“Asymptomatic multiple sclerosis” or “subclinical multiple sclerosis” describes a clinically silent disease state of multiple sclerosis discovered by chance, either by imaging or at autopsy, or with incidental findings shown by other diagnostic tools, that is consistent or highly suggestive of multiple sclerosis and that cannot be explained by any other disease or condition.
The use of MRI in various neurologic or other problems in individuals without any clinical symptoms and signs of multiple sclerosis infrequently reveals unsuspected brain lesions compatible with multiple sclerosis. This condition corresponds to a subclinical state of multiple sclerosis and is termed “radiologically isolated syndrome” and therefore, by definition is a form of "asymptomatic multiple sclerosis”.
Although some of these individuals are going to convert to clinical disease, not all do. Because the long-term clinical behavior of this condition is not clear, questions remain regarding the implications of this condition for further understanding multiple sclerosis, how to follow these people, and whether to treat or not. This article discusses all of these issues and reviews up to date data on radiologically isolated syndrome.
Multiple sclerosis is an immune-mediated, neuroinflammatory and neurodegenerative disease of the central nervous system with a highly heterogeneous clinical presentation and unpredictable course (73; 06; 66). Most commonly, its first clinical manifestations appear in young adults between the ages of 20 to 40. It then remains as a lifetime disease with different clinical expressions and progression in an age-dependent manner (94). The disease is diagnosed in individuals who present with central nervous system symptoms and signs and with MRI findings consistent with multiple sclerosis according to a set of criteria. In the final revision of this set of criteria, named as McDonald 2017 Criteria, the MRI findings should fulfill the concept of dissemination in space and dissemination in time, with cerebrospinal fluid studies replacing the MRI dissemination in time criteria when absent (87). The dissemination in space criteria require at least 1 or more lesions in 2 of the 4 sites -- periventricular, cortical/juxta-cortical, posterior fossa, and spinal cord. It is well known that at the time of diagnosis, regardless of whether the clinical presentation is monosymptomatic or polysymptomatic, the MRI will show a number of silent (nonenhancing) lesions independent of the clinical symptomatology in most of these individuals. This observation makes it clear that most multiple sclerosis patients already have preclinical disease, indicating that pathological disease changes develop over time in the central nervous system without corresponding clinical expression of neurologic symptoms and signs.
With the increased availability and widespread use of MRI globally and excess evaluation of people for primary headache disorders and other conditions unrelated to multiple sclerosis symptoms, the incidence of people with incidental MRI findings suggestive of multiple sclerosis, defined as radiologically isolated syndrome, is increasing. There is not a clear-cut consensus on whether these people should be diagnosed as having multiple sclerosis or not, whether they should be treated or not, and how they should be evaluated.
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• The incidental findings on brain and/or spinal cord magnetic resonance imaging suggestive of multiple sclerosis in individuals without any history and clinical symptoms or signs of the disease are named “radiologically isolated syndrome”.
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• With the widespread use of MRI, the incidence radiologically isolated syndrome is increasing. There is no clear-cut consensus on whether these people should be diagnosed as having multiple sclerosis or not, whether they should be treated or not, and how they should be studied.
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• Studies confirm that radiologically isolated syndrome is an early/preclinical stage of multiple sclerosis, with about half of these people converting to clinical disease within 10 years of their MRI diagnosis.
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• The presence of spinal cord and posterior fossa lesions on the MRI, enhancing MRI lesions, the oligoclonal bands in the CSF, and younger age are predictive factors for clinical conversion to clinical multiple sclerosis.
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• Radiologically isolated syndrome provides a unique opportunity to understand further the pathogenesis of the disease and to discover factors related to clinical expression of multiple sclerosis.
Historical note and terminology
Historical note and the evolution of the radiologically isolated syndrome concept and its terminology.
Postmortem studies: the emerging concept of asymptomatic multiple sclerosis. Pathology typical of multiple sclerosis has been documented on autopsies in people who were asymptomatic during life. Sixty-six cases of pathologically demonstrated multiple sclerosis were detected in a cohort of 15,644 autopsies studied in 1961 at the Basel Institute of Pathological Anatomy, giving a postmortem multiple sclerosis prevalence rate of 0.4 % or 400/100,000 (30). Fifty-four of these cases had a confirmed clinical diagnosis of multiple sclerosis or other neurologic diseases. However, it was noteworthy that in the other 12 cases, the autopsy findings were “incidental,” as these cases were not known to have any neurologic disease in their lifetime. This corresponds to an 18% rate (72/100,000) of “clinically silent” disease of a postmortem multiple sclerosis cohort. These unsuspected cases are probably among the first “asymptomatic multiple sclerosis cases” to be reported. This report was soon followed by other postmortem studies reporting asymptomatic multiple sclerosis cases in autopsy series and that a subclinical form of multiple sclerosis is real and probably not infrequent! Following this initial report, Mackay and Hirano reported 2 more cases of pathologically proven multiple sclerosis without preceding clinical evidence of the disease (56). Three such cases were reported from France (14). In their report of unsuspected multiple sclerosis in another large autopsy series of 2540 routine autopsies from Canada, Gilbert and Sadler found lesions consistent with multiple sclerosis in 5 cases (31). A similar work from Scotland was also in line with these observations (74). In a study of all autopsied cases of multiple sclerosis from 1965 to 1986 recorded in the Danish MS Register it was calculated that each year about 40 persons would die with clinically silent multiple sclerosis, which corresponded roughly to 25% of deceased persons with a clinical diagnosis of multiple sclerosis (25). All of these neuropathological (autopsy) studies indicate that multiple sclerosis may remain clinically silent for an entire lifetime in a significant number of individuals. This suggests that for every 3 to 4 clinically diagnosed multiple sclerosis patients there is probably 1 additional asymptomatic individual with the disease.
