J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.238 on 1 February 2000. Downloaded from 238 J Neurol Neurosurg Psychiatry 2000;68:238–241

SHORT REPORT

Late onset levodopa responsive Huntington’s disease with minimal masquerading as Parkinson plus syndrome

I Reuter, M T M Hu, T C Andrews, D J Brooks, C Clough, K Ray Chaudhuri

Abstract appreciated.5 However, the mean age of onset Huntington’s disease is characterised by of “rigid Huntington’s disease” documented in hyperkinetic movements, mainly chorea, this review ranged from 22.2 years to 37.8 cognitive dysfunction, and psychiatric ab- years, which is substantially younger than that normalities. Non-dopa responsive parkin- of our patients. To our knowledge, only two sonism occurs in the later stages of patients with late onset Huntington’s disease choreic disease or as the predominant and levodopa responsive have feature of juvenile patients (Westphal been previously reported. Trosch and Le Witt8 variant). Late onset Huntington’s disease reported one patient with late onset Hunting- presenting as levodopa responsive parkin- ton’s disease with parkinsonism responsive to sonism is rare. A series of four patients levodopa and Racette and Perlmutter9 reported with late onset Huntington’s disease pre- the case of a 38 year old man with an akinetic- senting as levodopa responsive parkinson- rigid syndrome, loss of balance, and mild ism and cardiovascular , relieved by high doses of levodopa. In initially misdiagnosed as multiple system this paper, we report a series of four patients atrophy (MSA) in three patients, is re- with genetically confirmed late onset (mean The Regional ported. Levodopa treatment did not un- age of onset 56.75 years) Huntington’s disease Movement Disorders mask significant chorea. These cases presenting with levodopa responsive parkin- Unit, Department of sonism along with combinations of limb dysto- , Regional suggest the presence of a distinct pheno- Neurosciences Centre, typic variant of Huntington’s disease to be nia, gait apraxia, torticollis, and King’s College added to the diVerential diagnosis of other causing considerable diagnostic confusion. Hospital, Guy’s, akinetic rigid syndromes. Three patients were initially misdiagnosed as King’s, and St Thomas (J Neurol Neurosurg Psychiatry 2000;68:238–241) having (MSA). Addi-

School of Medicine, tional features of note in these patients http://jnnp.bmj.com/ London, UK Keywords: Huntington’s disease; chorea; dopa- included an uncertain family history, minimal I Reuter responsive; multiple system atrophy; postural hypoten- chorea, and minimal cognitive impairment. MTMHu sion C Clough K Ray Chaudhuri Case reports MRC Cyclotron Unit, The classic presentations of Huntington’s CASE 1 Imperial College disease, an autosomal dominant neurodegen- A 63 year old right handed white man with a School of Medicine, erative disorder associated with a CAG triplet presumptive diagnosis of MSA was referred for on September 28, 2021 by guest. Protected copyright. Hammersmith repeat expansion in the IT 15 gene, includes tertiary opinion. He gave a 3 year history of Hospital, London, UK chorea, and tics, a range of neuropsy- slowly progressive ataxic gait, falls, abnormal MTMHu chiatric abnormalities, dementia, and disorders posturing of his right arm, and slurred speech. T C Andrews 1–3 D J Brooks of gait. Considerable heterogeneity, however, On examination, he had a dominantly axial has been recognised in relation to the clinical akinetic rigid syndrome with a wide based gait, University Hospital phenotype.4–6 Non-levodopa responsive parkin- impaired postural reflexes, and a tendency to Lewisham, London, sonism may be the dominant presenting fall backwards. Dystonic posturing of his right UK feature in young patients, the so called “West- arm and mild chorea of the left fingers were K Ray Chaudhuri phal” variant, which seems to account for noted and rigidity was more marked in the Correspondence to: about 85% of childhood onset Huntington’s right upper limb. He had mild diYculties on Dr K Ray Chaudhuri, disease.57 Other phenotypic variants such as routine cognitive testing and eye movements Department of Clinical patients with adult onset disease with minimal showed a saccadic pursuit movement but no Neurosciences, Mapother House, King’s College cognitive impairment and pure chorea have supranuclear gaze palsy. There were no py- Hospital, Denmark Hill, been reported.4 In adults non-iatrogenic par- ramidal signs. Family history was that of London SE5 9RS, UK kinsonism as a presenting feature of late onset “probable Parkinson’s disease” in a paternal email [email protected] Huntington’s disease (onset after 50 years age) aunt and “” in a maternal aunt. He had is rare. Bittenbender and Quadfasel reviewed mild urinary frequency but sphincter electro- Received 7 April 1999 and in the literature on akinetic and rigid forms of myography (SEMG) studies were highly ab- revised form 17 September 1999 Huntington’s disease and concluded that the normal. Neuropsychometry showed a verbal Accepted 21 October 1999 rigid form is commoner than generally IQ of 81 and performance IQ of 76, with an J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.238 on 1 February 2000. Downloaded from Late onset Huntington’s disease 239

