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ハンチントン病

著者: 五十嵐修一 新潟市民病院

監修: 高橋裕秀 昭和大学藤が丘病院 脳神経内科

著者校正/監修レビュー済:2022/03/02
患者向け説明資料

概要・推奨   

  1. うつ症状、不安、易刺激性、強迫症状に対しオランザピン、リスペリドンが有効かもしれない(推奨度2)
  1. コリンエステラーゼ阻害薬がハンチントン病の認知機能障害に対して有効かもしれない(推奨度3)
  1. ミノサイクリンがハンチントン病の認知機能改善に効果があった報告がある(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
五十嵐修一 : 特に申告事項無し[2022年]
監修:高橋裕秀 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. ハンチントン病は認知症、人格変化、舞踏運動などの運動機能障害を主徴とする神経変性疾患である。
  1. わが国での発症頻度は10万人あたり0.5人と比較的まれな疾患である。
  1. 常染色体優性遺伝性の疾患で、浸透率が高いこともあり、家族歴を有することが多い。
  1. 発症年齢は小児期から老年まで幅が広いが、30歳代から40歳代に多い。
  1. 慢性進行性の経過をたどる。
  1. 頭部CT、MRIでびまん性の脳萎縮に加え、尾状核の萎縮が特徴的である。
  1. 原因はhuntingtin遺伝子内のCAG繰り返し配列が、正常では36リピート以下であるが、ハンチントン病では配列数の増加があるため、遺伝子診断での確定診断が可能である。
  1. ハンチントン病は、厚生労働省選定の指定難病であり、その一部(Barthel Indexを用いて85点以下、または、障害者総合支援法における障害支援区分における「精神症状・能力障害二軸評価」を用いて精神症状評価2以上若しくは能力障害評価2以上)などでは、申請し認定されると指定医療機関での医療費の一部が公費負担として助成される。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
病歴・診察のポイント  
  1. 常染色体優性遺伝疾患のため、同胞に同様な症状を有する方がいないかの家族歴の問診が重要となる。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

Jerson Laks, Marlos Rocha, Claudia Capitão, Romeu Côrtes Domingues, Giovanna Ladeia, Maurício Lima, Eliasz Engelhardt
Functional and motor response to low dose olanzapine in Huntington's disease: case report.
Arq Neuropsiquiatr. 2004 Dec;62(4):1092-4. doi: /S0004-282X2004000600030. Epub 2004 Dec 15.
Abstract/Text Previous reports on the use of olanzapine in Huntington's disease (HD) used doses ranging from 10-30 mg. We report a case of HD with marked delusions and behavioral impairment assessed by the Unified Huntington's Disease Rating Scale at baseline and four months later treated with a low dose of olanzapine. The patient improved in motor, psychiatric and activity of daily living symptoms after four months of treatment. The response to a low dose of olanzapine in HD may be an indicator of efficacy in similar cases. Further randomized controlled trials can properly assess these findings.

PMID 15608976
F Squitieri, M Cannella, A Porcellini, L Brusa, M Simonelli, S Ruggieri
Short-term effects of olanzapine in Huntington disease.
Neuropsychiatry Neuropsychol Behav Neurol. 2001 Jan;14(1):69-72.
Abstract/Text OBJECTIVE: The aim was to describe the short-term (6 months) effects of olanzapine on behavioral and motor clinical manifestations in a group of 11 patients with Huntington disease.
METHOD: An open-pilot study of olanzapine (5 mg) in patients with clinical and genetic diagnosis of Huntington disease was used. The Unified Huntington Disease Rating Scale for clinical assessment and the Total Functional Capacity score for the disease-stage evaluation were used. A statistical analysis was performed to compare the effects of olanzapine on the Unified Huntington Disease Rating Scale scores at time 0 (baseline) and at time 1 (6 months). Comparisons of motor scores, of single behavioral items, and of TFC scores were performed within the group.
RESULTS: The behavioral assessment score of items regarding depression, anxiety, irritability, and obsessions showed a significant improvement (range of p, 0.0134-0.048). Given the total behavioral scores (sum of all the items investigated), five patients significantly improved their behavioral score after a 6-month treatment (range of p, 0.013-0.047). Choreic movements improved, although not significantly (0.05 < or = p < or = 1).
CONCLUSIONS: Olanzapine is a potentially useful antipsychotic drug, with significant short-term effects on behavioral changes, mainly in patients with severe psychiatric symptoms at the onset. It might be considered as a possible therapeutic choice for treatment of Huntington disease.

