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Multiple Sclerosis; Diagnosis
Multiple Sclerosis; Diagnosis RK Shin, University of Maryland School of Medicine, Baltimore, MD, USA r 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Donald W Paty, volume 3, pp 244–253, r 2003, Elsevier Inc.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (brain, brainstem, spinal cord, and the optic nerves) that primarily affects young adults. Most patients present between the ages of 15 and 50 years with a mean age of onset of approximately 30 years. MS affects females more than males at a ratio of between 2:1 and 3:1 with the age of onset being slightly younger for females than for males. The incidence of MS is greatest in people of northern European descent. There is a striking geographic variation in frequency, with higher MS prevalence rates at higher latitudes. MS typically begins with subacute episodes (also known as attacks, relapses, or exacerbations) of neurological dysfunction with spontaneous remission (Table 1). Subsequent relapses over time occur with variable frequency, and eventually patients may develop permanent neurological deficits. Over time, relapses may become less common and be replaced by a gradually progressive course. Less commonly, patients may have a gradually progressive course at onset. (See Clinical Subtypes of MS below.) An MS attack is defined to be a neurological episode lasting for a minimum of 24 h. Symptoms must be separated by at least 30 days in order to be considered separate attacks. The use of magnetic resonance imaging (MRI) has improved our ability to make a diagnosis of MS. MRI has also opened a window on the brain for understanding the evolution of the pathology over time. There remains, however, no unequivocal diagnostic laboratory test for MS, and the gold standard for the diagnosis of MS remains a clinical one, based on a carefully documented history and examination. (See Diagnosing MS below.)
Historical Description of Multiple Sclerosis Charles Prosper Ollivier d’Angers may have described a case of MS as early as 1824. His patient was a 20-year-old who initially presented with transient weakness of his right foot. Over the next decade, he developed bilateral leg weakness, bilateral hand numbness and ataxia, and urinary retention and dysarthria. Hot baths reportedly worsened his symptoms. Table 1 Symptom
Initial symptoms of multiple sclerosis Frequency (%)
Sensory symptoms (numbness and tingling) 33 Visual changes (unilateral vision loss or double vision) 23 Motor symptoms (acute or progressive) 14 Bladder symptoms o5 Cognitive changes o5 Paroxysmal symptoms (sensory or motor) o1
148
It is Jean-Martin Charcot, however, who is credited with first identifying the disease as a clinical/pathological entity in 1866. According to D.M. Bourneville, one of Charcot’s students, Charcot asked a woman with some motor problems to serve as his housemaid. He was thus able to watch her clinical deterioration for many years. When she eventually became significantly disabled, Charcot arranged for her to be admitted to the Salpeˆtrie`re, and after she died, he examined her brain and spinal cord, identifying the characteristic plaques of MS. Many of Charcot’s insights from over a century ago remained relevant to our understanding of the disease today.
Typical Clinical Presentations Sensory Symptoms Approximately 30% of MS patients initially have sensory symptoms at onset (Table 1). Sensory symptoms include numbness, tingling, loss of vision, or a combination of these. A commonly described presentation is an abnormal sensation in the distal portion of a limb that gradually spreads proximally over several days. Sometimes, the numbness may extend across the trunk to involve the opposite side. Symptoms usually reach their maximum extent in the first week. Sensory symptoms can be purely radicular and may be painful. Early sensory symptoms may not be associated with any functional abnormality of the limbs or bladder, even when clearly of spinal cord origin. The majority of such patients with acute sensory symptoms improve spontaneously, and the symptoms usually resolve completely. A classic MS symptom is Lhermitte’s phenomenon – a tingling sensation or vibration, like an electric current going down the back and legs, brought on by flexion of the neck. Though he was not the first to describe it, Jean Lhermitte published the seminal article on the phenomenon in 1924. Lhermitte’s phenomenon was first noted in patients with traumatic diseases of the cervical spinal cord; Lhermitte pointed out, however, that the symptom occurred frequently in patients with MS. An unusual sensory symptom, specific to MS, is the sensory ‘useless hand’ syndrome. A patient may develop loss of discriminatory sensations, such as vibratory sense, twopoint discrimination, and proprioception that can be so severe that the hand becomes functionally useless even though there is no actual motor involvement. The ‘useless hand’ in MS is usually unilateral but has occasionally been described as bilateral. It can be identified by noting apparent hand weakness when tested with the patient’s eyes closed that is improved when the hand is under visual control.
