ORIGINAL ARTICLE
`
`Lipoatrophy in Patients with Multiple
`Sclerosis on Glatiramer Acetate
`
`Catherine M. Edgar, Donald G. Brunet, Paul Fenton, E. Vee McBride,
`Peter Green
`
`ABSTRACT: Background: Patients with relapsing remitting multiple sclerosis on the disease modifying therapy of glatiramer acetate
`may be experiencing an adverse reaction of lipoatrophy at the sites of their subcutaneous injections. The purpose of this study was to
`complete a full examination of the injection site areas for users of glatiramer acetate, and to examine the relationship between
`lipoatrophy and patient characteristics. Methods: Glatiramer acetate users were identified by means of chart review. Over six months,
`during regular clinic appointments, assessment included a full examination of injection site areas including visual inspection and manual
`palpation. Additional patient and clinical characteristics were obtained by means of chart review and patient questioning. Results:
`Seventy-six patients had been or were current users of glatiramer acetate. Of these, 34 (45%) had evidence of lipoatrophy in at least one
`injection site area. All were female, and five had severe, nine had moderate and 20 had mild lipoatrophy. In some cases, lipoatrophy
`occurred within months of therapy initiation. Case reviews are included for five of the 34 patients, along with photographs of the
`lipoatrophy, a magnetic resonance image and comments on skin biopsies. Conclusions: Prevalence of lipoatrophy was much higher than
`expected. Possible reasons for this adverse reaction are explored and suggested treatment recommendations are reviewed. Lipoatrophy
`can be very disfiguring and is thought to be permanent, and the psychological impact can be significant. It is, therefore, important that
`patients be aware of the possibility of lipoatrophy, be able to identify it and discontinue injecting in areas where it is identified.
`
`R(cid:201)SUM(cid:201): La lipoatrophie chez les patients atteints de sclØrose en plaques traitØs par l(cid:146)acØtate de glatiramŁre. Introduction: Les patients atteints
`de la forme rØmittente de sclØrose en plaques qui prennent de l(cid:146)acØtate de glatiramŁre, peuvent avoir de la lipoatrophie aux points d(cid:146)injections sous-
`cutanØes comme effet secondaire du mØdicament. Le but de cette Øtude Øtait de procØder (cid:224) un examen complet des points d(cid:146)injections chez les
`utilisateurs d(cid:146)acØtate de glatiramŁre et d(cid:146)examiner la relation entre la lipoatrophie et les caractØristiques des patients. MØthodes: Les utilisateurs
`d(cid:146)acØtate de glatiramŁre ont ØtØ identifiØs par une revue de dossiers. Pendant six mois, ces patients ont subi un examen complet des sites d(cid:146)injection par
`inspection visuelle et palpation manuelle au moment de leur visite rØguliŁre (cid:224) la clinique. La revue de dossiers et une entrevue avec les patients ont
`permis de complØter le profil du patient et ses caractØristiques cliniques. RØsultats: Soixante-dix-huit patients utilisaient ou avaient utilisØ l(cid:146)acØtate de
`glatiramŁre. Parmi eux, 34 (43.6%) avaient de la lipoatrophie au niveau d(cid:146)au moins une rØgion servant de point d(cid:146)injection. Tous Øtaient des femmes et
`cinq avaient une lipoatrophie sØvŁre, neuf une lipoatrophie modØrØe et 20 une lipoatrophie lØgŁre. Dans certains cas, la lipoatrophie Øtait apparue en
`quelques mois aprŁs le dØbut du traitement. Les cas de cinq des 34 patientes sont rØvisØs avec photographies et imagerie par rØsonance magnØtique (cid:224)
`l(cid:146)appui, ainsi que des commentaires sur les biopsies cutanØes. Conclusions: La prØvalence de la lipoatrophie Øtait beaucoup plus ØlevØe que prØvue.
`Nous discutons des raisons possibles de cet effet secondaire et les recommandations de traitement non validØes sont rØvisØes. La lipoatrophie peut Œtre
`trŁs dØfigurante et elle est considØrØe comme permanente. Son impact psychologique peut Œtre important. Il est donc essentiel que les patients soient
`prØvenus qu(cid:146)ils peuvent prØsenter de la lipoatrophie et qu(cid:146)ils puissent la reconna(cid:238)tre et cesser les injections dans les rØgions atteintes.
