Which statement, by the patient, supports the diagnosis of multiple sclerosis

Abstract

Diagnosis of multiple sclerosis (MS) is based on the demonstration of dissemination of lesions in space (DIS) and in time (DIT), as well as on the exclusion of an alternative neurologic disorder. As a paraclinical tool brain and/or spinal cord magnetic resonance imaging (MRI), showing typical lesion morphology, characteristic distribution of lesions, or involvement or specific anatomic structures, can support the diagnosis of MS. But from an imaging perspective a considerable amount of inherited and acquired disorders may manifest with radiologic evidence of DIT, DIS, or both. Hypoxic-ischemic vasculopathy, specially small-vessel disease, inflammatory disorders, vasculitis, and non-MS idiopathic inflammatory disorders, as well as some toxic, metabolic, and infectious disorders, may present mimicking MS on MR examinations and should be included in the differential diagnosis of MS-like lesions. Careful evaluation of associated findings on MRI, the so-called MRI red flags, such as the presence of infarcts, microbleeds, meningeal enhancement, and calcifications among others, are very helpful in suggesting a diagnosis other than MS. Complement MRI findings to patient’s history, demographics, and serologic findings are crucial to achieve the correct diagnosis. We will review the most frequent radiologic appearance and differential features from the most frequent MS mimickers.

Making a diagnosis

The diagnosis of MS, in both children and adults, requires evidence of dissemination of disease activity within the CNS and over time (Polman et al., 2005; Krupp et al., 2007). Dissemination of disease “in space” requires clinical, neurophysiological, or MRI evidence of multiple regions of the CNS. MRI criteria that delineate the number and distribution of lesions with high specificity for MS have been well established for adults (Polman et al., 2005). In children, the number and distribution of lesions differs slightly from that in adults, especially for children who experience their first event under the age of 10 years (Hahn et al., 2004). While well-defined lesions (see Fig. 133.1A) and lesions perpendicular to the long axis of the corpus callosum (see Fig. 133.1D) are highly specific for MS in children (Mikaeloff et al., 2004a), fewer than 30% of children diagnosed with MS have such features on initial imaging. MRI criteria with heightened sensitivity for pediatric MS have been proposed and include the presence of two of the following: (1) five or more lesions on T2/FLAIR-weighted images; (2) two or more periventricular lesions; or (3) one brainstem lesion (Callen et al., 2008b). These criteria have 85% sensitivity and 98% specificity when used to evaluate children with a first demyelinating event compared to children with relapsing nondemyelinating inflammatory CNS disease. However, further refinement of these MRI criteria were required to identify children with MS for whom the first scan was obtained in the context of an ADEM-like first MS attack (acute, polyfocal deficits accompanied by encephalopathy). In such situations, the following criteria are proposed: (1) absence of diffuse, ill-defined lesions (as illustrated in Fig. 133.1B), and one or both of (2) two or more periventricular lesions, and (3) black holes (see Fig. 133.1C) (Callen et al., 2008a). Further validation of these MRI criteria is required.

The diagnosis of MS also requires evidence of dissemination of disease over time. Clinical attacks require a minimum of 1 month between onset of one attack and onset of a second event in order to ensure distinct events. Two or more relapses is sufficient to confirm a diagnosis of MS, with relapses being defined as the presence of new neurological deficits persisting for at least 24 hours. Deficits precipitated by illness, fever, or other intercurrent events are not considered as relapses unless the deficits persist for 24 hours following the acute precipitant. Uhtoff's phenomenon, typically experienced as reduction in visual acuity (although motor, sensory, or cerebellar deficits may also be experienced) in the context of fever, occurs in many patients with MS – such experiences are not considered relapses. For children with a first demyelinating event meeting criteria for ADEM, consensus criteria require that more than 3 months occur between the initial ADEM event and a second attack, and that two non-ADEM events be experienced before a diagnosis of MS is conferred (Krupp et al., 2007). Dissemination of disease in time can be confirmed by clinical relapse, but also by serial MRI. If gadolinium is administered, any enhancing lesion evident more than 4 weeks from the clinical attack is also sufficient to confirm active ongoing disease, as lesion enhancement is a transient event and would not be expected to persist for more than 4 weeks (Polman et al., 2005). At the present time, evolution of new lesions on serial imaging is used to confirm the diagnosis of MS in adolescents, but many clinicians prefer to confirm the diagnosis based on clinical evidence of relapses.

