The Importance of Early Diagnosis of Multiple Sclerosis
`
`JAMES R. MILLER, MD
`
`ABSTRACT
`
`OBJECTNE: To describe the current understanding of the diagnosis and treat-
`ment of multiple sclerosis (MS) and to explore the use of magnetic resonance
`imaging (MRI) assessment as a prognostic tool and an indicator in the diagnosis
`of MS.
`
`SUMMARY: MS is a chronic, progressive, demyelinating disease of the central
`nervous system that is associated with a significant economic burden. At this
`time, immunomodulatory agents (interferon beta-1a (IFNfi-1a) [Avonex], IFNp-1a
`[Rebif], |FN[3-1 b [Betaseron], and glatiramer acetate [Copaxone]) are first-line
`agents, which are reported to reduce relapse rates.
`The diagnostic criteria for MS have evolved over time to include MRI findings
`as an integral part of the diagnosis. However, the most recent criteria (McDonald)
`are focused on the diagnosis of definite MS and do not address the status of
`patients with a first demyelinating event (clinically isolated syndrome [ClS]).
`This is an important issue because a BIS is highly predictive of developing fur-
`ther inflammation and definite MS when the episode occurs in conjunction with
`lesions on the initial MRI. Many times, MRI findings do not correlate with clinical
`symptoms, and clinically silent lesions are identified. Therefore, the use of MRI is
`salient to the early diagnosis of high-risk patients.
`The evolution of thought concerning early treatment in MS is based on an
`increased understanding of the pathology of the disease Axonal loss occurs
`early in the disease process, and both white matter and gray matter are affected.
`Stud ies that have analyzed early treatment in patients highly likely to have MS
`(clinically isolated events with evidence of lesions on MRI) report significant
`benefits in delaying further changes on MRI and further attacks. Patients who
`begin treatment later do not reap the same benefits as those who begin
`treatment earlier during the disease course.
`
`CONCLUSION: Patients with clinically isolated events should be referred promptly
`to a neurologist for asessment, including MRI scans. An early recognition of
`the inflammatory process enables patients to begin treatment with an immuno-
`mod ulatory agent even before the technical diagnosis of definite MS so that the
`degenerative progression of MS can be retarded.
`
`KEYWORDS: Magnetic resonance imaging, Interferon beta, Glatiramer acetate,
`Multiple sclerosis, Diagnosis
`
`J Manag Care Pharm. 2004;10(3)(supp| S-b):S4-S11
`
`JAMES R MILLER, MD, was director (now retired), Multiple Sclerosis
`Center, Columbia-Presbyterian Medical Center, Columbia University,
`New Yarlr, New York.
`
`AUTHOR CORRESPONDENCE.‘ james R Miller, MD, 88 Fieldpoint Dr,
`Irvingtori, NY10533. Tel.‘ (914) 591 -4712,‘ Fax.‘ (914) 591 -0724;
`E-mail: jrm6@columl7ia.edu
`
`Copyright© 2004, Academy of Managed Care Pharmacy All rights reserved.
`
`ultiple sclerosis (MS) is an immune—mediated demyeli-
`nating disease of the central nervous system (CNS).
`This treatable but uncurable degenerative disease
`affects approximately 400,000 people in the United States.‘
`Common symptoms of MS include spasticity, fatigue, sexual dys-
`function, bladder dysfunction, pain, cognitive dysfunction,
`depression, bowel dysfunction, and weakness. The average age of
`onset of MS is 30 years? Because this is the age when individuals
`may be beginning a family and workers have not
`typically
`reached their full earning potential, it has a particularly devastat-
`ing impact on family, social, and professional relationships.
`MS is associated with a considerable economic burden.
