J Neurol Neurosurg Psychiatry 1998;65:577–579 577 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.577 on 1 October 1998. Downloaded from

SHORT REPORT

Levodopa responsive parkinsonism in an adult with Huntington’s disease

Brad A Racette, Joel S Perlmutter

Abstract to his lower limbs within one year. One year A patient is reported on with Huntington’s later, he developed diYculty with walking, disease who, as an adult, first developed freezing, and had subsequent loss of balance. severe parkinsonism with bradykinesia, He became stiVer and slower requiring maxi- rigidity, postural instability and festinat- mal assistance to walk. Speech became softer ing gait. His clinical signs were similar to and more diYcult to understand, and he devel- those of the Westphal variant of Hunting- oped occasional dysphagia. He denied cogni- ton’s disease except that he also had rest- tive impairment or mood disturbance. He had ing tremor and a supranuclear gaze palsy. no other medical problems, and no history of Magnetic resonance imaging showed cau- encephalitis, toxin exposure, or neuroleptic date and putamen atrophy. Genetic analy- use. His father, paternal uncle, and paternal sis disclosed 49 triple CAG repeats in grandmother had similar symptoms with aki- allele 1 and 17 in allele 2 confirming the nesia and rigidity beginning after the age of 40. diagnosis of Huntington’s disease. Treat- None of the “aVected” family members had ment with levodopa produced substantial genetic testing before they died and none of the functional motor improvement with a 17 asymptomatic relatives agreed to examination. point reduction in the unified Parkinson’s The phenotype of his mother’s grandfather was disease rating scale (UPDRS) motor sub- unknown except that he died of a “neurological scale including reduction of tremor, problem.” The figure shows the pedigree. bradykinesia, and postural instability. General examination disclosed multiple This is the first report of a patient with cigar burns on his limbs but was otherwise adult onset Huntington’s disease with par- normal. He was awake, alert, oriented to kinsonism responsive to levodopa. person, place, and time but was mildly inatten- tive. He could register three of three objects but (J Neurol Neurosurg Psychiatry 1998;65:577–579) recalled none of three at 5 minutes. Speech was

severely dysarthric and hypophonic but lan- http://jnnp.bmj.com/ Keywords: levodopa; Huntington’s disease; parkinson- guage was normal. He was unable to volition- ism ally look left or up with either eye but was able to look down and to the right with slow smooth The initial manifestations of Huntington’s dis- pursuits. He had preserved oculocephalics. ease typically include dementia, psychiatric There were no Kayser-Fleischer rings. He had disturbance, and chorea.1 Alternatively, brady- marked facial masking. He had diYculty open- Department of ing his mouth to command and could barely Neurology and kinesia and rigidity may be the first feature; this

protrude his tongue. While lying in bed, he on October 4, 2021 by guest. Protected copyright. Neurologic Surgery is the most common presentation in childhood (Neurology) onset Huntington’s disease. This “Westphal” held his arms flexed and legs extended. He had B A Racette variant accounts for 85% of childhood onset normal strength but severe rigidity and brady- J S Perlmutter Huntington’s disease whereas only 6% of kinesia in all four limbs. His right big toe was patients with adult onset Huntington’s disease dorsiflexed at rest and with action. Reflexes Mallinckrodt Institute 2 were symmetrically brisk in his upper and of Radiology, have these initial manifestations. Levodopa Washington University may provide symptomatic benefit in the child- lower limbs with sustained clonus at the knees School of Medicine, St hood onset Westphal variant3 but the response and ankles. Plantar reflexes were extensor Louis, MO 63110, USA in patients with adult onset has not been bilaterally. He hada3Hzlarge amplitude J S Perlmutter described. We now report that levodopa flexion-extension rest tremor in both upper limbs that persisted with action. He had exces- Correspondence to: provided symptomatic benefit in a patient with Dr Joel S Perlmutter, the adult onset Westphal variant of Hunting- sive flexion of the upper limbs while standing Campus Box 8225, 4525 ton’s disease. and circumducted both legs while walking. He Scott Avenue, St Louis, MO had severe postural instability and would fall 63110, USA. Telephone 001 314 362 6908; fax 001 314 spontaneously when not assisted. The UPDRS 362 0168. Case report motor subscale before treatment was 83 out of A 38 year old right handed white man had a a possible 108. Received 10 September 1997 main complaint of shaking of his arms. Four Brain MRI demonstrated marked caudate and in revised form 9 March 1998 years earlier he had noted the gradual onset of and putamen atrophy as well as mild diVuse Accepted 16 March 1998 resting tremor in both upper limbs that spread cortical atrophy. Genetic testing for Hunting- 578 Racette, Perlmutter J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.577 on 1 October 1998. Downloaded from

1 2 I

II 12

1237456819 0 III

Suicide 12 IV HD Unknown phenotype

Parkinsonism

Chorea

Pedigree. Squares indicate men and circles indicate women. Subjects in the third generation are represented as diamonds to protect anonymity. Diagonal lines represent deceased family members.