Encyclopedia of the Neurological Sciences, Volume 3
doi:10.1016/B978-0-12-385157-4.00602-3
Multiple Sclerosis; Diagnosis Optic Neuritis A sensory symptom that is of particular importance in the diagnosis of MS is acute loss of vision in one eye due to retrobulbar optic neuritis (ON). ON is very closely associated with MS and is the initial symptom in approximately 15% of MS patients. ON typically affects only one eye, although it can occasionally be bilateral, particularly in the pediatric population. A typical patient may report a blur or smudge in the center of the field of vision of one eye. In severe ON, visual loss can be complete. There is almost always associated pain on eye movement that can precede, accompany, or follow the visual loss; there may also be tenderness of the globe. Examination will typically show decreased vision acuity, decreased color vision, and (when unilateral) a relative afferent pupillary defect (APD). ON is associated with optic disk pallor and thinning of the retinal nerve fiber layer (RNFL) that can be detected using optical coherence tomography (OCT). OCT has also revealed asymptomatic thinning of the RNFL in patients with MS, even in clinically unaffected eyes. Most patients with ON recover functional vision within 6 months. Careful follow-up of patients with ON has shown that many will develop MS within 5 years, though the interval between an initial episode of ON and a second clinical attack of MS can be as long as 30 years.
Transverse Myelitis A combination of subacute motor and sensory symptoms referable to spinal cord demyelination is common in MS. Patients may present with a sensory level or Brown-Se´quard syndrome. Bladder symptoms may be noted. This acute transverse myelitis is usually unilateral or partial. Central or longitudinally extensive spinal cord demyelination may suggest a diagnosis other than MS, such as neuromyelitis optica (NMO).
Brainstem or Cerebellar Syndromes Occasionally, MS may present as an acute syndrome involving the brainstem or cerebellum. Symptoms of acute brainstem dysfunction may include incoordination, double vision, slurred speech, and vertigo. Demyelination of the medial longitudinal fasciculus within the brainstem results in internuclear ophthalmoplegia (INO), characterized by impairment of adduction (moving the eye medially), adduction lag, and abducting nystagmus (nystagmus of the abducting eye) in attempted horizontal gaze. An INO associated with limb or gait ataxia, particularly if the INO is bilateral, should raise the possibility of MS. Acute bilateral INO that resolves spontaneously is almost pathognomonic for MS.
Acute Hemispheric Lesions Cerebral syndromes with hemisensory loss, hemiparesis, or acute cognitive dysfunction are uncommon in MS. Rarely, MS patients may present with a large hemispheric demyelinating
149
lesion (tumefactive demyelination) that can mimic a brain tumor. An unnecessary brain biopsy can sometimes be avoided if additional lesions typical of MS are noted on MRI or if additional laboratory tests (such as cerebrospinal fluid (CSF) analysis) or visual evoked potentials (VEPs) suggest a diagnosis of MS.
Clinical Subtypes of Multiple Sclerosis Relapsing Remitting Multiple Sclerosis MS is typically characterized by recurrent episodes (‘relapses’) of neurological symptoms with complete or near complete recovery (‘remissions’) in between these episodes. Approximately 80% of MS patients initially have this ‘relapsing and remitting MS’ (RRMS) subtype. The key feature of RRMS is clinical stability between attacks, whether or not previous relapses have left behind any residual disability.
Secondary Progressive Multiple Sclerosis After years of RRMS, some MS patients begin to accumulate gradually progressive disability, typically slowly worsening gait impairment and incoordination. When a gradually progressive course follows an initially relapsing remitting course, this is referred to as ‘secondary progressive MS’ (SPMS). The key feature of SPMS is a steadily progressive decline after an initially relapsing–remitting course.
Primary Progressive Multiple Sclerosis Some MS patients never experience any clinical relapses and instead develop gradual neurological progression from the beginning. This uncommon (approximately 15% of all cases of MS) form of MS is referred to as ‘primary progressive MS’ (PPMS). The key feature of PPMS is steady progressive decline from the disease onset, in the absence of any clinical relapses.
Progressive Relapsing Multiple Sclerosis Rarely, MS patients may start out with a gradually progressive course that is subsequently punctuated by occasional clinical relapses. This only occurs in approximately 5% of cases on MS and is referred to as ‘progressive relapsing MS’ (PRMS).
