This article provides guidelines for identifying and
treating relapsing-remitting MS in the primary care setting and reviews
recent additions to treatment options for disease management. Approaches
for patient counseling and recommendations by the National Multiple
Sclerosis Society are also discussed.
Suggested citation: Early Diagnosis and Intervention in Multiple
Sclerosis. Krupkin Whitney, D. Int J MS Care [Serial on-line].
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of
unknown origin that causes multifocal demyelination, axonal damage, and
neuronal loss throughout the central nervous system: brain, brainstem, and
spinal cord. MS can present with a wide variety of neurologic symptoms.
The annual number of MS cases reported in the United States from 1990
through 1992 was 180,000, according to the Centers for Disease Control and
Prevention.1 The National Multiple Sclerosis Society (NMSS)
currently reports that between 250,000 and 350,000 Americans have MS.2
Women are three times more likely than men to get MS.2 Also, MS
is disproportionately more common in whites than in people of other races.2
The greatest prevalence of MS is in the temperate regions of the globe,2
with isolated additional pockets of high prevalence elsewhere, including
parts of Australia and New Guinea. An individual’s geographic risk is
linked to the location where he or she lives during the first 15 years of
life.2 Onset of MS usually occurs between ages 20 and 40 years.
Although there are genetic risk factors,3-5 MS is not directly
inherited. A viral link, environmental factors, or a combination of any or
all of these factors may stimulate the pathogenesis of MS.3
While most primary care providers will encounter relatively few
patients with MS, as a group they are most likely to be the first to see a
patient initially presenting with MS symptoms, according to the NMSS.6
It is likely, therefore, that the primary care physician will be the first
to suspect or identify MS. Early diagnosis of MS has become particularly
important since disease-modifying therapies have become available.
MS can be classified as progressive or relapsing-remitting.4,5
As suggested by the terms, symptoms in progressive forms of MS continue
and steadily worsen. Remissions or plateaus can occur, but without total
recovery between exacerbations. Progressive MS steadily worsens, with or
without superimposed exacerbations. Relapsing-remitting MS (RRMS) differs
in that symptoms appear, remit, and relapse episodically with a stable
clinical baseline between exacerbations. In RRMS, there is full or partial
recovery between exacerbations, sometimes for extended periods.
RRMS is challenging to diagnose because of the myriad neurologic
symptoms with which it can present. MS can mimic and be mimicked by
numerous other conditions; hence the differential diagnosis is vast. Once
positive diagnostic criteria are fulfilled, MS is confirmed only after a
thorough neurologic evaluation eliminates other diseases. If a patient
switches physicians, a pattern of exacerbations may be missed entirely.
Many symptoms occur sporadically, and the same patient may have
different symptoms with each exacerbation (Table 1). Unfortunately, there
is no typical pattern of exacerbation and no way to predict a patient’s
likely pattern or prognosis based on symptom manifestation at diagnosis.
Symptoms Commonly Associated With MS.
in the extremities
disturbances, including decreased visual acuity,
diplopia, and scotomata
in the extremities, torso, or face
and coordination impairment
or bowel dysfunction
and emotional disturbances
Motor weakness in one or more limbs is the most common initial
manifestation of MS, occurring in about 40% of patients at the time of
diagnosis. The patient may have frank weakness, or may experience the
weakness as easy fatigability of the limb, dragging one leg, tripping, or
a subjective sensation of stiffness, which is a manifestation of
spasticity. The neurologic examination will likely reveal upper motor
neuron signs such as spasticity, hyperreflexia, or abnormal reflexes such
as the Babinski’s or Hoffmann’s sign. Lower motor neuron signs such as
fasciculations do not result from MS; atrophy, if present, is atrophy of
Optic neuritis is the presenting manifestation of MS in 22% of
patients, with heightened likelihood of progressing to definite MS if
white matter lesions are found on magnetic resonance imaging (MRI).
Sensory disturbances constitute the first MS symptoms in 21% of
patients. While some may report actual numbness, the subjective experience
is often more subtle, covering the range of hypesthesia, hyperesthesia,
dysesthesias, and allodynia. The patient may lack adequate vocabulary to
express these sensations or hesitate to report the more bizarre
dysesthesias, such as formication. Findings of the neurologic examination
will often be benign, but long tract signs, if present, enhance suspicion
of MS, and a Lhermitte’s sign may be elicited.
