ORIGINAL RESEARCH
`
`Multiple sclerosis presented as clinically isolated
`syndrome: the need for early diagnosis
`and treatment
`
`Sigliti-Henrietta Pelidou
`Sotirios Giannopoulos
`Sotiria Tzavidi
`
`Georgios Lagos
`Athanassios P Kyritsis
`
`Department of Neurology. University
`of loannina School of Medicine.
`Greece
`
`Correspondence: Sotirios Giannopoulos
`Dept. of Neurology, University of loannina
`School of Medicine. University Campus
`Ioannina, 45 I
`I 0. Greece
`Tel +30 265 I0 975 I4
`Fax +30 265 I0 970| I
`Email sgiannop@uoi.gr
`
`
`
`Objective: To aid in the timely diagnosis of patients who present with clinically isolated
`syndrome (CIS).
`_
`Patients and methods: We studied 25 patients (18 women, 7 men), originally presented
`in our clinic with a CIS suggestive of multiple sclerosis (MS). All patients underwent the full
`investigation procedure including routine tests, serology, cerebrospinal fluid (CSF) examinations,
`evoked potentials (EPs), and magnetic resonance imaging (MRI) of brain and cervical spinal
`cord. Patients were imaged at baseline, and every three months thereafier up to a year.
`Results: The CIS was consisted of optic neuritis in 12 cases, incomplete transverse myelitis
`(ITM) in 7 cases, Lhemiitte sign in 2 cases, internuclear ophthalmoplegia (INO) in 2 cases,
`mild brainstem syndrome in 1 case, and tonic-clonic seizures in 1 case. Using the baseline and
`three-month scans I8/25 (72%) patients developed definite MS in one year of follow up while
`7 (28%) had no fimher findings during this observation period. Immunomodulatory treatments
`were applied to all definite MS patients.
`Conclusion: In light of new treatments available, MRIs at 3 month intervals are helpfiil to
`obtain the definite diagnosis of MS as early as possible.
`Keywords: multiple sclerosis, clinically isolated syndrome, optic neuritis, transverse myelitis
`
`Introduction
`
`Multiple sclerosis (MS) is a clinical diagnosis based on the dissemination of lesions of
`the central nervous system (CNS) in time and space (Poser and Brinar 2001). Recent
`
`proposed diagnostic criteria for MS utilize MRI findings to document dissemination
`of CNS lesions in time and space (McDonald et al 2001; Polman et al 2005). Optic
`neuritis (ON) may be the heralding manifestation of MS (ONSG 1991; Hickman et al
`2002). More than 50% of adult patients who present with isolated ON will eventu-
`
`ally develop other signs of MS (ONSG 1997). The risk stratification for the future
`development of MS in patients presenting with ON can be assessed by the number of
`white matter lesions on the baseline cerebral MRI study (Bhatti et al 2005). The risk
`
`is increased in women and in those patients who have oligoclonal bands (OCB) in the
`cerebrospinal fluid (CSF) (Ghezzi et al 1999).
`Incomplete transverse myelitis (ITM) can be the presenting feature ofMS. Patients
`with ITM who develop MS are more likely to have asymmetric clinical findings,
`
`predominant sensory symptoms with relative sparing of motor systems, spinal cord
`lesions extending over less than two spinal segments, abnormal brain MRI, and OCB
`in the CSF (Miller et al 1989; TMC 2002). Measurement of spinal cord atrophy that
`reflects destructive, irreversible pathology in patients presenting with ITM has impor-
`tant implications for the early treatment of MS (Lin et al 2004).
`
`
`
`Therapeutics and Clinical Risk Management 2008:4(3) 627-630
`© 2008 Pelidou et al. publisher and licensee Dove Medical Press Ltd.This is an Open Access article
`which permits unrestricted noncommercial use. provided the original work is properly cited.