`
`Can. J. Neurol. Sci. 2004; 31: 58-63
`
`is a chronic inflammatory
`(MS)
`Multiple sclerosis
`demyelinating disease of the central nervous system. The most
`common form of the disease is relapsing-remitting MS (RRMS)
`where patients experience multiple exacerbations, or (cid:147)relapses(cid:148)
`over time. There are a number of proven treatments available for
`RRMS, one of them being glatiramer acetate. Given on a daily
`basis by subcutaneous injection,
`it has shown to reduce
`annualized relapse rate by 32%.1 Despite its claimed excellent
`adverse event profile1 there is increasing concern with skin
`reactions and the occurrence of lipoatrophy with the use of
`glatiramer acetate.2 As described in the 1995 pivotal trial, (cid:147)The
`most commonly recognized adverse event was a localized
`
`injection-site reaction consisting of mild erythema and
`induration, which sometimes persisted for several days. It was
`observed at least once during 730 days of treatment in 90% of the
`copolymer 1-treated patients(cid:148).1
`
`From the MS Clinic, Kingston General Hospital and Department of Medicine, Queen(cid:146)s
`University, (CME, DGB, EVM); Department of Radiology, Kingston General Hospital
`and Queen(cid:146)s University, (PF), Kingston, Ontario; and Department of Dermatology,
`University of Ottawa, Ontario (PG), Canada.
`RECEIVED APRIL 1, 2003. ACCEPTED IN FINAL FORM JULY 10, 2003.
`Reprint requests to: Cathy Edgar, MS Clinic, Connell 7, Kingston General Hospital, 76
`Stuart Street, Kingston, Ontario K7L 2V7 Canada
`
`58
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`Lipoatrophy, described as loss of subcutaneous fat, can occur
`with the use of
`intradermal or
`subcutaneous
`injection
`medications including corticosteroids,
`insulin, vasopressin,
`human growth hormone,
`iron dextran, diphtheria-pertusus-
`tetanus immunization and antihistamines. The mechanism is
`probably different for each drug.3 We have noted in the
`outpatient clinic setting that patients who are on glatiramer
`acetate for
`treatment of
`their RRMS are experiencing
`lipoatrophy at their injection sites. This can occur over a short
`period of time after initiation and it can occur in multiple sites. It
`does not necessarily seem to be related to long-term use of
`subcutaneous injections in the same location since most patients
`are very diligent about rotating their injection site areas right
`from the start of treatment. Patients need to be educated at
`initiation of treatment that they must observe their injection sites
`for lipoatrophy and discontinue injecting into the site if
`lipoatrophy occurs. Lipoatrophy is thought to be permanent and
`can be disfiguring.
`The purpose of this study was to complete a full examination
`of the injection site areas for patients who currently were, or had
`ever been, on glatiramer acetate for treatment of their RRMS,
`and to examine the relationship between presence of lipoatrophy
`and a number of patient characteristics.
`
`METHODS
`
`The MS Clinic at Kingston General Hospital in Kingston,
`Ontario follows approximately 600 patients with MS on a
`regular basis. It is an outpatient clinic that approaches MS care
`by means of a multidisciplinary team approach. The neurologist
`and the nurse coordinator assess all patients and, if indicated, the
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`LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
`
`occupational therapist and physiotherapist also assess the patient.
`Patients come to their clinic assessments from a large
`geographical area of southeastern Ontario, with a radius of up to
`250 kilometers. The number of patients on immunotherapy for
`RRMS is approximately 200.