Diagnosis

The diagnosis of MS is dependent on evidence of CNS involvement separated in both time and space; i.e., there must be evidence that two areas of the CNS are involved and a history that this involvement occurred at two different times and without any other identifiable cause. A diagnosis can be made solely on clinical criteria, but this can result in long delays in diagnosis and treatment. The current criteria permit a diagnosis to be made with less clinical evidence if specific features are present on magnetic resonance imaging (MRI) (Polman et al., 2011). Results of cerebrospinal fluid analysis can also be used to support the diagnosis of MS, but in most cases clinical and imaging data are sufficient.

Aquaporin 4 and Neuroinflammation

The role of auto-antibodies to aquaporin 4 (AQP4) in neuromyelitis optica was first suggested by studies in which human sera was reacted with mouse tissue sections. Sera from patients with NMO showed a pattern of immunoreactivity that highlighted CNS microvessels and the pia (Lennon et al., 2004). This and the pattern of immunoreactivity in kidney and stomach suggested that AQP4 was the target antigen, and this was proven to be the case (Lennon, et al., 2005). Studies on tissue from NMO patients showed that there is loss of AQP4 immunoreactivity and complement deposition in the lesions of inflammatory demyelination, but not in uninvolved tissue. At the time, AQP4 was known to be the predominant water channel in the brain and had a role in brain edema formation in response to a variety of etiologies. The possible involvement of AQP4 in neuroinflammation had never been investigated. Several groups explored the pathogenic role of antibodies to AQP4 in rodent models (see Li et al. 2011 for references). These studies showed that administration of anti-AQP4 antibodies to animals with EAE or along with complement to naïve animals produced pathology characteristic of NMO. When EAE was induced in AQP4 knockout mice, the animals had attenuated symptoms and CNS inflammation compared to wild-type controls. This group went on to perform a systematic exploration of the mechanism by which AQP4 deficiency protected animals from the inflammatory pathology of EAE (Li et al., 2011). The major difference between the two groups was that the knockout mice showed a decreased inflammatory response to intracerebral injection with lipopolysaccharide (LPS). In vitro analysis of microglia-free astrocyte cultures showed that LPS induced secretion of TNF-alpha and IL-6 into the medium, but this was reduced in the knockout animals compared to controls. Transfection studies demonstrated that cytokine secretion was directly related to expression of AQP4 by cells. These recent data provide new hypotheses for investigating the role of the water permeability function of astrocytes in neuroinflammation.

There are a variety of MRI imaging protocols used in the diagnosis and monitoring of patients with MS (Fox, 2008). T2-weighted MRI is the most sensitive sequence for identification of lesions in brains of MS patients, but is not specific because both inflammatory demyelination and ischemic necrosis result in increased signal. T2-weighted images also cannot distinguish new from old lesions. T1-weighted imaging after the administration of gadolinium can identify new lesions in which the blood–brain barrier has been compromised. Serial studies of patients with early relapsing–remitting MS have shown that the first event in the development of a new MS lesion is the appearance of a gadolinium-enhanced lesion, which can occur during periods of clinical stability in many patients. Newer imaging techniques, such as magnetic resonance spectroscopy, magnetization transfer ratio, and diffusion tensor imaging, provide additional characterization of lesions over time, and correlations of MRI of postmortem brains with histopathology (e.g., Fisher et al., 2007), can validate the interpretations of lesions identified by different techniques and help to focus ongoing research.

