Huntington’s disease: ED presentations, evaluation, and management

Authors: Kevin McGurk, MD (@KJMcGurk, EM Resident Physician, Cook County Hospital) and Sean Dyer, MD (@SpyderEM, Attending Physician, Cook County Hospital) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case

A 51-year-old male with no significant medical history presents to your emergency department with his wife due to suicidal ideation. You notice the patient has had multiple previous visits to your ED for similar complaints and is usually transferred to an inpatient psych facility. This encounter the patient’s wife describes a change in his behavior over the past several months with chronic irritability and several episodes of explosive anger. After a recent job loss, the patient confessed to his wife that he was considering suicide. He has no additional complaints and denies drug, alcohol, or tobacco use.  He is unaware of any significant family medical history but notes that his father killed himself when the patient was young.

The patient’s wife adds that it seems her husband’s memory is getting worse. She also thinks he’s been dropping small objects like keys and silverware more often.

Vital signs at the time of your exam are HR 80, BP 130/70, T 37.2 C, RR 16, SaO2 99% on RA.

On careful physical exam, you notice a subtle delay in the initiation of rapid eye movements between your finger and a penlight held with the other hand. When asked to track between the examiner’s finger and the penlight, the patient pauses briefly and blinks before he alters the direction of his gaze. The remainder of your neurologic exam including strength, reflex, and gait testing is otherwise normal. Your workup reveals no abnormalities, including a negative urine toxicology screen and a normal head CT.

Background and Epidemiology

Huntington’s disease (HD) is a devastating neurodegenerative disorder that leads to progressive motor, cognitive and psychiatric dysfunction and ultimately death. The disease is inherited as an autosomal dominant trait and affects between 5-10 per 100,000 people in North America, including approximately 30,000 people in the United States.¹It is less common in non-Caucasian populations and shows equal prevalence between males and females.²Symptoms can first manifest over a wide age range, including childhood, but peak onset occurs in the fourth and fifth decades of life.³

Pathophysiology

Remember your genetic classes? Huntington’s disease is the result of a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin gene on chromosome 4p. HD will always occur in patients with 40 or more CAG repeats, anda longer series of repeats correlates with an earlier onset of disease.^4,5This expansion results in intracellular accumulation of mutant huntingtin protein and subsequent neuronal dysfunction and cell death. Toxic effects occur widely throughout the brain, but atrophy is most prominent in the striatum and cerebral cortex.

The median time from initial symptoms to death is 15-17 years, but the range can vary widely.⁶  The most common HD related cause of death is pneumonia followed by suicide.⁷

Clinical features and emergent presentations

HD presents a diagnostic challenge, in part because it is an uncommon disease with no “classic” presentation. Furthermore, physicians must be careful not to reflexively attribute new symptoms or complaints to normal disease progression in patients with a known HD diagnosis. While the disease results in a myriad of physical and cognitive symptoms, the progression is predictably gradual and slow. This is less characteristic of psychiatric symptoms, including acute psychosis, which may occasionally present more suddenly. In general, functional decline occurs over the span of years.⁸ New or rapid changes should prompt clinicians to consider alternative diagnoses.

Motor

Motor dysfunction is the most common initial clinical feature in patients with HD. As many as 70% of patients present with abnormal motor function at the time of their initial diagnosis.⁹

• The most classically identifiable manifestation of HD is the development of chorea, an involuntary pattern of rapid and irregular movements. These motor symptoms can vary widely and may include subtle tics, sudden movements involving the limbs or trunk, abnormal swallowing or gait and speech impairment. In their early stages, these changes may be mistaken for restlessness and often go unnoticed by the patient.

Examples of choreiform movements can be seen below:

https://www.youtube.com/watch?v=howpAqojT-o

https://www.youtube.com/watch?v=3Qwufr-vH_U

• As the disease advances, dystonic and postural symptoms may develop. The presence of gait and swallowing abnormalities are particularly troublesome as these increase the risk of falls and aspiration respectively, both of which contribute significantly to the morbidity and mortality of HD.
• Though the motor abnormalities associated with late stage HD can be quite dramatic, a multitude of milder changes may precede the development of the more identifiable chorea including:
  • Delayed initiation of saccades (rapid eye movements between fixed points as described in the case above) This latency is more prominent in vertical eye movements and may be accompanied by head thrusting or eye blinking to initiate the motion.¹⁰
  • Difficulties with anti-saccades movements whereby a finger is placed in their left or right visual field and the patient is asked to rapidly look to the opposite side.¹¹
  • Complaints of restlessness or fidgeting
  • Subjective clumsiness or worsened balance
  • Unexplained weight loss
  • Changes in sleep patterns
  • Sexual dysfunction

Behavioral/psychiatric

Though motor symptoms in HD are often particularly prominent, behavioral and cognitive symptoms are likely to have developed first. Importantly, though cognitive and motor changes tend to develop slowly, psychiatric symptoms develop with a far less predictable course.¹

• Patients are at significant risk of suicide with rates between 5-10% while suicidal ideation was present in more than 20% of those with the disease.¹²The associated risk of suicide in patients with HD is higher even than other progressive neurologic disorders, including amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease.¹³
• HD patients are also at increased risk of acute psychosis, with as many as 11% of affected individuals displaying psychotic symptoms. Importantly, these symptoms can also occur before the onset of apparent motor abnormalities.¹⁴ Other common clinical features can include obsessive-compulsive symptoms and emotional lability.

