[handbook of clinical neurology] multiple sclerosis and related disorders volume 122 || diagnosis of...

Chapter 14

Diagnosis of multiple sclerosis

TRACY M. DEANGELIS AND AARON MILLER*

Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, New York, NY, USA

INTRODUCTION

In the absence of pathognomonic symptomatology ordefinitive laboratory tests, multiple sclerosis (MS) con-tinues to pose a diagnostic challenge to clinicians. Datingback to the observations of Jean-Martin Charcot (1868),the diagnosis of MS has required the presence of multi-ple white-matter lesions in the central nervous system(CNS) that are disseminated in both space and time. Evi-dence for the presence of such white-matter lesions canbe based on clinical history, on neurologic examination,or on paraclinical data such as that from magnetic reso-nance imaging (MRI), cerebrospinal fluid (CSF) analy-sis, or the recording of evoked potentials. Clinicalevidence for dissemination in space can be derived fromneurologic examination demonstrating abnormalitiesindicative of involvement of at least two separate areasin the CNS. Furthermore, a history of two or more clin-ical attacks (exacerbations) provides definitive clinicalevidence for dissemination in time. Frequently, however,history and examination fail to meet diagnostic criteria,resulting in the need for paraclinical data to provide sup-portive evidence of the diagnosis. Consequently, clini-cians must be well versed in both the common anduncommon clinical manifestations in order to diagnoseMS properly. Because the diagnosis requires the exclu-sion of alternative disorders, clinicians must also havea broad knowledge of the differential diagnostic entitiesthat can mimic MS. Moreover, they should be familiarwith the current established diagnostic criteria definedby international expert consensus (Polman et al., 2011)and their application in clinical practice.

The ultimate goal for clinicians should be to establishan accurate diagnosis as early as possible. With the con-tinuing emergence of effective therapies, early diagnosiscan permit the expeditious initiation of disease-modifying

treatments with the primary goal of altering the long-termdisease course and improving patients’ quality of life.

CLINICALMANIFESTATIONS

The common clinical features ofMS have been reviewedby numerous previous authors (Muller, 1949; Kurtzke,1970; Matthews, 1985; Paty, 2000). Nevertheless, evenwith such widespread knowledge about MS, approxi-mately 5–10% of patients diagnosed with MS do notactually have the disease (Herndon and Brooks, 1985;Engell, 1998), underscoring the need for clinicians tobe cautious. Because of the protean nature of its poten-tial clinical manifestations of CNS dysfunction, MS canpresent with symptoms referable to any part of the cen-tral neuraxis, including the brain, brainstem, spinal cord,and optic nerves. Clinical signs and symptoms areextremely diverse and include vision loss, abnormal sen-sations, motor weakness, clumsiness, unsteady gait, andbladder, bowel, and sexual dysfunction, as well as cog-nitive disturbances, changes in mood or personality, heatintolerance, and fatigue.

Common presenting symptoms and their frequencyat onset are presented in Table 14.1 (Paty et al., 1997).Sensory disturbances and unilateral vision loss second-ary to optic neuritis are the most common presentations,followed by motor deficits and diplopia. There are alsoless typical and seemingly rare presentations of whichthe clinician should be aware. For instance, neuropsycho-logic presentations including cognitive changes andmood disturbances have become increasingly recognizedin MS (Bobholz and Rao, 2003) and can occasionally bethe presenting feature (Zarei et al., 2003).

At presentation, patients may not be able to recall orvolunteer any past episodes of neurologic dysfunction

*Correspondence to: Aaron Miller, M.D., Medical Director and Professor of Neurology, Corinne Goldsmith Dickinson Center forMultiple Sclerosis, Icahn School of Medicine at Mount Sinai New York, New York, USA. Tel: þ1-212-241-6854, Fax: þ1-212-241-

5333, E-mail: [email protected]

Handbook of Clinical Neurology, Vol. 122 (3rd series)Multiple Sclerosis and Related DisordersD.S. Goodin, Editor© 2014 Elsevier B.V. All rights reserved

and the onus rests upon the clinician to search for a his-tory of prior attacks in order to satisfy the criterion ofdissemination in time. One should always inquire aboutepisodes of vision loss, a past Bell’s palsy, trigeminalneuralgia (TGN), episodic vertigo, or a prior diagnosisof “carpal tunnel syndrome” with sensory symptomsinvolving all five fingers rather than those correspondingto a median nerve distribution.

To qualify as an MS attack, neurologic symptomsshould be present for at least 24 hours. They may evolveslowly or present abruptly, which may result in theirbeingmistaken for an acute ischemic event, for example,a lacunar syndrome. A brain MRI with restricted diffu-sion in a vascular distribution on a diffusion-weightedMRI can be helpful to diagnose an acute infarct,although active demyelinating lesions can also demon-strate restricted diffusion.

Sensory complaints are frequently one of the earliestsymptoms of MS, reportedly occurring in 21–55% ofindividuals (Muller, 1949; Adams and Sutherland,1950; Kurtzke, 1970; McAlpine, 1972). Sensory symp-toms are generally referable to lesions involving the pos-terior columns rather than the spinothalamic tracts(McAlpine, 1972). Vibratory loss is quite common earlyon and has been recognized to precede any impairmentof joint position sense (Miller, 1998).

Patients often have difficulty describing sensory phe-nomena and the clinician may be unable to demonstrateobjective abnormalities on neurologic examination.Patients often report “numbness,” but their subjectivedefinition of this complaint must be explored further;for example, by “numbness” does the patient mean anabsence of or decrease in sensation or does she or hemeana positive phenomenon such as tingling, burning, pruritus,paresthesias, hyperpathia, allodynia, or dysesthesias?Patients often liken the feeling to “novocaine wearingoff” or strange sensations such as the feeling that a limbis swollen or that a garment is cloaking the skin. Sensorysymptoms resulting from myelitis or myelopathy can

cause patients to experience a tight band-like sensationabout the trunk corresponding to a sensory level detectedupon examination.ABrown- Sequard syndrome, or hemi-cord syndrome, can occur and produce dissociated sen-sory findings, typically with ipsilateral posterior columnand motor deficits together with contralateral pain andtemperature loss. Lhermitte’s phenomenon (Lhermitteet al., 1924), the brief experience of an electric-like sensa-tion radiating down the spine with neck flexion, is often acomplaint in patients with cervical spine lesions. Althoughextremely characteristic, Lhermitte’s phenomenon is notpathognomonic ofMSbut can also be seen in other causesof cervical myelopathy, such as vitamin B12 deficiency ordegenerative disc disease.

Optic neuritis is another frequently presenting symp-tom of MS, occurring in approximately 14–23% of indi-viduals (Muller, 1949; Adams and Sutherland, 1950;Kurtzke, 1970; McAlpine, 1972). Patients often describethe dimming or blurring of vision, pain with eye move-ments, and occasionally photophobia. Examinationreveals a loss of acuity, the presence of an afferent pupil-lary defect, color desaturation, and a central scotoma.Early in the course, fundoscopic examination is usuallynormal (because the inflammation is typically retrobul-bar), but sometimes papillitis, with optic nerve headswelling, occurs and later in the course optic pallor(indicative of atrophy) may be evident. Visual evokedpotentials can help to identify subclinical optic nervelesions. Most commonly, this is indicated by a delay(compared to normal) in the latency of the P100 compo-nent of the response following pattern reversal stimula-tion (Halliday et al., 1972; Lowitzsch, 1980). In addition,low-contrast visual acuity testing with Sloan letter chartscan reveal very mild optic nerve abnormalities even inpatients with normal 20/20 vision to high-contrast stimuli(Balcer et al., 2000). Even when optic neuritis occurs inisolation, it has important implications regarding thelikelihood of becoming MS in the future. Thus, patientswith a history of optic neuritis have a 38% overall risk ofdeveloping MS after 10 years. In addition, of patientswith one or more lesions on brainMRI, 56%will developMS after 10 years, compared with 22% of patients with-out brain lesions (Beck et al., 2003).

Motor weakness secondary to corticospinal tractlesions is the presenting feature ofMS in 32–41% of cases(Muller, 1949; Adams and Sutherland, 1950; Kurtzke,1970; McAlpine, 1972). Weakness is often described asa sensation of heaviness in the limbs. Legs are affectedmore often than arms and unilateral symptoms are morecommon than bilateral deficits. Hyperactive deep tendonreflexes with clonus are often found in MS patients,although, unless asymmetric or accompanied by otherpathologic signs of upper motor neuron dysfunction,brisk reflexes can be a normal finding.

Table 14.1

Common symptoms seen at onset of multiple sclerosis

(University of British Columbia data)

Symptom Percent

Sensory symptoms in arms and legs 33Unilateral vision loss 16

Slowly progressive motor deficit 9Diplopia 7Acute motor deficit 5Polysymptomatic 14

Others 16

Reproduced from Paty et al. (1997).

318 T.M. DEANGELIS AND A. MILLER

Brainstem syndromes may occur at presentation andmanifest clinically as ocular motility impairment, gazeparesis, diplopia, oscillopsia, or skew deviation. Exami-nation can demonstrate nystagmus, commonly horizon-tal, as well as internuclear ophthalmoplegia (INO)secondary to lesions of the medial longitudinal fascicu-lus (MLF). Clinically, an INO appears (on rapid lateralgaze) as a paresis (or lag) of the medial rectus muscleipsilateral to the MLF lesion accompanied by a horizon-tal nystagmus of the contralateral abducting eye. Thissyndrome has also been referred to as “dissociatednystagmus.”

In addition to ocular phenomena, brainstem lesionscan cause dysarthria, dysphagia, vertigo, facial sensoryloss, and paresis, both upper and lower motor neurontype, the latter of which is sometimes diagnosed initiallyas a simple idiopathic Bell’s palsy. Unilateral hearingloss, although uncommon, can also occur (Drulovicet al., 1993; Sasaki et al., 1994). Bilateral brainstemlesions can produce an affective syndrome known aspseudobulbar palsy, which results in an emotional labil-ity (easily provoked laughing or crying) without the usu-ally associated affective state (i.e., mirth or sadness).Patients can present with episodes of inappropriatelaughter or, more commonly, crying spells which areattributed to the release of limbic functions. Supranuc-lear dysarthria and dysphagia can accompany the behav-ioral symptoms as well (Brust, 2005).