`
`National costs of MS are estimated to range from $6.8 to $11.9
`billion annually (approximately $34,000 per patient).’ The major
`components of these costs include earnings loss (incurred by the
`patient with MS) and costs of informal care (unpaid personal
`assistance)? According to a survey of MS patients, the annual loss
`in earnings was $17,900;
`this amount was even greater
`($41,000) for men younger than 65 years.’ In that same study,
`the annual expenditures for informal care were $6,452, which
`translated to about one fifth of the annual per-patient costs of
`MS.’ Other large expenditures included costs for hospitalization
`and physician visits.’
`In 90% of patients, MS's natural progression traditionally has
`been categorized in sequential stages, which include subclinical
`disease, monosymptomatic disease, relapsing-remitting disease
`(RRMS), and then secondary progressive MS (SPMS). Clinicians
`diagnose definite MS after a second attack occurs or evidence of
`new MS lesions are visualized on magnetic resonance imaging
`(MRI).* The clinical course of RRMS is described as clearly
`defined relapses with at least partial recovery of deficits. Periods
`between relapses are characterized by a lack of disease progres-
`sion.’ In contrast, SPMS occurs when some deficits begin to
`progress even between obvious relapses. Relapses occur less fre-
`quently than during the RRMS phase or do not occur at all.“
`The progression of MS is discernible when the recovery
`between relapses is incomplete, with a sustained worsening on
`the Expanded Disability Status Scale (EDSS) or other rating scales‘,
`lesion burden assessed by MRI is increased; cognitive dysfunction
`accumulates; and brain atrophy advances.” In some patients, the
`cognitive effects of MS may be more severe than the physical
`effects during the early stages of the disease.
`If MS is left
`untreated, patients with RRMS develop SPMS (50% by
`10 years; 90% by 30 years .13
`
`1 Treatment of Multiple Sclerosis
`
`Only a small subset of the medical community makes treatment
`decisions in patients with MS. Because MS is a chronic degener-
`ative disease, treatment must be continuous, not intermittent. At
`
`this time, immunomodulatory agents (IMAs) are considered first-
`
`S4 Supplement to Journal of Managed Care Pharmacy
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`JMCP jun: 2004
`
`mcporg
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`
`The Importance of Early Diagnosis of Multiple Sclerosis
`
` Summary of Studies Reporting Development
`of Clinically Definite Multiple Sclerosis [CDMS]
`in Patients Who Have Clinically isolated
`Demyelinating Events With Lesions Assessed
`by Magnetic Resonance Imaging at Baseline
`Baseline
`Findings
`Predictive of
`CDMS
`4 lesions,
`or 3 lesions
`with 1
`periventricular
`lesion
`
`Reference
`Paty et al.”
`
`Follow-up
`(Years)
`1
`
`Criteria
`for CDMS
`Schumacher
`criteria”
`
`Patients Who
`Developed CDMS
`95% (18/19)
`
`line treatments for patients with RRMS, including the following:
`intramuscular (IM)
`interferon beta-1a (IM IFNfl—1a)
`[Avonex,
`Biogen Idec Inc., Cambridge, MA]), subcutaneous (SC) IFNB-1a
`(SC IFNfi—1a
`[Rebif, Serono, Rockland, MA]), SC IFNB-1b
`(Betaseron, Berlex Laboratories, Montville, Nj), and SC glatiramer
`acetate (Copaxone, Teva Pharrnaoeutical Industries, Kansas City,
`MO). Another agent, mitoxantrone (Novantrone, Immunex Corp.,
`Seattle, VVA), is indicated for reducing the progression of neuro-
`logic disability and the frequency of clinical relapses in patients
`with secondary (chronic) progressive, progressive relapsing, or sig-
`nificantly worsening RRMS. IMA treatment goals include reducing
`inflammation, reducing the relapse rate, slowing disability, slowing
`the accumulation of cognitive dysfunction, reducing the progres-
`sion of brain atrophy, and improving quality of life.
`Several large randomized trials demonstrate that IMAs reduce
`attack rates.“”’ Direct comparisons among the trials are impossi-
`ble, but these data suggest that all agents reduoe relapse rates sim-
`ilarly For example, the phase III trial of IM IFNB-la reported a
`32% reduction in relapses among patients who were treated for
`2 years.“ Similarly, the mean percentage reduction in relapse rates
`over 2 years was 33% in patients who received SC IFNB-la.”
