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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
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Commentary: This patient with long-standing MS was
quite disabled with chronic bilateral optic nerve
demyelination and gait dysfunction requiring a walker.
Although some component of her reduced visual acuity and
visual impairment was from optic nerve disease, her
nystagmus directly caused oscillopsia and also likely
contributed to her poor visual acuity and visual function. She
was symptomatically helped and her nystagmus was reduced
by moderately high doses of gabapentin to treat APN.
Examination of eye movements in patients with MS should
include observation for any abnormal movement of the eyes as
the patient looks straight ahead, side to side, and up and down;
assessment of whether each eye moves completely up, down,
and to each side; evaluation of the smoothness of eye motion
as the eyes follow a slowly moving target (e.g., smooth
pursuit); evaluation of the accuracy and speed of fast eye
movements called saccades; and determination of whether or
not the eyes are aligned and making coordinated movements.
Abnormal smooth pursuit is common in MS; however, it is
typically not a cause of visual symptoms. A more typical cause
of visual symptoms is internuclear ophthalmoplegia,
abbreviated INO, which is caused by demyelination in a
structure called the medial longitudinal fasciculus (MLF) that
coordinates horizontal eye movements. INO leads to impaired
adduction (motion of an eye toward the nose) in one eye on
the same side as the demyelinating lesion in the brainstem and
abducting nystagmus in the opposite eye (to and fro
spontaneous motion of the opposite eye when it is placed in a
lateral or outward position toward the ear). For example, when
looking left, the right eye will incompletely, or more slowly,
turn in toward the nose because of a lesion in the right MLF. In
this scenario, the left (abducting) eye will try to maintain
paired gaze and as a result will manifest with nystagmus when
looking left, which can result in diplopia, blurry vision or “just
not seeing right.” INO can be the presenting feature of MS or
can occur acutely or be chronically present in established MS.
On occasion, INO can be simultaneously present on both sides
at the same time, in which case each eye has difficulty moving
toward the nose on horizontal gaze in the opposite direction.
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MRI is indicated when a patient develops new diplopia or
oscillopsia, although sometimes the examination is more
sensitive than the MRI in detecting an abnormality. For
example, the MLF is a very tiny structure, and although
examination may definitely prove the presence of an INO, a
lesion may not be detectable in the MLF on MRI. Several
specific treatment options are available for patients with
chronic diplopia or oscillopsia. Patching of one eye or prisms
in glasses can be used to eliminate diplopia. Prisms redirect
the angle of entry of a visual stimulus to realign the images so
that the two eyes again become “yoked.” For chronic diplopia
with stable ocular misalignment, for example, with chronic
bilateral INO, eye muscle surgery to mechanically realign the
eyes and better approximate the visual stimulus on the two
retinas can be considered.
In the case of APN, medications can be quite effective in
minimizing oscillopsia and maximizing visual acuity.
Gabapentin and memantine are the first choices for APN in
MS and have been shown to be effective in small randomized
controlled studies.
25
Conclusions
Systematic assessment of optic nerve function and eye
movements are required to detect the myriad visual
manifestations of MS. Steroids are the mainstay of acute
therapy but can have consequences, both ophthalmological
and systemic. It is important to realize that steroids may help
accelerate recovery from an MS attack but do not affect the
long-term natural history of MS. Fortunately, there are now
many options for the long-term treatment of MS. A low
threshold should be maintained for obtaining neuroophthalmologic consultation in patients with MS, as MS is a
condition that affects all parts of the central nervous system,
with frequent and significant impact on vision.
References
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multiple sclerosis: correlation with new measures of low and high contrast letter
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C H A P T E R 9
Cutaneous Disorders
Associated With Multiple
Sclerosis
Anna-Marie Hosking Joseph L. Jorizzo
Introduction
Patients with multiple sclerosis (MS) suffer from a variety of
characteristic cutaneous disorders. Patients with MS often
experience paroxysmal itching and dysesthesias and are at an
increased risk for injection site reactions or cutaneous
neoplasms with certain medications. In this chapter, we review
the cutaneous signs and symptoms seen in patients with MS,
the cutaneous side effects of disease-modifying therapies, and
the medication contraindications physicians should be aware
of when managing patients with MS and concomitant skin
disease.
Signs and Symptoms—Paroxysmal
Dysesthesias and Pruritus
MS is characterized by paroxysmal symptoms, including
dysesthesias, pruritus, and phantom sensations. Paresthesias,
frank dysesthesias, or pruritus may be the first presenting
symptom in a patient with MS. In 1979, Yabuki and Hayabara
reported seven cases of segmental burning dysesthesias of the
upper extremities in patients with MS. 1 Dysesthesias include
pins and needles sensations as well as burning, stabbing, or
tearing pain. Most commonly, chronic pain syndromes present
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with dysesthetic discomfort in the legs but may also involve
the trunk and upper extremities.