Cerebellar lesions can produce gait ataxia and incoor-dination and are a presenting symptom in approximately13% of cases (McAlpine, 1972). Patients may complainof vertigo, unsteadiness, clumsiness, loss of balance,and tremor. Examination may reveal scanning speech,rebound, appendicular or gait ataxia, dysmetria, andintention tremor. Romberg sign is often reported but,typically, the postural disturbance is present regardlessof whether or not the eyes are closed.

MS patients can experience recurrent, stereotypedphenomena, generically referred to as paroxysmal symp-toms. The best characterized of these syndromes are so-called tonic seizures (Joynt and Green, 1962) and the syn-drome of paroxysmal dysarthria and ataxia. Both of thesyndromes are characterized by very brief (10 seconds to2 minutes) recurrent episodes (10–40/day), not associ-ated with loss of consciousness or electrocerebral distur-bances on electroencephalogram, and often with theepisodes provoked by motion or hyperventilation. Tonicseizures consist of unilateral flexion contraction of anarm and hand, often accompanied by sensory symptoms(pain, heat) preceding the spasm in the contralateral limb(Heath and Nightingale, 1986). In these circumstances,the origin disturbance must be in the cervical spinal cord.When the spasm involves the ipsilateral face, the preced-ing sensory events are typically absent and the origin of

the disturbance in the brainstem. Paroxysmal dysarthriaand ataxia consists of very brief episodes of dysarthriaand incoordination and is thought to arise in the brain-stem. Because of the spread of symptoms and the absenceof any suggestion of cortical disturbance, the pathophys-iology of these paroxysmal symptoms is often thought toinvolve an acute irritative inflammatory lesion with spon-taneous impulse propagation, and ephaptic transmissionto chronically demyelinated fibers. Although these distur-bances are rarely reported in other conditions (e.g.,systemic lupus erythematosus (SLE)), they are so charac-teristic of MS as to be almost pathognomonic. Otherparoxysmal conditions also occur in MS, although theyare less well characterized and less specific to the diagno-sis. These include glossopharyngeal neuralgia, paroxys-mal itching, aphasia, abrupt loss of tone, kinesiogenicchoreoathetosis, hiccups, and segmental myoclonus.

Lhermitte’s phenomenon is also considered a parox-ysmal phenomenon and has been considered earlier.TGN is the most common paroxysmal disturbance (otherthan Lhermitte’s) and occurs with the classic history of alancinating pain radiating down the side of the faceabout the angle of the jaw. Patients with MS generallypresent with TGN at an earlier age and more often bilat-erally compared with patients who do not have MS(Brisman, 1987). However, unlike many of the other par-oxysmal symptoms, MS accounts for only a very smallfraction of the TGN encountered in routine practice.Therefore, the occurrence of TGN, unless the patientis young or there are unusual features, should not triggeran extensive evaluation for possible MS.

In addition to paroxysmal symptoms, MS patientscan experience true epileptic seizures, either focal orsecondarily generalized. Although not all reports areconsistent on this point (Nyquist et al., 2002), most stud-ies suggest that seizures occur in 1–5% of MS patients(Thompson et al., 1993; Koch et al., 2008; Kelley andRodriguez, 2009), which represents a small, butincreased, incidence compared to the general popula-tion. The pathologic basis of these seizures is thoughtto be related to acute or chronic plaques involving thecerebral cortex. Support for this notion derives fromolder pathologic studies that reported that 20% of MSplaques involve the cortex and 5% are confined to it,as well as newer reports that suggest that cortical demy-elination can be extensive (Pirko et al., 2007). In addition,juxtacortical lesions have been reported to be the epilep-togenic foci in 5MS patients, whose predominant man-ifesting symptoms were temporal lobe seizures(Gambardella et al., 2003).

Bladder, bowel, and sexual dysfunction are commonsymptoms in MS patients but occur more often withadvanced disease (Miller et al., 1965). They can, how-ever, present early on as part of a myelitis syndrome.

DIAGNOSIS OF MULTIPLE SCLEROSIS 319

Bladder complaints include a failure to store, to emptyadequately, or a combination of both. Failure to storeresults from detrusor hyperactivity and produces symp-toms of urgency, frequency, nocturia, and incontinence.These symptoms can also occur from overflow second-ary to retention caused by an inability to emptycompletely. Failure to empty is generally caused bydetrusor-sphincter dyssynergia and manifests as hesi-stancy and retention. Bowel dysfunction often resultsin constipation although, less often, results in urgencyor incontinence. Sexual deficits can present with erectiledysfunction and impotence in men and loss of libido andanorgasmia in women. An unusual patient presentationof hyperlibidinism has been reported (Gondim andThomas, 2001). Patients may not offer a history of sex-ual dysfunction spontaneously, so the clinician shouldalways inquire.

Fatigue is a common symptom that can accompanyMS exacerbations, but also occurs prominently in theabsence of attacks. It has been considered one of thethree most common disabling symptoms of MS, alongwith gait and bladder disturbances (Murray, 1985). Heatintolerance is a well-established, but uncommon, symp-tomof earlyMS and gave rise to the use of the “hot bath”test as an aid to diagnosis. Patients will develop a neuro-logic deficit in the setting of exposure to heat, eitherfrom an external source, such as a hot summer day orvigorous exercise. Elevated body temperatures second-ary to a febrile illness, such as an infection, can alsounmask a neurologic deficit.When the symptom is visualloss, this is referred to as Uhthoff’s phenomenon. Theetiology is related to the well-known neurophysiologiceffect that elevated temperature reduces the capacityof demyelinated nerve fibers to transmit impulses.Patients often report resolution of symptoms when theycool down or defervesce. It is important to remindpatients to carry ice water with them or have access toa cool environment when exercising or in hot weather,so they can avoid unwanted symptoms. Exercising in aswimming pool can likewise be helpful as a pool servesto dissipate heat efficiently.

Cognitive problems in MS have an estimated preva-lence of 50–75% (Miller and Coyle, 2004). They can alsooccasionally be the presenting symptom. A retrospectivecase series described 6 patients with MS who initiallypresented with progressive dementia with marked amne-sia andmood disturbance as well as cortical signs such asdysphasia, dyslexia, and dysgraphia (Zarei et al., 2003).The authors suggested a cortical variant ofMS as the eti-ology of their presentations. Mood disturbances, bothdepression and, much less commonly, euphoria, as wellas emotional lability and pseudobulbar affect occur inMS. Depression affects approximately 75% patients atsome point during their disease (Miller and Coyle, 2004).

Pain syndromes are frequently encountered and areespecially troublesome for MS patients. These mayappear at the outset of the disease more commonly thancurrently appreciated. In one survey, approximately 70%of MS patients reported pain at some point in their dis-ease course and reports of active pain were significantlygreater when compared with controls (Rae-Grant et al.,1999). Pain can be produced by several mechanisms. Forexample, ocular pain with optic neuritis, dysesthetic sen-sory symptoms, and paroxysmal disturbances such asTGN or painful tonic seizures can all result in pain.Low-back pain and radicular-like pain syndromes canalso occur in MS. Moreover, as a rule, structural disor-ders (e.g., from degenerative disc disease) and other eti-ologies need to be excluded carefully before attributingthe pain to MS.

DIAGNOSTIC CRITERIA

The diagnostic criteria for MS have continued to evolveover the past 40 years, beginning with Schumacheret al.’s initial scheme established in 1965. This classifica-tion (Table 14.2) identified patients as “clinically defi-nite, probable or possible” MS. In addition to therequirement of dissemination in space and time, thesecriteria included the onset between ages 10 and 50, thepresence of objective neurologic signs, predominant evi-dence of CNS white-matter disease, and the exclusion ofother conditions that could produce the same clinical pic-ture. The presence of five or six criteria, but alwaysincluding the absence of alternative explanations forthe condition, satisfied the requirements for clinicallydefinite MS. Patients with fewer than five or six, butincluding the absence of an alternative diagnosis, werediagnosed with either clinically probable or possible MS.

Between the 1970s and 1980s, the advent of techno-logic advances in neuroimaging and electrophysiologyenabled clinicians to support the diagnosis of MS using

Table 14.2

Schumacher criteria for the clinical diagnosis

of multiple sclerosis

1. Onset at an appropriate age (10–50 years)2. Central nervous system white-matter disease

3. Objective abnormalities on examination4. Lesions disseminated in space (involvement of two or more

non-anatomically contiguous areas)

5. Dissemination in time demonstrated by:● Attacks lasting over 24 hours, spaced at least 1 month

apart● Gradual or stepwise progression over 6 months

6. No alternative diagnosis

Reproduced from Schumacher et al. (1965).


additional paraclinical evidence. Subclinical lesionscould now be detected using imaging of the brain andspinal cord as well as by documenting abnormalitieson electrophysiologic testing of the optic nerves, brain-stem, auditory and spinal cord pathways. MRI hasbecome an invaluable tool in the diagnosis of MS,because of its ability to identify subclinical diseaseactivity. Typical MRI findings include white-matterhyperintense lesions on T2/FLAIR sequences which areovoid-shaped and oriented perpendicular to the ventri-cles. Typical lesion locations include the periventricularwhite matter, corpus callosum, juxtacortical areas, andbrainstem (Fig. 14.1). Enhancement with a characteristicopen-ring pattern is common. Despite the obvious valueofMRI, however, it is only an adjunct to the clinical eval-uation. Few neurologists today would use MRI criteriaby themselves to diagnose MS.

In addition to imaging and evoked potential studies,lumbar puncture provides additional data (Rudick andWhitaker, 1987). Immunoreactive markers found in theCSF, such as elevated immunoglobulin G (IgG) indexand oligoclonal bands, were found in high proportion inspecimens from MS patients, approximately 65–70%and 80–90%, respectively. However, these markers aresensitive but not specific for MS and can be found inpatients with other causes of CNS inflammation, suchas neuroborreliosis, neurosyphilis, neurosarcoidosis, andsubacute sclerosing panencephalitis.

After the development of the aforementioned para-clinical tests, a committee chaired by Charles Poserincorporated such studies to define modified diagnosticcriteria, which were published in 1983 (Poser et al., 1983).Initially designed primarily to help identify patients forclinical trial research, the Poser criteria (Table 14.3) were

Fig. 14.1. Classic multiple sclerosis.