`Two-year data from the SC IFNB-la trial revealed a 34% reduction
`in patients who received treatment.” Finally, in the glatiramer
`acetate study,
`the 2-year reduction in relapse rate was 29%."
`Although trial outcomes were similar, there may be important dif-
`ferences among these agents with regard to their demonstrated
`ability to slow disability progression. For example, both IM IFN[3-
`la and SC IFNB-la (44 mcg) have been associated with a signifi-
`cant reduction in sustained disability progression.“-1*
`Of note, sustained progression of disability must have occurred
`for 23 months during the SC IFNB-la trial and 26 months during
`the IM IFNB-la trial; the 6-month requirement provided a more
`stringent measurement of efficacy.“ Sustained disability progres-
`sion was not significantly affected during the IFNB-lb study”
`Reduction in sustained disability with glatiramer acetate was not
`statistically significant." Sustained disability progression is the
`most important clinical measure in MS because the major propor-
`tion of clinical deficit is caused by clinically silent events not man-
`ifested by relapses.
`
`1 Diagnosis of Multiple Sclerosis
`
`Over the last 40 years, an important evolution has occurred in the
`diagnostic rubric of MS: the diagnostic criteria progressed from
`being solely clinical symptom-based (Schumacher" and Poser”)
`to integrating MRI assessments (McDonald*). This salient advance
`in MS management allows for a more timely diagnosis and earlier
`treatment in patients with MS.
`In 1965, Schumacher et al. published the first criteria for diag-
`nosing MS." These early guidelines required the presence of CNS
`lesions disseminated in time and space and the exclusion of alter-
`native diagnoses. The 1983 Poser criteria updated the
`Schumacher criteria.” The latter guidelines reflected detection
`
`Barkhof et a1.”
`Optic Neuritis
`Study Group”
`
`22
`5
`
`9 lesions
`L3 lesions
`13 mm in size
`
`O‘Riordan et a1.“
`
`5-10
`
`Sailer et al.u
`
`Brex et alu
`
`10
`
`1
`
`21 asymptomatic
`lesion compatible
`with demyelination
`21 asymptomatic
`lesion compatible
`with demyelination
`21 gadolinium—
`enhancing lesion
`at baseline and
`at 3 months
`
`14.1
`
`Brex et al."
`
`21 asymptomatic
`lesion compatible
`with demyelination
`‘PPV = positive predictive value.
`
`Poser et all.”
`Second attack
`confirmed by
`examination,
`with new
`neurologic
`disability
`Poser et al.”
`
`80% PPV‘
`51% cumulative
`probability
`
`83% (45/54)
`
`Poser et al.1°
`
`82% (37/45)
`
`Poser et a1.”
`
`70% PPV
`
`Poser et al.1°
`
`88% (44/50)
`
`technique advances, such as MRIs and spinal taps, which identify
`lesions and other paraclinical evidence.
`Most recently, an international panel in association with the
`National Multiple Sclerosis Society of America recommended
`revised criteria, and the McDonald criteria were published.‘ These
`new criteria make use of advances in MRI imaging techniques and
`include criteria for dissemination of MS lesions in time and space.
`Prior to the McDonald criteria, a diagnosis of clinically definite MS
`(CDMS) might have taken several years. Still, these criteria focus
`on the diagnosis of CDMS and analyze inflammatory processes
`conservatively. They do not address the importance of MRI
`changes for the patient with a clinically isolated syndrome (CIS).
`For example, patients with an initial demyelinating event (such as
`optic neuritis, cerebellar syndrome, or spinal cord syndrome)
`must display changes over time in order to be diagnosed with def-
`inite MS. Despite the cautionary approach of the McDonald crite-
`ria, nearly 90% of patients with CISs who have MR1 lesions will
`develop definite MS over time."