`
`627
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`MYLAN PHARMS. INC. EXHIBIT 1039 PAGE 1
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`

`
`Pelidou et al
`
`Central nervous system involvement in MS may be
`difficult to differentiate from other autoimmune diseases such
`
`as systemic lupus erythematosus (SLE), antiphospholipid
`syndrome (APS), and Sjogren syndrome (SS). Thus, a large
`number of patients with APS or SLE may be misdiagnosed
`as MS, but the exact proportion is unknown and may receive
`
`inappropriate treatment (Ferreira et al 2005). A retrospective
`study in 82 patients with primary Sjogren syndrome reported
`that 40.2% had brain involvement, 15.8% optic neuropathy,
`and 35.4% spinal cord involvement (Delalande 2004). Thus,
`the differential diagnosis may require careful assessment of
`all clinical and MRI findings, serological results, and CSF
`
`analysis (Reske et al 2005).
`Our objective was to aid in the timely diagnosis of MS in
`patients who presented with CIS and thus employ the proper
`treatment early during the course of the disease.
`
`Patients and methods
`
`We studied 25 consecutive patients (18 women, 7 men), age
`30.6 (range: 17-49) presented in our clinic with CIS sugges-
`tive of MS. The inclusion and exclusion criteria of the CIS
`
`patients are listed in Table 1. The clinical, laboratory, and
`imaging findings were studied in all patients. Laboratory
`investigations included complete blood count, serum values
`of liver enzymes, bilirubin, albumin, glucose, creatinine,
`and urine analysis. In addition, erythrocyte sedimentation
`rate, C-reactive protein, antinuclear antibodies (ANA),
`double-stranded DNA (ds-DNA), complement C3/C4, and
`
`anti-cardiolipin (ACL) antibodies were also perfomed.
`All patients were evaluated for MS with CSF serology
`(cells, protein, glucose, IgG index), visual evoked poten-
`tials (VEPs), somatosensory evoked potentials (SEPs), and
`brain and cervical spinal cord MRI. Patients were imaged
`
`Table I List of inclusion and exclusion criteria
`Inclusion criteria
`Exclusion criteria
`
`Optic neuritis
`Head trauma
`Diplopia
`Neuropsychiatric disorder
`internuclear opthalmoplegia
`Diabetes mellitus
`Myelitis
`Hypertension
`Hemiparesis-paraparesis
`Cardiac failure
`Dysarthria
`Hepatic failure
`Sensory symptoms
`Renal failure
`MRI criteria:
`Thalassemia.
`Sickle cell disease,
`a. I GD enhancing lesion
`b. I infratentorial lesion
`Iron deficiency.
`B I 2 deficiency
`c. I iuxtacortical lesion
`d. 3 periventricular lesions
`Abbreviation: MRI. magnetic resonance imaging.
`
`at baseline, at three month intervals, and one year. CSF
`oligoclonal bands were not included in the evaluation since
`it is not an available test in our hospital laboratory. For MS
`diagnosis, the revised McDonald criteria were employed
`(Polman et al 2005). Dissemination in space was demon-
`strated by either MRI alone when three of the following
`conditions were met: a) at least one gadolinium-enhancing
`lesion or nine T2 hyperintense lesions if there was no
`gadolinium enhancing lesion; b) at least one infratentorial
`lesion; c) at least one juxtacortical lesion; and d) at least three
`periventricular lesions, or two or more MRI-detected lesions
`consistent with MS plus elevated CSF IgG index. Dissemi-
`nation in time was demonstrated by either MRI (detection
`of gadolinium enhancing abnonnality at least 3 months
`after the onset of the initial clinical event and if not at the
`
`site corresponding to the initial event detection of a new T2
`lesion if it appeared at any time compared with the baseline
`scan performed at least 30 days after the onset of the initial
`clinical event), or by a second clinical attack.
`None of the studied patients had history of head trauma,
`
`neuropsychiatric disorder, diabetes mellitus, hypertension,
`thalassemia, iron and B12 deficiency, cardiac, hepatic and
`renal failure (Table 1). Finally, the protocol was approved
`by the Institutional Review Board Committee.
`
`Results
`
`The characteristics of all CIS patients are depicted in Table 2.