Table 14.3

Washington Committee (Poser) criteria for the diagnosis of multiple sclerosis

Category Relapses (no.) Clinical lesions (no.) Paraclinical CSF studies

Clinically definite multiple sclerosis (CDMS)

CDMS A1 2 2 NA NA

CDMS A2 2 1 1 NALaboratory-supported definite mutiple sclerosis (LSDMS)

LSDMS B1 2 1 1 (þ)

LSDMS B2 1 2 NA (þ)LSDMS B3 1 1 1 (þ)Clinically probable multiple sclerosis (CPMS)

CPMS C1 2 1 (–) (–)CPMS C2 1 2 (–) (–)CPMS C3 1 1 1 (–)

Laboratory-supported probable multiple sclerosis (LSPMS)

LSPMS D1 2 (–) (–) (þ)

CSF, cerebrospinal fluid; NA, not applicable.

Reproduced from Poser et al. (1983).


used by practicing clinicians through the 1990s. As anextension of Schumacher et al.’s criteria, Poser’s schemeincludes supportive data from electrophysiologic test-ing, neuroimaging, and CSF analysis. However, thesecriteria required only a single documented lesion (byMRI or otherwise) that was remote from the area impli-cated on clinical grounds to establish dissemination inspace. Moreover, it provided no means of using paracli-nical data to help establish dissemination in time.

Principally in response to the increasing role of MRIin the diagnosis of MS, in 2001 a committee of theNational Multiple Sclerosis Society and the Interna-tional Federation of MS Societies, chaired by W. IanMcDonald, established new diagnostic criteria for useby the international MS community. In retrospectivestudies, the McDonald criteria (Tables 14.4–14.6) weremore sensitive and specific than prior schemes (espe-cially with their new use of MRI to establish dissemina-tion in time) and were able to predict the subsequentdevelopment of clinically definite MS (by Poser criteria)more often than its predecessors (Dalton et al., 2002;Barkhof et al., 2003; Tintore et al., 2003). Nevertheless,other studies and opinions from MS specialists(Frohman et al., 2003; Polman et al., 2005b) suggestedthat the criteria were not user-friendly, could be confus-ing in application for clinicians, and might utilize overlystringent MRI criteria for the documentation of dissem-ination in space. Their value was also questionable forapplication in non-western European populations.

Table 14.4McDonald criteria for the diagnosis of multiple sclerosis

Clinical (attacks) Objective lesions Additional requirements

2 or more 2 or more None; clinical evidence will suffice (additional evidence desirable but mustbe consistent with MS)

2 or more 1 Dissemination in space by MRI or positive CSF* and two or more MRIlesions consistent with MS or further clinical attack involving different

site1 2 or more Dissemination in time by MRI or second clinical attack1 (monosymptomatic) 1 Dissemination in time byMRI or positive CSF and two ormoreMRI lesions

consistent with MS and dissemination in time by MRI or second clinicalattack

0 (progression from

onset)

1 Positive CSF and dissemination in space by MRI evidence of nine or more

T2 brain lesions or two or more cord lesions or 4–8 brain and one cordlesion or positive VEP{ with 4–8 MRI lesions or positive VEP with lessthan four brain lesions plus one cord lesion and dissemination in time byMRI or continued progression for 1 year

*Positive CSF¼oligoclonal IgG bands in CSF (and not serum) or elevated IgG index.{Positive VEP¼delayed but well-preserved waveform.

MS, multiple sclerosis; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; VEP, visual evoked potential; IgG, immunoglobulin G.

Adapted from McDonald et al. (2001), with permission from John Wiley & Sons, Inc.

Table 14.5

International Panelmagnetic resonance imaging diagnostic

criteria for dissemination in space and time

Dissemination in space (requires at least three of the

following four criteria)*

1. Contrast-enhanced lesion, or nine T2 hyperintenselesions

2. One or more infratentorial lesions3. One or more juxtacortical lesions4. Three or more periventricular lesions

Dissemination in time

1. When first scan is performed 3 or more months after clinicalevent:● Contrast lesion (at independent site) demonstrates

dissemination in time● Negative-contrast scan: follow-up MRI 3 or more

months; new T2 or contrast lesion demonstratesdissemination in time

2. When the first scan is performed less than 3 monthsafter clinical event; on second scan 3 or more months after

event:● Contrast lesion demonstrates dissemination in time● Negative-contrast scan: follow-up third MRI 3 or more

months after first; new T2 or contrast lesiondemonstrates dissemination in time

*Lesions generally>3 mm; spinal cord lesion may substitute for brain

lesion.

MRI, magnetic resonance imaging.

Adapted from McDonald et al. (2001), with permission from John

Wiley & Sons, Inc.


In March 2005, the international committee recon-vened to revise the previously published criteria(Tables 14.7 and 14.8). Modifications were based on dataaccumulated since 2001. In one important change, basedon observations of Dalton et al. (2002), the appearance ofconspicuously new T2 lesions was considered useful fordemonstration of dissemination in time if detected anytime after a reference scan obtained at least 1 month afteronset of clinical symptoms.Moreover, the utility of spinalcord imaging was emphasized. For example, the clause“one spinal cord lesion can substitute for one brain

lesion” was modified as follows: A spinal cord lesion isconsidered equivalent to a brain infratentorial lesion; anenhancing cord lesion equals an enhancing brainlesion; along with individual brain lesions, discreteindividual cord lesions count amongst the tally of requi-site T2 lesions. Compared to the InternationalPanel’s prior diagnostic criteria for primary progressive(PP) MS (Table 14.6), which were based on recommenda-tions of Thompson et al. (2000), the revisions appeared to“liberalize” the comparatively more stringent original cri-teria. Also, simplified to exclude the absolute need forpositive CSF findings in PPMS, the new scheme definedmore specific brain and cord imaging requirements(Table 14.7).

In 2010, the International Panel met in Dublin and,based on data obtained subsequent to the 2005 iteration,again revised the diagnostic criteria (Polman et al., 2011)(Table 14.9). Major changes were made in the criteria fordissemination in space, which now simply require thepresence of at least one lesion in two out of four charac-teristic locations: periventricular, juxtacortical, infraten-torial, or spinal cord. The Panel did insist on the provisothat the lesions be counted only if they were not respon-sible for the clinical presentation. For dissemination intime, even greater simplification was made with the cri-teria now able to be satisfied if any new lesion developson MRI at any time after any prior MRI. Studies haveshown that the use of these new criteria sacrifice almostnothing in specificity, but gain considerably in sensitivity(Swanton et al., 2007; Tur et al., 2008).

Table 14.6

International Panel diagnostic criteria for primary

progressive multiple sclerosis

1. Abnormal CSF (þ oligoclonal bands or increasedimmunoglobulin G index)

2. Either:● Nine or more T2-weighted brain MRI lesions● Two or more spinal cord MRI lesions● Four to eight brain and one cord MRI lesion(s)● Four to eight brain MRI lesions and abnormal visual

evoked potentials● Fewer than four brain and one cord MRI lesion and

abnormal visual evoked potentials

3. Dissemination in time documented by MRI or continuedprogression for 1 year

CSF, cerebrospinal fluid; MRI, magnetic resonance imaging.

Adapted from McDonald et al. (2001), with permission from John

Wiley & Sons, Inc.

Table 14.7

Revised McDonald diagnostic criteria for multiple sclerosis (2005)

Clinical (attacks) Objective lesions Additional requirements

2 or more 2 or more None. Clinical evidence alone will suffice; additional evidence desirable butmust be consistent with MS

2 or more 1 Dissemination in space by MRI or two or more MRI lesions consistent withMS plus positive CSF or await further clinical attack implicating other site

1 2 or more Dissemination in time by MRI or second clinical attack1 1 Dissemination in space by MRI or two or more MRI lesions consistent with

MS plus positive CSF and dissemination in time by MRI or second clinicalattack

0 (progression from

onset)

1 or more Disease progression for 1 year (retrospective or prospective) and two out of

three of the following:1. Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive

VEP)

2. Positive spinal cord MRI (two or more focal T2 lesions)3. Positive CSF

MS, multiple sclerosis; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; VEP, visual evoked potential.

Reproduced from Polman et al. (2005a).


In another major change, the Panel now permitted,for the first time, the diagnosis to be made at the timeof the first clinical attack if the brain MRI simulta-neously demonstrates both a gadolinium-enhancinglesion (not responsible for the patient’s symptoms) andat least one additional T2 hyperintense lesion. The pre-sumption is that the latter lesion is old and the enhancinglesion is new, representing dissemination in time.

The 2010McDonald criteria alsomade somemodifica-tions of the 2005 criteria for the diagnosis of PPMS(Table 14.7) in order to “harmonize MRI criteria . . . for

all forms ofMS.” Thus, the Panel recommended retainingthe requirement to fulfill two of three MRI or CSF find-ings, but replaced the previous imaging criteria with thenew criteria of>1 T2 lesion in at least one area character-istic for MS (periventricular, juxtacortical, or infratentor-ial) and >2 T2 lesions in the cord (Table 14.10).

The revisedMcDonald criteria are based on data relatedprincipally to an adult population in North America andEurope. The Panel emphasizes that the reliability of thesecriteria for other populations, such as children, Asians,or Latin Americans, has not yet been established.

In this age in which MRI is so readily available, notinfrequently patients are encountered who undergo cra-nial MRI in circumstances in which there is no reasonto suspect MS and the imaging results demonstratelesions characteristic of MS. For example, a patientmay undergo imaging after minor head injury or becauseofmigraine headaches. Several series have been publishedwhich show that approximately one-third of such patientsdemonstrate clinical symptoms characteristic of MS dur-ing follow-up periods of 2–5 years (Lebrun et al., 2008;Okuda et al., 2009; Siva et al., 2009; Granberg et al.,2012). Even more demonstrate new MRI lesions charac-teristic of MS. Okuda et al. (2011) have reported thatthe presence of one or more lesions in the cervical spinalcord greatly increases the likelihood that the patient willdemonstrate clinical findings characteristic of MS inthe next few years. Also of great importance is the obser-vation that diagnoses other than MS have not becomeapparent during the period of follow-up in these patients.It is important to note that the Dublin revision of theMcDonald criteria has cautioned against making a diag-nosis of MS in patients with incidental findings on MRIin the absence of clinical evidence (Polman et al., 2011).