PMID 11234911
Abstract/Text
PMID 11012330
D Paleacu, M Anca, N Giladi
Olanzapine in Huntington's disease.
Acta Neurol Scand. 2002 Jun;105(6):441-4.
Abstract/Text OBJECTIVES: To study the effect of olanzapine (OL) in Huntington's disease (HD) patients.
DESIGN AND METHODS: Eleven HD patients (five men), aged 47.6 +/- 11.4 years and with disease duration of 11.2 +/- 3.3 years received OL. Assessment was carried out using the Clinical Global Impression of Change Scale (CGIC) and the Unified Huntington's Disease Rating Scale behavioral (UHDRS - b) and motor (UHDRS - m) at 6 month intervals.
RESULTS: Nine patients were treated for 9.8 +/- 5.9 months. The mean OL dose/patient was 11.4 +/- 8.5 mg/day (median 10 mg/day). Mean CGIC was 2.1 +/- 0.8. UHDRS - b improved significantly (P < 0.0001) and UHDRS - m did not change. Chorea improved in five patients and two dropped out because of drug eruption and lack of efficacy.
CONCLUSION: OL is a good alternative treatment in HD, mainly for the psychiatric symptoms and moderately effective for the motor symptoms, possibly because of its effect on chorea. We suggest OL should be used in HD patients with the adult onset form, severe chorea and/or severe psychiatric disturbances.

PMID 12027832
R M Bonelli, G Niederwieser, G G Tribl, P Költringer
High-dose olanzapine in Huntington's disease.
Int Clin Psychopharmacol. 2002 Mar;17(2):91-3.
Abstract/Text The few reports available on olanzapine in Huntington's disease (HD) are insufficiently documented and/or insufficiently dosed. We describe a 30-year-old woman with genetically confirmed HD who presented with severe chorea. She was not able to eat or dress without help and did not respond to haloperidol; the motor scale of the Unified HD Rating Scale (UHDRS-I) revealed 65 of a possible 124 points. After admission, we treated the patient with a high dose of olanzapine (30 mg daily). The chorea almost ceased in the next 2 days, she was able to eat and walk without assistance (UHDRS-I of 21 points), and fine motor tasks improved, as well as gait and eye movements. This effect lasted for 5 months. We conclude that high-dose olanzapine appears to be useful in grave choreatic attacks.

PMID 11890191
H C Dipple
The use of olanzapine for movement disorder in Huntington's disease: a first case report.
J Neurol Neurosurg Psychiatry. 1999 Jul;67(1):123-4.
Abstract/Text
PMID 10454874
Raphael M Bonelli, Peter Hofmann
A systematic review of the treatment studies in Huntington's disease since 1990.
Expert Opin Pharmacother. 2007 Feb;8(2):141-53. doi: 10.1517/14656566.8.2.141.
Abstract/Text Huntington's disease (HD) is an autosomal dominant, inherited, neuropsychiatric disease that gives rise to progressive motor, cognitive and behavioural symptoms. Current drug therapy has no effect on the progression of disability, and the need for any pharmacological treatment should be carefully considered. Hyperkinesias and psychiatric symptoms may respond well to pharmacotherapy, but neuropsychological deficits and dementia remain untreatable. Pharmacological intervention in the treatment of the movement disorder of HD is aimed at restoring the balance of neurotransmitters in the basal ganglia. A surprising amount of current drug therapy of HD in clinical practice is based on studies published before 1990. The authors conducted a systematic review of pharmacological therapy in HD using the available papers that were published between 1990 and 2006.