DIAGNOSIS

The diagnosis of MS is based on the demonstration of white-matter lesions disseminated in time and space, in the absence of another identifiable explanation. Because no single clinical feature or diagnostic test is sufficient for the diagnosis of MS, diagnostic criteria have included a combination of both clinical assessment and paraclinical studies. Newly revised diagnostic criteria were recently established by an international panel; these are now commonly known as the McDonald criteria7 (Table 65.1).

A diagnosis of MS can be based on clinical grounds alone if there have been two or more attacks with objective evidence of involvement of two or more areas of the CNS. If there have been two or more attacks, but

Key Concepts

Pathologically, multiple sclerosis is characterized by discrete inflammatory, demyelinating lesions of the white matter and gray matter, axonal degeneration, diffuse changes of ‘normal-appearing white matter,’ and remyelination

Multiple sclerosis is a biphasic disease characterized by an early inflammatory phase followed by a progressive neurodegenerative phase

there is objective evidence of involvement of only one area of the CNS, dissemination in space must be demonstrated by additional data. If there is history of only one clinical attack or if there has been insidious neurological deterioration, additional data are needed to confirm dissemination in time and space. The paraclinical studies that can be used to prove a suspicion of MS include magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and visual evoked potentials (VEP).

By MRI, MS lesions are typically larger than 6mm, have an oval shape (often with the long axis directed perpendicular to lateral ventricles), and have preferential location in the periventricular area, corpus callosum, and posterior fossa. The typical MS lesion evolves over time and this can be followed by MRI. If caught in the initial stages, gadolinium enhancement seen on a T1-weighted image done after the administration of gadolinium contrast will correlate with a new lesion on a T2-weighted image. The contrast-enhancing lesion indicates BBB disruption. Inflammation and edema will usually persist for no longer than 2 months and in most cases less than 1 month. As edema resolves the persistent T2-weighted lesion will often become smaller and more sharply delineated from the surrounding white matter. In some instances the lesion seen on the T2-weighted image will be seen as hypointense on a T1-weighted image. The low-attenuation T1 signal or ‘T1 black hole,’ which often becomes more common in secondary progressive MS, is thought to represent actual tissue loss8 (Fig. 65.2). Disease activity assessed by MRI, defined as either the number of new, recurrent, and enlarging lesions or the number of gadolinium-enhancing lesions, is usually higher than the clinical activity. The difference may be either because of the involvement of asymptomatic areas of the CNS or because of a pathophysiological difference between symptomatic and nonsymptomatic lesions based on the presence or absence of axonal dysfunction. Because of the high sensitivity of MRI for disease activity, periodic MRI have been helpful in determining treatment efficacy more quickly than monitoring relapse rate or disability level. For this reason, MRI has become an important tool in recent clinical trials.

MRI criteria for the diagnosis of MS have been formally incorporated into the diagnostic criteria for MS7, 9 (Tables 65.2 and (65.3). Importantly, MRI can be used to establish dissemination in either space or time. One implication of the revised diagnostic criteria is that a diagnosis of MS can potentially be made 3 months after a single clinical presentation consistent with MS (see Table 65.2). It is important to note that as with acute disease activity, there is only poor correlation between disability and lesion load (volume of white-matter abnormalities) determined by brain MRI. Severe clinical impairment with few MRI abnormalities, and the converse, occur. This disparity is partially explained by variable spinal cord involvement, but a pathophysiological difference may account for some of the discrepancy. The correlation between ‘T1 black holes’ and disability seems better. While other imaging techniques, including magetization transfer ratios and MR spectroscopy, have proved to be very useful research tools, to date they do not have a role in the diagnosis of MS.

