Self-Assessment and CME

Patient Management
Address correspondence to
Dr Claire S. Riley, Columbia
University Medical Center,
710 W 168th St, Suite 246,

ProblemPreferred New York, NY 10032,

csr53@cumc.columbia.edu.
Relationship Disclosure:

Responses Dr Riley serves as an advisory

board member for Biogen,
Novartis AG, Sanofi Genzyme,
and Teva Pharmaceutical
Claire S. Riley, MD Industries Ltd, and as an
editor for the Multiple
Sclerosis Resource Centre
website. Dr Riley receives
personal compensation for
Following are the preferred responses for the Patient Management Problem speaking engagements from
in this Continuum issue. The case, questions, and answer options are re- PeerView Press CME and
peated, and the preferred response is given, followed by an explanation and Medscape CME, research
support from Biogen and the
a reference with which you may seek more specific information. You are National Institutes of Health,
encouraged to review the responses and explanations carefully to evaluate and funding for personnel
support from MS Hope
your general understanding of the material. The comment and references for a Cure.
included with each question are intended to encourage independent study. Unlabeled Use of
To obtain CME credits for this activity, subscribers must complete this Products/Investigational
Use Disclosure:
Patient Management Problem online at www.aan.com/continuum/cme. Dr Riley reports no disclosure.
Upon completion of the Patient Management Problem, participants may * 2016 American Academy
earn up to 2 AMA PRA Category 1 Creditsi. Participants have up to 3 years of Neurology.

from the date of publication to earn CME credits. No CME will be awarded
for this issue after June 30, 2019.

Learning Objectives
Upon completion of this activity, the participant will be able to:
& Diagnose clinically isolated syndrome
& Identify and manage hypersensitivity reactions to monoclonal
antibody therapy
& Choose among available therapies for management of highly active
relapsing multiple sclerosis

Case
A 32-year-old left-handed woman presents to the emergency department
with brief 30- to 60-second episodes of tingling in her arms and legs that
have occurred 5 to 10 times per day over the past 3 days, without any
associated altered consciousness. She has had no antecedent illness or
vaccination. Her past medical history is notable only for intermittent
gastrointestinal symptoms attributed to irritable bowel syndrome.
Neurologic examination is normal with the exception of slight decrease in
vibratory sensation in her hands and feet and hyperactive deep tendon
reflexes bilaterally with one beat of clonus at each ankle. Babinski
response is absent. Upon neck flexion, she describes reproduction of the
sensory symptoms in her arms and legs as well as sharp shooting electrical
pain radiating from her neck into her limbs.

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 PMPPreferred Responses

b 1. A lesion in which of the following anatomic regions is most likely

responsible for this presentation?
A. cervical spinal cord
B . internal capsule
C. midbrain
D. primary sensory cortex
E . thalamus
The preferred response is A (cervical spinal cord). The description of
Lhermitte sign suggests the presence of a lesion in the cervical spinal cord.
The Lhermitte sign is described as sensory phenomena, including tingling
or shooting electrical pains down the spine or extremities, which are
triggered by neck flexion. The symptoms may also occur spontaneously.1
Lesions causing Lhermitte sign are most commonly located in the posterior
aspect of the spinal cord.2 Spinal cord demyelination, as may occur in
multiple sclerosis (MS), is a common cause of Lhermitte sign, but it can occur
with other cervical spinal pathologies, including, but not limited to, cervical
spondylosis, trauma, and syringomyelia.
1. Rae-Grant AD. Unusual symptoms and syndromes in multiple sclerosis. Continuum (Minneap
Minn) 2013;19(4 Multiple Sclerosis):992Y1006. doi:10.1212/01.CON.0000433287.30715.07.
2. Gutrecht JA, Zamani AA, Slagado ED. Anatomic-radiologic basis of Lhermittes sign in multiple
sclerosis. Arch Neurol 1993;50(8):849Y851. doi:10.1001/archneur.1993.00540080056014.

MRI of the cervical spine without contrast is obtained (PMP Figure 1).