MSCOURSESANDVARIANTS

Once the diagnosis is made, the type of MS should becategorized because disease course often dictates the

Table 14.8

Revised diagnostic criteria for dissemination in

space and time (2005)

Dissemination in space (requires at least three of the

following four criteria)

1. Gadolinium (Gd)-enhanced lesion, or cord lesion or nine T2hyperintense brain and/or cord lesions if there is no Gd-

enhancing lesion2. One or more brain infratentorial or cord lesions3. One or more juxtacortical lesions

4. Three or more periventricular lesionsNote: Individual cord lesions can contribute along withindividual brain lesions to reach required number of T2

lesions.Dissemination in time● A Gd-enhancing lesion detected in scan at least 3 months

after onset of initial clinical event at a site different frominitial eventor

● A new T2 lesion detected in a scan done at any time

compared to a reference scan done at least 30 days afterinitial clinical event


Table 14.9

Revised diagnostic criteria for dissemination in space and

time (2010)

Dissemination in space

�1 T2 lesion in at least two out of four MS-typical regionsof the CNS (periventricular, juxtacortical, infratentorial, orspinal cord)

Dissemination in time● Simultaneous presence of asymptomatic gadolinium-

enhancing and non-enhancing lesions at any timeor

● A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to abaseline scan

MS, multiple sclerosis; CNS, central nervous system; MRI, magnetic

resonance imaging.


Table 14.10

Proposed diagnostic criteria for neuromyelitis optica

Optic neuritis

Acute myelitisAt least two of three supportive criteria:1. Contiguous spinal cord MRI lesion extending over three or

more vertebral segments

2. Brain MRI not meeting diagnostic criteria for MS3. NMO-IgG seropositive status

MRI,magnetic resonance imaging;MS,multiple sclerosis; NMO-IgG,

neuromyelitis optica immunoglobulin G.

Reproduced from Wingerchuk et al. (2006).


appropriate therapy. In 1996, definitions for the mostcommon clinical patterns were proposed (Lublin andReingold, 1996) (Fig. 14.2). Four types of patterns weredescribed: relapsing-remitting (RR) MS, secondary pro-gressive (SP) MS, primary progressive (PP) MS, andprogressive-relapsing (PR) MS. Patients with RRMS,which accounts for approximately 85% of MS patients atonset, experience exacerbations with either total or incom-plete recovery and remain clinically stable between attacks.According to some natural history studies, within a decadehalf of these patients will convert to SPMS, which is char-acterized by an initially relapsing course and subsequentinsidious progression, sometimes accompanied by super-imposed relapses (Weinshenker et al., 1991). Other naturalhistory studies, however, suggest a less dire prognosis(Pittock et al., 2004; Sayao et al., 2007). Distinguishingbetween RRMS with incomplete recovery and SPMS isoften challenging for both clinicians and patients, as it isoften not clear whether disability accrued gradually overtime or as residua from prior exacerbations. PPMSpatients, on theotherhand, demonstrate agradual progres-sion of disability from the outset, unaccompanied by dis-crete attacks. Likewise, PRMS patients show a gradualdeclinefromonset, except that this steadilydownhill courselater becomes interrupted by one or more clinical relapses.

Several conditions involving CNS demyelinationresemble MS, but are sufficiently different thatthey have been considered to be clinical variants ofMS. Firstly, Marburg’s disease is an acute fulminantform of MS. Marburg initially reported the conditionin 1906 in a 30-year-old female who succumbed within 1month of onset. A monophasic illness of the young, theMarburg variant generally results in death withinweeks to months, most often from brainstempathology. Extensive, diffuse inflammation occurswith pathologic evidence of extensive macrophage infil-tration, widespread, confluent demyelination withmarked associated edema, severe necrosis and cavita-tion, and axonal loss, the latter being distinct from MS(Popescu and Lucchinetti, 2012). An autopsy of a27-year-old female demonstrating immature, unstable

myelin suggested a genetic susceptibility as the etiology(Wood et al., 1996). CSF studies are variable andmay notdemonstrate oligoclonal bands, perhaps as a result of theacute time course. Response to therapy with steroids andmannitol has been reported (Guibilei et al., 1997).

Secondly, Balo’s concentric sclerosis (BCS), firstdescribed in 1928, is another rare aggressive variant ofMS (Balo, 1928). Originally referred to as leukoence-phalitis periaxialis concentrica, BCS demonstrates char-acteristic large concentric perivascular bands ofdemyelination separated by layers of intact myelin(Moore et al., 1985). Clinically, patients present withan acute, fulminantmonophasic deterioration. The usualage of onset is between 20 and 50 years, and the condi-tion reportedly occurs more commonly in China and thePhilippines. In contrast to MS, clinical manifestations inBCS are largely supratentorial, with demyelination spar-ing the spinal cord, brainstem, cerebellum, and opticnerves. Itmay result in development of increased intracra-nial pressure. Clinical features include headache,depressed level of consciousness, cognitive decline, sei-zures, and dysphasia. Death generally results from herni-ation or aspiration pneumonia. Brain MRI demonstratesconcentric enhancing lesions, suggesting active synchro-nous demyelination (Kastrup et al., 2002). CSF studiescan resemble MS with positive oligoclonal bands and ele-vated IgG synthesis. Diagnosis, however, is generallymade postmortem by characteristic brain pathology. Arare entity pathologically similar to BCS is concentriclacunar leukoencephalopathy, which demonstrates exten-sive demyelination and axonal damage with alternatingareas of cavitation and bands of gliosis. The unusual con-centric arrangement is centered on a periventricular zoneof demyelination (Currie et al., 1970; Popescu andLucchinetti, 2012). There are reports of some therapeuticbenefit from high-dose steroids, immunosuppressantagents, and total plasma exchange (Spiegel et al., 1989;Louboutin and Elie, 1995; Sekijima et al., 1997); however,mortality rates remain high. The limited data availablesuggest that early aggressive treatment is associated withbetter outcomes.

Occasionally, MS lesions are tumefactive, resem-bling mass lesions, and can be mistakenly diagnosedas brain tumors. These are sometimes referred to as pla-ques of Kepes. Tumefactive lesions can radiographicallyresemble enhancing tumors such as glioblastoma multi-forme, primary CNS lymphoma, or infections such asbrain abscesses (Fig. 14.3). In contrast, enhancement gen-erally appears in an open-ring pattern. Presenting symp-toms often reflect those of a space-occupying lesion,such as headache, elevated intracranial pressure, alteredmental status, and seizures.

Myelinoclastic diffuse sclerosis, or Schilder’sdisease, first described in 1912, generally presents in

Progressive relapsing

Primary progressive

Secondary progressive

Relapsing-remitting

Fig. 14.2. Clinical patterns of multiple sclerosis. (Reproduced

from Lublin and Reingold (1996).)


childhood and, as such, is often referred to asjuvenile MS (Schilder, 1912). Significant diagnostic con-fusion has surrounded this disease in retrospect, as itappears several cases in the literature were actuallyadrenoleukodystrophy (ALD) or subacute sclerosingpanencephalitis. True Schilder’s disease is very rareand, in 1986, Poser established very specific diagnosticcriteria, which required the exclusion of alternative eti-ologies to help resolve diagnostic confusion; for exam-ple, these criteria include normal very-long-chain fattyacids, normal CSF studies, and no prior history of fever,infection, or vaccination (Poser et al., 1986). Pathologi-cally, Schilder’s disease demonstrates large areas ofasymmetric hemispheric demyelination without definitesparing of subcortical fibers (Kotil et al., 2002). Otherauthors have suggested a non-invasive diagnosis ofSchilder’s disease when there are one or two large subcor-tical cyst-like lesions, eventuallywith an open-ring patternof gadolinium enhancement, and absence of intracranialhypertension. Neoplasm may be further excluded bymeans of perfusion MR and consideration of abnormalglutamate/glutamine elevation on short-echo time mag-netic resonance spectroscopy (Bacigaluppi et al., 2009).Symptoms frequently include headache, vomiting, visualdisturbances, cortical blindness, and seizures. Treatmentwith steroids has shown very good response (Pretoriuset al., 1998; Kotil et al., 2002).

Two case reports of patients with unclear diagnosesdemonstrated evidence of disseminated subpial demye-lination and were considered by the authors to be rarevariants of MS (Galabruda et al., 1976; Neumannet al., 1988). The pathology showed a prominent predilec-tion for the brainstem, but also affected the forebrain.Both cases had positive CSF oligoclonal bands and ele-vated IgG synthesis.

In addition to MS variants, a distinct set of disordersexists that may occur independently but, in most cases,

ultimately is diagnosed as the first bout of MS. Thesedisorders include the monophasic syndromes of acutedisseminated encephalomyelitis (ADEM) as well as“clinically isolated syndromes” such as optic neuritis,transverse myelitis, and isolated brainstem and cerebel-lar syndromes.

ADEM is a monophasic illness often related to a pro-dromal infectious process or antecedent vaccination,explaining its alternative monikers, postinfectious orpostvaccinal encephalomyelitis. The hyperacute form isan acute hemorrhagic leukoencephalitis, also known asHurst’s syndrome. While several features are more sug-gestive ofADEMthanMS, no single feature or set of fea-tures clearly distinguishes ADEM from the first attack ofMS (Schwarz et al., 2001). The importance of encephalop-athy has been emphasized, particularly in the case of pedi-atric ADEM (Krupp et al., 2007). Although usuallypresent in adult ADEM as well, some cases do appearto lack this finding. ADEM is usually multifocal, involv-ing various parts of the CNS, and usually evolves overdays to weeks, but sometimes for as long as 3 months(Palace, 2011). The MRI most typically involves white-matter lesions (Fig. 14.4), butmay commonly involve deepgray structures as well. Lesions variably enhance withgadolinium administration, but enhancement is notrequired for the diagnosis. Simultaneous enhancementof all, or nearly all, lesions is particularly suggestive ofthe diagnosis. On the other hand, evidence of remotelesionsmay cast doubt on the diagnosis if there is no otherexplanation for them than remote demyelinating disease.

Considerable advances in our understanding of neu-romyelitis optica (NMO), also known as Devic’s syn-drome, have been made in recent years since thediscovery of the NMO-Ig antibody, now identified asdirected against aquaporin-4, the main water channelin the brain (Lennon et al., 2005; Morrow andWingerchuk, 2012; Sahraian and Radue, 2013).

Fig. 14.3. Tumefactive multiple sclerosis.