`There were 25 patients (18 women, 7 men), of 30.6 years
`mean age (range 17-49). The mean age of patients at onset
`of CIS varied from 26.9 years for ON to 29.2 years for the
`
`patient with seizures. The mean follow-up time was 18.9
`months in patients with ON, 17.5 months in patients with
`ITM, 18 months in patients with brainstem syndrome. The
`mean disease severity on the expanded disability status scale
`(EDSS) performed at least one month after the CIS varied
`from 0.41 to I. Only 12 woman had isolated ON, 7 had
`ITM, 3 had mild brainstem syndrome (2 with internuclear
`
`ophthalmoplegia (INO), 1 with dysarthria), and 1 had sudden
`onset of tonic-clonic seizures. The predominant neurological
`examination findings during the acute phase ofthe CIS were:
`reduced unilateral visual acuity in the patients with ON,
`
`paraparesis, Lhermitte sign, sensory symptoms, diplopia,
`dysarthria, and hemiparesis as shown in Table 3.
`The paraclinical data of the patients are shown in
`Table 4. Twenty four patients had abnormal brain MRI
`consisted of periventricular MS-like white matter lesions
`and 9 (36%) patients had evidence of myelitis. Both brain
`and cervical cord MRI were positive in 7 cases (28%).
`
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`

`
`Multiple sclerosis and clinically isolated syndrome
`
`Table 2 Characteristics of CIS patients
`
` ON ITM Brainstem syndrome
`
`
`2I|
`3/4
`I2/0
`Sex ratio (female!male)
`29.6 i I2 (24-49)
`28.9 i 8.7 (20-42)
`29.5 1 I6 (|7—46)
`Age at diagnosis mean +/— SD (range)
`29.I i 9.6 (2l—48)
`28.7 i 9.l (I9-37)
`26.9 i l0.3 (|7—43)
`Age at onset of CIS mean +I— SD (range)
`[8 (I 7-29)
`|7.5 (3-26)
`|8.9 (9-60)
`Follow up time mean months (range)
`l9.5 ( l 7-29)
`l9.3 (4-26)
`20.7 (9-6|)
`Duration of disease mean months, (range)
`
`Disease severity on EDSS‘ mean (range) I (I-I) 0.4| (0-I) 0.6 (0-2.5)
`
`
`Abbreviations: CIS. clinically isolated syndrome: ON. optic neuritis; ITM, incomplete transverse myelltis: EDSS. expanded disability status scale.
`Note: 'EDSS was assessed at least one month after the CIS.
`
`VEP’s were abnormal in 16 (64%) and SEP’s in 6 (24%)
`
`patients. Nineteen patients (76%) had increased IgG index,
`while in 6 patients it was normal.
`Serological features of the patients are demonstrated in
`Table 5. ANA were positive in 5 (20%) and anti-ds-DNA in
`
`2 (8%) of patients, but no patient had low complement (C3
`or C4). ACL-ab was positive in only 3 (12%) patients.
`Using the baseline and three-month MRI scans and the
`clinical and paraclinical data, 72% of patients with CIS
`
`developed definite MS according to the revised McDona1d’s
`criteria within one year, while 28% had no fLlI‘th€1' neurologi-
`cal and MRI findings during this observation period.
`
`Discussion
`
`Patients with CIS may develop MS (Miller et al 2005). Clini-
`
`cally the identification of patients with a CIS at high risk to
`develop clinically definite MS remains difficult (Kieseier et al
`2005). Monthly brain MRI scans in patients with CIS showed
`that the majority of patients with an abnormal baseline scan
`were diagnosed with MS afier three months (Pestalozza et al
`2005). Application of the new McDonald criteria to patients
`with CIS suggestive of MS doubled the rate of diagnosis of
`MS within one year of presentation (Dalton et al 2002). It
`has been suggested that monthly triple-dose Gd-enhanced
`
`MRIS accurately detected inflammation which is an important
`factor in the pathogenesis ofbrain tissue loss in CIS patients
`(Paolillo et al 2004).