CSF evaluation remains a valuable diagnostic tool for MS. A lymphocytic pleocytosis can be seen during acute exacerbations in about one-third of patients, but this seldom exceeds 50 cells per dl. High immunoglobulin levels due to intrathecal synthesis can be seen. The majority of CSF immunoglobulin is immunoglobulin G (IgG), although IgM and IgA can also be elevated. The IgG index and synthesis rate are elevated in 70–90% of MS patients. Agarose gel electrophoresis or isoelectric focusing of CSF proteins often reveals discrete bands of immunoglobulin, each representing a monoclonal antibody. Unique banding patterns in the CSF, not present in the serum, are known as oligoclonal bands (OCBs) and are indicative of intrathecal humoral immune response. Between 85% and 95% of MS patients have OCBs; however, early in the course of disease they are not as prevalent. Once present, OCBs persist and the pattern does not vary, although new bands occasionally appear. The antigenic specificity of OCBs is unknown.1

Evoked potentials are summed cortical electrical responses to peripheral sensory stimulation that can be used to localize sites of pathology and measure conduction velocity along sensory pathways. VEP and somatosensory evoked potentials can detect subclinical sites of demyelination, thus providing evidence of multifocality of MS lesions. Some 85% of patients with MS have abnormalities on VEPs, even when the history of ON is absent.1

Key Concepts

Multiple sclerosis is a multifactorial disease most likely due to exposure to environmental triggers in a genetically susceptible individual

The inflammatory phase is thought to be driven by autoreactive CD4 T cells specific for myelin epitopes

It is not clear if the neurodegenerative phase is a consequence of immune-mediated injury or has an unrelated cause

A set of criteria have also been established for the diagnosis of primary progressive MS. By definition, all patients with primary progressive MS have a slowly progressive and often monosymptomatic course, frequently consisting of spastic paraparesis without clinical signs of dissemination in the CNS. A proportion of patients may have multiple symptoms at onset.10 Just as in relapsing remitting MS, in addition to the clinical history, CSF findings, VEPs, and abnormal MRI are often helpful in making a diagnosis. In this case, exclusion of other causes of slowly progressive degenerative disease is essential11 (Table 65.4).

Laboratory Findings

The diagnosis of MS usually is made on the basis of information derived from the history, clinical examination, CSF analysis, sensory evoked potential studies, and magnetic resonance imaging (MRI) performed over time.57,61,62 The relapsing-remitting variant is diagnosed when two or more clinical attacks occur in a patient who has two or more affected CNS locations, or when a new MRI lesion appears after a second clinical attack.56,59,60 The disease also is diagnosed after one clinical attack when a new MRI lesion appears. MRI scans typically reveal multiple hypodense demyelinated regions (plaques) in white matter, usually near the ventricles (see Figure 27-10), brain stem cerebellum, and optic nerves.56,59,60 The CSF shows signs of low-grade inflammation, and protein and immunoglobulin levels are increased in 80% to 90% of patients. Antibodies to myelin basic protein also can be detected in the CSF. Myelin destruction causes slowing of conduction velocity. The conduction response to visual stimuli (visual evoked potential) or to somatosensory evoked stimuli usually is delayed and altered in amplitude.56,59,60

Clinical Comments

The clinical diagnosis of MS often is extremely difficult because of a frequently variable and conflicting patient presentation. Symptoms include weakness, paresis, and tremor of one or more extremities. Muscle atrophy and spasticity may be present with dysfunctional movement. Numbness, paresthesias, and visual disturbances are common. Incoordination, myasthenia, changes in mentation, and altered speech with facial and extremity pain can occur with frequency in MS. Charcot triad of signs is intention tremor, nystagmus, and scanning speech (INS). The Schumacher criteria for MS consists of (1) CNS dysfunction, (2) involvement of two or more parts of the CNS, (3) predominant white matter involvement, (4) two or more episodes lasting greater than 24 hours less than 1 month apart, (5) slow stepwise progression of signs and symptoms, and (6) onset at 10 to 50 years of age. The hallmark of MS is inconsistency in time and space. For example, a patient may have speech difficulties and weakness of one of the extremities followed by a period of remission. On exacerbation, the patient may complain of spasticity of a different extremity with visual disturbances. Diagnosis depends on the recognition of this extremely variable pattern and the judicious pursuit of appropriate laboratory testing and MRI.77,121 Rudick red flags suggest a diagnosis other than MS are (1) absence of visual disturbances, (2) no clinical remission, (3) totally localized disease, (4) no sensory findings, (5) no bladder involvement, and (6) no CSF abnormality. Laboratory tests include lumbar puncture and evoked potentials. Oligoclonal banding and immunoglobulin G index in the CSF are positive in approximately 90% of MS cases. Evoked potentials make use of slowed conduction in demyelinated neural structures to permit the assessment of subclinical MS. However, evoked potentials are of no value in patients with known lesions.198