Nonetheless, NMO manifests considerable variation inits spectrum of disease presentation and its natural his-tory. While some skeptics remain, most now considerNMO as clearly distinct from MS, although clinicaland MRI overlap can occur, sometimes rendering pre-cise diagnosis difficult, particularly in cases that areseronegative for the antiaquaporin-4 antibody. Whileclassically regarded as an acute monophasic illness ofsevere transverse myelitis and temporally associatedbilateral optic neuritis, it now appears that there is a wid-ening spectrum of presentations, including relapsingforms with longer interattack intervals and diseaseinvolvement beyond the optic nerves and spinal cord(Wingerchuk et al., 1999). UnlikeMS, classic NMO caseswere restricted to disease of the optic nerves and spinalcord and should have brain MRIs that are normal or atleast do not satisfy the criteria for MS (Fig. 14.5). Arecent retrospective case series of 60 patients from theMayo Clinic, however, describes an array of brain find-ings (Pittock et al., 2006). In addition, NMOpatients typ-ically have longitudinally extensive centrally locatedfusiform cord lesions, spanning greater than three seg-ments in craniocaudal length (Fig. 14.5).MS cord lesions,on the other hand, are shorter, generally not extendingmore than one to two levels, and are posteriorly located.Testing for the presence of antiaquaporin-4 antibody hasa reported sensitivity of 73% and a specificity of 91% forNMO, and so far has been uniformly negative in typicalMS patients (Lennon et al., 2004). The presence of theantibody has led to the term “NMO spectrum disorders”

to represent seropositive cases that do not meet thecriteria for the classic syndrome. Among thoseantibody-positive disorders are isolated myelitis (gener-ally with a longitudinally extensive lesion) or recurrentmyelitis alone, recurrent optic neuritis alone, intractablehiccups or nausea and vomiting, and posterior revers-ible leukoencephalopathy syndrome (Morrow andWingerchuk, 2012; Sahraian and Radue, 2013).

The Mayo Clinic’s revision of diagnostic criteriafor NMO incorporating broadened CNS involvement andNMO-IgG seropositivity is summarized in Table 14.10(Wingerchuk et al., 2006; Morrow andWingerchuk, 2012).

Although it was initially unclear whether the antibodyto aquaporin-4 was pathogenetic or simply an epiphe-nomenon, increasing evidence favors a causative role(Papadopoulos and Verkman, 2012). DistinguishingNMO from classic MS may have importanttherapeutic consequences. For example, a good responseto total plasma exchange (Lucchinetti et al., 2002;Wingerchuk, 2006) is often seen in the treatment ofacute attacks. In addition, results of an open-label studyof rituximab, amonoclonal antibody directed against theCD20 B-cell antigen, demonstrated promising results indecreasing attack rates and improving neurologic func-tion (Cree et al., 2005; Jacob et al., 2008).

DIFFERENTIAL DIAGNOSIS

The differential diagnosis ofMS is extensive and includesinfectious, inflammatory, toxic-metabolic, genetic,

Fig. 14.4. Acute disseminated encephalomelitis (ADEM): a 20-year-old male presenting with unsteady gait and left

lower-extremity numbness. Magnetic resonance imaging of the brain and spine imaging demonstrated multifocal white-matter

hyperintensities, the majority with associated enhancement.


neoplastic, neurodegenerative, and vascular etiologies.While several of these disease processes share commonclinical and paraclinical features with MS, unique differ-ences may facilitate narrowing the diagnostic possibilities(Miller et al., 2008). In the absence of stigmata reflectingother disorders, it is arguable whether any laboratoryinvestigations are warranted in patients presenting withtypical characteristics of MS. That being said, the cer-tainty of diagnosis is critical, and patients are often reas-sured by an extensive evaluation ruling out alternativediagnoses (Murray and Murray, 1984). We will limit thediscussion to the most common alternative etiologiesand some key distinguishing features that can help tailorthe diagnostic investigation in a reasonable manner.

Because infectiousmimickersofMSareoften treatableentities, exclusion at the outset of presentation is crucial.Common infections that can masquerade as MS includeLyme disease, human T-cell lymphotrophic virus (HTLV),herpesviruses such as zoster, syphilis, human immunodefi-ciency virus (HIV), progressive multifocal leukoencepha-lopathy (PML), and, rarely, Whipple’s disease.

Lyme disease often presents a particularly frustratingscenario for MS clinicians, as many patients are eitherconvinced or hoping that there is a chance they haveLyme and not MS. The neurologic manifestations ofneuroborreliosis continue to be a source of diagnosticcontroversy, especially in geographic areas of theUnited States where Lyme is endemic: New England,Mid-Atlantic, East-North Central, South Atlantic, andWest North-Central regions. Lyme disease resultsfrom infection by the spirochete Borrelia burgdorferi,whose common vector is the Ixodes tick. Like MS,

Lyme can affect the nervous system with extremeclinical variability and can easily be confused withother infectious and inflammatory conditions, particu-larly if there is no evidence of prior exposure. Asepticmeningitis, encephalomyelitis, cranial neuropathies, typ-ically unilateral or bilateral peripheral facial paresis, aswell as radiculoneuritis and peripheral neuropathy, areseen (Halperin et al., 1989; Pachner et al., 1989). Lesscommonly, optic neuritis and an inflammatory demye-linating polyneuropathy are seen. Neuroborreliosis-associated encephalomyelitis can resemble MS clinicallyand radiographically, demonstrating similar T2/FLAIRwhite-matter hyperintense lesions of the brain and spinalcordonMRI(Halperin, 2008).CSFanalysis oftendisclosesamoderatelyelevatedlymphocyticpleocytosis, atypical forMS with cell counts above 50/mL, and elevated protein.Intrathecal production of antibodies to Borrelia shouldbe present with increased IgG synthesis, and the presenceof oligoclonal bands (Coyle et al., 1993; Coyle, 2002). Ofnote, CSF Lyme polymerase chain reaction (PCR) carriesa lowsensitivity because of the small number of organismspresent in spinal fluid (Rupprecht et al., 2008).

In general, a history of, or presence of, systemic mani-festations of Lyme can help clinicians refine their diagnos-tic suspicions; for example, the classic antecedenterythema chronicum migrans rash, as well as arthritides,and cardiac involvement, including myocarditis, dysrhyth-mias and conduction block. In patients with intrathecalserologic evidence of Lyme disease, a course of high-doseparenteral antibiotic therapy iswarranted. In caseswhere itremains uncertain whether CNS disease is secondary toLyme orMS, patients may receive a course of intravenous

Fig. 14.5. Neuromyelitis optica: a 19-year-old female with recurrent bouts of optic neuritides since age 15 and one episode of

cervical myelitis. Magnetic resonance imaging of thebrain has been consistently normal. Cerebrospinal fluid studies demonstrated

absence of oligoclonal banding. Neuromyelitis optica immunoglobulin G antibody was positive.


antibiotics initially and thereafter, if clinical or radio-graphic activity occurs, ultimately be diagnosed with MS.

HTLV-1 infection causes a characteristic chronic, pro-gressive myelopathy (typically thoracic with motor pre-dominance), referred to as either HTLV-1-associatedmyelopathy (HAM) or tropical spastic paraparesis (TSP)(Sheremata et al., 1992; Vernant et al., 1987). The disorderis endemic to the Caribbean, South America, Africa, andJapan, equatorial regions where MS is rare. It shouldalways be considered in the differential of MS myelopa-thy, especially the primary progressive pattern (Poseret al., 1990). Themajority of patients presentwith an insid-ious progression of lower-extremity weakness, spasticity,pain, and sphincteric dysfunction. Evaluation of patientspresenting with a progressive spastic paraparesis shouldinclude a thorough history of travel, country of origin,and any history of exposure to blood-borne viruses, suchas transfusions. Thoracic spine MRI can demonstrateatrophyandwhite-matter lesions sometimeswith enhance-ment, and brain MRI, while often normal, can also dem-onstrate white-matter lesions (Gessain and Mahieux,2012). CSF may have oligoclonal bands, but frequently,serologic abnormalities in serum and CSF clarify the diag-nosis (Grimaldi et al., 1988; Takenouchi et al., 2004).

Viral myelitides can often present with inflammatoryintramedullary lesions on spinal MRI suggestive of demy-elinating disease. The Herpesviridae family, includingEpstein–Barr virus, cytomegalovirus, herpes simplex 1and2, andvaricella-zoster, is a commoncauseof transversemyelitis. Varicella-zoster myelopathy, in particular, can beeither progressive or relapsing, and potentially mimic MS(Gilden et al., 1994; Gilden, 2004). In addition to spinal cordinvolvement, herpes zoster can be associated with oculardisease, encephalitis, cerebellitis, and vasculopathiesincluding cerebral angiitis, all ofwhich can clinically be con-fused with MS (Mueller et al., 2008). A monocytic menin-gitis with elevated IgG index and oligoclonal IgG bands canbe seen, which can further complicate distinction.

Syphilis, often called the great masquerader, shouldalso be considered in the differential diagnosis of possibleMS. Like Lyme, syphilis can havemultiple and varied neu-rologic presentations easily confused with other CNSinflammatory conditions. Vasculitis occurring with sero-coversion to secondary syphilis has been associated withacute unilateral vision loss, which can mimic an episodeof MS-related optic neuritis (Smith, 1973; Bandettini diPoggio et al., 2010). Tertiary syphilis can cause chronicoptic neuropathy, myelopathy (tabes dorsalis as well astransverse myelitis), and dementia (general paresis of theinsane). Meningovascular syphilis pathologically causesan obliterative endarteritic angiopathy, with clinical symp-toms and white-matter lesions similar to MS plaques(Cohen and Rensel, 2000). Antibodies to the treponemalantigen are helpful to exclude the diagnosis, as these

remain positive for lifetime in a majority of individualswith a history of prior primary infection. Serum VenerealDisease Research Laboratory (VDRL), on the other hand,often reverts to normal after primary infection and canremain so even in patients with tertiary neurosyphilis.CSF analysis should demonstrate evidence of a positiveVDRL test, and, as in Lyme disease, the presence of oligo-clonalbands,which,unlike those inMS,arereactive to trep-onemal antigens (Vartdal et al., 1982; Kayal et al., 2011).