`In patients with C1Ss as well as with definite MS, MRI results
`usually reveal subclinical lesions. Data from a number of studies
`demonstrate that the presence of MRI-assessed lesions is strongly
`
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`The Importance of Early Diagnosis of Multiple Sclerosis
`
`our thinking about early treatment of MS to evolve. Current dogma
`states that MS is an episodic autoimmune disease. MS is largely
`T£ell—mediated and involves environmental factors. Immune cells,
`
`activated in the periphery, enter the CNS by migrating across the
`blood—brain barrier, where they attack myelin and oligodendroglia.
`Traditionally, researchers postulated that axonal loss occurs late in
`the disease, secondary to this process, and that MS is a disease of
`the white matter. However, the current dogma is being questioned.
`For example, evidence exists that the pathology of MS may dif-
`fer among patients, suggesting that several different diseases
`culminate in a final pathway: MS?“ Studies of brain biopsy spec-
`imens and autopsies of patients with MS reveal that about 20% of
`patients have a major anti-CNS antibody component during acute
`flare-ups. Other lesions are associated with inflammatory
`macrophages. It is unknown whether various subtypes of MS exist
`or if these processes are part of a disease continuum in which
`different processes are active at various time points.
`Evidence now suggests that axonal loss occurs early during the
`disease course and that it is prominent from the onset of MS?”
`Trapp et al. used autopsy findings from patients with MS to define
`changes in axons.“ Their findings demonstrated that irreversible
`axonal transection occurred in both active and chronic lesions of
`
`patients, some of whom had MS for as few as 2 weeks.“
`Transected axons were commonly found in lesions, and their fre-
`quency was related to the degree of inflammation within the
`lesion.“ These findings are critical; historically, axonal loss was not
`considered important in MS’s pathology.“ Moreover, axonal loss
`appears in normal-appearing white matter.‘”’ A study of a patient
`who had MS for 9 months reported that myelin was relatively
`preserved despite a 22% axonal loss in the ventral column."
`Reliable imaging of normal-appearing white matter and
`normal-appearing gray matter is challenging.” Results from
`magnetic transfer imaging and spectroscopy have demonstrated
`abnormalities in areas that appear normal on conventional scans.“
`Studies in which gadolinium is administered to patients before
`MRI
`to enhance MS lesions suggest
`that
`these gadolinium-
`enhanced (Gd+) lesions are preceded by abnormal findings on
`spectroscopy or magnetic transfer imaging.’“’
`Extensive evidence reveals that lesions occur in MS patients‘
`gray matter.’“° In fact, cortical lesions occur early and frequent-
`ly.”-“ One recent study reported that metabolic changes could be
`detected in the cortical gray matter of patients early in the disease
`course (mean duration of disease, 1.7 years).‘° Furthermore, meta-
`bolic changes in the cortical gray matter were related to disability
`as measured by the EDSS, Multiple Sclerosis Functional
`Composite, 9-1-lole Peg Test, and Paced Auditory Serial Addition
`Task.” Abnormalities in normal-appearing gray matter are report-
`ed to correlate with cognitive deficits.” Detection of gray matter
`lesions by conventional MRI is difficult because the relaxation
`characteristics of these lesions result in a poor contrast between
`them and the surrounding normal gray matter because of partial
`volume effects with cerebrospinal fluid (CSF).’°
`
` Final Diagnosis of Multiple Sclerosis
`as Year 14 Compared With Lesion Load
`at Disease Onset
`
`D Clinically isolated syndrome
`Probable MS
`I Definite MS
`
`89
`
`87
`
`88
`
`13
`
`4-10
`-3
`MR1 Lesions at Onset
`
`>10
`
`6 1
`
`100
`
`90
`
`80
`
`70
`
`60
`
`S0
`
`40
`
`30
`
`20
`
`10
`
`
`
`Patients(%)
`
`19
`
` Expanded Disability Status Scale Score
`at Year l4 Compared with Lesion Load
`at Disease Onset
`
`14
`
`12
`
`EDSS Score
`U >3
`>6
`I 10
`
`12
`
`Patients
`
`(N)
`
`4-10
`1-3
`MRI Lesions at Onset
`
`>10
`
`predictive of developing CDMS in patients who experience a clin-
`ically isolated event (Table 1)."'” The results of a prospective lon-
`gitudinal study of patients with CISs demonstrated that 88% of
`patients with abnormal MRI findings at baseline had developed
`CDMS at 14 years (Figure 1)." Furthermore, at 14 years, the EDSS
`score was correlated with the number of lesions on MRI at base-
`
`line, with higher EDSS scores in patients who had more lesions at
`baseline (Figure 2).”