The suggested explanations of the pathological changes consistent with multiple sclerosis in individuals who never had clinical signs and symptoms of the disease in their lifetime were either that the periventricular location of these lesions were in “silent” areas or low severity of inflammation (14; 31; 25). These leave us with the questions of whether number, size, severity, and location matter on the clinical expression of the disease and whether asymptomatic/subclinical multiple sclerosis is a very mild form of the disease or is a self-limited process. It is well known that symptomatic lesions in people with multiple sclerosis detected on MRI at onset and in the initial years of the disease are only a minority of the total lesions present in their central nervous system. Currently, it is known that clinical symptoms and signs of the disease are either due to the inflammatory lesions affecting anatomically critical sites causing significant damage to the axons and myelin and/or accumulating damage reaching a certain threshold of axonal and myelin damage. The symptomatic lesions are likely to represent the prominence of the neuroinflammatory component of the disease. On the other hand, the clinical expression of ongoing neurodegeneration seen in multiple sclerosis is more closely correlated with disability progression, secondary to damage caused by an accumulation of lesions, ongoing subclinical neuroinflammation, and probably a primary neurodegeneration. These asymptomatic individuals with multiple sclerosis-like pathology on imaging (MRI and more recently PET) provide a unique opportunity to understand the pathogenesis underlying the clinical expression in multiple sclerosis.
Incidental findings suggestive of multiple sclerosis on MRI and epidemiology of the lesions. The use of MRI in various neurologic or other problems unrelated to multiple sclerosis reveals unsuspected brain lesions compatible with multiple sclerosis. The rate of detection of silent MRI lesions suggestive of inflammatory/demyelinating disease in people without any clinical evidence of multiple sclerosis was between in 0.06% and 0.15% in systematic reviews and metaanalyses of observational studies (17; 65) and in a hospital-based study in 15- to 40-year-old subjects from Sweden (27). Interestingly, in an earlier hospital based-study from Pakistan, where multiple sclerosis prevalence is known to be low, this rate was at an unexpectedly high rate of 0.7%, but the study population was limited to the younger age group, less than 40 years (96). Asymptomatic family members of multiple sclerosis patients also have both MRI and CSF changes suggestive of multiple sclerosis (55; 90; 75). In another field study, up to 4% of asymptomatic relatives of sporadic multiple sclerosis patients have lesions consistent with multiple sclerosis on their MRI; this rate increases to 10% in families with multiple affected members (19) and the rate of detection of silent MRI lesions in the non-multiple sclerosis discordant monozygotic twins further increases up to 20% (95; 75; 88). There were also 2 earlier case reports in which 2 individuals who had an MRI study for reasons unrelated to multiple sclerosis were found to have incidental lesions consistent with multiple sclerosis. In the first a 39-year-old man had an MRI study as a normal control in a Parkinson disease study and remained free of any clinical symptoms or signs of multiple sclerosis despite continuing MRI activity for the next 9 years and then developed primary progressive disease (62). In the other case a French woman who had an MRI study because of headaches was found to have lesions suggestive of multiple sclerosis and then 3 years later developed relapsing-remitting disease (18). These 2 cases were among the first case reports suggesting that multiple sclerosis could be detected by MRI at a subclinical stage.
The emergence of the radiologically isolated syndrome concept. Although the above-mentioned studies described incidental brain lesions, mostly in family members of people with multiple sclerosis, they were limited by what? Around the same time 3 independent study groups found that such incidental lesions may mark the early phase of multiple sclerosis (49; 68; 83). Inclusion criteria were having an MRI for multiple sclerosis-unrelated reasons such as migraine, other primary headaches, and head trauma, and finding incidental brain MRI lesions fulfilling Barkhof-Tintore´ criteria. The Okuda study introduced the term “radiologically isolated syndrome,” now termed the “Okuda criteria” and is used in most radiologically isolated syndrome studies (Table 1).
Table 1. Radiologically Isolated Syndrome Diagnostic “Okuda” Criteria
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(1) Initial MRI demonstrating anomalies suggestive of demyelinating disease
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(2) Incidental anomalies identified on MRI of the brain or spinal cord with the primary reason for the acquired MRI being evaluation of a process not suggesting a first clinical event of multiple sclerosis
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(3) Central nervous system white matter anomalies meeting MRI criteria:
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(a) Ovoid, well-circumscribed, and homogeneous foci with or without involvement of the corpus callosum
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(b) T2-hyperintensities measuring > 3 mm2 and fulfilling 3 of 4 Barkhof criteria for dissemination in space
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(c) Central nervous system anomalies not consistent with a vascular pattern
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(d) Qualitative determination that central nervous system anomalies have a characteristic appearance of demyelinating lesions
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(4) MRI anomalies do not account for clinically apparent impairments