Disturbances of extraocular movements are the presenting symptoms of MS
in 12% of cases. The patient may report frank diplopia, but may have less
florid complaints, such as oscillopsia or vague visual dysphoria,
especially when looking at moving objects. Almost any abnormality of
extraocular movements may be found on examination, including nystagmus,
disconjugate gaze, and internuclear ophthalmoplegia.
Although vertigo is the presenting symptom in only 5% of cases, over
time 40% to 50% of MS patients will experience vertigo. Trigeminal
neuralgia in an individual younger than 50 years should arouse suspicion
of MS, as should recurrent trigeminal neuralgia.
MS presents with bladder disturbances in only 5% of cases, but over
time, almost every MS patient will encounter bladder difficulties. These
span the range from frank incontinence to complete urinary retention, but
a mixed picture is most common, with complaints such as hesitancy,
frequency, incomplete emptying, leaking, and frequent urinary tract
infections. Urodynamic testing will most often reveal detrussor-sphincter
dyssinergia. Bowel complaints often accompany bladder dysfunction,
constipation being the most frequent complaint. Absence of any bladder
disturbance after 10 years of other neurologic symptoms casts doubt upon a
diagnosis of MS.
Fatigue (usually neurogenic fatigue or "lassitude") is a
nearly ubiquitous symptom among MS patients. Fatigue may also arise
secondary to other neurologic symptoms, such as weakness. Depression,
while not a common presenting symptom, occurs as an organic manifestation
of MS at some point in the course of the disease in 42% of patients.
A history of two or more episodes of the most common symptoms separated
by periods of remission is generally reason to suspect MS.7
Diagnosis is indirect and based on clinical and laboratory findings. The
directed neurologic examination (Table 2), which takes only a few minutes
and can be performed in the office, is designed to evaluate heavily
myelinated tracts in the central nervous system. Examination may reveal
weakness, spasticity, hyperreflexia, optic pallor, nystagmus, ataxia, or
other evidence of central nervous system pathology. While neurologic
examination may reveal abnormalities which have not manifested in clinical
symptoms, it is nonetheless possible for a person with MS to have a normal
neurologic examination early in the course of the disease. In the primary
care setting, the directed neurologic examination can enhance suspicion of
MS, but it does not establish a diagnosis.
Directed Neurologic Examination.
a patient’s history is suggestive of MS but not
conclusive, the neurologic examination can provide
important diagnostic information. A directed neurologic
examination designed with the "possible MS"
situation in mind targets heavily myelinated tracts in the
central nervous system to look for evidence of silent
lesions. This directed neurologic examination should add
no more than two minutes to an office visit.
examination will reveal optic pallor if there has been a
prior attack of optic neuritis. A more subtle finding is
the afferent pupillary defect. This finding is elicited by
the "swinging flashlight test." A positive test
result consists of a paradoxical dilation to light.
tracts in the brainstem coordinate extraocular movements,
and any disorder of eye movements can conceivably be
caused by MS. Frankly disconjugate gaze is easy to spot.
Nystagmus is a frequent finding. The "INO" (internuclear
ophthalmoplegia) is a specific abnormality of extraocular
movements caused by lesions in the median longitudinal
fasciculus and is sometimes abbreviated as "MLF."
Classic INO involves ipsilateral abduction limitation.
There are numerous variants.
are usually aware of frank weakness but may not be aware
of inability to arise unassisted from the squatting
is a consequence of loss of inhibition from descending
motor tracts. The Babinski’s and Hoffmann’s signs are
special examples of loss of inhibition.
which is a disorder of deep tendon reflex loops, is a
companion of hyperreflexia. Spasticity is best elicited by
passively moving the limbs with the patient as relaxed as
movement, tremor, and past-pointing on finger-nose-finger
maneuver or heel-knee-shin maneuver reflect disruption of
most common abnormal finding in early MS is gait
positive result on Romberg’s test would be unlikely in
this setting, but inability to stand on one foot may be
evidence of abnormal station.
There is no definitive diagnostic test to confirm or exclude MS.