`Our understanding of the pathophysiology of MS has caused
`
`S6 Supplement to Journal of Managed Care Pharmacy
`
`JMCP June 2004
`
`mcp.org
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`The Importance of Early Diagnosis of Multiple Sclerosis
`
`1 Role of Magnetic Resonance Imaging
`
`MRI-based assessments briefly discussed in this section are impor-
`tant tools in the diagnosis and management of patients with MS.
`In fact, MR]-based assessments are the most important ancillary
`tests performed in patients with MS. Gd+ T1-weighted scans dis-
`play areas of blood—brain barrier disruption and are indicative of
`active inflammation and, therefore, reflect active disease.” Gd+
`
`lesions display a spectrum of appearances (e.g., ringlike, homoge-
`neous) and may be clinically silent (i.e., without symptoms). The
`sensitivity of these images may be increased with various tech-
`niques that are becoming more readily availabIe.“"°
`The most commonly used measure of disease burden is the
`presence and number (and, for research, volume) of hyperintense
`lesions on T2-weighted images" However, these images are rela-
`tively insensitive to the underlying pathology and show both active
`and inactive lesions.” Modifications of T2-weighted scans can pro-
`vide additional infomiation. Fluid-attenuated inversion recovery
`(FLAIR) sequences, for example, can visualize 2 to 3 times the
`number of lesions seen on conventional T2-weighted imaging."
`I-Iypointense lesions on T1-weighted images are also called
`“black holes." Persistent T1 lesions indicate axonal loss, gliosis, loss
`of intracellular matrix, and demyelination; these lesions are thought
`to be markers for areas of more destructive focal CNS damage in MS
`patients.“"’° T1 hypointense lesions are thought to have a greater
`correlation with the clinical features of MS than T2 lesions“; how-
`
`ever, more studies are needed to explore this relationship.
`Brain atrophy is the best MRI predictor of clinical status. In fact,
`the degree and rate of brain atrophy correlate with physical dis-
`ability, quality of life, depression, and cognitive dysfunction."’“"
`Therefore, the measurement of brain atrophy has become increas-
`ingly important. Several measures can be used to quantify brain
`atrophy, including whole-brain and regional measures.‘"'°3 These
`techniques are still not ready for general clinical use and remain
`research tools. However, visual inspection of MR] images alone
`can provide a reasonable sense of the degree of atrophy and com-
`parisons can be roughly made between scans at different times.
`A correlation has been observed between clinical status of
`
`patients with MS and spinal cord lesions and atrophy‘’”’ These
`findings have increased the role of spinal cord MRI in the man-
`agement of MS.°‘”° Spinal cord MRI scans reveal T2 lesions in
`approximately 50% to 90% of patients with MS." Spinal cord
`scans can provide additional information when brain scans and
`clinical status are equivocal and can correlate spinal symptoms
`(cervical and thoracic). The frequency at which spinal cord MRI
`should be performed has not been fully determined but is advis-
`able for tracking lesion load or atrophy.