Clinically Isolated Syndrome A single or first episode of central nervous system demyelination is referred to as a clinically isolated syndrome (CIS). Common forms of CIS include ON, transverse myelitis, or a brainstem syndrome (e.g., INO). When CIS presents with a normal brain MRI, the risk of developing MS subsequently is relatively low (approximately 15%). When the initial brain MRI is abnormal, however, the risk of future development of MS is high (approximately 80%).
150
Multiple Sclerosis; Diagnosis
Diagnosing Multiple Sclerosis Despite many advances in MRI technique and the availability of new serum and CSF studies, MS remains a clinical diagnosis, made primarily based on history and examination. Fundamentally, MS is diagnosed by documenting both ‘dissemination in space’ and ‘dissemination in time.’
Dissemination in Space ‘Dissemination in space’ refers to documenting more than one lesion affecting the brain, brainstem, optic nerves, or spinal cord. This diagnostic component may be satisfied based purely on clinical examination, if more than one neurological abnormality can be found. If the neurological examination is normal, however, MRI may be used to fulfill this diagnostic component. In its most recently (2010) revised form, the McDonald Diagnostic Criteria state that the dissemination in space requirement may be fulfilled by finding at least one T2 MRI lesion in two or more of the following four CNS regions: (a)
• • • •
periventricular, juxtacortical, infratentorial, spinal cord.
These new criteria have replaced earlier and more complicated requirements for documenting dissemination in space. Figures 1–4 show several of the different kinds of lesions that can be seen in MS.
Dissemination in Time ‘Dissemination in time’ is most easily documented in a patient who has had more than one clinical episode, separated by a minimum of 30 days. In a patient with CIS, however, who has had only a single clinical episode, dissemination in time has not yet occurred, by definition. One way to fulfill the requirement of dissemination in time would be to simply wait until the patient has a second clinical attack. At that point, assuming that both dissemination in space and dissemination in time have been documented, a diagnosis of MS can be made. The most recent revision of the McDonald diagnostic criteria offers two alternative ways to document dissemination in time based on MRI, without requiring the patient to wait for a second clinical attack. One way to use MRI to document dissemination in time would be to demonstrate a new T2 MRI lesion or a gadolinium-enhancing MRI lesion on a follow-up MRI when compared with a baseline scan. Studies have shown that multiple MRI lesions may develop asymptomatically in between clinical attacks. Serial MRI scans allow early documentation of disease activity even in the absence of symptoms. MRI can also be used to document dissemination in time based on a single MRI, if that scan shows simultaneous evidence of both gadolinium-enhancing and nonenhancing MRI lesions.
(b)
Figure 1 (a) An axial proton density MRI showing several typical MS lesions above the level of ventricles. (b) Sagittal proton density MRI showing several lesions above the level of the corpus callosum.
These revised recommendations replace previous requirements for additional MRI scans, which might otherwise complicate or delay the diagnosis of MS.
Other Paraclinical Studies In the past, VEP and CSF analysis looking for evidence of oligoclonal banding or an elevated immunoglobulin G (IgG) index have been incorporated into the MS diagnostic criteria. Other newer techniques, such as OCT, or novel biomarkers offer some promise in improving the ability to diagnose MS more accurately.
Multiple Sclerosis; Diagnosis
Figure 2 Several lesions are seen on an axial view. Note the subtle lesions indicated by arrows.
151
Figure 3 Lesions 1 and 3 have enlarged from 1 month previously (Figure 2). Lesion 2 has not changed in the interim.
At this time, however, there is insufficient information to recommend incorporating these measures into current MS diagnostic criteria, except in the case of insidious onset of progressive MS symptoms, suggesting the possibility of PPMS, in which case evidence of oligoclonal bands or elevated IgG index may aid in the diagnosis. To be specific, PPMS can be diagnosed in patients with 1 year of clinical disease progression and two of the following three criteria:
• • •
one or more brain lesions in a characteristic MS location (periventricular, juxtacortical, or infratentorial); two or more spinal cord lesions; abnormal CSF (oligoclonal bands or elevated IgG index).
Caveats On the basis of these diagnostic criteria, patients can be placed into one of the three categories:
• • •
MS (criteria fulfilled and there is no better explanation for the clinical presentation). Possible MS (suspicious for MS but criteria not fulfilled). Not MS (a better explanation for the clinical presentation exists).