2
Itching is a rare sensory symptom in neurological diseases,
including MS. 3 Paroxysmal itching as a manifestation of MS
was first recognized by Osterman and Westerberg in 1975.
4
Pruritus with MS is transient, comes on with intensity, and is
triggered by heat, movement, or sensory stimulation. 2 It has
been described on the upper and lower limbs as well as the
face and trunk. In a study of 377 patients, 17 presented with
paroxysmal itching, with one patient presenting with itching as
the only initial MS symptom. 3 Often, the itching is intense,
leading to vigorous scratching with subsequent skin
excoriation. Many patients also experience persistent
dysesthesias or sensory changes in the same location in
between paroxysmal episodes. Itching has been associated
with other paroxysmal symptoms, including tonic seizures or
trigeminal neuralgia. 3 Yamamoto et al reported three Japanese
women with MS with paroxysmal itching attacks with abrupt
onset and resolution, ranging from seconds to minutes,
occurring five to six times daily, often during sleep. These
itching attacks presented as the first and only MS symptom or
as a predictive symptom of MS exacerbation. 5 The
mechanism of itching in MS is unknown. It is thought to be
related to transversely spreading ephaptic activation of axons
in a partially demyelinated fiber tract in the central nervous
system, rendering the nerve fiber hypersensitive to minor
irritation.
4,6
Cutaneous Side Effects of DiseaseModifying Therapy
Injectable Therapies
Interferon-beta (IFN-β) and glatiramer acetate are both
effective disease-modifying therapies for MS. IFN-β is
available in four preparations: IFN-β 1b (Betaseron® or
Extavia®, Bayer Schering Pharma, Berlin, Germany)
subcutaneous injection every other day; IFN-β 1a (Rebif®,
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Merck Serono, Darmstadt, Germany) subcutaneous injection
three times weekly; IFN-β 1a (Avonex®, Biogen, Cambridge,
Massachusetts, USA) intramuscular injection once weekly;
and pegylated IFN-β 1a (Plegridy®, Biogen) subcutaneous
injection every 2 weeks. 7 Glatiramer acetate (Copaxone®,
Teva Sanofi Aventis, Paris, France) is an amino acid polymer
analog of myelin basic protein administered via subcutaneous
injection either daily (20 mg/mL) or three times a week
(40 mg/mL). These medications have excellent safety profiles;
however, injection site reactions are an important limitation in
the use of subcutaneous IFN-β and glatiramer acetate.
8,9
In a
prospective study of 412 patients with MS treated with
disease-modifying therapy for 2 years, none of the patients
given intramuscular IFN-β 1a reported missing a dose because
of injection site reactions, whereas 5.7% of patients given
subcutaneous IFN-β 1b, 7.1% of patients given subcutaneous
IFN-β 1a, and 4.3% of patients given subcutaneous glatiramer
acetate reported missing doses because of injection site
reactions. This is concerning, as missed doses were associated
with twice the likelihood of treatment discontinuation.
10
Nonadherence to disease-modifying therapy is associated with
poor clinical outcomes and increased risk of MS relapse.
11,12
Management of injection site reactions requires an ongoing
dialogue between the neurologist and dermatologist to manage
adverse cutaneous side effects and to tailor the appropriate
dose and type of disease-modifying therapy.
Injection Site Reactions
Injectable disease-modifying therapies can cause a wide range
of injection site reactions, from transient erythema and
eczemalike reactions to severe ulcers and necrosis, which may
require treatment cessation and surgical intervention. The most
common injection site reactions include erythema, bruising,
induration, immune-mediated inflammatory reactions,
lipoatrophy, cutaneous necrosis, and ulceration. 9 Rare
cutaneous reactions have been reported, including psoriasis
exacerbation, 13 granulomatous dermatitis with focal sarcoidal
features, 14 Raynaud phenomenon, 15 panniculitis,
16,17
vasculitis, 18 subacute cutaneous lupus erythematosus,
19
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morphea, 20 localized pigmentation disorders, 21 cutaneous
mucinoses, 22 and fixed drug eruptions. 23 Injection site
reactions most commonly occur during the first month of
treatment but have been reported up to 29 months after
initiating therapy. 24 Some reports suggest a decrease in the
incidence with increasing treatment duration. 25 Injection-site
reactions are observed more frequently in injection sites with
reduced subcutaneous fat (i.e., thighs and arms) than in areas
with increased subcutaneous fat (i.e., buttocks and abdomen).
26
There is a higher predominance in females than in males,
ranging from 2:1 to 8:1, although this may be an artifact of the
higher overall incidence of MS in women.
