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C H A P T E R 5
Internal Medicine I
Mary Ann Picone
Introduction
The primary care provider is a vital member of the multiple
sclerosis (MS) multidisciplinary team who often has the role
of coordinator of care and who is often called upon to refer
patients to neurologists or other specialists. Considering the
increased number of disease-modifying therapies (DMTs) for
patients with MS, this also leads to an increase in monitoring
and safety recommendations. It is of paramount importance for
internists to optimize and prevent comorbid medical
conditions. How to recognize a relapse, what vaccinations are
safe to use, what monitoring needs to be done with the various
DMTs are several of the topics that will be discussed below. In
this era of more efficacious therapies, it is increasingly
important that primary care practitioners work in partnership
with neurologists to help educate and maintain patients in the
best overall medical health possible to improve care.
Relapse Assessment
One facet of MS that internists should be prepared to check for
is an acute exacerbation of symptoms or a relapse. A relapse is
considered development of any new symptom lasting at least
24 hours in the absence of fever or infection or recurrence of a
previous symptom such as optic neuritis separated by a period
of at least 30 days of stability. 1 For example, if a patient had
left optic neuritis that improved and was stable for at least
30 days and then began to note blurred vision again in the left
eye for more than 24 hours, this would be considered a new
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relapse. Increase in body temperature by overheating can also
cause transient worsening of symptoms but should improve
once a patient cools down. Patients should be asked whether
they have any new or worsening MS symptoms and, if so, how
long they have been going on.
MS relapse tends to evolve over the course of 24 hours to a
few days. Vascular events, on the other hand, tend to be very
abrupt in onset. Inquiring whether the patient has been under a
period of undue stress or has not been sleeping well can also
be helpful. An exacerbation of symptoms during a period of
infection, often urinary tract infection, is considered a
pseudorelapse. Urinary tract or other infections can worsen
previous symptoms such as optic neuritis. Infections, even if a
patient is afebrile, can cause worsening of underlying disease
activity. Patients may have increase in symptoms such as
spasticity and present to a physician’s office, and this could be
due to infection.
Many patients may not present with typical symptoms of
dysuria, so urinalysis is recommended during suspected
relapse. Discerning the presence of a urinary tract or any
underlying infection is vital since initiating steroid treatments
when there is an underlying infection is unnecessary and risks
worsening the underlying condition. However, if symptoms
persist even when the infection clears, especially if symptoms
are interfering with daily activities, then this would be true
relapse that would require acute treatment, usually with
steroids. 1 A typical steroid course for treatment is Solu-
Medrol 1 g administered intravenously over 1 to 2 hours daily
for 3 to 5 days. If no underlying infection is present and there
is worsening of neurologic symptoms, referral to neurologist
should be made. See Figure 5.1 for algorithm for MS relapse
management. Although there is no guarantee that treatment
with steroids will bring about complete recovery from a
relapse, they do tend to expedite recovery. Occasionally, a
second course of steroids may be needed. Steroid taper is
usually not needed. The effects of a relapse can last days,
weeks, or even months before improvement is seen. Magnetic
resonance imaging (MRI) of the brain with gadolinium
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contrast at the time of relapse will often show areas of acute
inflammation.
FIGURE 5.1 Flow chart showing the algorithm for multiple
sclerosis (MS) relapse management.
Adapted by permission from Springer: Berkovich R. Treatment of
acute relapses in multiple sclerosis. Neurotherapeutics.
2013;10(1):97-105. Copyright © 2012 The American Society for
Experimental NeuroTherapeutics, Inc.
Malignancies in MS
In recent years, patients with MS are getting diagnosed earlier
and initiating treatment with DMTs. These treatments are not
without their drawbacks; in addition to the close monitoring
required with the DMTs, concerns arise about an increased
risk of malignancy with immunosuppressive therapies. This is
especially a concern in MS patients that have been diagnosed
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with cancer: Does the diagnosis mean they need to stop their
DMT’s? 2 Are there any DMT’s that patients may need to
avoid if they have history of cancer? And finally, is there a
higher incidence of cancer in MS patients?
