Multiple Sclerosis and Related Disorders (]]]]) ], ]]]–]]]
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Late onset multiple sclerosis: Is it really late onset? Pezhman Roohania,n, Tenbit Emirua, Adam Carpentera,1, Christopher Luzziob, Jerome Freemanc, Susan Scarberryd, Gary Beavera, Lisa Davidsone, Gareth Parrya a
Department of Neurology, University of Minnesota, 420 Delaware Street SE, MMC 295, Minneapolis, MN 55455, United States b Department of Neurology, University of Wisconsin, 20 South Park, Madison, WI 53715, United States c Sanford Clinic Neurology, School of Medicine of the University of South Dakota, 1210 W 18th Street, Suite 101, Sioux Falls, SD 57104, United States d Sanford Neuroscience Center, 700 1st Avenue S, Fargo, ND 58103, United States e Mankato Clinic, Department of Neurology, 1230 E Main, Mankato, MN 56002, United States Received 11 December 2013; received in revised form 10 February 2014; accepted 19 February 2014
KEYWORDS Late onset multiple sclerosis; Multiple sclerosis; Demyelinating disease in the elderly
Abstract Background: Multiple sclerosis (MS) is the most common demyelinating disease, and onset over the age of 50 years is referred to as late onset MS (LOMS). It has been thought that LOMS patients will be more likely to exhibit a primary progressive (PPMS) clinical course. Objective: To identify the clinical characteristics of demyelinating disease in patients over the age of 50 years from four different MS centers in the Northern Midwest USA. Methods: We reviewed medical records of all patients seen at the MS centers and identified those who were 50 years of age or more at the time of first spontaneously reported symptoms. We included those who were diagnosed with MS or clinically isolated syndrome (CIS) and excluded MS mimickers. Demographics, initial clinical course diagnosis, clinical characteristics, and any available five-year follow up data were collected. The clinical course was reevaluated in each patient with careful questioning regarding any prior focal neurological symptoms that had persisted for at least 48 h, not otherwise explained. Those with a prior event who were initially diagnosed with PPMS or CIS were reclassified as secondary-progressive MS (SPMS) and relapsing-remitting MS (RRMS) respectively. Results: We identified 124 patients from a total of 3700 patients, making LOMS 3.4% MS in our population. The initial clinical course was RRMS in 50 (40%), PPMS in 44 (36%), SPMS in 15 (12%), and CIS in 15 (12%) patients. After reclassification the clinical course was RRMS in 55 (44%),
n
Corresponding author. Tel.: +1 305 890 4913. E-mail addresses: [email protected] (P. Roohani), [email protected] (T. Emiru), [email protected] (A. Carpenter), [email protected] (C. Luzzio), [email protected] (J. Freeman), [email protected] (S. Scarberry), [email protected] (G. Parry). 1 Current address: Brain Sciences Center, 11B, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, United States. http://dx.doi.org/10.1016/j.msard.2014.02.004 2211-0348 & 2014 Published by Elsevier B.V.
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
2
P. Roohani et al. PPMS in 25 (20%), SPMS in 34 (28%), and CIS in 10 (8%) patients. The clinical syndrome was identified as acute for 77 patients (62%) with transverse myelitis (N= 25, 32%) as the most common type. The clinical syndrome was chronic for 47 patients (37%) and again transverse myelitis (N =24, 51%) was the most common type. Five-year follow up data was available for 44% of these patients. Discussion: LOMS is rare and RRMS is the most common clinical course. Reclassification of the clinical course, not done before in any other LOMS study, with careful questioning regarding a prior neurological event reveals that SPMS is the most common type of progressive MS and PPMS may be less common than previously thought. Transverse myelitis is the most common clinical presentation. & 2014 Published by Elsevier B.V.
1.
