Of these 28 cases, only eight have been fatal.

195 This may be due to the heightened

sensitivity to clinical changes that may suggest PML and aggressive immune

reconstitution with either plasma exchange or immunoabsorption if PML is

diagnosed. However, this immune reconstitution can lead to immune reconstitution

inflammatory syndrome (IRIS), which is itself life-threatening. IRIS usually presents

as an acute worsening of MS symptoms and is treated with high-dose

corticosteroids.

195 Several groups have developed recommendations for natalizumab

use to reduce the risk of PML (Table 57-11).

Table 57-11

Recommendations for Use of Natalizumab

93,194,215

Patients Who Should Not Receive Natalizumab

Immunocompromised

Active viral hepatitis

Active malignancy that requires treatment

Inability to get MRI

Recommendations for Use

Monotherapy with natalizumab only

After failure of interferon or glatiramer acetate

Therapy-free interval of 14 days after interferon or glatiramer acetate, 3 months after azathioprine, or 6 months

after mitoxantrone

Baseline Testing

Clinical neurologic examination

Human immunodeficiency virus testing

Complete blood count

Liver function tests

MRI with IV contrast

Monitoring

Neurologic examination at 3 months, 6 months, and then yearly

MRI with IV contrast at 6 months and then yearly

IV, intravenous; MRI, magnetic resonance imaging.

Several serious adverse effects, infusion reactions, autoimmune conditions, and

malignancies, associated with alemtuzumab use have caused the FDA to require a

limited distribution program for this agent. Infusion reactions associated with

alemtuzumab are triggered by cytokine release, may include rash, fever, headache,

itching, nausea, and chills and occur in about 90% of patients; serious reactions

occurred in 3% of patients.

74

,

76

,

205 Patients should be monitored for 2 hours after each

infusion, but reactions may occur later than that time period.

205 Premedication should

consist of methylprednisolone 1,000 mg infused immediately before the first infusion

and for the first 3 days of each treatment course. Antihistamines and acetaminophen

may also be helpful premedications.

205 Autoimmune diseases have been associated

with alemtuzumab therapy and may include thyroid disorders (34%), immune

thrombocytopenia (2%), and anti-glomerular basement membrane disease

(0.3%).

76

,

177

,

205 Thyroid disorders have been seen up to 60 months after the initial

treatment with alemtuzumab.

177 Of thyroid dysfunction seen, 79% is hyperthyroidism

and 21% is hypothyroidism.

218 Patients receiving alemtuzumab had higher rates of

some malignancies, including thyroid cancer and melanoma at a rate of 0.3% each.

205

Infections were more common in patients treated with alemtuzumab than those treated

with interferon β, including urinary tract infections (17%), herpes virus infections

(16%), respiratory infections (16%), and fungal infections (12%).

76

,

177

,

205 The herpes

virus infections are most common in the month following the infusion and can be

significantly reduced by prophylaxis.

74 The recommendation is that patients receive

anti-viral prophylaxis for herpetic viral infections starting on the first day of each

treatment course and continuing for a minimum of 2 months following treatment or

until the CD4

+

lymphocyte count is ≥ 200 cells/mcL, whichever occurs later.

205 The

dosing of alemtuzumab is unique for MS medicines in that it is a 12 mg/day infusion

for 5 days and then an additional 12 mg/day infusion for 3 days 12 months after the

first treatment course.

205 No vaccines should be administered during treatment and all

should be completed at least 6 weeks prior to treatment, including varicella zoster

virus vaccine, if patients have not been vaccinated and do not have a history of

infection.

205 Monitoring recommendations can be found in Table 57-12.

p. 1231

p. 1232

Table 57-12

Recommended Monitoring for Use of Alemtuzumab

205

Test Monitoring Frequency

CBC with differential Baseline and monthly for 48 months following the last

dose

Serum creatinine Baseline and monthly for 48 months following the last

dose

Urinalysis with urine cell counts Baseline and monthly for 48 months following the last

dose

Thyroid-stimulating hormone Baseline and every 3 months for 48 months following

the last dose

Skin examination Baseline and yearly

Human papilloma virus Yearly

Tuberculosis Baseline

Of these options, N.R. should probably be started on alemtuzumab or natalizumab.

Both of these therapies carry substantial adverse effects about which, she will need

to be informed. Additionally, she will need to enroll in the restricted distribution

systems for the chosen medicine. Another area that requires consideration is that she

may be at higher risk for PML or other opportunistic infections when beginning one

of these medicines after taking teriflunomide. Conversely, being completely without

medicine allows for return or possible “rebound” of disease activity. Possible

strategies include undergoing accelerated elimination procedures for the

teriflunomide and then: (1) allowing for a washout period during which the patient

receives no treatment, (2) providing a monthly regimen of methylprednisolone while

allowing for a washout period, or (3) switching directly to another therapy without a

washout period.

219

It is not known which of these options is the best for a patient.

CASE 57-2, QUESTION 4: N.R. experiences another relapse while she is considering which therapy to

begin. One month after completing corticosteroid treatment for this relapse, she returns to the neurology clinic

for a follow-up appointment. N.R. explains that she has been experiencing episodes of uncontrollable laughing.

When these episodes first began, she thought they might be an adverse effect of the corticosteroid treatment

for her relapse. However, 1 month after stopping corticosteroid treatment, she is still having these episodes. She

states that the episodes are very embarrassing, often occurring at inappropriate times such as in movie theaters,

at parent–teacher conferences, and in grocery stores. She is diagnosed with pseudobulbar affect. What

treatment is available for pseudobulbar affect, and how should N.R. be counseled regarding this treatment?

Dextromethorphan with quinidine is effective for reducing the rate of pseudobulbar

affect episodes and was recently FDA-approved for this indication. It is dosed one

capsule (dextromethorphan 20 mg/quinidine 10 mg) orally twice daily.

220 Adverse

effects related to the dextromethorphan component may include dizziness and the

possibility of serotonin syndrome. Adverse effects associated with quinidine are an

immune-mediated thrombocytopenia, lupus-like syndrome, hepatotoxicity, dosedependent QTc interval prolongation, and anticholinergic effects.

220

There are several drug interactions associated with dextromethorphan–

quinidine.

220

It is contraindicated with monoamine oxidase inhibitors, requiring a 14-

day washout before starting therapy. Similarly, caution should be exercised when this

therapy is used concomitantly with selective serotonin reuptake inhibitors and

tricyclic antidepressants. It is contraindicated with drugs that prolong the QT interval

and are metabolized by CYP 2D6. Dextromethorphan–quinidine should be used with

caution with drugs that inhibit CYP 3A4. Because quinidine inhibits CYP 2D6, dose

adjustments for CYP 2D6 substrates are necessary. Quinidine also inhibits Pglycoprotein, requiring caution and perhaps dose adjustments when this treatment is

used in combination with digoxin.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

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Thompson AJ et al. Pharmacological management of symptoms in multiple sclerosis: current approaches and

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Yadav V et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple

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Key Websites

National Multiple Sclerosis Society. http://www.nationalmssociety.org.

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