`Interestingly, 5 to 10 times more lesions occur on MRI than are
`manifested clinically.’”’ Possible explanations for this discrepancy
`include inattention to cognitive aspects of the disease,
`lesions
`located in noneloquent areas of the brain, lack of histopathologic
`specificity, absence of spinal cord involvement, underestimation of
`the damage to norrnal-appearing white and gray matter, and
`
`masking effects of brain adaptation.“ Recent improvements in
`MRI measures and techniques have increased their predictive
`value and improved their correlation with clinical status"
`MRI findings are needed to support the diagnosis of MS and
`are useful in evaluating patients with MS for other pathology.
`The appearance of Gd+ lesions in the appropriate clinical cir-
`cumstances is particularly helpful in supporting the diagnosis of
`an inflammatory process. Furthermore, baseline MRI findings
`are helpful in detennining patient prognosis. Therefore, Gd+
`scans are recommended at diagnosis because Gd+ lesions are an
`indicator of active disease and have predictive value regarding
`the short-terrn course of MS”"‘-’ In patients with a CIS, MRI will
`support a diagnosis of MS if there are a significant number of
`lesions.‘ In addition,
`the longitudinal management of MS is
`increasingly utilizing MRI-based assessments.
`
`I Effect of Early Treatment on Multiple Sclerosis
`
`The presence of MS lesions in the brain or spinal cord as detected
`by MRI indicates that the disease is active in the nervous system.
`If treatment is delayed until MS manifests clinically, irreversible
`damage may occur. Subclinical disease activity and axonal loss
`occur early in the disease process; hence, MS should be treated as
`early as possible. The earliest stage that patients can be diagnosed
`and treated is after a first clinical demyelinating event. A number
`of trials have studied the effects of early treatment in patients with
`suspected MS.“"“" Data from these trials reveal important clinical
`and MRI benefits in patients with syndromes that are suggestive of
`early disease who are treated promptly
`During the earliest randomized, placebo-controlled trial (the
`Controlled High Risk Subjects Avonex Multiple Sclerosis
`Prevention Study [CHAMPS]), patients with CISs were treated
`with 1M IFNB-la to determine whether the time to the develop-
`ment of CDMS could be prolonged.” ClSs were defined as those
`that involved the optic nerve (unilateral optic neuritis), spinal cord
`(incomplete transverse myelitis), or brainstem or cerebellum
`(brainstem or cerebellar syndrome)."° Patients also must have had
`evidence of demyelination confirmed by MRI.” Results from this
`study showed that early treatment delayed or prevented CDMS
`and reduced the frequency of new lesions that would have allowed
`the diagnosis of definite MS by McDonald criteria.°° The probabil-
`ity of developing CDMS was 44% lower in patients who received
`IM IFNB-Ia than in those who reoeived placebo.” Furthermore,
`changes in lesion volume were significantly different between
`groups, and, at 18 months, there were 58% fewer new or enlarg-
`ing lesions and 71% fewer Gd+ lesions in patients who received
`treatment than in those who received placebo.“
`Results from a subsequent study (Early Treatment of Multiple
`Sclerosis
`[ETOMS]) were consistent with the findings of the
`CHAMPS trial." During ETOMS, the effects of SC IFNfl-la were
`studied in patients who had unifocal or multifocal neurologic syn-
`dromes and 24 T2 lesions (or 3 white-matter lesions if I lesion was
`
`infratentorial or Gd+)" Over 2 years, 24% fewer patients who
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`
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`The Importance of Early Diagnosis of Multiple Sclerosis
`
` Current Understanding of
`Multiple Sclerosis Treatment Effects
`mtiirn L‘ r ,.rs;*. cf Rise? =9
`
`LIN! IIKCVUIIIOII
`
`Disability
`
`TI r.-cztr" r."t
`
`Cl‘. Lllag”-Jsls
`
`Disease Onset
`
`received treatment developed CDMS than those who received
`placebo. Annual relapse rates were also lessened in the active treat-
`ment compared with the placebo group .5‘ Moreover, MRI end
`points, including number and volume of T2 lesions, were signifi-
`cantly better in the treatment group than in the plaoebo group.“
`The use of IM IFNfl-la may be even more beneficial in patients
`at highest risk for MS.” A subgroup of patients from the CHAMPS
`trial was analyzed to study the effects of 1M IFNB-1a in patients
`with 29 T2 lesions and 21 Gd+ lesion on baseline MRI scans, find-
`
`ings that are highly predictive of the development of CDMS."°*“ Of
`the total CHAMPS population, nearly one quarter met the criteria
`for the subanalysis (IFNB-lb group, n = 51; placebo group, n =
`40).” CDMS was identified in half of patients in the placebo group
`and in approximately one fifth of patients in the treatment group at
`2 years.” This effect was maintained at 3 years because nearly one
`quarter of patients in the treatment group developed CDMS as
`compared with more than half in the placebo group.“ The risk
`of developing CDMS was reduced by 66% at year 3 and by 63%
`at year 2.” IM IFNB-1a is approved in the United States and
`Europe for use in patients who have a CIS associated with MRI
`scan changes consistent with an inflammatory-demyelinating
`process.