Patient characteristics

Levodopa Disease CAG duration Initial Estimated Repeat Dose Family Age (y) diagnosis IQ length mg/day Response history Chorea Dystonia SEMG

63 5 MSA 91 18/43 400 ++ P ± −AB 67 7 PD/MSA 95 19/44 800 +++ P − CC/LL ND 52 7 ARS 94 17/46 200 + C/HD − UL ND 68 4 MSA NA 17/42 400 ++ P/E/M ± LL ND

P=parkinsonism; C=chorea; E=; M=motor disease; ARS=akinetic-rigid syndrome; NA=not available; ND=not done; CC=craniocervical; LL=lower limb; UL=upper limb; AB=abnormal. estimated IQ of 91. Verbal subtests showed ing slowness and diYculty in walking. She had average results and non-verbal reasoning and a family history of movement disorders includ- memory functioning was borderline defective. ing chorea and one sister was known to have Language functioning and perception was parkinsonism, later diagnosed as Huntington’s good. MRI showed generalised atrophy disease. On examination, she had an akinetic and single photon emission tomography rigid syndrome with frequent gait freezing and (SPECT) indicated left temporoparietal. hy- reduced left arm swing with dystonic posturing poperfusion. A standardised levodopa chal- of the left hand. She had reduced saccadic and lenge test showed greater than 30% improve- pursuit upgaze but no supranuclear downgaze ment on the modified King’s College Hospital paresis, impersistence of tongue protrusion, or Parkinson’s disease rating scale chorea. The initial diagnosis was thought to be (KCHPDRS).10 However, because of coexist- a variant of akinetic rigid syndrome. Levodopa ent mild chorea and a family history of parkin- therapy at a dose of 600 mg produced moder- sonism, genetic tests for Huntington’s disease ate benefit but unmasked slight chorea of her and dentatorubro-pallidoluysian atrophy face and limbs after therapy for 1 year. (DRPLA) were carried out and testing for Neuropsychometry showed a verbal IQ of 90 Huntington’s disease was positive (table). At 2 and a performance IQ of 95 with an estimated year follow up, the patient has continuing levo- IQ of 94. Other tests were rated as average. A dopa responsiveness (400 mg/day) with mini- genetic test for Huntington’s disease was posi- mal chorea and no deterioration in cognitive tive (table). Levodopa therapy had to be function. discontinued because of and de- creased response with time. CASE 2 A 67 year old right handed white man was referred witha6yearhistory of slowness of CASE 4 manual dexterity and gait. He and his carer A 68 year old white man presented with a 4 denied history of cognitive decline, falls, or uri- year history of unsteady gait and swallowing nary diYculties although there was erectile diYculties. There was history of parkinsonism, dysfunction. His father was thought to have epilepsy, , and narcolepsy Parkinson’s disease and family history was oth- in the family. On examination, he had mild asymmetric parkinsonism with global hyper-

erwise negative. On examination, he had a http://jnnp.bmj.com/ bradykinesia dominant akinetic rigid syndrome reflexia, extensor plantar responses, heel-toe with a left sided emphasis and impaired , dystonia of lower limbs, but normal eye postural reflexes. In addition, there was a right movements. There was a mild dysdiadochoki- laterocollis and dystonic posturing of his left nesis. The diVerential diagnoses included hand. Eye movements showed breaking up of , MSA, and other heredi- smooth pursuit but no supranuclear gaze palsy tary degenerative akinetic rigid syndromes. or impersistence of tongue protrusion. A levo- Levodopa therapy (300 mg) improved bradyki- nesia and rigidity and the patient continues

