Guideline sources The following summarized guidelines for the evaluation and management of Huntington's disease (HD) are prepared by our editorial team based on guidelines from the American Academy of Neurology (AAN 2020; 2012), the European Huntington's Disease Network (EHDN 2019), and the Huntington's Disease Expert Group (HD-EG 2018). 1 2 3 4 5 6 6 7 8 Definition HD is an adult-onset, autosomal dominant inherited neurodegenerative disorder characterized by the progressive development of chorea, psychiatric symptoms, and cognitive impairment. 5 Epidemiology Primary neuropathophysiology occurs in the neostriatum with atrophy, neuronal loss and gliosis in the caudate nucleus, thalamus, and, ultimately, the cortex. HD is caused by a cytosine-adenine- guanine (CAG) trinucleotide repeat expansion at the 5' end of the huntingtin gene. 6 Pathophysiology The cumulative incidence rate of HD in the United States is estimated at 1.22 per 100,000 persons (95% CI 1.53-1.65). Mean age at onset ranges from 35-44 years. 6 Disease course https://web.pathway.md/diseases/recD8XAEAPBsmglJb 1/6 6/24/23, 12:44 PM Huntington's disease Pathway Initial clinical manifestations include motor dysfunction (chorea, athetosis, oculomotor disorders), hyperreflexia and hyperhidrosis. Advanced stages progress to movement dysfunction (dystonia, rigidity, bradykinesia, dysarthria, gait disturbance, facial grimacing), cognitive decline (dementia), and psychiatric disturbances (major depressive disorder, psychosis, obsessive-compulsive symptoms, suicidal ideation). Additionally, ataxic gait and seizure may occur. 7 Prognosis and risk of recurrence Huntington disease progresses to disability, and eventually death approximately 15-20 years after onset. Intercurrent illnesses such as aspiration pneumonia are the most common cause of death. 8 Guidelines 1. Diagnostic investigations Clinical assessment: Elicit symptoms from patients with HD when possible, and collateral information from carers. E Assess for comorbid medical conditions, medications, environmental factors, and coexisting psychiatric symptoms of HD contributing to the presenting symptoms. E 2. Medical management General principles: decide on drug choice in HD depending on coexisting symptoms and the stage of the disease. E Show 2 more Management of chorea: As per EHDN 2019 guidelines, consider initiating drug treatment if chorea causes distress or discomfort. Prefer monotherapy for chorea management because combination therapy increases the risk of adverse effects and may complicate the management of non-motor symptoms. Show 2 more As per AAN 2012 guidelines, offer tetrabenazine (up to 100 mg/day), amantadine (300-400 mg/day), or riluzole (200 mg/day) in patients with HD, if treatment of chorea is required. B Show 5 more Management of dystonia and rigidity: offer active and passive physiotherapy as a preventive measure to maintain the range of joint motion, limit postural and musculoskeletal deformities, and prevent the development of contractures. B Show 5 more Management of motor deterioration: https://web.pathway.md/diseases/recD8XAEAPBsmglJb 2/6 6/24/23, 12:44 PM Huntington's disease Pathway As per AAN 2020 guidelines, offer aerobic exercise (moderate intensity, 55-90% HR maximum) paired with upper and lower body strengthening 3 times weekly for a minimum of 12 weeks to improve fitness and to stabilize or improve motor function in patients with HD. B As per EHDN 2019 guidelines, offer physiotherapy and/or personalized exercise programs, in combination with pharmacological treatments, for overall functional ability, motor function, and independence in HD. B Show 2 more Management of gait disturbance: As per AAN 2020 guidelines, offer one-on-one supervised gait training to improve spatiotemporal measures of gait (such as walking speed and step length) in patients with HD. B Show 3 more As per EHDN 2019 guidelines, initiate interventions for gait and balance as early as possible and continue and adapt throughout the progression of the disease. B Offer physiotherapy B and falls prevention programs, gait, core stability, and balance interventions, B and attentional training. Show 3 more Management of dysphagia: obtain regular assessments of swallowing disorders throughout the progression of the disease, and refer to a speech and language therapist as soon as the disorders appear. B Show 6 more Management of respiratory muscle weakness: as per AAN 2020 guidelines, consider offering breathing exercises, including inspiratory and expiratory training, to improve respiratory muscle strength and cough effectiveness in patients with HD. C Management of respiratory decline: as per EHDN 2019 guidelines, consider offering a home- based respiratory muscle training program to improve pulmonary function, recognizing that it has only a small effect on swallowing function, dyspnea, and exercise capacity. C Management of bruxism: consider injecting botulin toxin A into the masseter muscles as first-line therapy for bruxism. C Show 5 more Management of dental pain: provide verbal and written instructions on how to provide good oral hygiene at home. B Show 3 more Management of urinary incontinence: assess for a precipitating factor (urinary infection, prostate disease) in case of urinary incontinence. Assess for the presence of diurnal unexpected complete urination (complete and sudden bladder emptying, without urge) and consider offering carbamazepine for it. B Show 3 more Management of sexual disorders: attempt to identify sexual disorders and determine their triggers and their impact on relationships. Consider offering psychological support and/or referral https://web.pathway.md/diseases/recD8XAEAPBsmglJb 3/6 6/24/23, 12:44 PM Huntington's disease Pathway to a specialist in psychosexual disorders. Show 4 more Management of cognitive impairment: consider offering