Clinical Neurology and Neurosurgery 115S (2013) S1–S5
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Asymptomatic MS夽 Aksel Siva ∗ MS Clinic and Department of Neurology, Cerrahpas¸a School of Medicine, Istanbul University, Istanbul, Turkey
a r t i c l e
i n f o
Keywords: Multiple sclerosis Asymptomatic multiple sclerosis Subclinical disease Radiologically isolated syndrome Treatment
a b s t r a c t “Asymptomatic multiple sclerosis (MS)” or “subclinical MS” describes “a clinically silent disease state of MS” discovered by chance either by imaging or at autopsy, or with incidental findings shown by other diagnostic tools that are consistent or suggestive of MS, and that cannot be explained by any other disease or condition. Since the early 1960s there have been a number of autopsy studies reporting cases, in which histopathological brain changes consistent with MS were found, despite that none had any clinical symptom or sign of the disease during their lifetime. Several reports have also shown that asymptomatic first-degree relatives of MS patients may have oligoclonal bands in their cerebrospinal fluids or may turn out to have abnormal evoked potential studies. With the extensive availability of MRI lately, the incidence of individuals having these studies performed for indications other than suspicion of inflammatory demyelinating disease of the central nervous system (CNS) such as primary headaches or trauma, revealing unsuspected brain and/or spinal cord lesions compatible with MS had raised. A number of such case-series reported recently had resulted in increased awareness of this finding and to its relationship to clinical multiple sclerosis. This situation is now referred as “radiologically isolated syndrome (RIS)” and is the most common type of “asymptomatic MS”. Since it is well known that MS has an asymptomatic period of unknown duration in many individuals preceding its initial presentation, either as a clinically isolated syndrome or in rare instances as primary progressive-MS, it is likely that a number of MS patients will be diagnosed by chance as RIS at an early stage before converting to clinical disease. Currently this issue has gained a wide interest as there are no established protocols regarding how to study and follow these individuals or whether they should be treated or not! However, not all patients with RIS are predestined to develop clinical disease and it was recently shown that the rate of conversion to clinical MS is about one-third of RIS cases at five years. Although that there may be some risk factors suggestive of a higher or earlier conversion to clinical disease, none are definite and the current evidence is not supportive of initiating treatment in patients diagnosed as RIS. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is an immune-mediated, neuroinflammatory and neurodegenerative disease of the central nervous system (CNS) with a highly heterogeneous clinical presentation and unpredictable course [1–3]. Most commonly, its first manifestations appears in young adults between ages 20–40 and then remains as a lifetime disease with different forms of clinical expressions and progression in an age dependent manner in some [4]. Its prevalence also shows variations correlated with
夽 This work is an updated review based on a talk given at the Dubrovnik International Conference on MS, which took place between May 10–13, 2012 in Dubrovnik. ∗ Correspondence to: Haci Emin Sok.Hasan Hilmi Pasa apt 40/7, Nis¸antas¸ı 34365, Istanbul, Turkey. Tel.: +90 532 615 8781. E-mail addresses: [email protected], [email protected] 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.012
the genetic background of the individual as well as in a latitude depending geographical distribution in some areas [5]. MS is most common in the north-western Caucasian populations and rare in the eastern-Asian population relatively independent of their location. An increase in MS incidence has been observed and reported in recent years. However, whether MS is really increasing or just diagnosed earlier and more commonly due to several factors such as increased awareness, more common use of MRI in clinical practice and the development and use of other diagnostic tools remains controversial [5]. 1.1. Postmortem studies Pathology typical of MS has been documented on autopsy in persons apparently asymptomatic during life. Georgi in 1961 reported from a total 15,644 autopsies at the Basel Institute of Pathological
S2
A. Siva / Clinical Neurology and Neurosurgery 115S (2013) S1–S5