`
`It is essential to initiate treatment as early as possible in patients
`who are eligible to receive IMAs. Study findings reveal that com-
`pared with patients who begin treatment early, patients who begin
`treatment later do not reap the same benefits (i.e., what was lost
`cannot be regained). Comparing parallel groups from the PRISMS-
`4 study demonstrates the benefits of early treatment. Crossover
`groups in PRISMS-4 received plaoebo for 2 years followed by
`treatment with 22-mcg or 44-mcg doses of SC IFNB-la for an
`additional 2 years. Other groups received 22-mcg or 44-mcg
`doses of SC IFNB-la continuously for 4 years. After 4 years, the
`crossover groups had greater increases in EDSS, and disease bur-
`den was progressively higher than that in groups who received
`continuous treatment.“
`
`PRISMS-4's results are further supported by those of the
`CHAMPIONS study, an extension of the CHAMPS trial.” In
`CHAMPS, patients who experienced a first clinical demyelinating
`event immediately began treatment with 1M IFNB-1a or had treat-
`ment delayed for a median of 29.9 months (placebo group). In
`CHAMPIONS, all patients were offered 1M 1FNfl-la and followed
`for up to 5 years. The rate ratio for the development of CDMS over
`5 years was reduced by 35% in the group of patients who received
`immediate treatment. Relapse rates and MR1 results also signifi-
`cantly favored immediate treatment. Based on these findings, it is
`apparent that early treatment initiation can reduoe disease activity
`and can slow the progression of disability (Figure 3).
`
`1 Identifying Patients at High Risk for Multiple Sclerosis
`
`One of the most important questions is how to identify patients at
`risk for MS who should be referred to a neurologist to reap the
`benefits of [MA treatment. A key reason to refer patients to a neu-
`rologist is the sudden appearance of a focal neurologic event such
`as paresthesias, numbness, visual changes, or aphasia. The most
`important determinant of high risk for the development of CDMS is
`the confirmation of a first, well-defined neurologic event that is con-
`sistent with demyelination associated with MRI scan abnormalities.
`These types of events involve the optic nerve (unilateral optic neu-
`ritis), spinal cord (incomplete transverse myelitis), or brainstem or
`cerebellum (brainstem or cerebellum syndrome)?” MRI findings
`should reveal lesions in the brain that are 23 mm in diameter, at
`
`least one of which is ovoid or periventricular.
`Patients with a C15 who have 21 lesion on MRI are at a sig-
`nificantly higher risk for the development of CDMS.“ In the
`Optic Neuritis Treatment Trial, the 10-year risk of developing
`MS after an initial episode of optic neuritis was 38% .°" However,
`in the subgroup of patients with 21 lesion, the risk increased to
`56%, while the risk in those with no lesions at baseline was
`
`22%. Over 2 years, 86% of untreated patients with 21 new or
`enlarging lesion went on to develop MS compared with 38% of
`untreated patients without lesions.“
`MS lesions typically are >5 mm in diameter and ovoid or oval.