Introduction
Demyelinating disease initially presenting after the age of 50 years is not common. Multiple sclerosis (MS), the most common form of demyelinating disease, usually has onset in early adulthood. Late-onset MS (LOMS) has been defined as MS in which the first recognized manifestation of disease appears after the age of 50 years (Bauer and Hanefled, 1993; Polliack et al., 2001; White et al., 1990; Martinelli et al., 2004) while MS initially presenting after the age of 60 has been defined as very late onset MS (Azzimondi et al., 1994; Hooge and Redekop, 1992). The primary objective of this study was to identify the clinical characteristics of demyelinating disease in patients over the age of 50 years from four different MS centers in Northern Midwest USA. We postulated that LOMS would most often be of the progressive type, either primary progressive MS (PPMS) or secondary progressive MS (SPMS). In our clinics we have seen several patients whose MS was initially first recognized after the age of 50 years but in whom further questioning unearthed a history of prior neurological events suggestive of an earlier MS relapse. We, therefore, specifically questioned all subjects in this study to determine the proportion of LOMS patients with such a history.
2.
Design and methods
We reviewed medical records of patients seen at University of Minnesota in Minneapolis, University of Wisconsin in Madison, Sanford Clinic Neurology in Sioux Falls, South Dakota and Fargo, North Dakota. Patients who were 50 years of age or more at time of first recognized symptom thought to be due to MS were included. Patient over the age of 50 years were identified to have LOMS (Bauer and Hanefled, 1993; Polliack et al., 2001; White et al., 1990; Martinelli et al., 2004) and those over the age of 60 years were identified as having VLOMS (Azzimondi et al., 1994; Hooge and Redekop, 1992). Because this was a retrospective study and many patients were first seen more than 10 years ago, MS diagnosis was based on Poser criteria or the original McDonald criteria (Poser et al., 1983; McDonald et al., 2001). In reviewing the records we tried to ensure that a more plausible diagnosis could not explain the clinical presentation. Specifically, we sought clinical, imaging or
laboratory evidence of neuromyelitis optica, cerebrovascular disease, connective tissue disease, Lyme disease, CADASIL, sarcoidosis, fragile X syndrome, vitamin B12 deficiency, or copper deficiency. Gender, date of symptom onset, and age at symptom onset were recorded. The initial MS clinical course was identified as relapsing remitting (RRMS), primary progressive (PPMS), or secondary progressive (SPMS) (Lublin and Reingold, 1996). Some patients had isolated events and were identified as clinically isolated syndrome (CIS) (Miller et al., 2008). The percentage of patients who presented with each clinical course was calculated and reported. Patients presenting with the clinical course of PPMS and CIS were carefully questioned to determine if a previous episode of neurological dysfunction, highly suggestive of demyelinating disease, had occurred. To be included as an episode suggestive of an earlier MS relapse, prior symptoms had to be focal in distribution and must have persisted for at least 48 h. Subjects were questioned by the evaluating neurologist either at the time of the initial presentation, at a subsequent clinic visit or by way of a follow up telephone call. The nature of the questioning was at the discretion of the evaluating neurologist but patients were specifically questioned regarding transient monocular visual loss, diplopia, vertigo and focal weakness, numbness or paresthesias. Vague and nonspecific symptoms such as fatigue, isolated sphincter disturbances, dizziness without vertigo and nonfocal weakness or sensory symptoms were not regarded as evidence suggestive of prior relapse. The age at which any prior symptom had occurred was recorded as accurately as possible. Those patients from whom the stated history was identified were then reclassified. Patients who were initially diagnosed with PPMS were reclassified as SPMS and similarly, patients who were initially diagnosed with CIS were reclassified as RRMS. After reclassification, the percentage of individuals with each clinical course was then calculated again. Also, given that the mean age of onset was now different, the mean age of onset after reclassification was calculated and reported. The clinical syndrome at the time that MS was initially recognized was defined as an acute relapse if symptoms developed over a period of days, or as chronic, if symptoms began insidiously. The exact nature of the clinical syndrome was categorized based on the neurological examination and MRI appearance as transverse myelitis, optic neuritis, brainstem or cerebellar disease, subcortical motor, subcortical sensory,
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
Late onset multiple sclerosis
3
multifocal, or cerebral, such as cognitive impairment, seizure or fatigue. The percentage or proportion of patients with each clinical syndrome was calculated and reported. Magnetic resonance imaging (MRI) and laboratory data obtained during the initial presentation and any available five-year follow up information obtained through chart review were also recorded. The initial MRI's were personally reviewed by the evaluating neurologists in the course of their routine clinical assessments of the patient; no standardized approach to lesion assessment was used. The percentage or proportion of specific lesion types were calculated and reported. Lumbar puncture was not routinely performed; therefore insufficient data was available to permit analysis.