Anatomy 66 cases of anatomically demonstrated multiple sclerosis given a postmortem MS prevalence rate of 0.4% [6]. Of these cases 55 had a confirmed clinical diagnosis of MS or other neurological disease. However, it was noteworthy that in 12 cases the autopsy finding was “incidental” as these cases were not known to have neurological disease in their lifetime giving a noteworthy rate of 18% “clinically silent” disease of a postmortem MS cohort. These unsuspected cases are probably among the first “asymptomatic MS cases” reported. This report was soon followed by other postmortem studies reporting that finding asymptomatic MS cases in autopsy series is not coincidental and that such a subclinical form is real and probably not so infrequent! Following this initial report, Mackay and Hirano reported two more cases of pathologically proven MS without preceding clinical evidence of the disease [7], and then Gilbert and Sadler in their report of unsuspected MS in another large autopsy series of 2540 routine autopsies from Canada, they found lesions consistent with MS in five cases [8]. A similar work from Scotland was also consistent with these observations [9]. In a study of all autopsied cases of MS from 1965–86 recorded in the Danish MS Register it was calculated that each year about 40 persons would die with clinically silent MS, which corresponded roughly to 25% of deceased persons with an in vivo diagnosis of MS [10]. All these neuropathological (autopsy) studies indicate that MS may remain clinically silent for an entire lifetime in a significant number of individuals suggesting that for every diagnosed MS patient, there may be up to one or two asymptomatic ones with the disease. The likely explanations of finding pathological changes consistent with MS in individuals who never had clinical signs and symptoms of the disease in their lifetime were the periventricular location of these lesions considered to be in silent areas, as well as the probable low severity of inflammation [8,10]. These leave us with the questions on whether asymptomatic/sub clinical MS is a very mild form of the disease, or is it a self-limited process and whether number, severity and location matters on the clinical expression of the disease? 1.2. Incidental findings on MRI – subclinical disease The increasing use of MRI in various neurological or other problems not suggestive of MS also infrequently reveals unsuspected brain lesions compatible with MS. The rate of detection of silent MRI with lesions suggestive of inflammatory/demyelinating nature in the non-MS populations were reported to be
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Asymptomatic MS夽 Aksel Siva ∗ MS Clinic and Department of Neurology, Cerrahpas¸a School of Medicine, Istanbul University, Istanbul, Turkey
a r t i c l e
i n f o
Keywords: Multiple sclerosis Asymptomatic multiple sclerosis Subclinical disease Radiologically isolated syndrome Treatment
a b s t r a c t “Asymptomatic multiple sclerosis (MS)” or “subclinical MS” describes “a clinically silent disease state of MS” discovered by chance either by imaging or at autopsy, or with incidental findings shown by other diagnostic tools that are consistent or suggestive of MS, and that cannot be explained by any other disease or condition. Since the early 1960s there have been a number of autopsy studies reporting cases, in which histopathological brain changes consistent with MS were found, despite that none had any clinical symptom or sign of the disease during their lifetime. Several reports have also shown that asymptomatic first-degree relatives of MS patients may have oligoclonal bands in their cerebrospinal fluids or may turn out to have abnormal evoked potential studies. With the extensive availability of MRI lately, the incidence of individuals having these studies performed for indications other than suspicion of inflammatory demyelinating disease of the central nervous system (CNS) such as primary headaches or trauma, revealing unsuspected brain and/or spinal cord lesions compatible with MS had raised. A number of such case-series reported recently had resulted in increased awareness of this finding and to its relationship to clinical multiple sclerosis. This situation is now referred as “radiologically isolated syndrome (RIS)” and is the most common type of “asymptomatic MS”. Since it is well known that MS has an asymptomatic period of unknown duration in many individuals preceding its initial presentation, either as a clinically isolated syndrome or in rare instances as primary progressive-MS, it is likely that a number of MS patients will be diagnosed by chance as RIS at an early stage before converting to clinical disease. Currently this issue has gained a wide interest as there are no established protocols regarding how to study and follow these individuals or whether they should be treated or not! However, not all patients with RIS are predestined to develop clinical disease and it was recently shown that the rate of conversion to clinical MS is about one-third of RIS cases at five years. Although that there may be some risk factors suggestive of a higher or earlier conversion to clinical disease, none are definite and the current evidence is not supportive of initiating treatment in patients diagnosed as RIS. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is an immune-mediated, neuroinflammatory and neurodegenerative disease of the central nervous system (CNS) with a highly heterogeneous clinical presentation and unpredictable course [1–3]. Most commonly, its first manifestations appears in young adults between ages 20–40 and then remains as a lifetime disease with different forms of clinical expressions and progression in an age dependent manner in some [4]. Its prevalence also shows variations correlated with
夽 This work is an updated review based on a talk given at the Dubrovnik International Conference on MS, which took place between May 10–13, 2012 in Dubrovnik. ∗ Correspondence to: Haci Emin Sok.Hasan Hilmi Pasa apt 40/7, Nis¸antas¸ı 34365, Istanbul, Turkey. Tel.: +90 532 615 8781. E-mail addresses: [email protected], [email protected] 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.012
the genetic background of the individual as well as in a latitude depending geographical distribution in some areas [5]. MS is most common in the north-western Caucasian populations and rare in the eastern-Asian population relatively independent of their location. An increase in MS incidence has been observed and reported in recent years. However, whether MS is really increasing or just diagnosed earlier and more commonly due to several factors such as increased awareness, more common use of MRI in clinical practice and the development and use of other diagnostic tools remains controversial [5]. 1.1. Postmortem studies Pathology typical of MS has been documented on autopsy in persons apparently asymptomatic during life. Georgi in 1961 reported from a total 15,644 autopsies at the Basel Institute of Pathological
S2
A. Siva / Clinical Neurology and Neurosurgery 115S (2013) S1–S5
Anatomy 66 cases of anatomically demonstrated multiple sclerosis given a postmortem MS prevalence rate of 0.4% [6]. Of these cases 55 had a confirmed clinical diagnosis of MS or other neurological disease. However, it was noteworthy that in 12 cases the autopsy finding was “incidental” as these cases were not known to have neurological disease in their lifetime giving a noteworthy rate of 18% “clinically silent” disease of a postmortem MS cohort. These unsuspected cases are probably among the first “asymptomatic MS cases” reported. This report was soon followed by other postmortem studies reporting that finding asymptomatic MS cases in autopsy series is not coincidental and that such a subclinical form is real and probably not so infrequent! Following this initial report, Mackay and Hirano reported two more cases of pathologically proven MS without preceding clinical evidence of the disease [7], and then Gilbert and Sadler in their report of unsuspected MS in another large autopsy series of 2540 routine autopsies from Canada, they found lesions consistent with MS in five cases [8]. A similar work from Scotland was also consistent with these observations [9]. In a study of all autopsied cases of MS from 1965–86 recorded in the Danish MS Register it was calculated that each year about 40 persons would die with clinically silent MS, which corresponded roughly to 25% of deceased persons with an in vivo diagnosis of MS [10]. All these neuropathological (autopsy) studies indicate that MS may remain clinically silent for an entire lifetime in a significant number of individuals suggesting that for every diagnosed MS patient, there may be up to one or two asymptomatic ones with the disease. The likely explanations of finding pathological changes consistent with MS in individuals who never had clinical signs and symptoms of the disease in their lifetime were the periventricular location of these lesions considered to be in silent areas, as well as the probable low severity of inflammation [8,10]. These leave us with the questions on whether asymptomatic/sub clinical MS is a very mild form of the disease, or is it a self-limited process and whether number, severity and location matters on the clinical expression of the disease? 1.2. Incidental findings on MRI – subclinical disease The increasing use of MRI in various neurological or other problems not suggestive of MS also infrequently reveals unsuspected brain lesions compatible with MS. The rate of detection of silent MRI with lesions suggestive of inflammatory/demyelinating nature in the non-MS populations were reported to be