Magnetic resonance imaging is the most sensitive noninvasive imaging
technique; it will detect demyelinated areas, or plaques, in the brain
and/or spinal cord of 95% of patients with definite MS. Actively inflamed
areas can be distinguished from old plaques using gadolinium contrast
enhancement, as the blood-brain barrier is damaged in active lesions. A
normal MRI, by itself, does not rule out MS. Central delays in
visual-evoked responses, brainstem auditory– evoked responses, or
somatosensory-evoked responses may be caused by demyelination.7
These findings, however, are nonspecific and require thoughtful clinical
correlation. Cerebrospinal fluid is abnormal in the majority of MS
patients,4 but normal cerebrospinal fluid does not rule out a
diagnosis. The presence of oligoclonal bands, indicating immunoglobulin G
synthesis within the blood-brain barrier, is a common finding in MS
While diagnosis is not the responsibility of the primary care
physician, it is usually the primary care doctor who is best positioned to
recognize early signs and symptoms suggestive of MS and initiate referral
to a general neurologist or MS specialist to establish a definite
diagnosis, whether of MS or of another neurologic condition.
It is generally accepted that onset and progression of MS occur before
overt clinical symptoms begin, and progression continues even during
periods of apparent remission.8,9 Specifically, there is
evidence substantiated by MRI and pathologic analysis that MS causes
axonal damage even when there are no clinical signs or symptoms of the
disease.8 Since the disease-modifying effects of
immunomodulating agents have been demonstrated, and since disease activity
is ongoing between exacerbations and even prior to the first clinical
manifestation, early intervention has become the standard of care, and
therapy should not be discontinued during apparent remissions.6
Comprehensive management of RRMS includes treating the underlying
disease process, minimizing specific symptoms, managing exacerbations, and
attending to quality of life for both patient and family.7
Until recently, there were no pharmacologic agents that were shown to
modify the underlying pathophysiology of MS. There are now three
immunomodulating agents approved in the United States for treatment of
RRMS, as well as a recombinant interferon beta-1a agent (Rebif®)
available for use in Europe, Canada, and Australia. In addition,
mitoxantrone (Novantrone®), an antineoplastic agent, is the
one drug approved by the US Food and Drug Administration for the treatment
of progressive MS.
The three agents currently available in the United States for treatment
of RRMS are interferon beta-1a (Avonex®), interferon beta-1b (Betaseron®),
and glatiramer acetate (Copaxone®). Clinical studies indicate
that all three of these agents are effective in reducing the frequency and
severity of exacerbations and the development of brain lesions, as
measured by MRI.10-12 Interferon beta-1a is administered weekly
by intramuscular injection; interferon beta-1b is administered every 48
hours by subcutaneous injection; and glatiramer acetate is administered
daily by subcutaneous injection. With proper training in injection
technique, patients can self-administer any of these treatments. Most
importantly, physicians must help patients understand the necessity of
continuing therapy, even during symptom-free periods.
Compliance with injectable medications is a challenge, especially when
symptoms are minimal, and side effects present a further challenge to
compliance. Close to two thirds of patients using interferon therapy will
experience flulike symptoms, sometimes accompanied by low-grade fever, for
up to 24 hours following injection. This reaction wanes, and for most
patients ceases altogether by the end of three months of treatment. During
that time, the flulike symptoms can be blunted by acetaminophen or a
nonsteroidal anti-inflammatory drug taken orally before injection and
repeated after four to six hours if necessary. Some patients whose flulike
side effects are severe and refractory to first-line management will
benefit from pretreatment with prednisone 5 mg orally.
Injection site reactions can occur with interferon beta-1b (85% of
patients injecting drug vs 37% of those injecting placebo),
glatiramer acetate (66% of patients injecting drug vs 37% of those
injecting placebo), and, less commonly, with interferon beta-1a. Usually
these are minor and resolve spontaneously. Rare cases of infection and
tissue necrosis have been reported with interferon beta-1b (5%). Injection
site reactions can be minimized by meticulous injection technique,
including the use of automatic injection devices. Icing the skin before
and after injection may help. Most patients embarking on self-injection of
MS treatment receive one or more visits from a home health nurse to teach
injection technique and provide support.
Glatiramer acetate injections may be followed within 30 minutes by a
systemic reaction variously characterized by facial flushing, chest
discomfort, palpitations, and dyspnea, lasting from 30 seconds to 30
minutes. This is a benign and self-limited reaction and was reported by
15.2% of glatiramer acetate recipients and 3.2% of placebo recipients in
an extended trial. The reaction occurs unpredictably and irregularly. Of
those who experience this reaction, most experience it only once; in
others it may recur at wide intervals. Overall, it occurred in about 1 of
840 daily injections in an extended trial.13
Leukopenia and elevated transaminases can result from interferon
therapy, rarely so profound or so persistent as to require discontinuation
of treatment. Complete blood cell count and transaminases should be
measured at three-month intervals. Depression, which occurs commonly as a
primary symptom of MS, can also be caused by interferon beta-1a on
Both interferons are classified as Pregnancy Category C; glatiramer
acetate is classified as Pregnancy Category B.
