EHDN International Guidelines for the Treatment of Huntington's Disease (2019)
This is a condensed summary of the European Huntington's Disease Network (EHDN) international guidelines (Bachoud-Lévi et al., 2019). The task force reviewed 637 publications from 1965–2015 using a formalized consensus method adapted from the French Health Authority (HAS). Quality grades were assigned based on levels of scientific evidence (Grade A = established proof from high-power RCTs/meta-analyses; Grade B = scientific presumption from lower-power RCTs/cohort studies; Grade C = low-level proof from case-control studies/case series). When evidence was lacking, recommendations were based on professional agreement. 219 consensus statements were retained after two rounds of international multidisciplinary expert voting from 25 countries.
Bottom Line: Key Recommendations
- Chorea: Tetrabenazine (Grade A) is first-line; second-generation neuroleptics (Grade B) preferred when behavioral/psychotic symptoms coexist; deutetrabenazine (Grade A) is an alternative where available
- Depression: SSRI or SNRI first-line (Grade B); mirtazapine/mianserin if sleep disruption present; ECT for resistant cases (Grade C)
- Irritability/Aggression: SSRIs first-line for irritability (Grade C); neuroleptics first-line for aggressive behavior (Grade C); mood stabilizers if refractory
- Psychosis: Second-generation neuroleptics first-line (Grade C); clozapine for akinetic forms with parkinsonism
- Cognition: No pharmacological treatment recommended; rehabilitation strategies may help (Grade B)
- Rehabilitation: Physiotherapy and exercise programs beneficial for overall motor function (Grade B); early referral recommended
- Swallowing: Regular assessment and early SLT referral (Grade C); PEG should be discussed proactively
Motor Disorders
Chorea
| Intervention | Grade | Notes |
|---|---|---|
| Tetrabenazine | Grade A | First-line unless patient has poorly managed depression or suicidal thoughts |
| Deutetrabenazine | Grade A | Alternative to tetrabenazine where marketing authorization is obtained (e.g., USA); added from 2015–2019 literature update |
| Second-generation neuroleptics | Grade B | First-line when chorea coexists with personality, behavioral, or psychotic disorders |
- Drug treatment should be considered only if chorea causes patient distress or discomfort
- Monotherapy preferred — combination therapy increases risk of adverse effects and complicates management of non-motor symptoms
- Protective measures during meals and instrumental ADLs should be implemented
Dystonia
- Active and passive physiotherapy recommended to maintain joint range of motion and prevent contractures
- Botulinum toxin injection for focal dystonia or prevention of secondary deformities (performed by trained professional)
- Customized seating for dystonia-related deformities
Rigidity
- May be increased or induced by neuroleptics or tetrabenazine — dose reduction should be considered if functional impact occurs
- Levodopa may provide partial, temporary relief of akinetic-rigid symptoms, especially in juvenile forms (Grade C); total daily dose usually lower than in Parkinson's disease
- Physiotherapy recommended to maintain mobility and prevent contractures (Grade C)
Gait and Balance
- Interventions should start early and be continued throughout disease progression (Grade C)
- Physiotherapy (Grade B), falls prevention programs, core stability and balance training (Grade C), and attentional training recommended
- Pharmacological management of chorea may improve walking and balance (Grade C) but may also aggravate gait through adverse effects
- Four-wheeled walkers (Grade B) and other assistive devices as recommended by therapists
Other Motor Symptoms
| Symptom | Management | Grade |
|---|---|---|
| Myoclonus | Sodium valproate or clonazepam (alone or combined, escalating doses); levetiracetam as alternative; piracetam for cortical myoclonus without seizures | Grade C |
| Akathisia | Investigate iatrogenic cause first (tetrabenazine, neuroleptics, SSRIs); reduce dose or change treatment | Grade C |
| Bruxism | Botulinum toxin A into masseter muscles (first-line); customized mouth guards; consider reducing neuroleptics/SSRIs that may cause bruxism | Grade C |
| Manual dexterity | Physiotherapy and occupational therapy (Grade B); adaptive aids; neuroleptics/tetrabenazine may improve dexterity by reducing chorea but may aggravate bradykinesia | Grade B/C |
Swallowing Disorders
- Can occur early and become a major problem in later stages (aspiration, bronchopulmonary infections)
- Regular assessment throughout disease progression (Grade C)
- Early SLT referral recommended as soon as disorders appear (Grade C)
- Ancillary assessments: motor skills, respiratory status, dental health, mood, cognition, nutrition
- Treating chorea may help but side effects (sedation, parkinsonism) may also worsen swallowing
- PEG should be anticipated and discussed with patients while they can still make informed decisions
Cognitive Disorders
No pharmacological treatment is recommended for cognitive symptoms. Cognitive deficits frequently precede motor symptoms and are a major cause of family disruption.