common (Table 1) while SPMS and CIS were much less common. This was true regardless of gender. Based on reporting of a prior focal neurological event on specific questioning, some patients initially diagnosed with PPMS and CIS were reclassified (Table 2). 43% of the PPMS patients and 33% of CIS patients recalled a prior focal neurological event and were reclassified as SPMS or RRMS respectively. The final classification of patients was, therefore, RRMS in 55 (44%), PPMS in 25 (20%), SPMS in 34 (28%),
Table 2 Clinical course classification before and after reclassification based on careful questioning regarding a prior focal neurological deficit. Clinical course Initial diagnosis Reclassified diagnosis
3.
Results
After excluding all patients for whom there was a more plausible explanation of symptoms we identified 124 MS patients (Table 1) whose first spontaneously reported symptom developed after the age of 50 years from a total of 3700 patients seen in our four MS centers. LOMS, therefore, constituted 3.4% of this MS population. Twenty six (21%) of LOMS patients experienced the first symptom at the age of 60 years or more and nine (7%) at age 70 years or more. Patients with onset after the age of 60 years were classified as very late-onset MS (VLOMS) (Hooge and Redekop, 1992; Azzimondi et al., 1994). The median age was 55 years for females (range 50–72) and 55.5 years for males (range 50– 77). Table 1 shows the demographics, clinical course, and clinical syndrome of the patients. Based on the initial clinical impression, that is, before closer questioning regarding earlier symptoms suggestive of prior relapses, RRMS and PPMS were approximately equally Table 1
RRMS PPMS SPMS CIS
40% 36 12 12
(N =50) (N =44) (N =15) (N =15)
44% 20 28 8
(N =55) (N =25) (N =34) (N =10)
Table 3 Age of onset stratified by clinical course before and after reclassification. Mean age (years)
Clinical course
Before reclassification RRMS PPMS SPMS CIS
56.8 56.7 56.8 56.2
(s =5.4) (5.6) (6.2) (6.1)
After reclassification 55.4 56.2 49.4 54.5
(s =7.3) (5.5) (8.9) (5.9)
Clinical course diagnosis and clinical syndrome sub analyzed by gender.
Demographics Median age (range)
Female 64% (N =79) 55 (50–72)
Male 36% (N =45) 55.5 (50–77)
Total (N =124) 55.2 (50–77)
Clinical course RRMS PPMS SPMS CIS
42% 34 13 11
(N =33) (N =27) (N =10) (N =9)
38% 38 11 13
(N= 17) (N= 17) (N= 5) (N= 6)
40% 36 12 12
(N =50) (N =44) (N =15) (N =15)
Clinical syndrome – acute Transverse myelitis Multifocal Optic neuritis Subcortical sensory Subcortical motor Cerebral Brainstem/cerebellar
29 23 12 14 8 8 6
(N =15) (N =12) (N =6) (N =7) (N =4) (N =4) (N =3)
38 15 12 4 7 12 12
(N= 10) (N= 4) (N= 3) (N= 1) (N= 2) (N= 3) (N= 3)
32 21 12 10 8 9 8
(N =25) (N =16) (N =9) (N =8) (N =6) (N =7) (N =6)
Clinical syndrome – chronic Transverse myelitis Subcortical motor Other
50 (N =14) 18 (N =5) 32 (N =9)
53 (N= 10) 10 (N= 2) 37 (N= 7)
51 (N =24) 15 (N =7) 34 (N =16)
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
4
P. Roohani et al.
Table 4
Clinical course classification by age groups.