While an acute inflammatory leukoencephalopathyresembling ADEM or MS can occur at the outset ofHIV seroconversion (Tavazzi et al., 2011), in general, theextensive neurologic manifestations of HIV, includingvacuolar myelopathy, HIV encephalopathy and dementiacomplex, andperipheralneuropathy, areusually easilydis-tinguishable from MS (Berger et al., 1992). CSF in HIVpatients often reveals a lymphocytic pleocytosis and ele-vated protein, and oligoclonal bands can be seen but areofuncertain clinical significance (Hall et al., 1992).Differ-ential diagnosis for HIV-associated opportunistic infec-tions should be strongly considered in this context.

Admittedly, HIV and MS are pathophysiologic oppo-sites. As such, the development of MS in anHIV-infected individual theoretically seemsunlikely.Nev-ertheless, the HIV/AIDs- associated PML caused byopportunistic infection with the JC virus can mimic MS(McArthur, 1987; Padgett and Walker, 1973). JC virusinfection is highly prevalent in western adults, with 60–80% demonstrating seropositivity to JC virus dependingon the assay used (Bozic et al., 2011). PML occurs exclu-sively in immunocompromised states (Brooks andWalker, 1984), which in addition to HIV can be relatedto impaired cellular immunity, lymphoid cancers, andimmunosuppressive drug therapy, such as natalizumab,one of the novel biologic agents in MS therapeutics. Amonoclonal antibody toalpha-4-integrin, anadhesionmol-ecule on the surface of lymphocytes which permits trans-fer across the blood–brain barrier into the CNS (Rudicket al., 2006), natalizumab carries the risk of causingPML in patients treated with the drug (Kleinschmidt-DeMasters and Kyler, 2005; Langer-Gould et al., 2005;Van Assche et al., 2005). Risk of infection increasessignificantly if patients screen positive for the JCV anti-body,havebeenontherapyforover24months,and/orhavea history of prior immunosuppression. PML causes aninsidious constellation of symptoms, some of which canoverlap with MS, including progressive motor and visualdisturbances (e.g., field defects and cortical blindness),ataxia, and neuropsychiatric symptoms such as behavioraldisinhibition and cognitive impairment. Most symptomsreflect PML’s anatomic predilection for the frontal andparieto-occipital regions; however, diffuse periventricularand callosal white-matter disease also occurs, occasionallywith enhancement, making distinction from MS difficult


(Whiteman et al., 1993). A high index of suspicion forPML needs to be maintained in natalizumab-treated MSpatients who present with progressive clinical and radio-graphic disease. Apart from the presence of positivePCR for JC virus DNA, the CSF profile is usually normal.

A rare infection by the bacterium Tropheryma whip-plei can also on occasion clinically mimic MS. CNSWhipple’s disease can produce a myriad of neurologicsymptoms, ranging from a subacute dementing illness,brainstem symptoms, including ophthalmoplegia, andthe virtually pathognomonic movement disorder of ocu-lomasticatory myoclonus. Myelitides have also beenreported. The presence of systemic symptoms, such asdiarrhea and weight loss, along with migratory polyar-thropathies, can help divert clinical suspicions to thisalternative, and often difficult-to-make, diagnosis; how-ever, isolated CNS Whipple’s has been described(Mohamed et al., 2011). MRI of the brain findings canbe distinguished from MS by the presence of infarctsand meningeal enhancement, but posterior fossa T2hyperintensities can easily resemble MS plaques(D€onmez et al., 2010). While serum and CSF PCR forT. whipplei are both sensitive and specific, they can benegative and in the appropriate clinical context a brainbiopsy may be necessary (Mohamed et al., 2011). Whengastrointestional symptoms are present, enteroscopywith small-bowel biopsy may reveal evidence of periodicacid–Schiff-positive bacterial polysaccharides.

A vast array of inflammatory conditions secondary tocollagen vascular diseases can demonstrate considerableclinical overlap with MS. These range from rheumato-logic disorders such as SLE, Sj€ogren’s syndrome, vascu-litides such as Wegener’s granulomatosis and isolatedangiitis of the CNS, to antiphospholipid antibody syn-drome, Behcet’s disease, and granulomatous disorders,such as neurosarcoidosis.

Neuropsychiatric SLE can present with multifocalinflammatory syndromesofboth thecentral andperipheralnervous systems. These include aseptic meningitis, lupuscerebritis, seizures, myelitis, cranial neuropathies, periph-eral neuropathy and myositis, among others. In contrasttoMS,neurologic presentationsgenerally occur in the con-text of concomitantmultisystemicorgan involvement suchas nephropathy, arthropathy, serositides, blood dyscrasias,and characteristic skin lesions, such as the malar butterflyrash or discoid lesions (Muscal and Brey, 2010). Whileabnormal serologies suchas apositive antinuclear antibody(ANA) or double-stranded DNA antibody are compelling,a low-level ANA titer is a typical finding in MS patientsbecause of hyperimmune states. In the absence of addi-tional systemic stigmata (Dore-Duffy et al., 1982), this isunlikely to be of clinical significance. Of note, unlikeMS, MRI lesions in SLE tend to be more non-specific inmorphology, suggestive of vascular disease involving the

subcortical white matter rather than the characteristic peri-ventricular and pericallosal areas seen in MS (Luyendijket al., 2011). Furthermore, SLE patients can also presentwith longitudinally extensive myelitides that share closerclinical andmorphologic resemblance to, and overlapwith,NMO (Zavada et al., 2013).

Sj€ogren’s syndrome is an autoimmune disorder present-ingwiththesiccacomplexofxerophthalmiaandxerostomiawith lacrimal and salivary gland involvement. In addition,keratoconjunctivitis and rheumatologic symptoms canoccur.Neurologic involvement is generallymultifocal,withperipheral nervous system manifestations being the mostcommon. These include sensory neuronopathy, dysautono-mias, mononeuritis multiplex, and painful small-fiber sen-sory neuropathy (Alexander et al., 1982; Birnbaum, 2010).CNS involvement can mimic MS with clinical syndromesranging from optic neuropathy, TGN, aseptic meningitis,vasculitis, and transverse myelitis (Alexander et al., 1986;Chai and Logigian, 2010). Elevated anti-Ro (SS-A) andanti-La (SS-B) antibodies are present in approximately60% of patients; however, their presence is not specificfor Sj€ogren’s. AlthoughMRI of the brain can demonstratewhite-matter lesions similar in appearance toMS, again, asin lupus, these tend to be non-specific in location and mor-phology (Alexander et al., 1988). Salivary biopsy can beuse-ful in demonstrating the typical inflammatory lesions.

Neurosarcoidosis canmasqueradeasMS,butgenerallypatients have a history of systemic disease such as pulmo-nary and dermatologic findings (Nozaki and Judson,2013). CNS involvement occurs in approximately 5% ofcases of sarcoidosis (Gasperini, 2001), but only rarely asthe sole manifestation. Neurologic symptoms can includeheadaches, seizures, hydrocephalus, polycranial neuritis,and uveitis, as well as optic neuritis and myelitis resem-bling MS. The characteristic leptomeningeal involvementof neurosarcoidosis, however, is an important distinguish-ing feature. Furthermore, granulomatous disease has adistinct predilection for the hypothalamic–pituitary axisproducing endocrinopathies, such as diabetes insipidus,amenorrhea, as well as hyperphagia and temperaturedysregulation. Computed tomography scan of the chestlooking for hilar adenopathy, as well as gallium andwhole-body positron emission tomography scanning,can be extremely helpful in isolating extraneuralsites to biopsy for a definitive tissue diagnosis. Serumangiotensin-converting enzyme (ACE) levels can be ele-vated but are often non-specific and have been found tobe elevated in MS patients with no history of sarcoidosis(Constantinescu et al., 1997). CSF ACE levels can beabnormal in approximately 30–55% of patients withneurosarcoidosis, but are also non-specific and canappear in many other infectious, inflammatory, and neo-plastic conditions (Perinietal., 2001).Frequently, neuroim-aging (Fig. 14.6) demonstrates persistently enhancing


parenchymal brain or cord lesions as well as leptomenin-geal enhancement, all radiographically atypical for MS(Lexa and Grossman, 1994; McLean et al., 1995; Nozakiand Judson, 2013). CSF findings can overlap with thoseofMS, butmore classically demonstrate amarked pleocy-tosis, elevatedprotein, and lowglucose.Oligoclonal bandsaswellaselevatedIgGsynthesiscanbe seen (Boruckietal.,1989; Joseph and Scolding, 2009).

Behcet’s syndrome is a chronic inflammatory disor-der involving orogenital mucocutaneous ulcerations,uveitis, and skin lesions ranging from erythema nodo-sum to folliculitis and acneiform lesions. Diagnosisrequires recurrent oral ulcerations and two of the follow-ing: recurrent genital ulcers, uveitis or retinal vasculitis,and a positive pathergy skin test. The latter involves ahyperirritability reaction of the skin to needle puncture,producing a characteristic pustular papule within 48hours. Behcet’s most commonly affects individualsfrom the geographic region of the silk route from theMediterranean to Japan. HLA-B51 is strongly associatedwith the disease in high-prevalence areas (Siva andSaip, 2009). Neuro-Behcet’s, which has been reportedin 5% of patients meeting diagnostic criteria forBehcet’s, can clinically and radiographically mimicMS, particularly in the absence of systemic stigmata(Ashjazadeh et al., 2003). A subacute brainstem menin-goencephalitis is the most common presentation,reported in 50% of patients, but headaches, intracranialhypertension, encephalopathy, ischemic strokes, venoussinus thromboses, seizures, and cranial neuropathieshave been reported (Ashjazadeh et al., 2003). MRI gen-erally reveals large multifocal enhancing brainstemlesions (Siva et al., 2004). Brainstem lesions typicallyextend to the basal ganglia and diencephalon, which isatypical forMS, and themore typical demyelinating per-ventricular and callosal lesions are uncommon (Siva and

Saip, 2009). CSF more often demonstrates a pleocytosisand, rarely, oligoclonal bands (Serdaroglu, 1998).