PMP FIGURE 1 Axial T2-weighted MRI of the cervical

spine showing high signal involving
the posterior columns. On sagittal
noncontrast images (not shown), the lesion was at the
C2 vertebral body level only.

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b 2. Which of the following is the most appropriate next step in diagnostic
evaluation of this patient?
A. lumbar puncture
B . Lyme antibody testing
C. MRI of the brain and cervical and thoracic spinal cord with and without
contrast
D. serum neuromyelitis optica (NMO) IgG
E . visual evoked potentials

The preferred response is C (MRI of the brain and cervical and thoracic
spinal cord with and without contrast). Imaging of the spinal cord lesion
with contrast will assist with differential diagnosis, as will the presence or
absence of white matter lesions in the brain.1 While all of the other options
may eventually be useful in establishing a diagnosis, the best next diagnostic
step is MRI of the brain and spinal cord with and without contrast.
1. Sombekke MH, Wattjes MP, Balk LJ, et al. Spinal cord lesions in patients with clinically isolated
syndrome: a powerful tool in diagnosis and prognosis. Neurology 2013;80(1):69Y75.
doi:10.1212/WNL.0b013e31827b1a67.

b 3. If the spinal cord lesion had extended for more than three segments of the
cervical spinal cord, which of the following diagnostic tests would have
been most appropriate to order next?
A. dilated funduscopy
B. NMO IgG
C. Sjogren syndrome A (SSA)/Sjogren syndrome B (SSB) antibody
D. somatosensory evoked potentials
E. spinal cord biopsy

The preferred response is B (NMO IgG). A contiguous spinal cord lesion

extending three or more vertebral segments is considered a longitudinally
extensive lesion. Longitudinally extensive spinal cord lesions are more
consistent with the diagnosis of NMO than MS.1 NMO IgG is a highly sensitive
and specific assay for the diagnosis of NMO.2
1. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for
neuromyelitis optica spectrum disorders. Neurology 2015;85(2):177Y189. doi:10.1212/
WNL.0000000000001729.
2. Jarius S, Wildemann B. Aquaporin-4 antibodies (NMO-IgG) as a serological marker of
neuromyelitis optica: a critical review of the literature. Brain Pathol 2013;23(6):661Y683.
doi:10.1111/bpa.12084.

The patient undergoes MRI of the brain and cervical and thoracic
spinal cord with and without contrast. The brain MRI demonstrates
two periventricular lesions, one of which is contrast enhancing. The
cervical spinal cord lesion is redemonstrated at the C2 level and shows
contrast enhancement.

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 PMPPreferred Responses

b 4. Which of the following terms describes the most accurate overall current
diagnosis and why?
A. clinically isolated syndrome because the asymptomatic enhancing lesion
establishes dissemination in time, but the spinal cord lesion is excluded in
the count for dissemination in space
B . clinically isolated syndrome because the asymptomatic enhancing
periventricular lesion establishes dissemination in time and the
periventricular and spinal cord lesions establish dissemination in space
C. isolated transverse myelitis because the symptomatic lesion is a myelitis
and is an active lesion
D. primary progressive MS because no improvement of the clinical attack
symptom has been reported
E . relapsing-remitting MS because the asymptomatic enhancing
periventricular lesion establishes dissemination in time and the
periventricular and spinal cord lesions establish dissemination in space

The preferred response is A (clinically isolated syndrome because the

asymptomatic enhancing lesion establishes dissemination in time, but the
spinal cord lesion is excluded in the count for dissemination in space).
The diagnosis of clinically isolated syndrome (CIS) requires a demyelinating
event with a suspicious-looking MRI that does not entirely satisfy McDonald
criteria for the diagnosis of relapsing MS.1 This is a shrinking diagnostic
category in the era of the 2010 McDonald criteria. In this example, exclusion
of the symptomatic lesion in the spinal cord leads to a diagnosis of CIS rather
than MS by failure to meet dissemination in space criteria. This exclusion
of symptomatic brainstem and spinal cord lesions serves to retain sensitivity
in the CIS diagnosis, excluding isolated transverse myelitis, for example.
Dissemination in space requires two of four characteristic areas to be
involved but excludes a spinal cord or brainstem lesion from the space count
if that is the presenting clinical symptom. So this patient ends up with only
the periventricular lesion counting, meaning only one of four classic locations
is involved. Dissemination in time is met, in this example, by the
simultaneous presence of asymptomatic enhancing and nonenhancing lesions.
1. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010
revisions to the McDonald criteria. Ann Neurol 2011;69(2):292Y302. doi:10.1002/ana.22366.

