AMDA Dedicated to Long Term Care Medicine 2013 Annual Meeting

March 27-31, 2013; Washington, DC

Examining Treatment of Xenazine for Huntington’s Disease Patients With Chorea

Huntington’s disease (HD) is a relatively rare neurodegenerative, genetic disorder characterized by motor, psychiatric, and cognitive symptoms. The disorder is caused by an expansion of a repeating CAG triplet series in the huntingtin gene on chromosome 4.

Approximately 25,000 individuals in the United States are symptomatic. The average age of becoming symptomatic is 30 to 50 years. Death usually occurs 10 to 30 years after onset. Diagnosis of adult-onset HD is usually made upon the start of chorea (abnormal involuntary movements). Because of the degenerative nature of HD, individuals may require long-term care (LTC). However, identifying an LTC facility to meet patients’ needs is a challenge.

The FDA-approved Xenazine (tetrabenazine) for the treatment of chorea associated with HD in August 2008. Because Xenazine is not stocked in retail pharmacies, it is available through a treatment form and specialty pharmacy distribution.

In a product theater at the AMDA conference, Adam Rosenblatt, MD, professor of psychiatry and neurology, director of geriatric psychiatry at Virginia Commonwealth University, Richmond, discussed chorea associated with HD and therapy with Xenazine. Annals of Long-Term Care^® (ALTC) had the opportunity to interview Rosenblatt about HD, management of the disease in LTC, and treatment considerations.

ALTC: How many LTC facilities are familiar with HD?

Dr. Rosenblatt: A majority of HD patients at the end of their life will end up in LTC. Many LTC facilities do not have much experience with HD patients. While it is not a typical experience, I have known of LTC facilities turning away HD patients. There are a small number of LTC facilities that have enough experience with HD patients, and they are the go-to places. When there is a close relationship between the expert [eg, physician] and the LTC facility and good communication between all involved parties, these placements are most successful.

How do patients with HD differ demographically from the average LTC resident?

They are younger than the average patient admitted into an LTC facility; can have more severe movement, psychiatric, and/or behavioral disorders; and lack serious comorbid medical diagnoses on admission.

What are some of the challenges LTC facilities face in caring for these patients?

Patients with HD are at risk for other psychiatric disorders, including depression. Since the condition is progressive, patients are at risk of falls and lack insight that they could fall. They need help to ambulate. They have trouble eating by mouth because of the involuntary movements, making it difficult for them to maintain their weight. When movement becomes extravagant, they become physically hard to manage in LTC settings. Some patients require specialized reclining chairs or beds that are low to the ground.

What are the hallmark symptoms of HD?

Symptoms can vary between individuals. It manifests as a triad of motor, cognitive, and psychiatric symptoms. Motor symptoms include involuntary movement (chorea) and impairment of voluntary movements. Cognitive function is characterized by a reduction in speed and flexibility of mental processing and difficulty planning and prioritizing. With psychiatric symptoms, the most common diagnosis is depression, found in 40% of cases. While personality changes can be subtle, patients can exhibit impulsivity, apathy, irritability, and obsessionality.

When is a diagnosis of adult-onset HD usually made?

It is not black and white. In adults, the condition usually presents as cognitive or psychiatric, although some patients do exhibit abnormal movements. Often, the patient is unaware of it and family members or physicians may be the first to notice the symptoms.

Chorea affects about 90% of individuals with HD at some stage in their illness. How does it progress?

It can present at first subtly in the hands and feet, but it may include neck, shoulder, trunk, and leg movements as it progresses. As movements eventually occur throughout the body, it can become quite disabling. In time, chorea may plateau and decline, or continue to worsen.

How is chorea severity assessed?

Various scales can be used. The Unified Huntington’s Disease Rating Scale (UHDRS) is often used in research. You score patients 0 to 4 in different parts of the body; the total score ranges from 0 to 28. It is useful if you are going to treat a patient. I use the scale to rate the patient before starting treatment and again a few weeks after starting treatment to see if there is a difference.

Is there any treatment available to slow, stop, or reverse the progression of HD?

Currently, there is no treatment proven to alter the progression of the disease. This is not to say that you cannot alter the outcome, as you can still intervene in fundamental areas to improve quality of life. For example, if a patient is severely depressed, you can treat the depression.

How does Xenazine improve chorea?

The precise mechanism by which Xenazine exerts its antichorea effects is unknown, but it is thought to be related to the agent’s effect as a reversible depletor of monoamines from nerve terminals. Vesicular monamine transporter subtype 2 (VMAT2) transports and concentrates monamines (including dopamine) into presynaptic storage vesicles. Xenazine reversibly binds to VMAT2 and reduces uptake of dopamine into synaptic vesicles.

What did the pivotal trial of Xenazine show in total chorea score (TCS) and how long did improvement last versus placebo?

The efficacy of Xenazine was demonstrated in a randomized, double-blind, placebo-controlled, multicenter trial. A total of 84 ambulatory patients with HD were randomly assigned to receive Xenazine (n=54) or placebo (n=30) for 12 weeks. The primary end point was the reduction in TCS using the UHDRS. A reduction of 3 or more was defined as clinically meaningful per the study protocol. The results showed that 69% of patients had a statistically significant improvement in TCS compared with 23% of patients receiving placebo (P<.0001). Significant improvement in chorea was observed by week 3 and improvement continued throughout the trial. TCS returned to baseline levels during the washout period.

Xenazine carries a boxed warning for increased risk of depression and suicide. What steps should clinicians take when prescribing Xenazine to patients who already have or are at risk for depression and suicidal thoughts?