dopa challenge test was strongly positive with on September 28, 2021 by guest. Protected copyright. greater than 40% improvement in KCHPDRS with 400 mg of levodopa at 2 year follow up. and he was thought to have Parkinson’s disease Formal neuropsychometry could not be per- or the parkinsonian variant of MSA (MSA-P). formed but a mini mental state examination Neuropsychometry showed a verbal IQ of 105 documented a score of 25/30. Brain MRI and a performance IQ of 93 with an estimated showed generalised cerebral and caudate atro- IQ of 95. All other neuropsychological testing phy. A genetic test for Huntington’s disease was was rated at the average level with no positive (table). significant impairment. Brain MRI showed In all patients the following tests were abnormal enhancement at the striatal region. normal or negative: an autoantibody and acan- Genetic tests performed because of family his- thocyte screen, thyroid function tests, vitamin tory of parkinsonism and dystonia at onset of B12/folate concentrations, angiotensin con- illness was negative for DRPLA but positive for verting enzymes, lysosomal enzymes, urinary Huntington’s disease (table). At 2 year follow organic and amino acids, slit lamp examination up the patient continues to be dopa responsive of eye, and serum copper and caeruloplasmin (levodopa dose 800 mg) with mild progression (case 3). of clinical signs (table). Autonomic signs and symptoms were evi- dent in all patients and included mild but CASE 3 significant systolic postural hypotension in A 52 year old white left handed woman was three patients (figure). Additionally, urinary referred because ofa5yearhistory of increas- frequency was present in patients 1 and 4 and J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.238 on 1 February 2000. Downloaded from 240 Reuter, Hu, Andrews, et al

180 these cases was 15.2 years, suggesting that Supine 160 these were of juvenile onset and thus diVerent Erect 140 from our patient group. While reviewing the 120 literature, these authors documented 64 cases 100 of rigid Huntington’s disease with varying 80 combinations of chorea, family history, cogni- 60 tive impairment, and a mean age of onset of 5 SBP (mm Hg) 40 22.2 years. 20 The clinical phenotype and the unusual 0 family histories in our patients led to misdiag- Patient 1 Patient 2 Patient 3 Patient 4 nosis of these cases as MSA (patients 1, 2, and Changes in systolic blood pressure (SBP) while supine and 4); supported by an abnormal sphincter EMG after 3 minutes standing in four patients with Huntington’s in patient 1, query Parkinson’s disease (patient disease. 2), and an atypical akinetic-rigid syndrome (patient 3). These diagnoses were further sup- facial hyperhidrosis in patient 1. As noted pre- ported by a positive levodopa response without viously, SEMG studies were highly abnormal unmasking chorea (a feature used to test for in patient 1. Huntington’s disease before genetic testing), cardiovascular dysautonomia particularly pos- Results tural hypotension, the presence of early falls POSITRON EMISSION TOMOGRAPHY (PET) and craniocervical and limb , and a PET was performed in patients 1, 2, and 3. lack of chorea and appreciable cognitive Patient 1 had a striatal fluorodopa uptake dysfunction. The diagnosis of Huntington’s within the normal range and patient 2 demon- disease was suspected on the basis of the atypi- strated markedly reduced and asymmetric cal signs described above and the fact that fluorodopa uptake in the putamen (right more MSA is rarely familial. There was a family his- aVected than the left) with relative caudate tory of Huntington’s disease in one patient 11 sparing. C raclopride PET studies in patient 2 (patient 3). However, a high index of suspicion showed supranormal D2 receptor binding in is required as otherwise our patients could have the right putamen suggesting an up regulation been included in a familial Parkinson’s disease of postsynaptic D2 receptors in response to or MSA study or clinical trial. reduced dopamine release. The caudate D2 In choreic and asymptomatic carriers of the receptor binding in this patient was reduced, Huntington’s disease gene, workers have re- suggesting early Huntington’s disease. Patients ported a selective depletion of enkephalin 11 1 and 3 had reduced caudate and putamen C immunoreactive terminals (colocalised in the raclopride binding. indirect D2 expressing external striatopallidal pathway).11 12 However, in patients with Discussion akinetic-rigid Huntington’s disease a near total This series of four patients illustrates that (a) loss of both indirect and direct striatopallidal levodopa responsive parkinsonism may be a fibres containing encephalin as well as GABA presenting feature of late onset Huntington’s and substance P have been reported.13 14 Stud- disease; (b) these patients may be misdiagnosed ies using PET have shown that reduced striatal as MSA or atypical akinetic rigid syndromes; glucose metabolism and dopamine receptor http://jnnp.bmj.com/ (c) dysautonomia may complicate clinical binding occurs in symptomatic patients in diagnosis in favour of MSA; and (d) a family Huntington’s disease and reduction of striatal