A diagnosis of CIS is established after serum studies, (antinuclear antibody,

panel of antibodies to extractable nuclear antigens including anti-SSA and
anti-SSB, antiYdouble-stranded DNA, vitamin B12, angiotensin-converting
enzyme, Lyme enzyme-linked immunosorbent assay [ELISA] and Western
blot, rapid plasma reagin) for MS mimics are negative and do not suggest
an alternative diagnosis to explain the demonstrated lesions. Treatment
with IV corticosteroids is discussed with the patient, but deferred given her
strictly sensory symptoms that are not interfering with her daily function.
The intermittent sensory symptoms resolve over several weeks, although
the Lhermitte sign occasionally recurs after she takes a hot shower or
exercises outside on a warm day.

Continued on page 1007

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 Continued from page 1006
On a follow-up visit 1 month later, further treatment options are
discussed. She is counseled to start on a disease-modifying therapy to delay
the development of clinically definite MS. The patient reveals that she is
planning a pregnancy in the next 2 years.

b 5. Which of the following disease-modifying therapies is most appropriate for

the treatment of CIS in this patient?
A. alemtuzumab
B . fingolimod
C. glatiramer acetate
D. interferon beta
E . teriflunomide
The preferred response is C (glatiramer acetate). No evidence exists
that glatiramer acetate has deleterious consequences for fertility or fetal
development, and thus many neurologists employ this agent in the setting
of pregnancy. Furthermore, it is approved by the US Food and Drug
Administration (FDA) for the treatment of CIS.1 A controlled study of
teriflunomide in CIS, Phase III Study With Teriflunomide Versus Placebo in
Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC), showed
benefit in delaying clinically definite MS. However, the pregnancy Category X
status of teriflunomide makes this medication much less appealing in this
circumstance. Fingolimod and alemtuzumab have not been tested in CIS.
Although potentially effective in this disease state, the teratogenicity of
these agents makes them poor initial choices. Dimethyl fumarate also has not
been tested in CIS. Interferon beta may be used, and certain preparations
are labeled by the FDA for CIS, but would need to be discontinued at the
time of an attempt to conceive.
1. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically
definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a
randomised, double-blind, placebo-controlled trial. Lancet 2009;374(9700):1503Y1511.
doi:10.1016/S0140-6736(09)61259-9.

The patient is reluctant to start on a disease-modifying therapy because

of her fear of needles and instead decides to pursue a holistic approach
to management. She does not return for recommended surveillance MRIs
or follow-up visits. Two years later, 3 months after the delivery of a healthy
child, the patient returns reporting double vision. Examination demonstrates
adduction paresis in the left eye on attempted rightward gaze with
associated horizontal nystagmus in the abducting right eye. She is also noted
to have mild spasticity in the right leg and a right Babinski sign.

b 6. What of the following is the most likely anatomic localization for the
oculomotor syndrome described?
A. abducens nucleus
B . frontal eye field
C. medial longitudinal fasciculus (MLF)
D. optic nerve
E . paramedian pontine reticular formation

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 PMPPreferred Responses

The preferred response is C (medial longitudinal fasciculus [MLF]). This

patient is presenting with an internuclear ophthalmoplegia, which localizes to
the MLF.1 This is a common cause of diplopia in MS. The MLF normally
connects the abducens nucleus in the pons to the contralateral medial rectus
subnucleus of the oculomotor nucleus in the midbrain, allowing for
conjugate horizontal gaze. A lesion of the left MLF, as in this patient, will
manifest with inability to adduct the left eye on rightward gaze with
associated horizontal nystagmus in the abducting right eye. Interestingly, the
MLF is among the earliest structures to myelinate in the developing brain.
1. Frohman EM, Zhang H, Kramer PD, et al. MRI characteristics of the MLF in MS patients with
chronic internuclear ophthalmoparesis. Neurology 2001;57(5):762Y768. doi:10.1212/
WNL.57.5.762.