Clinicians have to balance the risk of suicide and depression with the benefits of Xenazine. I probably would not give Xenazine to someone who has tried to kill himself or herself, is in a depressive state, or has no support system. In LTC, there is a high level of supervision; however, these patients generally do not communicate well and cannot express they are depressed. Therefore, staff needs to closely watch for warning signs in these patients, including withdrawal and lack of sleep.

What is the recommended dosing for Xenazine?

There is no single target dose for Xenazine. Dosing should be individualized based on patient response. The starting dose is 12.5 mg per day. After 1 week, the dose should be increased to 25 mg per day given as 12.5 mg twice daily. Xenazine should be titrated up slowly at a weekly interval of 12.5 mg daily until a patient experiences clinical effect or an adverse event occurs that is not tolerated. Dosing above 100 mg daily is not recommended for any patient.

This product theater was sponsored by Lundbeck.

Tackling the Clostridium difficile Dilemma in Nursing Homes

Long-term care (LTC) providers nationwide are facing increasing incidences of Clostridium difficile infection (CDI) among their residents, and it is currently the most common infectious cause of acute diarrhea in this setting. In addition, more severe infections are being observed, making prevention crucial. During an educational session at the AMDA conference, presenters discussed various preventive and treatment strategies for CDI, including the proper use of antibiotics and following recommendations set forth by the Society for Healthcare Epidemiology (SHEA) and Infectious Diseases Society of America (IDSA). The role of probiotics and antibiotic stewardship programs were also reviewed.

Preventing and Managing CDI

The Centers for Disease Control and Prevention (CDC) report that antibiotics are the most commonly prescribed medication in LTC settings, with up to 70% of LTC residents receiving an antibiotic each year. Presenter Amy Mathers, MD, assistant professor, Division of Infectious Diseases and International Health, University of Virginia, who discussed the prevention of CDI, noted that CDI most commonly occurs after antibiotic use. During the session, one study was discussed that showed that 33% of LTC residents had C difficile in their stool after taking antibiotics, even if they did not develop diarrhea.

“Learning how antibiotics are used in your facility is important in preventing C difficile,” Mathers told attendees. She noted that antibiotics are often misused in LTC settings, such as by being given when they are not needed, continued when they are no longer necessary, and given at the wrong dose.

When CDI infections occur despite best efforts to prevent them, appropriate and timely treatment is essential to prevent morbidity and mortality. Mathers recommended that the SHEA and IDSA 2010 practice guidelines for C difficile be implemented. These guidelines make the following treatment recommendations:

•    For an initial episode of mild-to-moderate CDI, prescribe oral metronidazone 500 mg three times daily for 10 to 14 days.

•    For severe CDI, prescribe oral vancomycin 125 mg four times daily for 10 to 14 days.

•    For complicated or severe CDI, prescribe oral vancomycin (or per rectum if ileus is present) with or without intravenously administered metronidazole. The oral vancomycin dosage is 500 mg four times a day and the rectal dosage is 500 mg in approximately 100 mL normal saline every
6 hours as a retention enema. If metronidazole is given, the dose is 500 mg intravenously every 8 hours.

Role of Probiotics

Probiotics may offer an alternative for preventing and possibly treating CDI, said Glynis Kolling, PhD, microbiologist, Division of Infectious Diseases and International Health, University of Virginia, noting that probiotics can help restore normal flora that are altered with antibiotics. She said studies have shown that probiotics can help prevent antibiotic-associated diarrhea and therefore may be beneficial in the setting of CDI.

Although the SHEA and IDSA 2010 practice guidelines for C difficile do not recommend the use probiotics to prevent primary CDI because the data to support this approach have been limited and there is a potential risk of bloodstream infection, Kolling noted that the new guidelines that are targeted for release later this year may include an updated recommendation on probiotics.

Probiotics have an excellent overall safety record, but Kollings and Mathers warned that they should be used with caution in patients with an immune deficiency and are contraindicated in patients with an impaired epithelial barrier, such as a diarrheal illness or intestinal inflammation.

“Probiotics may not be for everyone. You have to determine if probiotics will benefit the patient,” concluded Mathers.

Antimicrobial Stewardship

C difficile is a community infection that does not stay confined to the hospital or nursing home, warned presenter Laurie Archbald-Pannone, MD, MPH, assistant professor, Department of Internal Medicine, University of Virginia. Because it follows patients as they move in and out of any facility, antibiotic stewardship programs are at the forefront of preventing its spread. Her colleague Mathers defined anti-biotic stewardship as “selecting the most appropriate drug at its optimal dose and duration of therapy to eradicate an infection while minimizing toxicity and impact on selective pressure [ie, any cause that reduces reproductive success in a proportion of a population].” She noted that medical directors are responsible for fostering stewardship. These healthcare professionals should routinely review facility microbiology and antibiograms for local resistance trends, implement policies for prudent antimicrobial prescribing, and put in place nursing protocols for monitoring.

In addition, before any antibiotic is prescribed, Mathers recommended that all healthcare providers follow the CDC’s Get Smart for Healthcare (www.cdc.gov/getsmart/healthcare/index.html) program, which includes the following three-step process aimed at preventing inappropriate antibiotic prescribing:

1.   Ensure all antibiotic orders include dose, duration, and indication.

2.   When placing orders, make certain that they include laboratory cultures.

3.   When the culture results come back in 24 to 48 hours, take an “antibiotic time-out” and reassess therapy.

—Eileen Koutnik-Fotopoulos

The presenters of this educational session reported no relevant financial relationships.