Note the qualifying statement that the clinical presentation must not be better explained by a process other than MS. Even in the most expert hands, diseases with symptoms similar to those of MS can fool the clinician. Therefore, in the follow-up
Figure 4 A gadolinium-enhanced scan performed at the same time as Figure 3. Note that all three lesions enhance as an indication of active inflammation.
152
Table 2
Multiple Sclerosis; Diagnosis
Conditions that mimic multiple sclerosis
Disease
Dissemination in time
Dissemination in space
Comments
Neuromyelitis optica (NMO)
þ
Acute disseminated encephalomyelitis (ADEM) Cerebrovascular disease (CVD)
þ
þ
þ
þ
þ
Prominent involvement of optic nerves and spinal cord; NMO-immunoglobulin G (IgG) may be detected in serum ADEM can look just like multiple sclerosis radiologically but is a monophasic disorder (no dissemination in time) Cerebrospinal fluid (CSF) studies and visual evoked potentials (VEPs) will be normal in CVD Characteristic magnetic resonance imaging (MRI) lesions
þ
þ
Central nervous system (CNS) lymphoma CNS vasculitis
Table 3
Headache may be prominent; may be associated with other autoimmune diseases
Early prognostic variables in multiple sclerosis
Variable
Worse prognosis
Better prognosis
Sex Age at onset MS subtype at onset
Male Older Primary Progressive Brainstem/Spinal Cord Many
Female Younger Relapsing Remitting Optic Nerve
Initial system involved Number of relapses in early years
bound within 15 years, the outlook for patients with MS today is much brighter. There are currently ten FDA-approved brands of MS disease-modifying therapies available in the US, and more are likely to be approved in the near future. As MS treatments become increasingly well tolerated and effective, the need for timely and accurate MS diagnosis will remain critically important.
Few
of patients, even those with a prior diagnosis of MS, one must be alert for other conditions with symptoms similar to those of MS. Table 2 lists several important conditions that may need to be ruled out in the differential diagnosis of MS. Additional multifocal CNS diseases that may manifest episodically include neurosarcoid, neurosyphilis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, Lyme disease, thyroid disease, and vitamin B12 deficiency. These diseases may mimic MS but can generally be ruled out clinically or through laboratory and radiologic studies.
Multiple Sclerosis Prognosis Every patient when first seen and given the diagnosis of MS wants to know what the future will bring. Early in RRMS, it is very difficult to assign a prognosis, though there are some initial symptoms in MS that carry a relatively poor prognosis (Table 3). For example, the early onset of a permanent neurological deficit, especially motor deficits or limb ataxia, especially in older men, is a poor prognostic sign. In contrast, young women with resolving sensory symptoms tend to have a relatively good prognosis. The prognosis of MS patients has improved tremendously since the advent of disease-modifying therapies in the early 1990s. Whereas previously it was common to predict that 90% of patients with RRMS would go on to develop SPMS, or that 50% of patients of MS patients would become wheelchair
See also: Brainstem Syndromes. Multiple Sclerosis and Acute Disseminated Encephalomyelitis: Immunology. Multiple Sclerosis; Epidemiology
Further Reading Brex PA, Ciccarelli O, O’Riordan JI, et al. (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. New England Journal of Medicine 345: 158–164. Compston A and Coles A (2008) Multiple sclerosis. Lancet 372: 1502–1517. Fazekas F, Barkhof M, Filippi M, et al. (1999) The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 58: 448–456. McDonald WI, Compston AS, Edan G, et al. (2010) Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Annals of Neurology 69: 292–302. O’Riordon JI, Thompson AJ, Kingsley DPE, et al. (1998) The prognostic value of brain MRI in clinically isolated syndromes of the CNS: A 10-year follow-up. Brain 121: 495–503. Paty DW, Noseworthy JH, and Ebers GC (1997) Diagnosis of multiple sclerosis. In: Paty DW and Ebers GC (eds.) Multiple Sclerosis. Contemporary Neurology Series. Philadelphia: FA Davis. Polman CH, Reingold SC, Banwell B, et al. (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology 69: 292–302. Poser CM, Paty DW, Scheinberg L, et al. (1983) New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of Neurology 13: 227–231. Schumacher GA, Beebe G, Kibler RF, et al. (1965) Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Annals of the New York Academy of Sciences 122: 552–568. Weinshenker BG and Ebers GC (1987) The natural history of multiple sclerosis. Canadian Journal of Neurological Sciences 14: 255–261.