Cognitive

Around 15-30% of patients with HD initially present with diminished cognition, though the true number may be higher.¹⁵ The symptoms can include decreased memory or attention and worsened executive function. The decline is slow but progressive and often renders patients entirely dependent on caregivers for day-to-day activities. In time, these effects may mimic the symptoms of progressive dementias including Alzheimer’s disease or frontotemporal dementia. While these effects ultimately prove devastating for patients and their families, the gradual arc of progression makes diminished cognition a less likely indication for emergent presentation to the hospital.

Diagnostic approach

Patients with HD are frequently misdiagnosed during the early course of their illness as the psychiatric and behavioral symptoms may initially be misdiagnosed with pathologies such as Alzheimer disease or schizophrenia.¹⁵ The wide variety of presenting symptoms makes for a broad differential and therefore difficult to make the diagnosis in the Emergency Department.

Genetic testing for HD is both highly sensitive and specific.¹⁶ Molecular analysis allows for the measurement of CAG repeats and may aid in predicting whether the symptoms are likely to manifest early or later in life.

Emergent neuroimaging in suspected HD may be employed to rule out other pathologies, as the presenting symptoms create a broad differential diagnosis, but plays no significant role in the definitive diagnosis of HD. MRI and PET scans have identified structural and metabolic changes to the brain in HD such as decreased putamen and caudate volumes are common findings.¹⁷ These imaging modalities may aid in monitoring disease progression but have little to no utility in the emergent setting.

Scoring systems, including the Unified Huntington’s Disease Rating Scale (UHDRS) are used to quantify disease progression and clinical changes. The UHDRS takes approximately 30 minutes to administer which limits its usefulness in an emergency department.¹⁸ More rapid assessments, including the Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA), are also used to evaluate cognitive impairment in HD.¹⁹

Additional lab tests or procedures that may be used to rule out alternative diagnoses, including lumbar puncture, metabolic panel, and complete blood count, are not helpful in diagnosing HD.

Management Considerations

At present, there is no cure or disease-modifying agent to treat HD. Providers may instead aim to achieve symptomatic relief.

Psychiatric: In HD patients with depression, standard therapeutic management has been applied with reasonable effectiveness. SSRIs are common first line agents with SNRIs as an alternative medication.¹² No formal guidelines exist for the management of acute psychotic symptoms in HD though case reports have documented efficacy with the use of risperidone in these situations.²⁰

Tetrabenazine and deutetrabenazine are FDA approved for treatment of chorea, though tetrabenazine is contraindicated in patients with active depression or suicidality.²¹ Additional medications that have been used off label for the treatment of choreiform movements include the anti-psychotics olanzapine, quetiapine, and risperidone. In small studies, each medication has demonstrated efficacy in improving chorea with the added benefit of improvement in behavioral/psychiatric symptoms.

• Airway: Due to a significantly increased risk of aspiration, especially in more advanced disease, intubating patients with HD poses additional challenges. Awake fiberoptic intubation, when appropriate, has been described as a means to mitigate that risk.²²
• Medications: Additional consideration for the emergency medicine provider should be paid to drug selection in this specialized patient population. Though there is no clear consensus on the exact risk or mechanism, case reports have documented abnormally prolonged apnea and paralysis after the administration of succinylcholine in HD patients.²³ Providers should also be aware that certain medications, including anticholinergic agents and metoclopramide, might worsen symptoms of chorea in these patients.
• Finally, conventional approaches to common bedside procedures may also be complicated in advanced disease by uncontrolled and continuous choreiform movements. A laceration repair or lumbar puncture may be substantially more difficult in the setting of these uncontrolled movements. Alternative approaches to sedation may be required, including the potential use of general anesthesia when necessary.²⁴

Case Conclusion

The patient is medically admitted and ultimately diagnosed with Huntington’s disease. At the time of his discharge, he is scheduled for follow up in neurology clinic. His family plans to meet with genetic counselors to discuss potential future testing for the causative gene.

Take Home Points

– The clinical effects of HD are progressive but develop slowly. New or rapid changes in a patient’s motor function or cognition should prompt consideration of alternative etiologies or concurrent illness.

– HD patients may present with acute psychiatric symptoms even before the development of motor symptoms. Risperidone is the med of choice for acute psychosis in HD.

– Patients with HD need to be carefully screened for suicidal ideation. Their risk of suicide is significantly higher than the general population.