b 7. Which of the following is the most appropriate next step in management

of the acute relapse in this patient?
A. alemtuzumab
B . high-dose IV methylprednisolone
C. IV immunoglobulin (IVIg)
D. natalizumab
E . plasma exchange

The preferred response is B (high-dose IV methylprednisolone). High-dose

IV steroids have been established as an effective therapy to hasten recovery
after MS relapse and are generally well tolerated with a good safety profile.
Natalizumab was evaluated in acute MS attacks and not found to be beneficial
for clinical recovery.1 Plasma exchange may be used as a second-line
treatment when corticosteroids are not successful.
1. OConnor PW, Goodman A, Willmer-Hulme AJ, et al. Randomized multicenter trial of
natalizumab in acute MS relapses: clinical and MRI effects. Neurology 2004;62(11):2038Y2043.
doi:10.1212/01.WNL.0000128136.79044.D6.

The patient undergoes treatment with 3 days of high-dose IV

methylprednisolone, followed by a 10-day taper of oral prednisone.
A repeat MRI of the brain demonstrates development of 15 new
T2-hyperintense lesions, three of which are contrast enhancing, and
she is given the diagnosis of MS. She is now interested in pursuing a
disease-modifying therapy for MS. A panel of serum studies are negative
for latent tuberculosis, JC virus antibody, varicella-zoster virus IgG, and
human immunodeficiency virus types 1 and 2. Complete blood count with
differential and hepatic function panel are normal.

b 8. Following acute relapse treatment, which of the following disease-modifying

therapies is the most appropriate option for this patient?
A. dimethyl fumarate
B . fingolimod
C. glatiramer acetate
D. interferon beta
E . natalizumab

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 The preferred response is E (natalizumab). While the patient has not been
on any prior treatment, she has robust inflammatory activity with multiple
enhancing lesions. Natalizumab is effective in this population,1 and she is a
good candidate for this agent as a first-line treatment given her negative JC
virus antibody status.2 Fingolimod is less preferred given her varicella-zoster
virus nonimmune status; she would require varicella vaccination prior to
starting fingolimod. Dimethyl fumarate is a potential option, although
rendered somewhat less desirable in this case because of her history of
irritable bowel symptoms. Her fear of needles makes the injected
disease-modifying therapies, glatiramer acetate and interferon beta, less
optimal for her.
1. Cobo-Calvo A, Bau L, Matas E, et al. Effectiveness of natalizumab in patients with highly active
relapsing remitting multiple sclerosis. Eur Neurol 2015;73(3Y4):220Y229. doi:10.1159/000375371.
2. Plavina T, Subramanyam M, Bloomgren G, et al. Anti-JC virus antibody levels in serum or
plasma further define risk of natalizumab-associated progressive multifocal
leukoencephalopathy. Ann Neurol 2014;76(6):802Y812. doi:10.1002/ana.24286.

The patient agrees to start monthly infusions of natalizumab. She is

counseled on the importance of regular dosing intervals and advised to
have a brain MRI every 6 months. She is counseled that natalizumab is
pregnancy Category C and a secure method of contraception is
recommended while being treated with natalizumab.

b 9. How often should JC virus antibody testing be repeated in this patient?

A. annually
B. every month, at the time of each infusion
C. every 6 months, at the time of each brain MRI
D. monthly at the time of each infusion
E . repeat only if she demonstrates new symptoms concerning for progressive
multifocal leukoencephalopathy

The preferred response is C (every 6 months, at the time of each brain MRI).
Testing every 3 to 6 months for JC virus antibody status is common practice
for surveillance of JC virus antibody negative patients.1
1. Nicholas JA, Racke MK, Imitola J, Boster AL. First-line natalizumab in multiple sclerosis:
rationale, patient selection, benefits and risks. Ther Adv Chronic Dis 2014;5(2):62Y68.
doi:10.1177/2040622313514790.