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (brain, brainstem, spinal cord, and the optic nerves) that primarily affects young adults. Most patients present between the ages of 15 and 50 years with a mean age of onset of approximately 30 years. MS affects females more than males at a ratio of between 2:1 and 3:1 with the age of onset being slightly younger for females than for males. The incidence of MS is greatest in people of northern European descent. There is a striking geographic variation in frequency, with higher MS prevalence rates at higher latitudes. MS typically begins with subacute episodes (also known as attacks, relapses, or exacerbations) of neurological dysfunction with spontaneous remission (Table 1). Subsequent relapses over time occur with variable frequency, and eventually patients may develop permanent neurological deficits. Over time, relapses may become less common and be replaced by a gradually progressive course. Less commonly, patients may have a gradually progressive course at onset. (See Clinical Subtypes of MS below.) An MS attack is defined to be a neurological episode lasting for a minimum of 24 h. Symptoms must be separated by at least 30 days in order to be considered separate attacks. The use of magnetic resonance imaging (MRI) has improved our ability to make a diagnosis of MS. MRI has also opened a window on the brain for understanding the evolution of the pathology over time. There remains, however, no unequivocal diagnostic laboratory test for MS, and the gold standard for the diagnosis of MS remains a clinical one, based on a carefully documented history and examination. (See Diagnosing MS below.)
Historical Description of Multiple Sclerosis Charles Prosper Ollivier d’Angers may have described a case of MS as early as 1824. His patient was a 20-year-old who initially presented with transient weakness of his right foot. Over the next decade, he developed bilateral leg weakness, bilateral hand numbness and ataxia, and urinary retention and dysarthria. Hot baths reportedly worsened his symptoms. Table 1 Symptom
Initial symptoms of multiple sclerosis Frequency (%)
Sensory symptoms (numbness and tingling) 33 Visual changes (unilateral vision loss or double vision) 23 Motor symptoms (acute or progressive) 14 Bladder symptoms o5 Cognitive changes o5 Paroxysmal symptoms (sensory or motor) o1
148
It is Jean-Martin Charcot, however, who is credited with first identifying the disease as a clinical/pathological entity in 1866. According to D.M. Bourneville, one of Charcot’s students, Charcot asked a woman with some motor problems to serve as his housemaid. He was thus able to watch her clinical deterioration for many years. When she eventually became significantly disabled, Charcot arranged for her to be admitted to the Salpeˆtrie`re, and after she died, he examined her brain and spinal cord, identifying the characteristic plaques of MS. Many of Charcot’s insights from over a century ago remained relevant to our understanding of the disease today.
Typical Clinical Presentations Sensory Symptoms Approximately 30% of MS patients initially have sensory symptoms at onset (Table 1). Sensory symptoms include numbness, tingling, loss of vision, or a combination of these. A commonly described presentation is an abnormal sensation in the distal portion of a limb that gradually spreads proximally over several days. Sometimes, the numbness may extend across the trunk to involve the opposite side. Symptoms usually reach their maximum extent in the first week. Sensory symptoms can be purely radicular and may be painful. Early sensory symptoms may not be associated with any functional abnormality of the limbs or bladder, even when clearly of spinal cord origin. The majority of such patients with acute sensory symptoms improve spontaneously, and the symptoms usually resolve completely. A classic MS symptom is Lhermitte’s phenomenon – a tingling sensation or vibration, like an electric current going down the back and legs, brought on by flexion of the neck. Though he was not the first to describe it, Jean Lhermitte published the seminal article on the phenomenon in 1924. Lhermitte’s phenomenon was first noted in patients with traumatic diseases of the cervical spinal cord; Lhermitte pointed out, however, that the symptom occurred frequently in patients with MS. An unusual sensory symptom, specific to MS, is the sensory ‘useless hand’ syndrome. A patient may develop loss of discriminatory sensations, such as vibratory sense, twopoint discrimination, and proprioception that can be so severe that the hand becomes functionally useless even though there is no actual motor involvement. The ‘useless hand’ in MS is usually unilateral but has occasionally been described as bilateral. It can be identified by noting apparent hand weakness when tested with the patient’s eyes closed that is improved when the hand is under visual control.