`All active patients who are on glatiramer acetate or have ever
`been on glatiramer acetate were identified by means of chart
`review. Over a six-month period, at their regular follow-up clinic
`appointments, the clinic (nurse) coordinator included in her
`nursing assessment a full examination of all injection site areas
`including visual inspection and manual palpation. Skin changes
`were subjectively assessed but atrophy was not formally
`measured. This is a limitation of this study. An estimate by eye
`and touch only was done by the nurse coordinator. Assignment
`of severity included subjective designation based on surface area
`affected, number of areas in one injection site location, number
`of overall injection site areas affected, length of time on the
`therapy and stature of the patients. For example (cid:147)mild(cid:148) would
`include patients with one to four areas of atrophy no less than
`3 cm in diameter in one or two areas of injections and
`approximately 1 cm in depth. If an area was questionable it was
`not counted. (cid:147)Moderate(cid:148) included greater than four areas of
`atrophy greater than 3 cm2 and less than 10 cm2 in multiple
`injection sites. If the patient was slight in stature (thin) the same
`area and number would be estimated as severe being a far larger
`percentage of total subcutaneous fat. An example of moderate
`severity would be Case #5. A designation of (cid:147)severe(cid:148) would
`include very large areas of depressions greater than 10 cm square
`and greater than 1.5 cm depth in at least two areas plus multiple
`smaller areas in all injection sites used. An example of severe is
`Case #4. Often, for the moderately and severely affected, the
`
`Table: Characteristics of Entire Sample and of those With and Without Lipoatrophy
`
`Characteristic
`
`Sample
`n = 76
`
`Lipoatrophy
`n = 34
`
`Without Lipoatrophy
`n = 42
`
`p-value*
`
`29 (cid:150) 64
`43.3 (8.1)
`
`0 (cid:150) 5.5
`2.5 (1.5)
`
`Age in years
`Range
`Mean (SD)
`EDSS
`Range
`Mean (SD)
`Duration of MS in months
`21 - 257
`Range
`92.2 (58.5)
`Mean (SD)
`Time on glatiramer acetate in months
`Range
`1 (cid:150) 62
`Mean (SD)
`25.3 (14.1)
`Gender
`Female
`Male
`Fair or Red Hair
`Stature
`Slight
`Medium
`Large
`
`66
`10
`24 (31.5%)
`
`26 (34.2%)
`37 (48.6%)
`13 (17.1%)
`
`30 (cid:150) 64
`43.1 (9.0)
`
`1 (cid:150) 5.0
`2.5 (1.1)
`
`21 (cid:150) 257
`97.1 (63.2)
`
`7 (cid:150) 54
`28.2 (13.8)
`
`34 (100.0%)
`0 (0.0%)
`20 (58.8%)
`
`15 (44.1%)
`14 (41.2%)
`5 (14.7%)
`
`29 (cid:150) 57
`43.3 (7.5)
`
`0 (cid:150) 5.5
`2.5 (1.7)
`
`27 (cid:150) 250
`88.3 (54.9)
`
`1 (cid:150) 62
`22.8 (14.0)
`
`32 (76.2%)
`10 (23.8%)
`4 (9.5%)
`
`11 (26.0%)
`23 (54.5%)
`8 (19.0%)
`
`.907
`
`.790
`
`.518
`
`.098
`
`< .001
`.002
`
`.261
`
`* p-value is based on the two-sample t-test for continuous data and the Chi-square test for categorical data
`EDSS = Expanded Disability Status Scale ; SD = standard deviation
`
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`areas are not circular, appearing more like a valley or trough and
`are very patchy and uneven with multiple areas of lipoatrophy
`nmning into one another. Further questioning at the time or by
`telephone was done to obtain information on injection site
`reactions, stature, hair colour and skin sensitivity, as well as use
`of the autoject device. Because the majority of the first seven
`patients identified in our sample had red or blonde hair, were
`slight
`in stature and stated they had sensitive skin,
`these
`additional characteristics were selected for investigation.
`Documentation of skin sensitivity was anecdotal and based on
`patient perception, which was another limitation to this study. It
`should be noted also that the clinic coordinator examines all
`
`patients seen on other immunotherapies so it is known how many
`patients on other subcutaneous immunotherapies for MS have
`lipoatrophy. Although these assessments are not blinded and can
`not be used as strict controls, lipoatrophy seldom occurs with
`interferon treatment. The characteristics of those with and
`
`without lipoatrophy were compared using the two-sample t—test
`for the continuous data (age, duration of MS, time on glatiramer
`acetate and Expanded Disability Status Scale) and Chi-square
`analyses for the categorical data (gender, hair colour and stature).
`
`Risurrs
`
`The chart review produced 76 patients with RRMS who were
`currently, or had been, on glatiramer acetate. The Table contains
`the characteristics of these patients. The majority was female
`(86.8%) and all were Caucasian, mostly of European decent.
`Forty—four (57.9%) reported site reactions all or most of the time.