The patient receives her first dose of natalizumab and a second dose
4 weeks later without incident. Her third dose is delayed by 3 weeks, and
during that infusion she develops hives, a headache, and a scratchy throat.
She feels tired for 2 days after the infusion. She has a similar reaction to
her fourth natalizumab dose despite pretreatment with diphenhydramine.

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 PMPPreferred Responses

b 10. Which of the following serum studies should be ordered at this time?
A. antinatalizumab antibodies
B . complete blood count with differential
C. C-reactive protein
D. JC virus antibody
E . JC virus polymerase chain reaction

The preferred response is A (antinatalizumab antibodies). Irregular dosing

intervals can place patients at higher risk for the development of neutralizing
antibodies to natalizumab. Hypersensitivity reactions such as the one
described in this patient are highly associated with persistently positive
antinatalizumab antibodies.1 The hypersensitivity reaction described suggests
antinatalizumab antibody formation, not a presentation of progressive
multifocal leukoencephalopathy.
1. Calabresi PA, Giovannoni G, Confavreux C, et al. The incidence and significance of
anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology
2007;69(14):1391Y1403. doi:10.1212/01.wnl.0000277457.17420.b5.

b 11. If antinatalizumab antibodies are positive, which of the following is an

appropriate next step for management of this patient?
A. continue natalizumab and monitor clinically for future hypersensitivity
reactions
B . continue natalizumab and premedicate with diphenhydramine and
methylprednisolone
C. continue natalizumab and repeat antinatalizumab antibodies 6 weeks
after the first assay
D. discontinue natalizumab and start dimethyl fumarate immediately
E . discontinue natalizumab and wait 1 month to start another
disease-modifying therapy

The preferred response is D (discontinue natalizumab and start dimethyl

fumarate immediately). Although option C could be a reasonable approach,
the likelihood of resolution of antinatalizumab antibodies after two
hypersensitivity reactions is relatively low.1 Since this patient has had
significant inflammatory disease activity and has not been on any other
disease-modifying therapy, rapid transition to dimethyl fumarate appears
to be the most appropriate course of action. Since antinatalizumab
antibodies are present, there is no need to delay initiation of another
disease-modifying therapy. When neutralizing antibodies are present, the
action of natalizumab is blocked, so there is no need for a washout of the
immunomodulatory effect from a safety perspective.
1. Calabresi PA, Giovannoni G, Confavreux C, et al. The incidence and significance of
anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology
2007;69(14):1391Y1403. doi:10.1212/01.wnl.0000277457.17420.b5.

The patient starts dimethyl fumarate and tolerates it well. After 6 months,
a brain MRI shows two new T2 hyperintense lesions and no enhancing
lesions. The patient has had complete resolution of the internuclear
ophthalmoplegia and now reports only occasional stiffness in her right leg.

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b 12. Which of the following surveillance monitoring tests is most appropriate
to perform for the patient at this visit?
A. hepatic function panel
B . JC virus antibody
C. lymphocyte count for lymphopenia
D. ophthalmologic examination for macular edema
E . thyroid-stimulating hormone (TSH)

The preferred response is C (lymphocyte count for lymphopenia).

Regular monitoring of lymphocyte count is recommended with dimethyl
fumarate therapy. Approximately 5% of patients develop grade 3 (less than
0.5 to 0.2 x 109/L) or higher lymphopenia.1 Persistent lymphopenia of grade
3 or higher may be indication to transition to a different disease-modifying
therapy to avoid risk of infection.
1. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer
in multiple sclerosis. N Engl J Med 2012;367(12):1087Y1097. doi:10.1056/NEJMoa1206328.

The patient tolerates dimethyl fumarate well and is found to have a stable
brain MRI and clinical exam after 18 months on treatment.

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