A review was done by Marrie et al, 3 utilizing PUBMED,
SCOPUS, Web of Knowledge, and EMBASE databases to
investigate incidence and prevalence of cancer in persons with
MS. Although the findings were inconsistent, the review
demonstrated that risk of any cancer was most often reported
to be lower in MS than in the general population. If anything,
the incidence of meningioma and urinary system cancer
appeared to be slightly higher than expected; however, this
finding could be a result of the increased number of brain
MRIs done as part of MS disease monitoring and findings
from referrals to urologists because of urinary tract issues
common to MS.
3
Oftentimes, once patients are diagnosed with MS, they have
been known to neglect their general medical care and assume
that many symptoms may be related to MS. MS patients are
typically not immune deficient, and there has not been
increased cancer risk seen in the disease itself. 2 As patients
age, however, there can be increased malignancy risk, so it is
important to follow established standard of care of preventive
maintenance, such as screening colonoscopies, mammography
for women, and prostate-specific antigen testing for men.
Disease-Modifying Therapies and
Malignancies
Another question often asked is whether DMTs increase
cancer risk. The interferon therapies, both interferon beta 1b
and interferon beta 1a, and glatiramer acetate have not shown
any increase in cancer incidence. Information regarding the
following DMTs is based primarily on clinical trial
information:
Natalizumab (Tysabri)
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In the NAtalizumab Safety and EFFIcacy in Relapsing
Remitting MS clinical trial of Tysabri versus placebo with 932
patients studied, 1 patient died from malignant melanoma.
This patient had history of melanoma and noted a skin lesion
after first natalizumab dose. Patient received a total of five
doses before melanoma diagnosis. Six cases of cancer were
noted in the AFFIRM trial. Five cases were in the Tysabritreated patients and one in placebo. Five out of the 627 Tyasbri
patients and one out of the 315 placebo patients were
diagnosed with cancer. Of all the patients diagnosed with
cancer, there were three cases of breast cancer, one cervical
cancer, and one new malignant melanoma. There has not been
any increased cancer signal seen in postmarketing
surveillance, and no increased screening requirements are
required for patients on natalizumab.
4,5
Fingolimod (Gilenya)
In the clinical trial of fingolimod versus placebo with 281
patients studied, 189 received treatment for the full 24 months.
During the core study, one basal cell and one squamous cell
carcinoma were reported in the fingolimod group. 6 The
patient with basal cell carcinoma had a history of multiple skin
lesions. During the extension phase of the trial, one case of
basal cell carcinoma was reported in the placebo-fingolimod
group. Among all reported clinical trials, basal cell carcinoma
was reported in 2% of patients receiving fingolimod. 7 A
potential increased risk of basal cell carcinoma has been added
to the fingolimod prescribing label. A skin examination before
initiation of treatment is recommended and should be repeated
yearly.
Ocrelizumab (Ocrevus)
In ocrelizumab clinical trials, six cases of breast cancer were
reported. None were seen in the placebo-treated patients.
There has not been any increased postmarketing signal noted
since the drug became approved in 2017. No additional
screening is recommended.
8
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Alemtuzumab (Lemtrada)
Alemtuzumab may increase the risk of thyroid cancer. In
clinical trials, three of 919 (0.3%) Lemtrada-treated patients
developed thyroid cancer. This may have been related to
increased vigilance and screening during clinical trial protocol.
Two additional instances of thyroid cancer were noted in
uncontrolled studies. Patients and clinicians are encouraged to
monitor for any lumps or swellings in the neck, persistent
hoarseness, voice changes, trouble swallowing, and any
persistent cough not related to underlying upper respiratory
tract infection. Greater concern with alemtuzumab is
secondary thyroid autoimmunity, which can occur in
approximately 34% of alemtuzumab-treated patients. 9 Patients
on alemtuzumab are also recommended to have baseline and
yearly general skin checks to monitor for skin cancer. In
uncontrolled studies, four of 1486 (0.3%) alemtuzumabtreated patients developed melanoma or melanoma in situ.
Cases of lymphoma and lymphoproliferative disorders have
occurred in alemtuzumab-treated patients. Careful
consideration has to be given regarding initiating therapy with
alemtuzumab with anyone who has any preexisting or existing
cancer. 9 Yearly dermatologic screening for all patients on
DMT is generally recommended as good medical practice.