`Of the 76, 34 (44.7%) patients had evidence of mild, moderate or
`severe lipoatrophy in at least one injection site area. Table 1 also
`contains the characteristics of those with lipoatrophy. All were
`female, and five (14.7%) had severe, nine (26.5%) had moderate
`and 20 (58.8%) had mild lipoatrophy, and all reported site
`reactions all or most of the time. Their ages ranged from 30 to
`64, mean duration was just over eight years, and Expanded
`Disability Status Scale scores at the time of examination ranged
`from 1 to 5. Concomitant medications were noted and there was
`
`no obvious connection. Time on glatiramer acetate therapy
`ranged from seven months to 54 months. Table 1 also contains
`characteristics of those without lipoatrophy. Although they had
`no lipoatrophy, 10 (23.8%)
`reported that
`they always
`experienced site reactions, 7 (16.7%) reported a reaction initially
`and 19 (45.2%) reported that they never had site reactions. This
`information was unknown for another 6 (14.3%). There were no
`significant differences between those with and without
`lipoatrophy for any of the continuous variables, although
`differences in time on glatiramer acetate approached significance
`(p = .098). There were significant differences in the proportion
`of females and males, and those with fair or red hair, between the
`groups.
`Of the 34 patients with lipoatrophy, 12 have discontinued
`therapy. Lipoatrophy and skin abnormalities were the most
`common reason (33%)
`for discontinuing treatment or
`nonadherence with glatiramer acetate in the MS Clinic.‘ In this
`sample lipoatrophy was more common and more significant on
`thighs and arms. Mancardis and Drago3 also found it much more
`prevalent in the arms and thighs. As a result of the examination,
`three patients were referred to a dermatologist for further
`
`assessment and skin biopsy. Two were referred for magnetic
`resonance imaging (MRI) examination of the most affected areas
`of lipoatrophy. It is noteworthy that we have only been able to
`identify three patients on subcutaneous interferon who have
`developed lipoatrophy out of a larger sample size over a longer
`period of time. Several patients are described in more detail
`below.
`
`CASE REPORTS
`
`Case #1
`
`This 51-year-old female had been on therapy for 45 months.
`She described her injection site reactions as “every one like a bee
`sting”, a red area with raised white swelling in the centre. Severe
`lipoatrophy was noted as all injection site areas were involved
`and multiple areas of lipoatrophy were seen in abdominal and
`thigh sites. The arm sites were not being used due to pain. She is
`slight in stature (wt - 55kg, ht — 157cm) therefore the “loss of fat”
`was more significant in the fact that she was “running out of
`areas to inject”. Patient reported a decrease in self-esteem and
`had poor self-image. The lipoatrophy is thought to be permanent,
`and the dermatologist could offer no specific treatment.
`
`Case #2
`
`This 40-year-old female describes her injection site reactions
`“like a bee sting”. Therapy had been initiated a little over three
`years ago. All injection sites were affected. She had discontinued
`using the upper outer arm injection site areas approximately 18
`months previously due to lipoatrophy and painful injections.
`Magnetic resonance image examination of the most affected arm
`showed significant
`thinning of subcutaneous fat
`in a focal
`distribution. The underlying musculature was uninvolved. Skin
`
`Figure 1: Case #2 — MRI of right upper arm, posterior aspect
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`Figure 2: Case #4 (cid:150) Anterior right thigh, large area
`of lipoatrophy
`
`Figure 3: Case #5 (cid:150) Anterior thighs, multiple uneven skin
`depressions
`
`Figure 4: Case #5 (cid:150) Posterior aspect of left
`upper arm
`
`Figure 5: Case #5 (cid:150) Lipoatrophy, lower abdomen at sites of
`injection
`
`biopsy was not done on the arm sites because she had not been
`injecting in those areas for over 18 months, so the biopsy was
`taken from the abdominal site where she was still injecting. Skin
`biopsy
`showed
`normal
`immunofluorescence
`and
`no
`inflammatory infiltrate. The surface area of lipoatrophy on the
`arms over the year and a half while not injecting did not decrease
`and does seem to be permanent. Figure 1 shows the MRI image
`of the thinning of subcutaneous fat distribution.
`
`Case #3
`This 48-year-old female has been on glatiramer acetate for
`two years and six months. Mild areas of lipoatrophy were
`identified on both thighs at injection sites. Magnetic resonance
`image examination reported nonspecific findings. Skin punch
`biopsy also was normal. She has severe fatigue and has chosen
`to continue on therapy using the abdominal and buttock injection
`site areas only, which are not affected.