PMID 17257085
Timothy Graeme Johnston
Risperidone long-acting injection and Huntington's disease: case series with significant psychiatric and behavioural symptoms.
Int Clin Psychopharmacol. 2011 Mar;26(2):114-9. doi: 10.1097/YIC.0b013e3283407775.
Abstract/Text There is currently no known disease-altering treatment for Huntington's disease (HD). Successful symptomatic treatment often involves antipsychotic medication, including risperidone, yet the evidence base is limited to case reports. Although noncompliance to oral antipsychotic drugs can be a practical problem, especially when significant psychiatric manifestations of HD are present, the effect of depot antipsychotic medication in HD remains largely unknown. A period of nondrug compliance to oral risperidone in five patients with HD, and significant psychiatric and behavioural symptoms, after appearing to show symptomatic improvement, suggested a possible role for risperidone long-acting injection. The patients gave informed consent before receiving a fortnightly injection at a dose of 25 mg. At the end of 2-15 months (mean 1 year) they appeared to show an unexpected sustained symptomatic improvement (chorea, functioning and insight). In conclusion, this case series suggests risperidone long-acting injection may be a viable symptomatic treatment strategy in similar HD patients. If replicated, these findings have the potential to offer an effective strategy to manage some of the most difficult patients with HD to achieve symptomatic relief.

PMID 21119522
Eylem Sahin Cankurtaran, Elvan Ozalp, Haldun Soygur, Aysegul Cakir
Clinical experience with risperidone and memantine in the treatment of Huntington's disease.
J Natl Med Assoc. 2006 Aug;98(8):1353-5.
Abstract/Text We described a 32-year-old woman with Huntington's disease (HD) who presented with severe chorea, psychosis and cognitive abnormalities. We started risperidone at 2 mg p.o./d and increased to 4 mg p.o./d after six weeks. Psychotic and motor symptoms were markedly improved. Since there was no change in cognitive functions, we added memantine at 5 mg p.o./d and gradually increased the dose to 20 mg p.o/d after five weeks. We continued risperidone and memantine for nearly six months. The patient did not show any progression of cognitive symptoms or motor abnormalities. We did not observe any psychotic symptoms.

PMID 16916137
Kevin Duff, Leigh J Beglinger, Margaret E O'Rourke, Peg Nopoulos, Henry L Paulson, Jane S Paulsen
Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington's disease.
Ann Clin Psychiatry. 2008 Jan-Mar;20(1):1-3. doi: 10.1080/10401230701844802.
Abstract/Text BACKGROUND: Huntington's disease (HD) is a progressive, neuropsychiatric disorder, and limited reports indicate that risperidone might improve motor and psychiatric functioning for these patients.
METHODS: In a retrospective, chart review study to evaluate the effectiveness of risperidone on motor, psychiatric, and cognitive functioning in HD, 17 patients taking risperidone in the course of clinical care and 12 patients not taking any antipsychotic medication were compared across a year.
RESULTS: Patients taking risperidone demonstrated significantly improved psychiatric functioning and motor stabilization, whereas patients not taking risperidone were stable psychiatrically and worsened motorically.
CONCLUSIONS: Although controlled clinical trials are clearly needed, these preliminary results support the use of risperidone in patients with HD in treating their psychiatric and possibly motor symptoms.

PMID 18297579
Melissa J Armstrong, Janis M Miyasaki, American Academy of Neurology
Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology.
Neurology. 2012 Aug 7;79(6):597-603. doi: 10.1212/WNL.0b013e318263c443. Epub 2012 Jul 18.
Abstract/Text OBJECTIVE: To develop an evidence-based guideline assessing pharmacologic options for treating Huntington disease (HD) chorea.
METHODS: We evaluated available evidence from a structured literature review performed through February 2011.
RESULTS AND RECOMMENDATIONS: If HD chorea requires treatment, clinicians should prescribe tetrabenazine (up to 100 mg/day), amantadine (300-400 mg/day), or riluzole (200 mg/day) (Level B) for varying degrees of expected benefit. Occurrence of adverse events should be discussed and monitored, particularly depression/suicidality and parkinsonism with tetrabenazine and elevated liver enzymes with riluzole. Clinicians may also prescribe nabilone for modest decreases (1- to <2-point changes on the Unified Huntington's Disease Rating Scale [UHDRS] chorea score) in HD chorea (Level C), but information is insufficient to recommend long-term use, particularly given abuse potential concerns (Level U). Clinicians should not prescribe riluzole 100 mg/day for moderate (2- to < 3-point UHDRS chorea change) short-term benefits (Level B) or for any long-term (3-year) HD antichoreic goals (Level B). Clinicians may choose not to prescribe ethyl-EPA (Level B), minocycline (Level B), or creatine (Level C) for very important improvements (>3-point UHDRS chorea change) in HD chorea. Clinicians may choose not to prescribe coenzyme Q10 (Level B) for moderate improvements in HD chorea. Data are insufficient to make recommendations regarding the use of neuroleptics or donepezil for HD chorea treatment (Level U).