Comorbidities
Comorbidity is the occurrence of one or more other diseases in
individuals with an index disease, in this case, MS. 10 MS is a
chronic illness often associated with escalating disability over
time that impacts an individual’s quality of life and ability to
function independently. 11 Many medical conditions can often
be present concurrently with MS and can impact disease
activity. Recognizing comorbidities and treating them
appropriately can improve outcomes of patients with MS. As
we will discuss, there are worsened disease outcomes when
MS is complicated by comorbid conditions. As new treatment
options become available, MS patients are able to live longer
with the disease. This presents a challenge to internists treating
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MS because they must discern whether MS, part of the normal
aging process, or an underlying comorbidity causes symptoms.
Although there is a need for further investigation into the
incidence of comorbidities in MS, a review of existing studies
found that the comorbidities with the highest incidence noted
were cancer, hypertension, and stroke, and those with the
highest prevalence were depression, anxiety, hypertension,
hyperlipidemia, and chronic lung disease. 12 As this study was
based on information from mostly North America and Western
Europe, there is a need for data regarding comorbidity in MS
populations of Africa and Central or South America. The
potential role of underlying comorbidities remains a challenge
for physicians and researchers alike, owing to the
heterogeneous outcomes of patients with MS. Other factors
contributing to the difficulty of discerning MS symptoms from
other comorbidities are the frequency of relapse rate, age at
onset, and initial presenting neurological symptoms.
Comorbidities can lead to diagnostic delays, can increase
disability, and have an impact on quality of life, mortality, and
cognition.
13,14
Given the complexity of comorbidities in MS,
collaboration between physicians from relevant specialties is
essential to improving patient outcomes.
Impact of Medical Comorbidities on
Multiple Sclerosis Activity
Management of medical comorbidities is important not only
for overall good medical health and quality of life, but also can
prevent the rate at which a patient relapses. Kowalec et al
showed that high comorbidity burden (three or more
conditions) such as hypertension, depression, and
hyperlipidemia can increase relapse rate activity in MS
patients. 15 Migraine was also associated with an increase in
relapse rate. As conditions like hypertension and diabetes are
seen more frequently in the aging MS population, close
monitoring is required to optimize medical treatment, with the
goal of minimizing, or preventing, hospitalizations. The
internist should assure that the patient is being effectively
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counseled and managed to try to achieve healthy weight,
optimal diet, and exercise regimen.
A retrospective electronic medical review study looking at
influence of hypertension, diabetes, obstructive lung disease,
and hyperlipidemia showed that patients with three
comorbidities had slower walking abilities and self-reported
worse outcomes compared with those who did not have these
coexisting conditions. 16 Analysis of patients from the North
American Research Committee on MS (NARCOMS) registry
showed that the presence of 1 vascular comorbidity at the time
of MS diagnosis was associated with a 51% increased risk of
early gait disability, and the presence of 2 comorbidities was
associated with a 228% increased risk of ambulatory disability.
16
Existence of Comorbidities Can Impact
Treatment Initiation
Studies have shown the greater the number of comorbidities a
patient has, the less likely they are to initiate a DMT.
14
Considering what we know about the importance of initiating
therapy early to slow the progression of disability, this delay
can be significant. Presence of comorbidities can also impact
adherence to therapy once initiated, for example, there is
strong evidence demonstrating that MS patients with
underlying migraines could experience migraine worsening if
the patient is treated with interferon beta. 17 This often
necessitates a shift in DMT to another therapy that would help
reduce migraines but be less effective in combating MS
progression. Comorbidities can also worsen underlying MS
symptoms. 18 In particular, pain and fatigue can be exacerbated
by a comorbid condition. Rheumatoid arthritis, inflammatory
bowel disease, migraine, chronic obstructive pulmonary
disease, hypertension, autoimmune thyroid disease, and
depression have been associated with increased pain
complaints.
19
When evaluating patients with preexisting comorbidities who
present with new symptoms of potential neurologic origin, the
nonneurologist must investigate whether the new symptom is
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