`These lesions are usually in the periventricular, perivenular
`(Dawson’s fingers),
`juxtacortical, and infratentorial
`regions.
`MS lesions are visualized in the corpus callosum and spinal cord.
`The morphology of Gd+ lesions may be ringlike or homogeneous.
`The duration of ringlike lesions is longer than that of homoge-
`neously enhancing lesions, and ringlike lesions are thought to be
`related to aggressive disease activity and a higher level of tissue
`damage.“"’° T1 black holes, a marker for considerable matrix
`destruction and axonal loss, are found most often in patients who
`have SPMS and higher EDSS scores.”
`A number of diseases can cause MRI-signal hyperintensities of
`the white matter.” However, the signal abnormality patterns asso-
`ciated with these disorders usually differ from those associated
`with MS such that the potential for misdiagnosis is low. In the
`diagnosis of MS, the physician should evaluate MRI scans to rule
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`mcporg
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`EXHIBIT NO. 1013 Page 5
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`The Importance of Early Diagnosis of Multiple Sclerosis
`
`out other illnesses such as demyelinating or hypoxic-ischemic dis-
`orders, immune-mediated vasculopathies, infectious and inflam-
`matory diseases, and leukodystrophies and toxic metabolic dis-
`eases (very rare).91 For example, normal aging is associated with
`punctuate or patchy white matter signal hyperintensities, and
`hypertension and migraine are associated with a higher frequency
`of lesions randomly distributed throughout the deep and subcor-
`tical white matter; the intratentorial regions are usually not affect-
`ed. Patients with subcortical arteriosclerotic encephalopathy have
`irregular and sometimes extensive periventricular hyperintensities
`on MRI, with confluent signal changes that usually spare subcor-
`tical U-fibers. However, in contrast with lesions, the center of a
`lacune appears isointense to CSF on all sequences because of com-
`plete tissue destruction.91
`Primary care physicians should refer patients to a neurolo-
`gist for further assessment, including an MRI, after the sugges-
`tion of a first clinical demyelinating event. In patients with
`spinal cord symptoms, MRI along the entire spinal cord is sug-
`gested.91 Moreover, it is important to educate patients regarding
`the signs and symptoms of MS and to gain their full coopera-
`tion to optimize disease management. Patients should be able to
`recognize the symptoms of MS so that they are able to better
`inform their physician about their status.
`
`II Conclusions
`
`Early diagnosis and early treatment are critical to prevent irre-
`versible long-term sequelae in patients with MS. Prior to the use
`of MRI, patients with a first clinical demyelinating event may
`have had to wait several years before receiving a diagnosis of
`CDMS. However, the use of MRI is emerging as one of the most
`important tools in the management of MS. The presence of
`≥1 lesion is highly prognostic in the development of CDMS in
`patients who have experienced a clinically isolated neurologic
`event. In fact, the number of baseline lesions predicts the sever-
`ity of future disability in patients who do not receive treat-
`ment.92 MRI data show that there can be significant subclinical
`disease activity, including axonal loss and brain atrophy, prior
`to a diagnosis of CDMS, and, many times, the number of
`lesions visualized on MRI does not correlate well with clinical
`symptoms. Importantly, it has been shown that axonal loss
`occurs very early in the disease process. Hence, MRI assess-
`ments are recommended after a first demyelinating event to
`allow for the identification of patients who are at high risk of
`CDMS (newer diagnostic criteria include MRI).
`Several studies demonstrate that early treatment significant-
`ly reduces the risk of developing CDMS; this benefit is more
`pronounced in patients who have a high burden of disease at
`baseline. Thus, all patients with a clinically isolated demyeli-
`nating event should be referred to a neurologist for a more
`thorough examination and MRI testing. The effects of disease-
`modifying agents are greater in patients who begin treatment
`early.
`
`DISCLOSURES
`
`Funding for this paper was provided by Biogen Idec Inc. Author James R.
`Miller received an honorarium from Biogen and participates in the Biogen
`lecture bureau.
`
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