PMID 22815556
Huntington Study Group
Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial.
Neurology. 2006 Feb 14;66(3):366-72. doi: 10.1212/01.wnl.0000198586.85250.13.
Abstract/Text BACKGROUND: Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type 2 vesicular monoamine transporter. Open-label reports indicate TBZ is effective in treating chorea.
OBJECTIVE: To examine the safety, efficacy, and dose tolerability of TBZ for treating chorea in Huntington disease (HD).
METHODS: The authors randomized 84 ambulatory patients with HD to receive TBZ (n = 54) or placebo (n = 30) for 12 weeks. TBZ was increased over 7 weeks up to a maximum of 100 mg/day or until the desired antichoreic effect occurred or intolerable adverse effects supervened. The primary outcome was the change from baseline in the chorea score of the Unified Huntington's Disease Rating Scale (UHDRS) RESULTS: TBZ treatment resulted in a reduction of 5.0 units in chorea severity compared with a reduction of 1.5 units on placebo treatment (adjusted mean effect size = -3.5 +/- 0.8 UHDRS units [mean +/- SE]; 95% CI: -5.2, -1.9; p < 0.0001). There was also a significant benefit on ratings of clinical global improvement. There were five study withdrawals in the TBZ group and five serious adverse events (SAEs) in four subjects (drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer) compared with one withdrawal and no SAEs in the placebo group.
CONCLUSION: Tetrabenazine (TBZ), at adjusted dosages of up to 100 mg/day, effectively lessens chorea in ambulatory patients with Huntington disease. TBZ should be dosed individually based on ongoing assessment of possible adverse side effects.

PMID 16476934
Donepezil for Huntington's disease.
Mov Disord. 2000 Jan;15(1):173-6.
Abstract/Text
PMID 10634264
Marina de Tommaso, Nicola Specchio, Vittorio Sciruicchio, Olimpia Difruscolo, Luigi Maria Specchio
Effects of rivastigmine on motor and cognitive impairment in Huntington's disease.
Mov Disord. 2004 Dec;19(12):1516-8. doi: 10.1002/mds.20235.
Abstract/Text To evaluate the efficacy of rivastigmine on motor and cognitive impairment in Huntington's disease (HD), we carried out a prospective, open-label, randomized, controlled study. Twenty-one HD patients were enrolled: 14 were randomly sorted into medication and 7 to no-treatment groups. Clinical and demographic features were similar between groups. After 8 months, an efficacy evaluation was carried out to compare the two groups. The improvement of cholinergic transmission in HD patients seemed to have a slight effect in ameliorating cognitive performance and slowing motor deterioration.

2004 Movement Disorder Society.
PMID 15390067
P Petrikis, C Andreou, A Piachas, V P Bozikas, A Karavatos
Treatment of Huntington's disease with galantamine.
Int Clin Psychopharmacol. 2004 Jan;19(1):49-50.
Abstract/Text We present the case of a patient with Huntington's disease and psychosis, whose motor and psychiatric symptoms improved after administration of galantamine, an acetylcholinesterase inhibitor.