Key Concepts

MS is a demyelinating disease of the CNS.

MRI is the preferred imaging modality in the diagnosis of MS.

The pattern of symptoms in MS is extremely variable, often characterized by relapses and remissions.

Lumbar puncture is specific and sensitive for MS.

Clinical Phenotype

The diagnosis of MS requires evidence of separation in space and time. Older criteria required two discrete clinical attacks, but the 2010 International Panel Criteria for Clinically Definite Multiple Sclerosis (CDMS) allows these criteria to be met with a combination of clinical and radiologic findings (Polman et al., 2011). Elevated immunoglobulin G index and unique oligoclonal bands in the CSF are supportive of but not mandatory for the diagnosis of relapsing MS. Those who experience a clinical attack consistent with demyelinating disease but do not meet criteria for dissemination in time are diagnosed with clinically isolated syndrome (CIS). Conversion from CIS to CDMS ranges from 30% to 70% depending on clinical, imaging, and CSF markers (Miller, Barkhof, Montalban, Thompson, & Filippi, 2005). Treatment with an MS disease-modifying therapy is indicated for patients with high-risk CIS. A subgroup of patients with radiologically isolated syndrome was identified in which brain MRIs obtained for indications such as head trauma or migraine revealed lesions meeting radiologic criteria for MS but the disease was clinically silent. In available case series, some but not all of these patients go on to develop CDMS; 34% of patients in one series experienced a clinical event at 5 years (Lebrun et al., 2009; Okuda et al., 2011, 2014).

MS follows one of four disease courses: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), or progressive-relapsing (Lublin & Reingold, 1996). In most patients (80–85%), the disease follows an RR course characterized by subacute onset of neurologic dysfunction evolving over a period of days to weeks followed by gradual, partial, or complete recovery. Some patients with RRMS go on to experience a more progressive decline without superimposed relapses. These patients are characterized as having SPMS. In a pretreatment cohort, 50% of patients with relapsing onset developed SPMS at 10 years (Weinshenker & Ebers, 1989). Newer longitudinal data will shed more light on rates of conversion to SPMS in a treated cohort. A smaller subset of patients (10–15%) presents with PPMS, defined by insidious and irreversible accumulation of disability from onset without clear superimposed attacks. PRMS is increasingly thought not to represent a truly a distinct course, but rather highlights that patients with progressive MS may experience rare attacks (Lublin, 2014).

Typical presentations of relapsing MS include optic neuritis, brain stem dysfunction (eg, internuclear ophthalmoplegia), and partial myelitis. Multifocal presentations also occur. Over time, patients may develop impairment of vision or other cranial nerve functions, spastic paresis, sensory dysfunction, ataxia, disturbance of bowel or bladder function, or cognitive dysfunction. Fatigue and neuropathic pain are common.