`
`Although a CIS could be indicative ofMS, it might occa-
`sionally be the first manifestation of systemic autoimmune
`diseases such as SLE, APS, and SS. In these cases not only
`
`the clinical presentation but the MRI findings may be similar
`(Theodoridou and Settas 2006). Thus, serology tests, eg,
`ANA, C3, C4, and antiphospholipid antibodies, could help
`in the differential diagnosis of MS from the various connec-
`tive tissue diseases. In the present study 20% of CIS patients
`
`had positive ANA and a few patients had other autoantibod-
`ies but there were no other findings to indicate evidence
`
`of SLE, primary SS, and APS according to the currently
`used criteria (Tan et al 1982; Wilson et al 1999; Vital et al
`2002). Presence of various autoantibodies such as ANA in
`the serum ofpatients with MS is a frequent finding (Specaile
`et al 2000). Brain MRI can be inconclusive in patients with
`CIS but intrathecal synthesis of OCB are helpful in estab-
`
`lishing the diagnosis of MS (Sastre-Garriga et al 2003; Rot
`and Mesec 2006), thus the lack of OCB measurements is a
`limitation of our study. A new OCB test may also improve
`the conversion of a CIS to MS (Masjuan et al 2006). Predic-
`tion of conversion from CIS to MS can be improved if CSF
`
`
`Table 3 Clinical data of CIS patients
`No. of patients (36)
`Neurological symptoms and signs
`
`I2 (48%)
`Optic neuritis
`7 (28%)
`Myelitis
`2 (8%)
`lnternuclear opthalmoplegia
`I (4%)
`Seizures
`S (25%)
`Paraparesis
`2 (8%)
`Lherrnitte sign
`9 (36%)
`Sensory symptoms
`3 (l2%)
`Diplopia
`I (4%)
`Dysarthria
`
`Hemiparesis I (4%)
`Abbreviations: CIS. clinically isolated syndrome.
`
`Table 4 Paraclinical data of CIS patients: Initial 2/25
`Parameters
`(+)
`(-)
`Initial brain MRI
`23/25 (92%)
`2/25 (8%)
`Brain MRI‘
`24/25 (96%)
`1/25 (4%)
`Cervical SC MRI‘
`9 (36%)
`I6 (64%)
`VEP's
`I6/25 (64%)
`9/25 (36%)
`SEP’s
`6/25 (24%)
`I9/25 (76%)
`CSF“/WBC
`I125 (4%)
`24/25 (96%)
`
`CSF”/IgG INDEX 6/24 (24%) I9/25 (76%)
`
`Abbreviations: CIS, clinlcally isolated syndrome: SC. splnal cord:VER visual evoked
`potentia|s;SER somatosensory evoked potentia|s;CSF. cerebrospinal fluid.
`Notes: ‘Brain and cervical SC MRls were considered (+) when findings were observed
`at any time during the 3 month Intervals up to a year;"CSF serology was performed
`during the baseline evaluation.
`
`
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`MYLAN PHARMS. INC. EXHIBIT 1039 PAGE 3
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`Pelidou et al
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`Table 5 Serological features of the patients
`Parameters
`(+)
`(—)
`
`Not done
`
`3 ( I 2%)
`I7 (68%)
`5 (20%)
`ANA
`6 (24%)
`I7 (68%)
`2 (8%)
`Anti-ds-DNA
`0
`22 (88%)
`3 (I2%)
`ACL-ab
`0
`25 (loo%)
`o
`c3/c4
`Abbreviations: CIS. clinically isolated syndrome;ANA, antinuclear antibodies: ds-
`DNA, double-stranded DNA;ACL-ab. anticardiolipin antibodies; C3/C4, complement
`fractions C3 and C4.
`
`markers (either elevated tau or neurofilaments [Nfi-ISMI35]
`are combined with MRI findings (Brettschneider at al 2006).
`On the contrary, serum antimyelin antibodies did not seem
`to permit earlier diagnosis of MS (Lim et al 2005). Intrathe-
`cal B-cell clonal expansion in the CSF of patients with CIS,
`
`often precedes both OCB and multiple MRI lesions and is
`associated with a high rate of conversion to definite MS
`(Qin et al 2003).
`
`Conclusion
`
`Patients with MS deserve an accurate diagnosis, because new
`
`effective immunomodulatory treatments could modify the
`
`disease progression. It is obvious that definite diagnosis of
`MS must be obtained as early as possible in order to initiate
`
`early immunomodulatory treatment. We believe that frequent
`MRI scans during the first year after the CIS facilitate the
`early and accurate diagnosis of definite MS.
`
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