Clinical course
Age 50–59 (N =89)
RRMS PPMS SPMS CIS
40% 34 14 12
VLOMS 60–77 (N= 35)
(N =36) (N =30) (N =12) (N =11)
40% 40 9 11
(N =14) (N =14) (N =3) (N =4)
MRI brain MRI spine
72 60
41 39
Lesion distribution (%) Periventricular Corpus callosum Juxtacortical Brainstem Cerebellar Spinal
83 39 29 26 17 22
88 44 24 15 22 21
and CIS in 10 (8%) patients. Table 2 shows the reclassified clinical course. For those with CIS reclassified as RRMS the mean and median age of onset is 41. For those with PPMS reclassified as SPMS the mean age of onset is 44 and median age of onset is 43. Age of onset by clinical course, before and after reclassification, is shown in Table 3. Thirty five patients presented with VLOMS. In those whose first symptom occurred between age 60 and 69 years (N =26) the clinical course was RRMS in 12 (46%), PPMS in 10 (38%), SPMS in one (4%), and CIS in three (12%) patients. In those whose first symptom occurred after the age of 70 years (N = 9) the clinical course was: RRMS in two (22%), PPMS in four (45%), SPMS in two (22%), and CIS in one (11%) patient. Table 4 shows the clinical course divided by age group, including for VLOMS. Seventy seven (62%) patients presented with an acute focal neurological syndrome. The most common type of acute clinical syndrome was transverse myelitis (N= 25, 32%). Other clinical patterns included multifocal deficits, optic neuritis, subcortical sensory, subcortical motor, brainstem or cerebellar deficits, and other cortical deficits (Table 1). Forty seven (38%) patients presented with a chronic neurological syndrome. The most common type of chronic clinical presentation was transverse myelitis (51%). Seven (15%) patients had subcortical motor deficits (Table 1). Brain MRI results were available in 113 (91%) patients, 72 (64%) of whom had the acute onset and 41 (36%) who had the chronic onset. Spinal MRI was obtained in 99 (80%) patients, 60 (60%) of whom had acute onset and 39 (40%) who had chronic onset. The number of available MRI results
Number of patients
Chronic
(N =12) (N =10) (N =1) (N =3)
22% 45 22 11
(N =2) (N =4) (N =2) (N =1)
25 20 15 10 5 0 A
B
C
D
Figure 1 (A) No difficulty with ambulation, (B) ambulation impaired but can walk without assistance, (C) uses a cane, walker, wheelchair or scooter and (D) confined to wheelchair. Disease course status at 5 year follow up Number of patients
Acute
46% 38 4 12
VLOMS470 (N=9)
Ambulation at 5 year follow up
Table 5 Number of patients with MRI imaging available and the proportion of images (in %) with localized lesions in different areas. Imaging modality
VLOMS 60–69 (N= 26)
25 20 15 10 5 0 A
B
C
D
Figure 2 (A) neurologically normal, (B) static residual deficit, (C) recurrent relapse and (D) progressive deficits.
and the proportion of patients with different types of MRI lesions are reported in Table 5. Five-year follow up data was available for 54 patients (44%), the other patients were either lost to follow up or they had not yet reached the five years from initial evaluation. Fifty (93%) had difficulty with ambulation at that time (Figure 1). In 39 (31%) patients, whose course status was assessed; three (8%) were neurologically normal, 22 (56%) had static residual deficits, 10 (26%) experienced at least one relapse, and four (10%) patients had worsening of neurological deficits (Figure 2).
4.