Wegener’s granulomatosis is a small tomediumnecro-tizing vasculitis, whose clinical triad additionally involvesrenal and upper and lower respiratory tract disease. Neu-rologic involvement is reportedly seen in 50% of cases,most commonly affecting the peripheral nervous systemwithmononeuritismultiplex and neuropathy.CNSdiseaseis rare, typically secondary to, but can involvemultiple cra-nial neuropathies secondary to granulomatous lesions ofthe sinuses and pharynx (Gasperini, 2001). Optic neuropa-thy and a hypertrophic pachymeningitis have also beendescribed (Sakurazawa et al., 2007). Multiple cranial neu-ropathies, including optic neuropathy, can raise concernforMS, butMRI findings are generally not characteristicofMS,demonstratingdural thickeningwithenhancement,infarcts, and non-specific supra- and infratentoriallesions, typically from intracranial spreadoforbital, nasal,and paranasal disease (Murphy et al., 1999).

Certain toxic andmetabolic diseases, includingvitamindeficiency states, nutritional disorders, genetic diseases,as well as the side-effects to various medications and sub-stances, can resemble MS. Vitamin B12 deficiency, mostcommonly secondary to an autoimmune injury to gastricparietal cells, can result in a myeloneuropathy, preferen-tially involving the cervical posterior columns and lateralcorticospinal tracts (subacute combined degeneration),and a peripheral neuropathy. Cognitive dysfunction andoptic neuropathy can also occur. Spinal MRI can demon-strate white-matter lesionsmimickingMSwithmultifocalinvolvement of the lateral motor tracts and posterior col-umns (Fig. 14.7). White-matter lesions of the brain, typicalin location and morphology for MS, have also beendescribed (Chatterjee et al., 1996). As a treatable andreversible condition, B12 deficiency should always be con-sidered in the differential diagnosis of patients with

Fig. 14.6. Neurosarcoidosis: a 40-year-old female with sarcoidosis presenting with bilateral visual loss and hyperphagia. Mag-

netic resonance imaging of the brain revealed extensive enhancing white-matter lesions involving the orbitofrontal white matter,

bilateral optic nerves, and chiasm, as well as the pons. Brain biopsy demonstrated non-caseating granulomaswith negative staining

for tuberculosis, consistent with neurosarcoidosis.


suspected MS. Importantly, low normal serum levelsbetween 200 ng/L and 400 ng/L can still reflect true defi-ciency states, and additional metabolic markers such asmethylmalonic acid levels should be obtained for cer-tainty. Vitamin B12 deficiency can itself be mimicked clin-ically by nitrous oxide intoxication, which irreversiblyinactivates the cofactor for methionine synthase, methyl-cobalamin, resulting in a secondary B12 deficiency(Layzer, 1978). Clinically, a progressive myeloneuropathywith subacute combined degeneration can occur, butacute myelitis-like presentations have also been described(Ghobrial et al., 2012; Cheng et al., 2013). Disclosure ofrecreational abuse and recurrent exposure with dentalprocedures are important historic red flags that shouldraise suspicion. Similarly, copper deficiency (Kumaret al., 2004), usually accompanied by elevated zinc levelswhich can occur secondary to overingestion of denturecreams (Hedera et al., 2003), can also produce a sensoryataxic myelopathy, similar to B12 deficiency, and likewisebe mistaken for progressive MS. MRI of the spinal cordcan be normal but may also demonstrate posterior-cordintramedullary white-matter lesions suggestive of MS,and brainstem involvement has also been reported(Kumar et al., 2011).

Celiac disease or gluten enteropathy can clinically andradiographically resembleMS.A gastrointestional disor-der caused by dietary exposure to gluten or gluten break-down products, celiac disease can manifest withneurologic dysfunction in approximately 10% ofpatients (Ghezzi and Zaffaroni, 2001). Common clinicalfindings include cerebellar ataxia, also known as gluten

ataxia, as well as brainstem syndromes, seizures, andperipheral neuropathy (Ghezzi and Zaffaroni, 2001).MRI can demonstrate evidence of cerebellar atrophybut also may reveal white-matter lesions involving theposterior fossa that can mimic MS lesions (Ghezzi andZaffaroni, 2001). CSF oligoclonal bands have also beenreported (Ghezzi and Zaffaroni, 2001). Systemicsymptoms, such as weight loss, crampy abdominal pain,bloating, diarrhea, and steatorrhea, are often present.Laboratory abnormalities often reveal an iron-deficiency anemia and the presence of antigliadin andantiendomysial antibodies, the latter being more specificfor intestinal mucosal damage, but less so for neurologicinvolvement (Hadjivassilious et al., 1998). Small-bowelenteroscopy classically demonstrates flattened atrophicvilli. Unfortunately, clinical response of neurologicsymptoms to gluten restriction has been disappointing(Hadjivassilious et al., 1998).

Additional toxic insults that can produce a leukoence-phalopathy with lesions resembling demyelinating diseaseinclude illicit substances such as cocaine and opiates pro-ducing the radiographic “chasing the dragon” appearance(Lyoo et al., 2004). Tumor necrosis factor-a blockers usedin the treatment of rheumatologic conditions such as pso-riasis and inflammatory bowel disease (Thomas et al.,2004; Enayati and Papadakis, 2005) have also produceddemyelinating syndromes with abnormal white-matterlesions. Cyclosporine (Munoz et al., 2006) and intrathecalmethotrexate (Ziereisen et al., 2006) have also been asso-ciated with an acute toxic leukoencephalopathy, generallyreversible. In addition to pharmacologic effects, meta-bolic derangement of electrolytes, as seen in centralpontine myelinolysis, can also result in symptoms andwhite-matter lesions similar to those seen in MS.

Hereditary ataxias and spastic paraparesis can alsomimic symptoms of progressive MS. Hereditary spasticparaplegias comprise a genetically and clinically hetero-geneous group of disorders which, in the purest form,can present with a progressive spastic lower-extremityweakness mimicking PPMS. The most common modeof inheritance is autosomal dominant; however, reces-sive and sex-linked forms occur (Rowland, 2005). Com-plicated forms can also include optic neuropathy,hearing loss, ataxia, and peripheral neuropathy, andunlike MS can be associated with an autoimmune hemo-lytic anemia and thrombocytopenia, as well as ichthyosis.The presence of a positive family history and absence ofalternative possible diagnoses is paramount to facilitat-ing diagnosis. MRIs do not typically demonstrate abnor-mal white-matter lesions, but rather spinal cord andoccasionally corpus callosal atrophy. Both inheritedataxias and spastic paraparesis involve a vastly heteroge-neous spectrum of diseases, too broad in scope for thepurposes of this discussion.

Fig. 14.7. Vitamin B12 deficiency. A 37-year-old womenwith

distal-limb paresthesias and lower-extremity weakness.

Examination demonstrated involvement of the corticospinal

tracts and posterior columns. Brain magnetic resonance imag-

ing was normal. Thoracic spine imaging revealed diffuse pat-

chy abnormal signal throughout the cord, better visualized on

axial imaging. No gadolinium enhancement was appreciated.

Vitamin B12 level was 136 ng/L. Methylmalonic acid level

was significantly elevated.


Additional genetic diseases that can mimic MSinclude dysmyelinating disorders, which producewhite-matter lesions resulting from the abnormal forma-tion or maintenance of myelin usually secondary to aninherited enzymatic defect. These include lysosomalstorage diseases such as metachromatic leukodystrophy(MLD), Fabry’s disease and leukodystrophies such asALD, and Krabbe’s disease. Radiographically, in con-trast to MS, these disorders produce a more impressive,confluent, symmetrical T2 burden of disease.

MLD is an autosomal-recessive disorder resultingfrom a defect in the lysosomal enzyme arylsulfatase A,also called cerebroside sulfate sulfatase. It can presentat any age with infantile and adult forms. Typical clinicalfeatures include optic atrophy, weakness, spasticity, nys-tagmus, and cognitive decline with prominent psychiatricmanifestations.An important distinguishing feature fromMS is involvement of the peripheral nervous system in theform of a neuropathy, which can be demonstrated in theneurophysiology laboratory by delayed nerve conductionvelocities. Brain MRI characteristically reveals more dif-fuse, confluent, symmetrical white-matter changes com-pared to those seen in MS. Serum arylsulfatase A level isusually significantly low, except in early-onset forms sec-ondary to a deficiency in sphingolipid activator protein B,the protein activator of arylsulfatase A (Baumann andTurpin, 2000). Accumulation of sulfatides due to enzymedeficiency can produce sulfatiduria, another means ofidentification (Whitfield et al., 2001).

Fabry’s disease is an X-linked recessive disorderresulting from defective lysosomal alpha-galactosidaseactivity resulting in deposition of glycosphingolipids inthe skin, cornea, and small vessels of the kidney, heart,and central and peripheral nervous systems (Callegaroand Kaimen-Maciel, 2006). Affected males usually

present before adolescence with recurrent ischemicstrokes secondary to multifocal small-vessel occlusivedisease. Such episodes can clinically mimic MS attacks.In addition, systemic manifestations include cornealatrophy, skin lesions called angiokeratomas of the groinand buttocks, cardiac and renal failure, as well as painfulacroparesthesias and dysautonomia (Callegaro andKaimen-Maciel, 2006). MRI findings (Fig. 14.8) gener-ally demonstrate deep periventricular and posterior pre-dominant white-matter lesions (Mitsias and Levine,1996). Diagnosis can be confirmed by demonstrationof a very low alpha-galactosidase level.

ALD is an X-linked peroxisomal disorder character-ized by accumulation of very-long-chain fatty acids inblood and tissues, as well as CNS demyelination andadrenal dysfunction (Baumann and Turpin, 2000). Theclassic juvenile presentation is severe; however, inadults, the most common form presents as a slowly pro-gressive spastic paraparesis in the third decade with sen-sory abnormalities and urinary dysfunction, and usuallyinvolves adrenal insufficiency (Zwesloot et al., 1992;Baumann and Turpin, 2000). Brain MRI can demon-strate mild white-matter abnormalities as well as diffusecerebral demyelination with a parieto-occiptal predomi-nance (Fig. 14.9). MRI of the spine is generally normal.Female heterozygotes can present with a similar clinicalpicture and, consequently are frequently diagnosed asMS (Dooley andWright, 1985). A detailed family historyshould be elicited and diagnosis can be made with mea-surement of very-long-chain fatty acids in serum or cul-tured fibroblasts.