Between 40% and 70% of patients with MS experience cognitive dysfunction (Chiaravalloti & DeLuca, 2008). Affected domains include information processing speed, visual learning, and memory, with less frequent but still clinically important involvement of simple attention and verbal skills (DeLuca, Yates, Beale, & Morrow, 2015; Rocca et al., 2015b). MS-related cognitive impairment is considered a subcortical dementia, differing from cortical dementias such as AD in that aphasia, apraxia, and agnosia are uncommon (DeLuca et al., 2015), and memory dysfunction is usually not amnestic but more the result of a frontal lobe retrieval deficit. Symptoms are often subtle and frank dementia is rare (Chiaravalloti & DeLuca, 2008). Cognitive impairment can be detected early in MS and seems to be more prominent in progressive than relapsing forms of the disease (Achiron et al., 2013; Feuillet et al., 2007). Cognitive dysfunction increases with time. In one longitudinally followed cohort, 74% of patients were cognitively normal at baseline but only 44% of patients were considered cognitively normal at 10 years (Amato, Ponziani, Siracusa, & Sorbi, 2001). Although generally progressive, cognitive function may also worsen transiently during relapses (Benedict et al., 2014; Morrow, Jurgensen, Forrestal, Munchauer, & Benedict, 2011). Measurement of cognitive dysfunction in MS can be challenging. Patient-reported outcomes are influenced by comorbid depression and fatigue (Benedict, Carone, & Bakshi, 2004; Simioni, Ruffieux, Bruggimann, Annoni, & Schluep, 2007). Many cognitive screening assessments were not designed to detect MS-related cognitive dysfunction. The symbol digit modality test is an important screening tool for MS-related cognitive dysfunction. The Brief Repeatable Battery of Neuropsychological tests and Minimal Assessment of Cognitive Function in MS are more comprehensive, although time-intensive, metrics for quantifying cognitive impairment in MS (DeLuca et al., 2015; Rocca et al., 2015a).

Depression and anxiety are also common. Major depression occurs in patients at a rate two to five times higher than in the general population (Feinstein, Magalhaes, Richard, Audet, & Moore, 2014). It is important to rule out depression as a cause of cognitive impairment in MS. Psychosis is rare but reported (Marrie et al., 2015).

Clinical and diagnostic features

The clinical diagnosis of MS is based on the demonstration of demyelinating lesions disseminated in time and space. In addition to the neurologic symptoms, the finding of magnetic resonance imaging (MRI) lesions consistent with MS (Barkhof et al., 1997; Tintore et al., 2000), demonstration of oligoclonal bands in cerebrospinal fluid (CSF) (Link and Tibbling, 1977), and/or detection of abnormal visual evoked potentials (delay with a well-preserved wave form) are recommended to provide a correct diagnosis (McDonald et al., 2001). Patients with MS may present a monosymptomatic disease suggestive of MS (clinically isolated syndrome), a classic relapsing remitting course, or a primary or secondary progressive disease. Disease progression is defined as continuous deterioration of neurologic symptoms despite only a few new MRI lesions and a rare incidence of contrast-enhancing lesions. The majority of patients with MS start with a relapsing remitting MS, which later converts into a secondary progressive disease. In primary progressive MS the disease starts with continuous progression from its onset. The pathogenetic mechanism underlying progression is supposed to result at least in part from an ongoing inflammatory reaction behind a closed blood–brain barrier (BBB).

Conclusion

While the differential diagnosis of MS can be extremely challenging to clinicians, a detailed history, neurologic examination, and careful review of imaging and laboratory studies are the most important means to narrow diagnostic considerations and tailor an appropriate workup. The presence of atypical historic, clinical, and paraclinical findings should alert physicians to the prospect of an alternative diagnosis and need for further evaluations. At follow-up, the diagnosis of possible or probable MS should always be rechallenged, as symptomatology evolves or as new paraclinical studies become available. That being said, diagnostic efforts should aim to expedite achieving therapeutic goals. In the case of MS therapeutics, this translates into initiating appropriate disease-modifying therapies as early as possible, in order to prevent recurrent relapses, progression, and disability and, most importantly, preserve the neurologic function and quality of life of our patients.

What is the diagnosis for multiple sclerosis?

What statement about multiple sclerosis is true?

What are 4 clinical manifestations that most patients with multiple sclerosis present with?

What is the first step in diagnosing MS?