Decreased Concentration-
Decreased concentration is especially common within the first few weeks
of interferon therapy. Increased intake of water, juices, sports drinks
and non-caffeinated fluids may help reduce this side effect.
CONCENTRATION/MEMORY LOSS
Concentration and memory loss are common clinical problems for patients
taking
interferon-based therapy. All patients treated with peginterferon, with
or without
ribavirin, should be considered at some risk for the development of
cognitive side effects.
PATHOPHYSIOLOGY
There
are multiple mechanisms by which interferon may cause neuropsychiatric
side
effects, including effects mediated by neuroendocrine, neurotransmitter,
and cytokine
pathways.1
Interferon acts as a
central dopamine agonist, through an opioid-associated
mechanism resulting in psychomotor slowing and cognitive dysfunction
defined as:
decreased concentration, focus, memory loss, forgetfulness, and
dysphoria.1,2
In addition,
alterations of peripheral nonadrenergic receptor levels and serum
tryptophan levels have
also
been observed in patients receiving interferon. Serotonin depletion is
responsible for
the
dementia syndromes associated with cytokine therapy and HIV patients.
The
hypothesis that disregulation of norepinephrine and serotonin
neurotransmitters cause
depression-associated cognitive dysfunction was the basis for the
development of many
antidepressant medications, including tricyclic antidepressants (TCAs)
and newer
generation selective serotonin reuptake inhibitors (SSRIs).
Special
Note: Although combination therapy with peginterferon and ribavirin is
associated with neurocognitive fatigue and associated difficulties with
concentration,
focus,
and memory, these symptoms are also clinical manifestations of both HCV
and
HIV
infections and treatment. Since approximately 33% of all patients with
HIV are
coinfected with HCV and may be eligible for treatment, clinicians should
maintain a high
level
of suspicion for both diseases in the differential diagnosis when such
symptoms are
reported.
ASSESSMENT
1.
Perform baseline assessment and monthly during treatment for the
presence of
cognitive symptoms utilizing the Center for Epidemiological Studies
Depression
Scale (CES-D)3
and/or the Folstein
Mini Mental State Examination.
2. Use
more comprehensive screening tools (eg, Beck Depression Inventory, Zung
Self-
Rating Depression Scale, or Profile of Mood States) for more complex
situations.1
3.
Assess family support structure and family’s views on patient’s mood,
activity level,
and
sleep.
4.
Assess baseline neurologic status with attention to cerebellar and motor
function.
5.
Obtain complete medical history, including neurologic history, history
of exposure to
brain
irradiation, and educational experience and success.
6.
Perform laboratory evaluation including assessment of electrolytes,
liver function,
thyroid
status, and particularly antithyroid antibodies.
Side Effects Management
Handbook • X.
Neurologic/Ophthalmologic • p. 6
PREVENTIVE STRATEGIES
1.
Anticipate symptoms in high-risk populations: patients with previous
psychiatric
history, mood disorders (bipolar depression), or brain irradiation;
coinfection patients;
geriatric patients with altered metabolism, pre-existing cognitive
deficits, or altered
sleep patterns; as well as patients being treated with antidepressants
or hypnotics.1,4
All
should be monitored closely and dose reductions made as needed.
2.
Recommend strategies for improving concentration and “staving off
symptoms”
(eg,
doing crossword puzzles, playing card games, doing needlepoint). Advise
patients to decrease environmental distractions such as the TV or radio,
and to take
short
naps when fatigued.
TREATMENT STRATEGIES
1.
Discuss with patient any mood and cognitive effects as a result of
treatment. (There is
a
significant stigma associated with psychiatric illness and reporting of
symptoms.)
Do not
underestimate the value of reassurance. Include family
members/significant
others
as much as possible.
2. Rule
out a differential diagnosis of hydrocephalus, thyroid dysfunction, and
HIV
opportunistic infection.
3.
Evaluate concomitant medications, such as narcotic analgesics,
tranquilizers, or
sedatives, which may exacerbate cognitive changes.
4.
Advise patients to reorganize lifestyle and conserve energy to maintain
a reasonable
amount
of participation in normal activities.
5.
Recommend use of reorientation, prompts, or lists.
6.
Advise patients to maintain an exercise schedule and participate in
concentrating/focusing activities with repetitive actions (ie,
gardening, needlepoint).
7.
Consider pharmacologic therapy (in approximate order of preference):
a. Psychostimulants (bupropion [Wellbutrin®])
and modafinil (Provigil®);
avoid
pemoline (Cylert®).
These agents have amphetamine-like properties, and their
indirect dopamine-agonist actions may account for their efficacy in the
treatment
of
interferon toxicity. Efficacy has also been cited in adult and pediatric
glioma
patients, as well as cancer, other chronic illness, depression, and
hepatitis patients.
Psychostimulants are short acting although sustained-released formulas
are
available (methylphenidate [ConcertaTM,
MetaDate®,
Methylin®,
Ritalin®]
20 mg
SR; 8-hour duration of action).5
Caution may be needed
in patients with a history
of
substance abuse. A methylphenidate dose of 2.5 to 20 mg orally/d is
recommended for patients receiving interferon therapy. Concern that a
patient
with
HCV infection (and no history of drug abuse) may develop tolerance,
dependence, and addiction is not supported by the literature in reviews
of
methylphenidate use for patients with chronic illness. Remember, as with
all
medications used, check for drug-drug interactions, and also set firm
boundaries
for
appropriate use.
b. Opioid antagonist may be used as palliative agent. Naltrexone (ReVia®)
100 mg has been used, but limited study information is available.1
c.
Corticosteroids have been used to permit administration of optimum doses
of
interferon primarily in cancer patients.1
Caution: Steroids are
known to have a
mood-elevating effect; however, psychosis and steroid-induced depression
can
Side Effects Management
Handbook • X.
Neurologic/Ophthalmologic • p. 7
occur.
Therefore, it is imperative to monitor patient on a regular basis
(utilization
of CES-D
self-assessment tool will add validity and reliability to the
evaluation).
d.
Treatment with TCAs may increase norepinephrine and serotonin levels,
but have
a
sedative effect and become counterproductive in the management of
fatigue and
aggravate memory dysfunction.1
TCAs, particularly
those with pronounced
anticholinergic effects, are less desirable than other treatment
options,
potentiating cognitive dysfunction related to interferon or cirrhosis.
Furthermore,
TCAs
may be especially problematic for patients with suicidal ideation, given
their lethality in overdose.1
8.
Obtain neuropsychiatric or psychiatric consult.
REFERENCES
1. Valentine AD, Meyers CA, Kling MA,
Richelson E, Hauser P. Mood and cognitive side
effects of interferon-alpha therapy.
Semin Oncol. 1998;25(suppl 1):39-47.
2. Licinio J, Kling MA, Hauser P. Cytokines
and brain function: relevance to interferon-a-
induced-mood and cognitive changes.
Semin Oncol. 1998;25(suppl 1):30-38.
3. Johnson ME, Fisher DG, Fenaughty A,
Theno SA. Hepatitis C virus and depression in drug
users. Am J Gastroenterol.
1998;93:785-789.
4. Greenberg DB, Jonasch E, Gadd MA, et al.
Adjuvant therapy of melanoma with interferonalpha-
2b is associated with mania and bipolar
syndromes. Cancer. 2000;89:356-362.
5. Plutchik L, Snyder S, Drooker M, Chodoff
L, Sheiner P. Methylphenidate in post liver
transplant patients. Psychosomatics.
1998;39:118-123. |