ton’s disease showed heterozygosity of the Levodopa provided meaningful improvements CAG repeat region on 4p16.3 with a normal in quality of life including improvements in gait allele of 17 trinucleotide repeats and an abnor- and postural instability, as identified on the mal allele of 49 repeats. Genetic testing for the UPDRS motor subscale. Genetic testing and Machado-Joseph/spinocerebellar ataxia 3 gene MRI were consistent with Huntington’s dis- disclosed normal allele lengths (20 and 21 ease but other diseases may have coexisted. CAG repeats). Levodopa/carbidopa (200 Coexistent idiopathic Parkinson’s disease is mg/50 mg) provided symptomatic improve- possible but the relative symmetry of signs and http://jnnp.bmj.com/ ment with a 17 point reduction on the unified young onset makes this less likely. Parkinson- Parkinson’s disease rating scale (UPDRS) ism with rest tremor and response to levodopa motor subscale including improvement in does not necessarily indicate idiopathic Parkin- tremor, finger and hand dexterity, postural sta- son’s disease.45 Two large series of patients bility, and rising from a chair. While taking presenting with presumed Parkinson’s disease levodopa he could rise from a chair independ- based on clinical criteria showed only 76% ently and walk to the bathroom without assist- accuracy when followed up to necropsy. Over ance for the first time in 2 years. He could feed

half of their patients with non-idiopathic on October 4, 2021 by guest. Protected copyright. himself but still required assistance for dressing Parkinson’s disease had a “good” response to and bathing. Clinical improvement continued levodopa. The main confounding diagnoses to increase with doses of levodopa up to 800 included progressive supranuclear palsy, multi- mg a day but there was no additional benefit at ple systems atrophy, Alzheimer’s disease, vas- higher doses. He had no untoward eVects from cular disease, drug induced parkinsonism, and levodopa. He refused a trial of medication substantia nigra degeneration without Lewy withdrawal. He maintained benefit for at least 1 bodies. Our patient has features inconsistent year and did not develop fluctuations of his with idiopathic Parkinson’s disease such as parkinsonian symptoms throughout the day. corticospinal tract signs, supranuclear gaze He was subsequently lost to follow up. palsy, and relatively symmetric onset; however, Huntington’s disease should be considered in Discussion patients with atypical parkinsonism, regardless We report on a patient with Huntington’s of response to levodopa. disease with adult onset of manifestations The mechanism of action of levodopa for similar to the Westphal variant but he also had relief of parkinsonian symptoms in Hunting- rest tremor, supranuclear gaze palsy, and mild ton’s disease is unclear. Albin et al found loss of dementia. To our knowledge, this is the first striatal neurons projecting to the globus description of response to levodopa in a patient pallidus externa, globus pallidus interna, and with an adult onset with these features. substantia nigra in akinetic rigid Huntington’s Levodopa responsive parkinsonism in an adult with Huntington’s disease 579 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.577 on 1 October 1998. Downloaded from

disease6 with no reduction of neurons contain- onset Huntington’s disease had the most ing tyrosine hydroxylase in the substantia nigra consistent symptomatic response to levodopa whereas those patients with Huntington’s with reduction of parkinsonian manifestations.3 disease with chorea had relative preservation of Based on the experience with our patient, levo- projections to the globus pallidus interna. As dopa may provide symptomatic benefit to nigrostriatal neurons containing dopamine patients with adult onset Huntington’s disease were presumably preserved, they argued that with prominent parkinsonism. the additional degeneration of the direct path- way may underlie the parkinsonian Hunting- This work has been supported by NIH grants NS31001, ton’s disease phenotype. It would be tempting NS32318, and NS07205, a Seay Foundation Fellowship in to pose that the mechanism of action of Neuropharmacology, the Greater St Louis Chapter of the American Parkinson’s Disease Association, and the Clinical levodopa is to partially restore activity of Hypotheses Research Section of the Charles A Dana Founda- striatal projection neurons to the globus tion. pallidus interna but we have no data to support this notion. 1 Vessie PR. On the transmission of Huntington’s chorea for 300 years: the Bures family group. J Nerv Ment Dis Levodopa has been used for diagnostic test- 1932;76:553–73. ing and symptomatic treatment in Hunting- 2 Bruyn GW.Huntington’s chorea. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Amsterdam: North Hol- ton’s disease. Klawans and Paulson suggested land, 1969:6:298. that dopa induced chorea in presymptomatic 3 Jongen PJH, Renier WO, Gabreels FJM. Seven cases of Huntington’s disease in childhood and levodopa induced subjects could indicate increased likelihood of improvement in the hypokinetic-rigid form. Clin Neurol carrying the abnormal gene and subsequent Neurosurg 1980;82:251–1. 7 4 Hughes AJ, Daniel SE, Kilford W, et al. Accuracy of clinical development of Huntington’s disease. The diagnosis of idiopathic Parkinson’s disease: a clinico- lack of accuracy of this test and subsequent pathological study of 100 cases. J Neurol Neurosurg Psychia- try 1992;55:181–4. development of genetic testing have eliminated 5 Rajput AH, Rozdilsky Bl, Rajput A. Accuracy of clinical this as a reasonable alternative. Most attempts diagnosis in parkinsonism—a prospective study. Can J Neurol Sci 1991;18:275–8. to treat chorea in Huntington’s disease with 6 Albin RL, Reiner A, Anderson KD, et al. Striatal and nigral levodopa were unsuccessful or caused an exac- neuron subpopulations in rigid Huntington’s disease: 8 implications for the functional anatomy of chorea and erbation of the chorea ; although a few adults rigidity-akinesia. Ann Neurol 1990;27:357–65. with chorea as their primary motor manifesta- 7 Klawans HC, Paulson GW. Predictive test for Huntington’s chorea. Lancet 1970;1185–6. tion of Huntington’s disease had symptomatic 8 Sishta SK, Templer DI. Levodopa in Huntington’s chorea. benefit from levodopa. Patients with juvenile Can Med Assoc J 1976;114:798–9. http://jnnp.bmj.com/ on October 4, 2021 by guest. Protected copyright.