Encyclopedia of the Neurological Sciences, Volume 3
doi:10.1016/B978-0-12-385157-4.00602-3
Multiple Sclerosis; Diagnosis Optic Neuritis A sensory symptom that is of particular importance in the diagnosis of MS is acute loss of vision in one eye due to retrobulbar optic neuritis (ON). ON is very closely associated with MS and is the initial symptom in approximately 15% of MS patients. ON typically affects only one eye, although it can occasionally be bilateral, particularly in the pediatric population. A typical patient may report a blur or smudge in the center of the field of vision of one eye. In severe ON, visual loss can be complete. There is almost always associated pain on eye movement that can precede, accompany, or follow the visual loss; there may also be tenderness of the globe. Examination will typically show decreased vision acuity, decreased color vision, and (when unilateral) a relative afferent pupillary defect (APD). ON is associated with optic disk pallor and thinning of the retinal nerve fiber layer (RNFL) that can be detected using optical coherence tomography (OCT). OCT has also revealed asymptomatic thinning of the RNFL in patients with MS, even in clinically unaffected eyes. Most patients with ON recover functional vision within 6 months. Careful follow-up of patients with ON has shown that many will develop MS within 5 years, though the interval between an initial episode of ON and a second clinical attack of MS can be as long as 30 years.
Transverse Myelitis A combination of subacute motor and sensory symptoms referable to spinal cord demyelination is common in MS. Patients may present with a sensory level or Brown-Se´quard syndrome. Bladder symptoms may be noted. This acute transverse myelitis is usually unilateral or partial. Central or longitudinally extensive spinal cord demyelination may suggest a diagnosis other than MS, such as neuromyelitis optica (NMO).
Brainstem or Cerebellar Syndromes Occasionally, MS may present as an acute syndrome involving the brainstem or cerebellum. Symptoms of acute brainstem dysfunction may include incoordination, double vision, slurred speech, and vertigo. Demyelination of the medial longitudinal fasciculus within the brainstem results in internuclear ophthalmoplegia (INO), characterized by impairment of adduction (moving the eye medially), adduction lag, and abducting nystagmus (nystagmus of the abducting eye) in attempted horizontal gaze. An INO associated with limb or gait ataxia, particularly if the INO is bilateral, should raise the possibility of MS. Acute bilateral INO that resolves spontaneously is almost pathognomonic for MS.
Acute Hemispheric Lesions Cerebral syndromes with hemisensory loss, hemiparesis, or acute cognitive dysfunction are uncommon in MS. Rarely, MS patients may present with a large hemispheric demyelinating
149
lesion (tumefactive demyelination) that can mimic a brain tumor. An unnecessary brain biopsy can sometimes be avoided if additional lesions typical of MS are noted on MRI or if additional laboratory tests (such as cerebrospinal fluid (CSF) analysis) or visual evoked potentials (VEPs) suggest a diagnosis of MS.
Clinical Subtypes of Multiple Sclerosis Relapsing Remitting Multiple Sclerosis MS is typically characterized by recurrent episodes (‘relapses’) of neurological symptoms with complete or near complete recovery (‘remissions’) in between these episodes. Approximately 80% of MS patients initially have this ‘relapsing and remitting MS’ (RRMS) subtype. The key feature of RRMS is clinical stability between attacks, whether or not previous relapses have left behind any residual disability.
Secondary Progressive Multiple Sclerosis After years of RRMS, some MS patients begin to accumulate gradually progressive disability, typically slowly worsening gait impairment and incoordination. When a gradually progressive course follows an initially relapsing remitting course, this is referred to as ‘secondary progressive MS’ (SPMS). The key feature of SPMS is a steadily progressive decline after an initially relapsing–remitting course.
Primary Progressive Multiple Sclerosis Some MS patients never experience any clinical relapses and instead develop gradual neurological progression from the beginning. This uncommon (approximately 15% of all cases of MS) form of MS is referred to as ‘primary progressive MS’ (PPMS). The key feature of PPMS is steady progressive decline from the disease onset, in the absence of any clinical relapses.
Progressive Relapsing Multiple Sclerosis Rarely, MS patients may start out with a gradually progressive course that is subsequently punctuated by occasional clinical relapses. This only occurs in approximately 5% of cases on MS and is referred to as ‘progressive relapsing MS’ (PRMS).