24,27
Interferon-beta
Along with flulike symptoms, injection site reactions are the
most common side effect observed in patients using injectable
IFN-β, occurring in up to 90% of patients using subcutaneous
formulations and up to 33% of those using intramuscular
formulations.
9,28
In three controlled clinical trials investigating
the use of IFN-β 1b (Betaseron®), injection site reactions
occurred in 86% of patients compared with 37% with placebo.
Injection site necrosis occurred in 5% of patients compared
with none in the placebo cohort. Other reactions, including
inflammation (53%), pain (18%), hypersensitivity (3%), and
edema (3%) were significantly associated with IFN-β 1b
treatment. Approximately 76% of patients who developed
injection site reactions did so in the first 3 months of
treatment. 29 In addition, a placebo-controlled randomized trial
of IFN-β 1b for secondary progressive MS reported injection
site reactions in 43.6% of patients versus 10.3% with placebo.
Necrosis occurred in 4.7% compared with zero in the placebo
group and inflammation in 50% compared with 4.2% in the
placebo group. 30 A 30-month postlicensure study reviewed the
adverse event reports for IFN-β 1b following Food and Drug
Administration (FDA) approval in 1993. Adverse events
included erythema (51%), pain (30%), and necrosis (13%),
with 6% of patients with injection site reactions subsequently
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discontinuing therapy and 21% of patients with injection site
necrosis requiring surgical intervention.
24
In two multicenter studies evaluating the safety and efficacy of
IFN-β 1a (Rebif®) in patients with relapsing remitting MS,
injection site reactions occurred in 89% and 92% of patients
taking 22 µg and 44 µg three times weekly, respectively,
compared with 39% with placebo. Injection site necrosis
occurred in six patients (3%) taking 44 µg three times weekly
and two patients (1%) taking 22 µg three times weekly over
the course of 2 years.
31
Intramuscular administration (Avonex®) is associated with
fewer skin reactions when compared with subcutaneous
administration of IFN-β. In pooled placebo-controlled clinical
studies, injection site pain, inflammation, and injection site
reactions occurred in 8%, 6%, and 3% of patients,
respectively, compared with 6%, 2%, and 1% with placebo. To
date, there have been no reports of necrosis with the use of
Avonex®. However, lipoatrophy can occur when improperly
injecting intramuscular formulations subcutaneously, due to an
incorrect injection angle.
9,28
Panniculitis and Lipoatrophy
Panniculitis, the inflammation of subcutaneous adipose tissue,
has been described in patients treated with IFN-β therapy, with
subsequent lipoatrophy seen in up to 46% of patients.
9,32
Localized lipoatrophy is characterized by loss of subcutaneous
adipose tissue in the area of the injection site, resulting in
well-circumscribed areas of skin depression, seen most
commonly on the anterolateral surface of thighs or upper arms.
Histopathology shows atrophic and diminutive fat lobules in
the subcutaneous fat (Figure 9.1). Proposed mechanisms
include a direct toxic effect on adipocytes, inciting an
inflammatory response followed by a hypersensitivity reaction
and residual loss of subcutaneous fat. 33 Patients generally
present with pain, erythema, and induration at injection sites of
the arms or thighs (abdomen and buttocks are less common).
A minority of reactions are severe enough to cause difficulty
with ambulation or require surgical debridement. 34 Reports of
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both septal and lobular panniculitis have been described with
or without accompanying vascular thrombosis.
13,16,17,32,35-40
Lipoatrophy is a concerning side effect, as it may be
irreversible, resulting in disfiguring contours of the thighs and
arms. It is more commonly observed with glatiramer acetate
injection than with IFN-β. There are multiple potential
explanations for the occurrence of lipoatrophy with IFN-β,
including incorrect injection into the dermis, secondary
reaction from the high immunogenicity of IFN-β, and
administration of nonprewarmed medication.
10,22
FIGURE 9.1 Lipoatrophy. Atrophic and diminutive fat lobules
in the subcutaneous fat with minimal surrounding inflammation
(hematoxylin and eosin, 14×). See eBook for color figure.
Morphea
A rare and more recently reported cutaneous side effect of
IFN-β therapy is localized scleroderma, or morphea. Morphea
is a cutaneous fibrosing connective tissue disorder
characterized by excessive collagen deposition leading to
thickening of the dermis, subcutaneous tissue, or both (Figure
9.2). Cases of morphea have been reported with both IFN-β 1a
and IFN-β 1b.
20,41,42
In one case, woody induration consistent
with morphea appeared on the anterior thighs 6 months after
injection of IFN-β 1a. 20 Another case reported a morpheaform
reaction to IFN-β 1b injection on the thighs and abdomen after
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