Cultivation and regular reinforcement of realistic expectations for
therapy contribute positively to compliance. Patients who understand at
the outset that immunomodulating agents do not cure MS or reverse
neurologic deficits are less likely to discontinue treatment than are
those patients who harbor unrealistic expectations.
Intensive corticosteroid therapy is frequently used for acute
exacerbations of MS symptoms and can be administered intravenously or
orally. Patients should be advised about the potential side effects
associated with corticosteroid treatment, such as immune suppression, mood
swings, headaches, restlessness, weight gain, and, rarely, aseptic
necrosis of the femur and other bones. Corticosteroids should be reserved
for short-term therapy only, due to serious adverse effects of long-term
use, such as Cushing’s syndrome and osteoporosis.
Mitoxantrone, an immunosuppressive antineoplastic agent, has been shown
to slow progression of clinical disability in progressive forms
(relapsing-progressive and secondary progressive, but not primary
progressive) of MS, with corroborative MRI findings. Potential
cardiotoxicity excludes patients with cardiac risk factors and limits
total lifetime dose. Because of total lifetime dose limits, the timing and
duration of treatment are critical. Many neurologists intervene with
mitoxantrone to regain disease control in patients whose exacerbations
become more frequent or who show accelerated progression in spite of
treatment with interferon or glatiramer acetate treatment. In this
setting, mitoxantrone is administered intravenously every three months for
up to two years. Mitoxantrone is also used in place of methylprednisolone
to treat some exacerbations.
Symptom management includes a variety of measures, depending on the
symptom. Often, because of the diverse nature of symptoms—ranging from
fatigue to bowel or bladder dysfunction—it is advisable to refer the
patient to a specialist. See the section titled "Referral to Other
Care Providers" for information about treating specific symptoms.
the Diagnosis to the Patient
With the proliferation of managed care, primary care physicians face
increasing restrictions on the amount of time they can spend with each
patient. Nevertheless, physician-patient communication may be one of the
most important factors affecting treatment compliance and quality of life.7
Patients receiving an official diagnosis of MS generally need some
extra time beyond the usual office visit to learn about the implications
of the diagnosis and the rationale and choices for treatment, as well as
to ask questions and begin to process the news. A patient should learn the
diagnosis directly from the physician, not by letter or phone or from any
other member of the health care team. Sensitivity to the patient’s
emotions and coping style includes listening to what he or she is and is
not asking, and can help the physician tailor the scope and pace of
information offered to the patient. Delivering bad news can be painful for
both the patient and physician, so being prepared for an emotional
response from the patient is important.
In addition to personal communication from the physician, MS patients
and their families benefit from written information about the disease,
treatments, and available support services. This approach can reinforce
the information provided by the physician and help patients think of
questions to ask during follow-up visits. Subsequent discussion of
treatment options may be more productive if patients have had the
opportunity to inform themselves about available therapies in advance.
Patients in Treatment
Physicians should provide patients with information about therapeutic
options and, where appropriate, enlist their participation in selecting
treatment. Although not all patients will want to be involved in treatment
decisions, many will embark on a course of good compliance as a result of
collaborating with the physician. Since treatment is intended to last
indefinitely or until a better treatment or a cure is found, it is good
policy to take into account any patient preferences or lifestyle factors
that can affect willingness to adhere to long-term treatment.
Although immunomodulating agents may delay the progression of MS and
reduce the frequency of exacerbations, physicians should be certain
patients and families understand that these drugs do not cure MS or
reverse existing damage. This understanding is important to sustained
adherence to treatment. Potential side effects, their likely duration, and
their prevention and management should be discussed during the treatment
planning phase. Patients should be told what to expect and when to contact
to Other Care Providers
Most patients who experience MS symptoms will visit a primary care
provider first. MS is a complex disease, however, and in most cases will
eventually require the participation of one or more specialists and/or
other health care providers to address specific needs. In the diagnostic
phase, it is advisable to refer the patient to a general neurologist or MS
specialist to confirm the diagnosis and initiate treatment.