Clinically Isolated Syndrome A single or first episode of central nervous system demyelination is referred to as a clinically isolated syndrome (CIS). Common forms of CIS include ON, transverse myelitis, or a brainstem syndrome (e.g., INO). When CIS presents with a normal brain MRI, the risk of developing MS subsequently is relatively low (approximately 15%). When the initial brain MRI is abnormal, however, the risk of future development of MS is high (approximately 80%).
150
Multiple Sclerosis; Diagnosis
Diagnosing Multiple Sclerosis Despite many advances in MRI technique and the availability of new serum and CSF studies, MS remains a clinical diagnosis, made primarily based on history and examination. Fundamentally, MS is diagnosed by documenting both ‘dissemination in space’ and ‘dissemination in time.’
Dissemination in Space ‘Dissemination in space’ refers to documenting more than one lesion affecting the brain, brainstem, optic nerves, or spinal cord. This diagnostic component may be satisfied based purely on clinical examination, if more than one neurological abnormality can be found. If the neurological examination is normal, however, MRI may be used to fulfill this diagnostic component. In its most recently (2010) revised form, the McDonald Diagnostic Criteria state that the dissemination in space requirement may be fulfilled by finding at least one T2 MRI lesion in two or more of the following four CNS regions: (a)
• • • •
periventricular, juxtacortical, infratentorial, spinal cord.
These new criteria have replaced earlier and more complicated requirements for documenting dissemination in space. Figures 1–4 show several of the different kinds of lesions that can be seen in MS.
Dissemination in Time ‘Dissemination in time’ is most easily documented in a patient who has had more than one clinical episode, separated by a minimum of 30 days. In a patient with CIS, however, who has had only a single clinical episode, dissemination in time has not yet occurred, by definition. One way to fulfill the requirement of dissemination in time would be to simply wait until the patient has a second clinical attack. At that point, assuming that both dissemination in space and dissemination in time have been documented, a diagnosis of MS can be made. The most recent revision of the McDonald diagnostic criteria offers two alternative ways to document dissemination in time based on MRI, without requiring the patient to wait for a second clinical attack. One way to use MRI to document dissemination in time would be to demonstrate a new T2 MRI lesion or a gadolinium-enhancing MRI lesion on a follow-up MRI when compared with a baseline scan. Studies have shown that multiple MRI lesions may develop asymptomatically in between clinical attacks. Serial MRI scans allow early documentation of disease activity even in the absence of symptoms. MRI can also be used to document dissemination in time based on a single MRI, if that scan shows simultaneous evidence of both gadolinium-enhancing and nonenhancing MRI lesions.
(b)
Figure 1 (a) An axial proton density MRI showing several typical MS lesions above the level of ventricles. (b) Sagittal proton density MRI showing several lesions above the level of the corpus callosum.
These revised recommendations replace previous requirements for additional MRI scans, which might otherwise complicate or delay the diagnosis of MS.
Other Paraclinical Studies In the past, VEP and CSF analysis looking for evidence of oligoclonal banding or an elevated immunoglobulin G (IgG) index have been incorporated into the MS diagnostic criteria. Other newer techniques, such as OCT, or novel biomarkers offer some promise in improving the ability to diagnose MS more accurately.
Multiple Sclerosis; Diagnosis
Figure 2 Several lesions are seen on an axial view. Note the subtle lesions indicated by arrows.
151
Figure 3 Lesions 1 and 3 have enlarged from 1 month previously (Figure 2). Lesion 2 has not changed in the interim.
At this time, however, there is insufficient information to recommend incorporating these measures into current MS diagnostic criteria, except in the case of insidious onset of progressive MS symptoms, suggesting the possibility of PPMS, in which case evidence of oligoclonal bands or elevated IgG index may aid in the diagnosis. To be specific, PPMS can be diagnosed in patients with 1 year of clinical disease progression and two of the following three criteria:
• • •
one or more brain lesions in a characteristic MS location (periventricular, juxtacortical, or infratentorial); two or more spinal cord lesions; abnormal CSF (oligoclonal bands or elevated IgG index).
Caveats On the basis of these diagnostic criteria, patients can be placed into one of the three categories:
• • •
MS (criteria fulfilled and there is no better explanation for the clinical presentation). Possible MS (suspicious for MS but criteria not fulfilled). Not MS (a better explanation for the clinical presentation exists).