Krabbe’s disease is an autosomal-recessive disorderdue to deficiency of galactocerebrosidase activity.Common clinical manifestations range from weakness,tremor, ataxia, and nystagmus to cognitive decline and

Fig. 14.8. Fabry’s: a 65-year-old female with history of acroparesthetic pain for 10 years, diagnosed with multiple sclerosis and

later found to be a Fabry’s carrier after her sonwas diagnosed, having presented with similar symptoms.Magnetic resonance imag-

ing reveals diffuse periventricular white-matter lesions with slight posterior predominance.


peripheral neuropathy. In general, it occurs early in child-hood, but can manifest in adolescents and adults with aspastic paraplegia (Baumann and Turpin, 2000). MRIalso typically reveals diffuse, symmetric, periventricularwhite-matter lesions with a posterior predominance.

Mitochondrial diseases are multisystemic hereditarydisorders that produce a variety of clinically heteroge-neous syndromes, at times overlapping with typicalMS. Mitochondrial encephalopathy with lactic acidosisand stroke-like syndromes (MELAS) and mitochondrialencephalopathy with epilepsy and red ragged fibers(MERRF) result from genetic defects disruptingoxidative metabolic pathways. Red flags includerecurrent encephalopathy, sensorineural hearing loss,myoclonus, cyclic nausea and vomiting, pigmentary ret-inopathy, external ophthalmoplegia, endocrinopathies,seizures, and stroke-like episodes. In addition, physicalexamination can reveal short stature, endocrinopathies,optic atrophy, cardiac disease, andmyopathy (Fig. 14.10).MRI can demonstrate white-matter disease, often withposterior fossa lesions, but also often gray-matterinvolvement atypical for MS.Most patients have a lacticacidosis with elevation in both serum and CSF lactate/pyruvate ratios and genetic testing for mutations inmitochondrial DNA can confirm the diagnosis. Themostcommon mitochondrial disorder mistaken for MS isLeber’s hereditary optic neuropathy (LHON), whichcauses an acute or subacute bilateral optic neuropathyin early adult life. Optic atrophy can be accompaniedby spastic paraparesis and ataxia (Gasperini, 2001). Incontrast to MS, however, LHON demonstrates

hyperemic changes on fundoscopic examination. Youngmen are affected much more frequently than women.

A rare, predominantly upper motor neuron variant ofmotor neuron disease, primary lateral sclerosis, can alsopresent with a slowly evolving progressive spastic para-paresis, which is commonlymistaken forMS. Eventuallythe symptoms progress to involve the upper extremitiesas well as pseudobulbar dysfunction. Unlike MS, how-ever, sensory symptoms should be absent. Eventual devel-opment of fasciculations suggesting lower motor nerveinvolvement can occur, and electromyography may sup-port conversion to amyotrophic lateral sclerosis. MRIusually does not demonstrate demyelinating plaques,although symmetric T2 hyperintensities can be seen inthe bilateral corticospinal tracts and mistaken for MSlesions. CSF should be normal without the presence of oli-goclonal bands. Importantly, the diagnosis of primary lat-eral sclerosis is essentially one of exclusion, oftenrevealedwith passage of time in the absence of alternativeetiologies for a progressive spastic myelopathy.

Neoplastic processes, most commonly CNS lym-phoma, can also masquerade as MS, particularly becauseMS may present with large tumefactive ring-enhancinglesions that respond clinically and radiographically totreatment with steroids. The distinction generally requirestissue biopsy or the demonstration of abnormalCSF cytol-ogy and flow cytometry. Relapsing-remitting brainstemsyndromes have been described with gliomas and lym-phoma (Gasperini, 2001). MRI findings in CNS lym-phoma are varied but, in contrast to MS, candemonstrate dural, leptomeningeal, and gray-matter

Fig. 14.9. Adrenoleukodystrophy.


involvement, diffusion restriction, aswell as periventricu-lar lesions with diffuse subependymal persistentlygadolinium-enhancing lesions (Cohen and Rensel, 2000;Haldorsen et al., 2011).

Vascular conditions, such as small-vessel occlusivedisease, vasculitides such as primary CNS angiitis, andthe hereditary disorder cerebral autosomal-dominantarteriopathy with subcortical infarcts and leukoencepha-lopathy (CADASIL), should be considered as well in thedifferential of possible MS. CADASIL usually presentsbetween the ages of 30 and 50 years, typically withmigraine headaches, cognitive impairment, and recur-rent stroke-like episodes involving the subcortical whitematter. A positive family history for headaches or earlystroke and dementia raises suspicion. MRI typicallydemonstrates bilateral subcortical white-matter plaques(Fig. 14.11) with a penchant for the anterior temporal

lobes and external capsule (O’Riordan et al., 2002).Diagnosis is made using genetic analysis for mutationin the notch-3 gene and/or demonstration of the charac-teristic small-vessel microangiopathy on skin biopsy. Thelatter reveals pathognomonic deposition of granular,osmiophilic, electron-dense materal in the tunica mediacausing destruction of the vascular smooth vessel andwall thickening (Viitanen and Kalimo, 2000).

Antiphospholipid antibody syndrome (APS) is anothervascular disease entity that can overlap clinically and radio-graphically with MS and may create diagnostic confusion.APS classically presents with a history of recurrent throm-boses, either venousorarterial, alongwithahistoryofpreg-nancymorbidity. A history of deep venous thrombosis andrecurrent miscarriage, the latter generally beyond the firsttrimester, should raise suspicion. Additional clinical fea-tures atypical for MS but suggestive of APS include

Fig. 14.11. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Fig. 14.10. Mitochondrial encephalopathy with lactic acidosis and stroke-like syndromes: a 40-year-old female with short stature,

diabetesmellitus type 1, premorbid psychiatric history presentingwith cortical blindness, cortical deafness, fluctuating, alternating

hemipareses, and seizures. Serum lactate and pyruvate were elevated. Magnetic resonance imaging of the brain (diffusion-

weighted and FLAIR sequences, seen below) demonstrated bilateral parieto-occipital infarcts, which did not respect vascular ter-

ritories. Mitochondrial DNA analysis was positive for mutation.


transient stroke-like episodes, migraine headaches, sei-zures, mood disorders, Raynaud’s phenomenon, thrombo-cytopenia, and livedo reticularis (Ferreira et al., 2005).Nevertheless, optic neuritis and transverse myelitis havebeen increasingly reported in APS patients (Ferreira et al.,2005). Moreover, both entities can demonstrate abnormalwhite-matter lesions on MRI; however, APS lesions tendtobe locatedsubcorticallyanddonotdemonstrateenhance-ment (Chapman, 2004), andCSFoligoclonal bands are usu-ally not found in primary APS (Cuadrado et al., 2000).Moreover, while antiphospholipid antibodies have beenreported with variable frequency inMS patients – between2 and 44% (Ferreira et al., 2005) – they do not seem torequire serum factors to bind phospholipids and none ofthe MS patients had antibodies to B2-glycoprotein-1, theprincipal autoantigen inAPS (Chapman, 2004). Differenti-ating these two diseases has important therapeutic implica-tionsasAPSgenerally requiresantiplateletoranticoagulanttherapy, whereas the beta-interferons used to treat MStheoretically might exacerbate APS.

Another rare immune-mediated vascular disorder,which is often misdiagnosed as MS by MRI, isSusac’s syndrome, also known as retinocochleocerebralvasculopathy. Initially described in 1979 by Dr. JohnSusac, the syndrome involves an immune-mediatedsmall-vessel vasculitis, which causes microinfarcts ofthe retina, brain, and cochlea. It typically affects youngwomen aged 20–40 years old, but has been reported inmale patients as well. The classic clinical triad includesbilateral hearing loss and tinnitus, vision loss, headaches,and encephalopathy; however, initial presentationsmay involve only part of the triad. Referral should bemade to ophthalmology to evaluate for the pathogno-monic branched retinal artery occlusions (Menachemand Eliashar, 2005). Audiometry typically reveals a

low-frequency hearing loss. MRI of the brain can dem-onstrate multifocal supra- and infratentorial T2/FLAIRhyperintense white-matter lesions (Fig. 14.12), creating apitfall for misdiagnosis of MS. In contrast to MS, Sus-ac’s involves central callosal lesions, referred to as“snowballs” acutely but with a chronic punched-outappearance, whereas MS lesions more often involvethe undersurface of the callosum. Deep gray matter,basal ganglia involvement, and leptomeningeal enhance-ment are also seen. CSF will usually demonstrate a pleo-cytosis with elevated protein and negative oligoclonalbands. The clinical course is generally self-limited, last-ing for a few years, but relapses, mimicking MS flares,have been described.

Structural disease of the spine secondary to degener-ative disc disease or vascular malformations can also bemistaken for MS. Both cervical spondylosis and traumacan produce T2 hyperintense cord lesions with a typicalappearance of MS.

Cervical spondylitic myelopathy secondary to degen-erative disc disease can mimic MS by presenting withpolyradiculopathic weakness and sensory symptoms inthe upper extremities, along with a spastic hyperreflexicparaparesis in the legs. Symptoms suggestive of cervicalspondylosis include radicular neck pain, paraspinal ten-derness, and spasm. Intramedullary lesions at the levelof the herniating disc usually reflect either acute cordcompression or chronic myelomalacia, but can some-times be mistaken for demyelinating plaques.

Vascular malformations of the spinal cord, such asdural arteriovenous fistulas and true arteriovenous mal-formations, can also be mistaken for MS, commonlypresenting with an acute or progressive, relapsing tho-racic myelopathy (Cohen and Rensel, 2000). MRIs ofthe spinal cord can demonstrate patchy abnormal T2

Fig. 14.12. Susac’s syndrome. A 29-year-old female presenting with headache, confusion, blurry vision, and hearing loss.


hyperintensities with occasional enhancement and suspi-cious flow voids. Diagnostic distinction usually requiresselective segmental spinal angiography.

CONCLUSION

While the differential diagnosis of MS can beextremely challenging to clinicians, a detailed history,neurologic examination, and careful review of imagingand laboratory studies are the most important means tonarrow diagnostic considerations and tailor an appropri-ate workup. The presence of atypical historic, clinical,and paraclinical findings should alert physicians to theprospect of an alternative diagnosis and need for furtherevaluations. At follow-up, the diagnosis of possible orprobable MS should always be rechallenged, as symp-tomatology evolves or as new paraclinical studiesbecome available. That being said, diagnostic effortsshould aim to expedite achieving therapeutic goals. Inthe case ofMS therapeutics, this translates into initiatingappropriate disease-modifying therapies as early as pos-sible, in order to prevent recurrent relapses, progression,and disability and, most importantly, preserve the neuro-logic function and quality of life of our patients.

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