Although many neurologists can manage most MS symptoms, increasing
disability often requires assistance from other specialists. In
particular, since bladder dysfunction occurs at some point in the majority
of MS patients,7 early referral to a urologist is strongly
advised. Neurogenic bladder can be asymptomatic while causing irreversible
damage to the upper urinary tract. Spasticity, mobility problems, and
debilitating fatigue can be addressed by physiatrists and physical
therapists, who can use medication, exercise, and behavioral medicine to
help MS patients maintain mobility as long as possible.
Depression is a primary symptom of MS and may require treatment by a
psychiatrist or psychologist.14 Finding a mental health
specialist who has expertise with chronic disease or disability is
advisable, if possible. Family members of MS patients may also benefit
from counseling, as MS affects entire families, not just the individual
with the disease. This is particularly so since MS usually begins during
the most active years of child-rearing and career development.
Although patients with MS will benefit from specialist care, the
primary physician plays a vital role in overseeing the patient’s general
health. Patients with MS might be inclined to see all their health needs
in terms of their neurologic disease and neglect health maintenance
responsibilities such as cholesterol and blood pressure management,
Papanicolaou smears, or mammograms. The primary care physician is in a
unique position to be aware of all aspects of the MS patient’s care and
quality of life.
Organizations such as the NMSS, the Consortium of MS Centers, and
Rehabilitation in MS provide reliable information for anyone interested in
learning about MS. Through support groups, patients can interact with
others who have MS and find valuable information about the disease itself,
treatments, insurance issues, government policies, lifestyle concerns, and
much more. Many support organizations advocate in the arena of public
health policy, as well, providing a voice for issues that affect MS
patients, their families, and providers. Physicians may wish to include
contact information for support organizations in the written materials
they provide to patients upon diagnosis.
for MS Patients
The NMSS published a Disease Management Consensus Statement for RRMS.6
This Consensus Statement is based on current clinical data regarding
optimum treatment for MS and is intended for providers, insurers, and
patients. The purpose of the Consensus Statement is to educate everyone
who has an interest in or a need to know about the treatment of MS and to
establish clear objectives for optimal therapy.
The Consensus Statement emphasizes the need for early intervention with
one of the three immunomodulating agents currently indicated for the
treatment of RRMS. In addition, the NMSS strongly advocates full
flexibility in the selection and reimbursement of these three agents.
Formularies should not limit physicians’ choices to only one or two
agents because the agents act by different mechanisms, and no single agent
will be effective and tolerable for all patients.
Other objectives of the Consensus Statement are to dispel
misinformation that these therapeutic options are experimental and to
reinforce the idea that patients with relapsing forms of MS, regardless of
their level of disability, age, or frequency of exacerbation, should have
access to all available treatments. The absence of exacerbations, which is
a desirable result of therapy, should not prompt a patient to discontinue
therapy. Familiarity with the NMSS’s Consensus Statement recommendations
can provide a framework for primary care physicians who are unfamiliar
with recent trends in the treatment of RRMS.
Primary care physicians play a key role in identifying the early signs
of RRMS. Prompt diagnosis allows early intervention with disease-modifying
agents which can reduce the frequency and severity of exacerbations, slow
the accumulation of MRI lesion burden, and delay the development of
disability. Treating the underlying disease can proceed concurrently with
symptom management and psychosocial interventions.
Finally, ongoing education and sensitive communication with the patient
may improve adherence to treatment. Because continued treatment with an
immunomodulating agent is the only current option for sustained treatment
to slow disease progression, it is essential for patients to understand
how to self-administer injections and otherwise take an active role in
their own care. A multidisciplinary approach is necessary at times in
order to provide the best care for the patient. Primary care physicians
are encouraged to refer to the NMSS Consensus Statement for more
information about the care of patients with RRMS.
for this article was drawn from insights provided by a group of physicians
and allied health professionals who have been diagnosed with MS. Their
unique perspective as both providers and patients was particularly
valuable in forming recommendations about patient communication and
involvement. These contributors include: Margo Benner, RN; Suman Hariharan,
MD; Elisabeth Heininger, RD; Nancy Holland, RN, EdD; Roger M. Katz, MD;
Mark Levinson, MD; Mary Madsen, RN; Carol Matthews, MSN, CFNP/CPNP; David
A. Reich, MD; Susan M. Reynolds, RN; Susan Roys, RN, BSN; and Cindy
Wright, RN. The author also wishes to acknowledge Catherine Jarrell for
her assistance in preparing this article. This work was supported by an
unrestricted grant from Teva Marion Partners.
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