history of “Parkinson’s disease” may be a mis- D1 and D2 receptor binding in about 50% of at leading clue in these cases. risk asymptomatic adults and mutation We think that this is the first report of a series carriers.15 In our series, patient 1 had normal of patients with Huntington’s disease present- striatal fluorodopa uptake thus ruling out con- ing with a moderately levodopa responsive par- current Parkinson’s disease whereas in patient on September 28, 2021 by guest. Protected copyright. kinsonism, mild dysautonomia, and a family 2, fluorodopa uptake in the putamen was history of parkinsonism. Other atypical fea- reduced in an asymmetric fashion with relative tures include the late age of onset of disease sparing of caudate as seen in Parkinson’s

(56.75 years), asymmetric parkinsonism, ab- disease. However, in this patient , caudate D2 sence of eye or tongue movement abnormali- binding was reduced suggesting early Hunting- ties seen in Huntington’s disease, abnormal ton’s disease. Although the possibility of coex- sphincter EMG in one patient, lack of appreci- istent Parkinson’s disease in this patient exists, able limb chorea and cognitive abnormalities, clinically this is unlikely as there was early pos- and mild dysautonomia manifest as postural tural reflex impairment, laterocollis, and dysto- hypotension, urinary frequency, and hyperhid- nia at the onset of disease. Furthermore, we rosis. Reports of such patients are extremely have reported postmortem findings on another rare although recently two such patients have patient with late onset Huntington’s disease been described and one of these, reported on with levodopa responsive parkinsonism and by Racette and Perlmutter,9 had a family chorea who did not have Lewy bodies.16 This history of a tremor disorder. Rigid and akinetic also suggests that the levodopa responsiveness forms of Huntington’s disease were also in Huntington’s disease is unlikely to be due to reported by Bittenbender and Quadfasel, who concurrent Parkinson’s disease. The issue of described four “rigid” cases of Huntington’s dopa responsiveness and parkinsonism as the disease and reviewed the literature on this presenting feature in late onset Huntington’s subject.5 The mean age of onset of disease in disease is also unusual and merits discussion. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.238 on 1 February 2000. Downloaded from Late onset Huntington’s disease 241