Note the qualifying statement that the clinical presentation must not be better explained by a process other than MS. Even in the most expert hands, diseases with symptoms similar to those of MS can fool the clinician. Therefore, in the follow-up
Figure 4 A gadolinium-enhanced scan performed at the same time as Figure 3. Note that all three lesions enhance as an indication of active inflammation.
152
Table 2
Multiple Sclerosis; Diagnosis
Conditions that mimic multiple sclerosis
Disease
Dissemination in time
Dissemination in space
Comments
Neuromyelitis optica (NMO)
þ
Acute disseminated encephalomyelitis (ADEM) Cerebrovascular disease (CVD)
þ
þ
þ
þ
þ
Prominent involvement of optic nerves and spinal cord; NMO-immunoglobulin G (IgG) may be detected in serum ADEM can look just like multiple sclerosis radiologically but is a monophasic disorder (no dissemination in time) Cerebrospinal fluid (CSF) studies and visual evoked potentials (VEPs) will be normal in CVD Characteristic magnetic resonance imaging (MRI) lesions
þ
þ
Central nervous system (CNS) lymphoma CNS vasculitis
Table 3
Headache may be prominent; may be associated with other autoimmune diseases
Early prognostic variables in multiple sclerosis
Variable
Worse prognosis
Better prognosis
Sex Age at onset MS subtype at onset
Male Older Primary Progressive Brainstem/Spinal Cord Many
Female Younger Relapsing Remitting Optic Nerve
Initial system involved Number of relapses in early years
bound within 15 years, the outlook for patients with MS today is much brighter. There are currently ten FDA-approved brands of MS disease-modifying therapies available in the US, and more are likely to be approved in the near future. As MS treatments become increasingly well tolerated and effective, the need for timely and accurate MS diagnosis will remain critically important.
Few
of patients, even those with a prior diagnosis of MS, one must be alert for other conditions with symptoms similar to those of MS. Table 2 lists several important conditions that may need to be ruled out in the differential diagnosis of MS. Additional multifocal CNS diseases that may manifest episodically include neurosarcoid, neurosyphilis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, Lyme disease, thyroid disease, and vitamin B12 deficiency. These diseases may mimic MS but can generally be ruled out clinically or through laboratory and radiologic studies.
Multiple Sclerosis Prognosis Every patient when first seen and given the diagnosis of MS wants to know what the future will bring. Early in RRMS, it is very difficult to assign a prognosis, though there are some initial symptoms in MS that carry a relatively poor prognosis (Table 3). For example, the early onset of a permanent neurological deficit, especially motor deficits or limb ataxia, especially in older men, is a poor prognostic sign. In contrast, young women with resolving sensory symptoms tend to have a relatively good prognosis. The prognosis of MS patients has improved tremendously since the advent of disease-modifying therapies in the early 1990s. Whereas previously it was common to predict that 90% of patients with RRMS would go on to develop SPMS, or that 50% of patients of MS patients would become wheelchair
See also: Brainstem Syndromes. Multiple Sclerosis and Acute Disseminated Encephalomyelitis: Immunology. Multiple Sclerosis; Epidemiology
Further Reading Brex PA, Ciccarelli O, O’Riordan JI, et al. (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. New England Journal of Medicine 345: 158–164. Compston A and Coles A (2008) Multiple sclerosis. Lancet 372: 1502–1517. Fazekas F, Barkhof M, Filippi M, et al. (1999) The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 58: 448–456. McDonald WI, Compston AS, Edan G, et al. (2010) Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Annals of Neurology 69: 292–302. O’Riordon JI, Thompson AJ, Kingsley DPE, et al. (1998) The prognostic value of brain MRI in clinically isolated syndromes of the CNS: A 10-year follow-up. Brain 121: 495–503. Paty DW, Noseworthy JH, and Ebers GC (1997) Diagnosis of multiple sclerosis. In: Paty DW and Ebers GC (eds.) Multiple Sclerosis. Contemporary Neurology Series. Philadelphia: FA Davis. Polman CH, Reingold SC, Banwell B, et al. (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology 69: 292–302. Poser CM, Paty DW, Scheinberg L, et al. (1983) New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of Neurology 13: 227–231. Schumacher GA, Beebe G, Kibler RF, et al. (1965) Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Annals of the New York Academy of Sciences 122: 552–568. Weinshenker BG and Ebers GC (1987) The natural history of multiple sclerosis. Canadian Journal of Neurological Sciences 14: 255–261.