| Domain | Management |
|---|---|
| Executive function | Help patients organize and initiate activities; treating anxiety/depression may improve executive function; cognitive stimulation through rehabilitation (Grade C); monitor sedative drugs and neuroleptics |
| Bradyphrenia | Allow adequate time for information processing; avoid time-pressured situations; cognitive stimulation may help |
| Language/Communication | Early SLT referral (Grade C); reassess changing communication needs; augmentative communication tools while patient can still learn (Grade C); educate family members |
| Memory | Regular daily routines; rehabilitative approaches (speech therapy, neuropsychology); domain-specific transcoding; avoid sedative drugs that impair memory |
| Social cognition | Explain patient's disorders to family/colleagues; third-party intervention to stimulate social interaction; treat behavioral disorders to improve social integration |
| Disorientation | Investigate intercurrent confusional causes; establish regular routine with milestones |
Multiple rehabilitation strategies (speech therapy, occupational therapy, cognitive training, psychomotricity) may improve or stabilize cognitive functions (Grade B).
Psychiatric Disorders
Behavioral symptoms may appear before motor diagnosis and are, with cognitive symptoms, the major cause of family disruption and social isolation. Management should identify underlying triggers for mood and behavior changes.
Depression
- One of the most common psychiatric symptoms; may affect patients at any stage, even before motor manifestation
- Psychotherapy and CBT may enable early detection of mood changes
- First-line: SSRI or SNRI (Grade B)
- Sleep disruption present: Mianserin or mirtazapine as alternatives
- Recurrent depression: Long-term mood-stabilizer to prevent relapses
- Resistant or psychotic depression: Psychiatric consultation; ECT may be considered (Grade C)
- If depression is thought to be an adverse effect of other medication, gradually reduce the responsible drug
Suicidal Ideation
- Common in HD; correlates with family history, previous attempts, depression, especially in prodromal stages
- Assess risk irrespective of disease stage; heightened vigilance at diagnosis and when disease impacts daily life
- Prevention includes treating underlying depression, social isolation, and impulsivity
Irritability and Aggression
Treatment Algorithm for Irritability
- Step 1: Explore environmental causes; behavioral strategies; structured routine in calming environment; psychoeducation for family
- Step 2: SSRIs first-line for irritability (Grade C) — may need maximum recommended dose
- Step 3: Add mianserin or mirtazapine if SSRI alone insufficient, especially with sleep disorders
- Step 4: Neuroleptic first-line for aggressive behavior (Grade C); combine with sedative antidepressant if depression coexists
- Step 5: Add mood stabilizer if irritability does not respond to antidepressants and/or neuroleptics (Grade C)
Anxiety
- Common; linked to functional loss, family/social/economic burden; associated with depression and suicidality
- First-line: SSRI or SNRI, especially when associated with depression
- On-demand anxiolytics may help, but caution for fall risk
- Refractory anxiety: Neuroleptics as therapeutic alternatives (Grade C)
Apathy
- Most frequent psychological and behavioral symptom, especially in middle and later stages
- Apathy and irritability often coexist in the same patient at different times
- Personalized cognitive stimulation, establishing routines and structured activity programs
- Depression may increase apathy — trial of SSRI if depression suspected
- Sedative medications may worsen apathy; reduce unnecessary prescriptions
Obsessions and Perseveration
- True obsessions are uncommon, but perseveration is very common (middle/later stages)
- Perseveration has the most significant negative impact on caregiver quality of life
- SSRI for perseverative symptoms, especially with associated anxiety (Grade C)
- Olanzapine and risperidone for ideational perseverations, especially with irritability (Grade C)
- True OCD: CBT in non-cognitively impaired patients; SSRI first-line pharmacotherapy (Grade C)
Psychosis (Hallucinations/Delusions)
- Search for and discontinue psychotropic agents that may be causative
- First-line: Second-generation neuroleptics (Grade C)