Although both cases reported by Trosch and (4) Mild cardiovascular dysautonomia. LeWitt8 and Racette and Perlmutter9 were levodopa responsive, the first responded only We thank Drs C M Timberlake, NPS Bajaj, and D Collier for to large doses while in the second follow up helpful comments, A Dean for necropsy studies, and J information after 1 year is not available. Our Grimshaw for secretarial assistance. patients (except patient 3) continue to derive benefit from a moderate dose of levodopa 1 Bruyn GW. Huntington’s chorea: historical, clinical and laboratory synopsis. In: Vinken PJ, Bruyn GW, eds. Hand- (mean dose 533.3 (SD 52) mg) at 2 year follow book of clinical neurology. Vol 6. Amsterdam: North Press up. Benefit from levodopa in Huntington’s dis- Publishing 1968;6:298–378. 2 Huntington’s Disease Collaborative Research Group. A ease has previously only been reported in the novel gene containing a trinucleotide repeat that is juvenile hypokinetic-rigid variant.17 A recent expanded and unstable in Huntington’s disease chromo- 11 somes. Cell 193;72:971–83. C DTBZ PET study has shown that striatal 3 Folstein SE. Huntington’s disease. A disorder of families. vesicular monoamine transporter type 2 Baltimore: Johns Hopkins University Press, 1989. 4 Britton JW, Uitti RJ, Ahlskog JE, et al. Hereditary late onset (VMAT2) binding is markedly reduced in the chorea without significant dementia. Genetic evidence for posterior putamen of patients with akinetic substantial phenotypic variant in HD. Neurology 1995;45: 18 443–7. rigid Huntington’s disease. This would indi- 5 Bittenbender JB, Quadfasel FA. Rigid and akinetic forms of cate that the nigrostriatal pathway is addition- Huntington’s chorea. Arch Neurol 1962;7:37–50. 6 Bird MT, Paulson GW.The rigid form of Huntington’s cho- ally involved in akinetic rigid Huntington’s dis- rea. Neurology 1971;21:271–6. ease. The beneficial eVect of levodopa in these 7 Brion S, Comoy C. Rigidite et choree de Huntington: la forme infantile de la maladie de Huntington (etude d ùn patients with Huntington’s disease may reflect cas anatomo-clinique). Rev Neurol 1965;112:183–99. facilitation of neurotransmission through a 8 Trosch RM, LeWitt PA. Westphal variant Huntington’s dis- ease masquerading as MSA. Mov Disord 1996;11(suppl damaged nigrostriatal pathway. 2):181. All our patients had small expansions of 9 Raclette BA, Perlmutter JS. Levodopa responsive parkinson- ism in an adult with Huntington’s disease. J Neurol Neuro- CAG repeats in IT 15 (42–46, normal <38), as surg Psychiatry 1998;65:577–9. did the patient reported on by Racette and 10 Quinn NP, Marsden CD, Parkes JD. Complicated response 8 fluctuations in Parkinson’s disease: response to intravenous Perlmutter. Patients with juvenile onset par- infusions of levodopa. Lancet 1982;ii:412–15. kinsonian Huntington’s disease tend to have 11 Reiner A, Albin RL, Anderson KD, et al.DiVerential loss of striatal projection in HD. Proc Natl Acad Sci USA CAG repeats in excess of 60, which correlates 1988;85:5733–7. with a rapidly progressive course of Hunting- 12 Storey E, Beal MF. Neurochemical substrates of rigidity and chorea in Huntington’s disease. Brain 1993;116:1201–22. ton’s disease, by contrast with slowly progres- 13 Albin RL, Reiner A, Anderson KD, et al. Striatal and nigral sive disease seen in our patients. It may be neuron subpopulations in rigid HD: implications for the functional anatomy of chorea and rigidity-akinesia. Ann speculated that the small CAG repeat expan- Neurol 1990;27:357–65. sion in our patients accounts for their slowly 14 Bugiani O, Tabaton M, Cammarata S. Huntington’s disease: survival of large striatal neurons in the rigid progressive disease. variant. Ann Neurol 1984;15:155–6. In conclusion, we have described a distinct 15 Andrews TC, Brooks DJ. Advances in the understanding of early Huntington’s disease using the functional imaging variant of Huntington’s disease with the techniques of PET and SPET. Molecular Medicine Today following features: 1998;12:532–9. 16 Chaudhuri K Ray, Reuter I, Andrews T, et al. Late onset (1) Late onset parkinsonism with moderate Huntington’s disease presenting with dopa-responsive par- and persistent dopa responsiveness at 2 year kinsonism and minimal chorea. A new phenotypic variant. Mov Disord 1998;13(suppl 2):167. follow up, without inducing chorea. 17 Jongen PJH, Renier WO, Gabreels FJM. Seven cases of (2) Minimal or absent chorea or significant Huntington’s chorea in childhood and levodopa induced cognitive, eye and tongue movement abnor- improvement of hypokinetic-rigid form. Clin Neurol Neuro- surg 1980;82:251–61. http://jnnp.bmj.com/ malities. 18 Bohnen NI, Meyer P, Koeppe RA, et al. Decreased striatal (3) Family history of “parkinsonism” or monoaminergic terminals in Huntington’s disease demon- strated with (+)-[C-11]DTBZ PET. J Nucl Med 1998; other movement disorders. 5(suppl):125P. on September 28, 2021 by guest. Protected copyright.