PMID 15101572
Abstract/Text
PMID 12629257
Huntington Study Group DOMINO Investigators
A futility study of minocycline in Huntington's disease.
Mov Disord. 2010 Oct 15;25(13):2219-24. doi: 10.1002/mds.23236.
Abstract/Text This study assessed the futility of proceeding with a Phase 3 clinical trial of minocycline as a disease-modifying treatment for Huntington's disease (HD). One hundred fourteen research participants with HD were randomized, 87 to minocycline (200 mg/d) and 27 to placebo. The change in Total Functional Capacity (TFC) score from baseline to Mo 18 was prespecified as the primary measure of HD progression. By using a futility design, we tested the null hypothesis that minocycline would reduce the mean decline in TFC score by at least 25% compared to a fixed value obtained from a historical database, with a one-tailed significance level of 10%. The placebo group was included to facilitate blinding. Rejection of the null hypothesis would discourage a major definitive trial of minocycline in HD. For the primary analysis, missing data were handled by carrying forward the last available observation; a secondary analysis used multiple imputations. The mean TFC decline in the minocycline group was 1.55 (SD 1.85), and futility was not declared (P = 0.12) for the primary analysis. When multiple imputation was used to handle missing data, the mean TFC decline in the minocycline group of 1.71 (SD 1.96, P = 0.07) suggested futility, as was the case for prespecified secondary outcome measures. There were no safety abnormalities attributable to minocycline. Based on the threshold of 25% improvement in TFC, further study of minocycline 200 mg/d in HD was not warranted. Futility designs aid in screening potential therapies for HD.

PMID 20721920
Raphael M Bonelli, Anna K Hödl, Peter Hofmann, Hans-Peter Kapfhammer
Neuroprotection in Huntington's disease: a 2-year study on minocycline.
Int Clin Psychopharmacol. 2004 Nov;19(6):337-42.
Abstract/Text Huntington's disease (HD), a relentlessly progressive neurodegenerative disorder, is characterized by a clinical triad of psychiatric, cognitive and motor disturbances. The antibiotic minocycline, a caspase inhibitor exhibiting antiapoptotic properties, has been shown to prolong survival in the transgenic mouse model of HD. We administrated minocycline to 14 patients with genetically confirmed HD. The patients were psychiatrically, neurologically and neuropsychologically evaluated at baseline, and after 6 and 24 months of treatment, using the Unified HD Rating Scale and a neuropsychological test battery. After 12 months, three patients were lost to follow-up so that 11 patients were analysed at the endpoint. Minocycline was well tolerated. Unlike the expected natural course of HD, patients exhibited stabilization in general motor and neuropsychological function at endpoint, after improving in the first 6 months. Moreover, we found a significant amelioration of psychiatric symptoms that was not apparent after the first 6 months. In detail, the Mini-Mental State Examination, the Total Motor Score, the Total Functional Capacity Scale and the Independence Scale, as the most prominent scales in HD, were stabilized after 3 years of treatment. Our results confirm previous animal studies and indicate a neuroprotective effect of this agent in HD. A long-term, double-blind, placebo-controlled trial appears highly warranted for definitively establishing the value of minocycline in HD.

PMID 15486519
David Blum, Abdelwahed Chtarto, Liliane Tenenbaum, Jacques Brotchi, Marc Levivier
Clinical potential of minocycline for neurodegenerative disorders.
Neurobiol Dis. 2004 Dec;17(3):359-66. doi: 10.1016/j.nbd.2004.07.012.
Abstract/Text Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to the launching of various clinical trials. The present review summarizes the available data supporting the clinical testing of minocycline for these neurodegenerative disorders. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.

PMID 15571972
D P Leonard, M A Kidson, J G Brown, P J Shannon, S Taryan
A double blind trial of lithium carbonate and haloperidol in Huntington's chorea.
Aust N Z J Psychiatry. 1975 Jun;9(2):115-8.
Abstract/Text Six patients with a family history of Huntington's chorea (HC) participated in a double blind crossover trial involving four treatments--lithium carbonate, haloperidol, lithium carbonate and haloperidol, and placebo. Each treatment was administered for three weeks and, at the end of each treatment period, assessments were made of chorea and a number of psychological variables. None of the treatments significantly affected chorea measurements. With regard to the psychological variables, the levels of irritability, the frequency of angry outbursts and depression did appear to be affected in some patients by the treatment. Three patients improved on a combination of lithium carbonate and haloperidol while the remaining three did not. Haloperidol alone significantly raised depression ratings above levels for other treatments including placebo. It is suggested that lithium carbonate and haloperidol together should be seriously considered in the treatment of HC when patients are excessively irritable and impulsive.

PMID 125578

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