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`Case #4
`This 52-year-old female after two years of therapy has
`developed significant areas of fat
`loss in both thighs and
`abdomen and to a lesser degree mild lipoatrophy in the upper
`outer buttock sites. She describes injection site reactions like a
`(cid:147)hive(cid:148), yet not with every injection. When examined by the
`clinic coordinator, she did not know she had lipoatrophy and was
`quite distressed on realizing these areas were related to her
`injections and probably permanent. Figure 2 shows the
`lipoatrophy in the right thigh.
`
`Case #5
`This 57-year-old female had been on glatiramer acetate from
`April 2000 to December 2001. Due to multiple areas of
`lipoatrophy in both thighs, both arms, abdomen and, to a lesser
`degree buttocks, she was advised to discontinue. After
`discontinuing this treatment she noted gradual increase in the
`area of atrophy especially across her right thigh. Figures 3-5
`show the areas of lipoatrophy on her thighs, arms and abdomen
`approximately 10 months after discontinuing glatiramer acetate.
`
`DISCUSSION
`
`influencing the
`There may be multiple mechanisms
`development of lipoatrophy in patients on glatiramer acetate.
`The assumption that patients are not rotating their injection sites
`does not seem to be one of the factors. Most patients do rotate to
`most sites on a regular basis, although they may only use two or
`three spots in each area while rotating their sites. The arm sites
`tend to be discontinued most often because it is painful and
`awkward to use even with the autoject device.
`There may be more than one mechanism causing this adverse
`reaction. We believe that the most significant of three possible
`mechanisms is the localized (cid:147)allergic(cid:148) reaction at the site of the
`injection, experienced by all of these patients. The reactions are
`hard to quantify and measure because they vary in size, severity
`and frequency. For example one patient who had been on
`treatment over 18 months experienced a reaction she described
`as a raised white area circled by redness which she measured as
`12.5 cm x 17.5 cm which lasted up to 24 hours. We believe, like
`Hwang et al,6 that this (cid:147)local immune injection reaction(cid:148) is in
`some way responsible for injuring the subcutaneous fat.
`The second mechanism that may have an influence is the idea
`of mechanical injury over time. Drago3 refers to the acupuncture
`effects of injections over time. Some of our patients have been
`on glatiramer acetate over four years and we are just now
`identifying mild lipoatrophy. It is thought by some that this
`(cid:147)acupuncture lipoatrophy heals spontaneously(cid:148)3 and therefore
`may not be permanent. The third possible mechanism is a
`delayed mechanism of hypersensitivity or inflammation as
`described by Drago,3 yet two histological specimens examined
`failed to reveal an inflammatory response, nor were biopsies
`helpful in elucidating an explanation for the clinical findings.
`The punch biopsies looked at skin, including superficial and
`deep dermis which lacked an inflammatory response at the time
`of biopsy. Fat was not examined as the punch biopsies would not
`look that deep. Although there was a higher percentage of
`fair/red haired patients who developed lipoatrophy, it is not
`known if this has any significance. These patients did not
`necessarily self-report sensitive skin. The use of the autoject did
`
`62
`
`not seem to contribute to lipoatrophy. Most patients do use the
`autoject device so technique was not an issue and it allows
`patients to self-inject in all areas.
`The patient did not usually identify areas of lipoatrophy. In
`most cases it was identified by the clinic coordinator during her
`objective examination by visual inspection and manual palpation
`of all injection site areas used. However, it was occasionally
`noted by a family member. Two patients have subjectively
`reported that, after discontinuing glatiramer acetate, their mild
`lipoatrophy seemed to be lessening. Therefore it would be
`important to identify it as soon as it starts occurring.
`Suggested treatment recommendations
`It
`is of great
`importance to keep the subcutaneous skin
`healthy, especially when treatment can begin as a young adult
`and is expected to be long term. Patients should be aware that
`lipoatrophy can be a side effect of glatiramer acetate treatment
`and is a relatively common occurrence. Regular supervision and
`follow-up of treatment should include visual examination and
`manual palpation of all
`injection site areas and a general
`inspection of the health of the skin. In addition, the patient can
`be taught to do a self-inspection of their injection sites at the
`same time as a monthly self breast examination. The self-
`examination should also include visual
`inspection while
`undressed in front of a mirror, and manual palpation of all sites
`used. If areas of lipoatrophy are noted, no further injections
`should be given in these sites. There should be some
`consideration that if the areas are identified early they may
`lessen, although there does not seem to be much proof of this. At
`the very least, early identification and avoidance of affected sites
`would stop progression of lipoatrophy.
