic blepharospasm.2326 Golbe developed tonic contraction of the orbicularis et al noted that the duration and severity of oris and palatal muscles when attempting to disease in patients with disturbances of eyelid make certain sounds.3' Although they consid- function was not significantly different from ered that this was analogous to apraxia of eyelid those lacking this feature although they did opening, it may represent a form of facial dys- note the presence of more severe upgaze tonia. abnormalities.24 In our series, 31 patients Whereas one of our patients had a dystonic (40%) had disturbances of eyelid function grin with intermittent repetitive semirhythmi- including eight with blepharospasm alone, and cal movements of the muscles of her lower 12 with a combination of blepharospasm and face and one had sustained involuntary smiling apraxia of eyelid opening or closure. The ret- which appeared dystonic, many patients had rospective nature of our series, with insuffi- facial "stiffness" which was not clearly dys- cient recording of some clinical features, does tonic in nature. In these patients, the facial not allow us to confirm the findings of Golbe stiffness was accompanied by a concomitant et al of more severe upgaze impairment in increase in facial reflexes and we therefore these patients. However, in our patients, ble- considered this appearance to be due to spas- pharospasm tended to be a late manifestation ticity rather than dystonia. Although the of disease, occurring within one year of onset characteristic sustained eyebrow elevation Dystonia in progressive supranuclear palsy 355

commonly seen in PSP may represent dystonic went on to postmortem examination showed J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.352 on 1 April 1997. Downloaded from involvement of the frontalis muscle, it could other concurrent diseases (two had cere- also represent a variable combination of spas- brovascular disease and one had additional ticity, rigidity, and a response to difficulty with cortical findings). It is possible that limb dys- eyelid opening. In view of the uncertainty of tonia in PSP is an indicator of concomitant classification, we chose, for the purpose of this neuropathological changes, but it must be report, not to record the furrowing of the brow emphasised that a necropsy was more actively or the deepening of the nasolabial folds as fea- sought in those patients who had atypical tures of dystonia. clinical features. The pathological findings No patient in this series had spontaneous described in our three patients undergoing oromandibular dystonia. One patient with postmortem examination, therefore, may not long standing PSP, however, had jaw closure be representative of the entire subgroup of dystonia and blepharospasm while taking lev- patients with limb dystonia. However, it is odopa. On discontinuation of this medication, becoming increasingly recognised that cortical both dystonic symptoms resolved completely. pathology such as described in one of these It is important to emphasise that the cause and patients does occur in PSP.11-13 36 These effect relation between the dystonic symptoms changes may not necessarily imply the pres- and levodopa therapy was not readily apparent ence of a concurrent second disease but might in this patient until long term levodopa treat- simply represent part of the range of the dis- ment was withdrawn. The same is true of the ease. A recent clinicopathological conference one patient with limb dystonia induced by lev- in the New England Journal of Medicine,37 a odopa. Given our experience, the potential necropsied case of PSP with arm dystonia role of medication, especially levodopa, must described in the French literature,38 and be considered when dealing with dystonia in Steele's experience32 clearly show that limb patients with PSP. dystonia can be prominent in pathologically Despite a lack of emphasis on this feature in established typical PSP without any other the literature, we found limb involvement to associated disease. Our experience and that be the most frequent type of dystonia in our described in the New England Journal of series. When Steele, Richardson, and Medicine37 emphasise the potential for the Olszewski first described this condition in presence of focal limb dystonia to encourage a 1964, they reported seven necropsied cases misdiagnosis of cortical-basal ganglionic and two clinical cases. One of the necropsied degeneration. Caution then must be exercised cases had "athetoid posturing of the limbs"' in diagnosing ideomotor apraxia in the pres- and one of the clinical cases, which subse- ence of severe dystonic posturing, rigidity, and quently came to necropsy, developed a "hemi- bradykinesia. plegic dystonic posture".32 Although referral bias in this series may Very little emphasis has been placed on this have resulted in the accrual of a higher propor- feature since then. Jankovic et al reported the tion of atypical cases and, consequently, an only large clinical series in which limb dystonia overestimate of the frequency of dystonia in was not a rare or absent sign.22 They described PSP, our findings clearly indicate that dystonia "hand or foot deformity" that was elsewhere is a common manifestation of PSP. Limb dys-