multiple rehabilitation strategies (speech therapy, occupational therapy, cognitive and psychomotricity) to improve or stabilize transitorily cognitive functions. C Management of akathisia and irritability: assess for an iatrogenic cause of akathisia as a priority. Recognize that tetrabenazine B , neuroleptics, and SSRIs may cause akathisia in HD. Consider reducing the dose or changing the treatment. Show 3 more Management of communication difficulties: reassess changing communication needs throughout the course of the disease to plan effective management strategies. B Obtain a comprehensive assessment of language and other factors, such as mood, motivation, and behavior, during monitoring since communication disorders in HD is variable. Show 2 more Management of depression and anxiety: As per EHDN 2019 guidelines, recognize that treatment of anxiety and depression may help to improve executive function and cognitive stimulation through rehabilitation may improve planning and initiation more specifically. (Grade C) Monitor sedative drugs and neuroleptics closely as they impair executive functions and attention. Show 7 more As per HD-EG 2018 guidelines, treat coexisting psychiatric symptoms or comorbid medical conditions and modify environmental factors contributing to anxiety. E Show 6 more Management of apathy: differentiate apathy from the impaired ability of the patient to perform motor or cognitive tasks. E Show 4 more Management of sleep disorders: treat comorbid medical conditions, coexisting psychiatric symptoms, pain, or substance use contributing to sleep disturbance in HD. Assess and adjust the dosing schedule of drugs contributing either to daytime sleepiness or nocturnal insomnia. E Show 5 more Management of perseveration: Consider offering SSRIs if pharmacological treatment is required for perseverative symptoms, particularlt when symptoms are associated with anxiety. Offer olanzapine or risperidone for ideational perseverations, particularly when associated with irritability. C Offer psychological intervention, such as CBT, in non-cognitively impaired patients since true obsessive-compulsive phenomena are sensitive to psychological intervention. Offer SSRIs as first-line therapy, if pharmacological treatment is required for obsessive-compulsive phenomena. B Management of hallucinations: search for and interrupt the use of psychotropic agents in case of hallucinations and delusions. B https://web.pathway.md/diseases/recD8XAEAPBsmglJb 4/6 6/24/23, 12:44 PM Huntington's disease Pathway Show 4 more Management of agitation: identify and treat comorbid medical conditions precipitating acute agitation including infectious, metabolic, toxic, drug-related, substance use, or other medical causes of acute psychosis/delirium. E Show 7 more Management of psychosis: identify and treat comorbid medical conditions precipitating the acute onset of psychotic symptoms, including infectious, metabolic, toxic, drug-related, substance use, or other medical or acute psychosis/delirium. E Show 5 more 3. Nonpharmacologic interventions Nutritional support: ensure good nutritional care in the management of patients with HD. Obtain early assessment by a dietitian or nutritionist and regular timely reviews of nutritional needs. Take into consideration factors such as swallowing ability, cognitive changes, behavior, mood, and general functional ability to determine possible other causes of weight loss. B Ensure a multidisciplinary approach and consider including a speech-language therapist and an occupational therapist to assist with swallowing, positioning, and feeding aids. Use screening tools for malnutrition such as the MUST. Show 3 more 4. Patient education General counseling: Provide education about the nature and presentations of symptoms in HD. E Provide information about methods that may be helpful for modifying symptom triggers. E References 1. Anne-Catherine Bachoud-L vi, Joaquim Ferreira, Renaud Massart et al. International Guidelines for the Treatment of Huntington's Disease. Front Neurol. 2019 Jul 3;10 710. Open 2. Karen E Anderson, Erik van Duijn, David Craufurd et al. Clinical Management of Neuropsychiatric Symptoms of Huntington Disease: Expert-Based Consensus Guidelines on Agitation, Anxiety, Apathy, Psychosis and Sleep Disorders. J Huntingtons Dis. 2018;7 3 355 366. Open 3. Lori Quinn, Deb Kegelmeyer, Anne Kloos et al. Clinical recommendations to guide physical therapy practice for Huntington disease. Neurology. 2020 Feb 4;94 5 217 228. Open 4. 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. Open https://web.pathway.md/diseases/recD8XAEAPBsmglJb 5/6 6/24/23, 12:45 PM Huntington's disease Pathway 5. Francis O Walker. Huntington's disease. 2007 Jan 20;369 9557 218 28.2007 Jan 20;369 9557 218 28. Open 6. Emilie Bruzelius, Joseph Scarpa, Yiyi Zhao et al. Huntington's disease in the United States: Variation by demographic and socioeconomic factors. Mov Disord. 2019 Jun;34 6 858 865. Open 7. Raymund A C Roos. Huntington's disease: a clinical review. 2010 Dec 20;5 40.2010 Dec 20;5 40. Open 8. Filipe Brogueira Rodrigues, Daisy Abreu, Joana Dam sio et al. Survival, Mortality, Causes and Places of Death in a European Huntington's Disease Prospective Cohort. Mov Disord Clin Pract. 2017 May 26;4 5 737 742. Open 9. Raymund A C Roos. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010 Dec 20;5 40. Open 10. Emilie Bruzelius, Joseph Scarpa, Yiyi Zhao et al. Huntington's disease in the United States: Variation by demographic and socioeconomic factors. 2019 Jun;34 6 858 865.2019 Jun;34 6 858 865. Open 11. Filipe Brogueira Rodrigues, Daisy Abreu, Joana Damasio et al. Survival, Mortality, Causes and Places of Death in a European Huntington's Disease Prospective Cohort. 2017 May 26;4 5 737 742.2017 May 26;4 5 737 742. 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