- Akinetic forms with parkinsonism: Clozapine as first-line
- Perseverative ideation can mimic psychosis — may benefit from SSRI + atypical neuroleptic
- Refractory: ECT may be discussed with psychiatrist (Grade C)
Agitation
- Prioritize identifying somatic triggers (bladder distension, fecal impaction, pain), especially in advanced stages
- With anxiety: benzodiazepine as needed (minimize long-term use to reduce dependence and fall risk)
- With behavioral/personality disorders: prescribe neuroleptic (Grade C)
- Emergency situations: midazolam or similar short-acting benzodiazepine
Impulsivity and Sexual Disorders
- Impulsivity with depression/personality disorders: Neuroleptic + SSRI; long-term mood stabilizer for mood lability
- Decreased libido: Investigate iatrogenic cause (SSRIs); reduce dose or substitute
- Hypersexuality: Behavioral approach first; neuroleptic and/or SSRI (Grade C); anti-androgen if refractory (Grade C)
Other Disorders
| Symptom | Key Recommendations | Grade |
|---|---|---|
| Sleep disorders | Investigate underlying causes (depression, anxiety, chorea); lifestyle strategies first-line; short-duration hypnotics if needed; mianserin/mirtazapine/antihistamines for longer duration; melatonin for sleep phase inversion; evening neuroleptic if behavioral disorders or chorea coexist | Professional agreement |
| Weight loss | Early dietitian assessment (Grade C); maintain high-normal BMI; high-calorie/high-protein supplements (Grade C); Mediterranean diet may improve QoL (Grade C); prefer weight-gain-inducing medications when starting antidepressants/neuroleptics (Grade C) | Grade C |
| Swallowing | Regular SLT assessment; oral-facial exercise; posture advice; carer education; anticipate PEG discussion | Grade C |
| Urinary incontinence | Investigate precipitating factors; carbamazepine for sudden complete urination (Grade C); antimuscarinics for overactive bladder (monitor for confusion); urodynamic testing if conservative measures fail | Grade C |
| Hypersalivation | Scopolamine (transdermal), atropine (oral), or anticholinergic agents (amitriptyline); BTX into salivary glands if oral treatments ineffective | Professional agreement |
| Dental care | Multidisciplinary teamwork with dietitians (Grade C); oral hygiene instructions for patients and carers (Grade C); dental descaling at least annually; advanced treatment may require sedation (Grade C) | Grade C |
| Respiratory function | Home-based respiratory muscle training improves pulmonary function (Grade B); respiratory changes occur earlier than expected | Grade B |
| Pain | Behavioral change or worsening involuntary movements should trigger search for underlying pain source; communication disorders may mask pain | Professional agreement |
| GI disorders | Routine assessment for constipation, diarrhea, vomiting; investigate fecal impaction; consider reducing antichoreic agents if vomiting intractable | Professional agreement |
General Management Principles
- Any HD symptom may be worsened by stress, fatigue, and intercurrent disorders (anxiety, GI issues, infections, pain) — these must be assessed and treated alongside HD-specific symptoms
- While motor symptoms are the most visible, cognitive and behavioral symptoms are often the major source of family disruption
- Monotherapy is preferred to avoid adverse effect interactions
- Regular reassessment is essential as symptoms evolve throughout disease progression
- Multidisciplinary team approach including neurology, psychiatry, physiotherapy, occupational therapy, SLT, dietetics, and psychology
- Early advance care planning should address PEG, communication needs, and end-of-life preferences
Limitations
- Only one Grade A study was found among 376 analyzed publications — most recommendations are Grade B or C, or based on professional agreement
- HD is a rare disease, making large-cohort placebo-controlled studies difficult
- The consensus method combining evidence-based medicine and expert agreement was adapted specifically for rare diseases
- Literature review extended to 2015 with supplementary 2015–2019 update (17 additional studies); expert input extended to October 2018
- Four recommendations did not reach full consensus after two rounds of voting
Reference
Bachoud-Lévi A-C, Ferreira J, Massart R, et al. International Guidelines for the Treatment of Huntington's Disease. Front Neurol. 2019;10:710. doi: 10.3389/fneur.2019.00710