called dystonia, in 14% of a series of 104 tonia, although sometimes indicative of other http://jnnp.bmj.com/ patients. Unfortunately no further details were concurrent pathology, may be the presenting given regarding these patients. Similarly, De symptom of this disorder. Recognition of this Bruin and Lees reported that 18 of 90 patients may avoid misdiagnosis of cortical-basal gan- with PSP had "segmental dystonia" on glionic degeneration or some other condition. necropsy but no further details were provided Our series also shows the potential for here either.'7 It is not clear if all of these dopaminergic medication to induce dystonia patients had limb dystonia or if some had in PSP. Although this may be an infrequent craniocervical dystonia. The same difficulty cause, when dystonia is noted in patients on on September 26, 2021 by guest. Protected copyright. exists with the series of 21 necropsied cases such medications, the dosage should be cau- reported by Veiny et al.33 Two of these patients tiously reduced or eliminated in an attempt to with typical pathologically established PSP establish the role of drug therapy in the causa- were reported to have "focal or segmental dys- tion of this disabling complication. tonia". A review of the text suggests that they Further study of community based popula- were referring to limb dystonia, but this was tions with associated clinical-pathological cor- never clarified. Leger et al described two oth- relation is necessary if the true frequency and erwise typical clinical cases of PSP with iso- anatomical substrates of the dystonic manifes- lated upper limb dystonia as a presenting tations of this disorder are to be clarified. feature34 and Rafal and Friedman described the presence of limb dystonia in eight of 30 We are indebted to Dr C Bergeron for the careful neuropatho- patients (27%) with clinically diagnosed logical assessment of the cases described. PSP.35 In the last series, the dystonia occurred 1 Steele JC, Richardson JC, Olszewski J. Progressive before the onset of the typical abnormalities of supranuclear palsy. Arch Neurol 1964;10:333-59. 2 Singh S, Smith BH, Lal A. Progressive supranuclear palsy: eye movement in half of the patients. In our report of 4 cases with particular reference to ble- larger series, we noted limb dystonia in a simi- pharospasm and levodopa therapy. India 1974; 22:65-71. lar proportion with 22 of 83 patients being 3 Jackson JA, Jankovic J, Ford J. Progressive supranuclear affected. This was a presenting feature in a palsy: clinical features and response to treatment in 16 patients. Ann Neurol 1983;13:273-8. small proportion (6/22 or 27%). 4 Kristensen MO. Progressive supranuclear palsy-20 years All of our patients with limb dystonia who later. Acta Neurol Scand 1985;71:177-89. 356 Barclay, Lang

supranu- supranuclear palsy. Am J7 5 Duvoisin RC, Golbe LI, Lepore FE. Progressive tations in progressive J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.352 on 1 April 1997. Downloaded from clear palsy. Can Neurol Sci 1987;14:547-54. Ophthalmol 1972;74: 1179-84. 6 Khunadom N, Kalumpaheti R, Saipetara K. Blepharo- 22 Jankovic J, Friedman DI, Pirozzolo FJ, McCrary JA. in progressive supranuclear palsy. The first case in Progressive supranuclear palsy: motor, neurobehavioural Thailand. J7ournal of the Medical Association of Thailand and neuro-ophthalmological findings. In: Streifler MB, 1979;62:89-92. Korczyn AD, Melamed E, Youdim MBH (eds). Raven 7 Mastaglia FL, Grainger E, Kee F, Sadka M, Lefroy R. Press, New York, Advances in Neurology 1990;-53: Progressive supranuclear palsy (The Steele-Richardson- 293-304. Olszewski syndrome). Clinical and electrophysiological 23 Maher ER, Lees AJ. The clinical features and natural his- observations in eleven cases. 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Rev Neurol 1993;149:30-6. http://jnnp.bmj.com/ on September 26, 2021 by guest. Protected copyright.