– Use caution before administering succinylcholine as there may be an increased risk of prolonged apnea and muscle paralysis in this patient population. Certain medications, including anticholinergics and metoclopramide, may contribute to worsened chorea.

– Consider awake fiberoptic intubation when appropriate. Patients with advanced HD have a high risk of aspiration.

References / Further Reading

1. Anderson KE, Marshall FJ. Behavioral symptoms associated with Huntington’s disease.Adv Neurol. 2005;96:197-208.
2. Kang J-M, Chung J-Y, Han JH, Kim Y-S, Lee BJ, Yi J-W. Anesthetic management of a patient with Huntington’s chorea -A case report-. Korean Journal of Anesthesiology. 2013;64(3):262-264.
3. Coppen EM, Roos RAC. Current Pharmacological Approaches to Reduce Chorea in Huntington’s Disease. Drugs. 2017;77(1):29-46.
4. Chaganti SS, McCusker EA, Loy CT. What do we know about Late Onset Huntington’s Disease? Journal of Huntington’s Disease. 2017;6(2):95-103
5. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR; International Huntington’s Disease Collaborative Group. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length.Clin Genet. 2004 Apr;65(4):267-77. Erratum in: Clin Genet. 2004 Jul;66(1):81.
6. Videnovic A. Treatment of Huntington Disease. Current treatment options in neurology. 2013;15(4):424-438.
7. Roos RA. Huntington’s disease: a clinical review. Orphanet Journal of Rare Diseases. 2010;5:40.
8. Dorsey ER, Beck CA, Darwin K, Nichols P, Brocht AF, Biglan KM, Shoulson I; Huntington Study Group COHORT Investigators. Natural history of Huntington disease.JAMA Neurol. 2013 Dec;70(12):1520-30.
9. Koutsis G, Karadima G, Kladi A, Panas M. Late-onset Huntington’s disease: Diagnostic and prognostic considerations. Parkinsonism Relat Disord. 2014;20(7):726–30.
10. Termsarasab P, Thammongkolchai T, Rucker JC, Frucht SJ. The diagnostic value of saccades in movement disorder patients: a practical guide and review.J Clin Mov Disord. 2015 Oct 15;2:14.
11. Patel SS, Jankovic J, Hood AJ, Jeter CB, Sereno AB. Reflexive and volitional saccades: biomarkers of Huntington disease severity and progression. J Neurol Sci. 2012;313:35–41.
12. Epping EA, Paulsen JS. Depression in the early stages of Huntington disease. Neurodegenerative disease management. 2011;1(5):407-414.
13. Eliasen A, Dalhoff KP, Horwitz H. Neurological diseases and risk of suicide attempt: a case-control study.J Neurol. 2018 Mar 21.
14. Nagel M, Rumpf HJ, Kasten M. Acute psychosis in a verified Huntington disease gene carrier with subtle motor signs: psychiatric criteria should be considered for the diagnosis.Gen Hosp Psychiatry. 2014 May-Jun;36(3):361.e3-4.
15. Lipe H, Bird T. Late Onset Huntington Disease: Clinical and Genetic Characteristics of 34 Cases. Journal of the neurological sciences. 2009;276(1-2):159-162.
16. Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B, Bassett A, Almqvist E, et al. A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats.N Engl J Med. 1994 May 19;330(20):1401-6.
17. Niccolini F, Politis M. Neuroimaging in Huntington’s disease. World Journal of Radiology. 2014;6(6):301-312.
18. Unified Huntington’s Disease Rating Scale: reliability and consistency. Huntington Study Group.Mov Disord. 1996 Mar;11(2):136-42
19. Mestre TA, Bachoud-Lévi AC, Marinus J, Stout JC, Paulsen JS, Como P, Duff K, Sampaio C, Goetz CG, Cubo E, Stebbins GT, Martinez-Martin P; Members of the MDS Committee on Rating Scales Development. Rating scales for cognition in Huntington’s disease: Critique and recommendations.Mov Disord. 2018 Feb;33(2):187-195. doi: 10.1002/mds.27227. Epub 2017 Dec 26. Review.
20. Videnovic A. Treatment of Huntington Disease. Current treatment options in neurology. 2013;15(4):424-438.
21. Chen JJ, Ondo WG, Dashtipour K, Swope DM. Tetrabenazine for the treatment of hyperkinetic movement disorders: a review of the literature. Clin Ther. 2012;34:1487–1504.
22. Ovassapian A, Krejcie TC, Yelich SJ, Dykes MH. Awake fibreoptic intubation in the patient at high risk of aspiration. Br J Anaesth. 1989;62:13–16.
23. Kang J-M, Chung J-Y, Han JH, Kim Y-S, Lee BJ, Yi J-W. Anesthetic management of a patient with Huntington’s chorea -A case report-. Korean Journal of Anesthesiology. 2013;64(3):262-264.
24. Kivela JE, Sprung J, Southorn PA, Watson JC, Weingarten TN. Anesthetic management of patients with Huntington disease.Anesth Analg. 2010 Feb 1;110(2):515-23.