`Extra caution should be given to patients experiencing
`localized inflammatory site reactions commonly described by
`the patient as redness with a raised white area in the middle
`which can last up to 24 hours. For patients who experience this
`side effect and choose to continue treatment, the abdominal
`injection site area seems to be the least affected. Since
`lipoatrophy can be disfiguring, thought to be permanent and can
`affect a person(cid:146)s self image, self respect and self confidence, it
`needs to be identified as soon as it starts occurring and monitored
`carefully.
`To lessen site reactions, it may be possible to place ice on the
`injection site for five minutes before and five minutes after
`injection. One could speculate that
`if the acute localized
`inflammatory reaction could be reduced,
`the occurrence of
`lipoatrophy would be less. In addition, we recommend that
`teaching materials and the product monograph for glatiramer
`acetate include lipoatrophy as a common occurrence. Teaching
`materials could include illustrations of potential skin problems.
`Further research is needed to know whether this occurrence
`truly is permanent, and the nature of the specific cause.
`Exploring the possibility of blocking the localized inflammatory
`reaction is a need for further study, in that the damaging effects
`to the subcutaneous tissue could be lessened. There is also a need
`for investigation into the possibility that damaged subcutaneous
`tissue may decrease absorption and, therefore, efficacy.
`The fact that lipoatrophy affected only females compares with
`the literature. All but one reported case (Mancardi5) are female.
`In addition, it is unknown as to the sex of the one case referred
`to by Wolinsky7 in his editorial on the 1995 pivotal
`trial
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`
`suggesting there was (cid:147)a single occurrence of focal lipoatrophy at
`injection sites noted in the trial(cid:148). The majority of females were
`unaware they had lipoatrophy until noted by a health
`professional or family member. This leads one to question if
`there might be a hormonal basis or are there skin structure
`differences between males and females? Is
`the male
`subcutaneous fatty tissue less fragile in some way than females?
`Does a smaller stature and thinness have any significance?
`There is also a need for research into the psychological
`impact of lipoatrophy. Multiple sclerosis patients already
`experience significantly reduced quality of life as compared to
`their peers8,9 in most domains of the Medical Outcomes Trust 36-
`item Health Survey (SF-36).10 Lipoatrophy is physically
`disfiguring and may adversely affect quality of life domains such
`as social functioning, role emotional functioning and mental
`health. Finally, further research could examine the use of the
`autoject device, although there was not a strong connection in
`this study.
`
`CONCLUSIONS
`
`The prevalence of lipoatrophy in patients on glatiramer
`acetate treatment for RRMS is much higher than expected. In
`this study it approaches 45% (34/76). It only occurred in females
`and it can be very disfiguring and permanent. The psychological
`impact can be significant. It is very important that patients be
`aware of the possibility of lipoatrophy, be able to identify it and
`discontinue injecting in areas where it is identified. In some
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`instances of severe lipoatrophy with multiple sites affected,
`discontinuation of treatment may be indicated.
`
`REFERENCES
`1.
`Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces
`relapse rate and improves disability in relapsing-remitting
`multiple sclerosis. Neurology 1995;43:1268-1276
`2. Drago F, Rongioletti F, Battifoglio ML, Rebora A. Localized
`lipoatrophy after acupuncture [letter]. Lancet 1996;347:1484.
`3. Drago F, Brusati C, et al. Localized lipoatrophy after glatiramer
`acetate injection in patients with remitting-relapsing multiple
`sclerosis. Arch Dermatol 1999;138:1277-1278.
`to
`4. McBride EV, Brunet DG, Edgar CM. Nonadherence
`immunmodulation in multiple sclerosis. Int J MS Care 2002;4:85.
`5. Mancardi GL. Localized lipoatrophy after prolonged treatment with
`copolymer-1. J Neurol 2000;247:220-221.
`6. Hwang L, Orengo I. Lipoatrophy associated with glatiramer acetate
`injections for
`the treatment of multiple sclerosis. Cutis
`2001;68:287-288.
`7. Wolinsky JS. Copolymer-1 a most reasonable alternate therapy for
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