Discussion
This study confirms that LOMS is uncommon; 3.4% of MS patients from the upper Midwest region of the US presented after the age of 50, consistent with previous findings (Phadke, 1990; Crossburn et al., 2012; Bove et al., 2012; Tremlett and Devonshire, 2006). Women were more commonly represented, with a female:male ratio of 1.7:1. We had anticipated that the most common clinical course would be a progressive disorder, but found that relapsing and progressive courses were nearly equally common. The most
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
Late onset multiple sclerosis common clinical course diagnosed at our centers were RRMS and PPMS, however, several patients with PPMS and CIS were subsequently reclassified as SPMS and RRMS, making SPMS and RRMS a more common diagnosis than initially recognized. VLOMS is present in about 1% of the total MS population in our centers. In VLOMS, PPMS and SPMS constitute two-thirds of the diagnoses over the age of 70 years. The most common clinical syndrome acutely and chronically was transverse myelitis and progressive paraperesis, respectively. Among patients for whom five year clinical outcome was available, the majority required assistance to walk or were confined to a wheelchair. The disease course that was most common was static disease with residual deficits. MS presenting before the age of 50 years is generally accepted to have a female predominance of 2–3:1 (Bove et al., 2012; Steinman, 1993; Confavreux et al., 1980; Rosati, 2001; Pugliatti et al., 2006). Studies of LOMS have also shown a female predominance (Bauer and Hanefled, 1993; Cazzullo et al., 1978; Compston and Cole, 2002). In our study a female predominance is present but males are relatively more common compared to younger patients, as the female to male ratio is 1.7:1. Other gender differences have been reported in the past and our study failed to reproduce the same significant differences. In some studies, PPMS was found to be more common in males (Crossburn et al., 2012; Martinelli et al., 2004; Bove et al., 2012). Polliack et al. (2001) reported a large difference in LOMS based on gender; while 63% of female patients had RRMS, 73% of their male counterparts had PPMS. Sub analysis based on gender in our study did not recapitulate these findings. Some studies have shown a marked predominance of PPMS in LOMS (Tremlett and Devonshire, 2006; Kis et al., 2008). Bove et al. (2012) on the other hand reported RRMS to be more common, as was seen in our study. It is clear though, that despite the predominance of RRMS, PPMS is more common in the late onset population in comparison to adult onset MS (AOMS) in whom it has been most frequently reported to be about 15% (Confavreux et al., 1980; Thompson et al., 1997; Weinshenker et al., 1989). In our study, we sought to determine if patients presenting after the age of 50 had experienced an event for which the most plausible explanation was a prior demyelinating lesion, but who had not sought medical attention or had been undiagnosed. Several patients with initial diagnosis of CIS and PPMS reported prior events, thus we were able to identify probable disease onset prior to the age of 50 years in these patients and reclassified those patients initially thought to have CIS to RRMS and those initially thought to have PPMS to SPMS. The reclassification demonstrates that RRMS is more common than initially thought and SPMS is the commonest progressive clinical course. We acknowledge that reclassification was based on subjective reporting of events that occurred, in some cases, many years earlier. VLOMS has been defined as MS with onset after the age of 60 years (Azzimondi et al., 1994; Hooge and Redekop, 1992). In our study several patients presented with VLOMS. We found that the clinical course shifted towards a progressive type in those aged 70 years and more, although the sample size was very small. Other studies have reported that VLOMS occurs in 0.8–1.33% of MS patients (Bove et al., 2012; Tremlett and Devonshire, 2006). In another study 80% of LOMS patients
5 presented between the ages of 50 and 59 (Qiu et al., 2010). These studies are consistent with our findings. The clinical syndrome at presentation in our study is different from MS presenting earlier in life. In the acute onset patients 32% presented with TM and 21% presented with multifocal findings while only 12% presented with ON. In contrast ON is the initial diagnosis in 20–38% of MS patients presenting at the more typical younger age (Shams and Plant, 2009; Sellner et al., 2008) while TM has been reported as the initial event in o14% of patients (Paolino et al., 1996). The high incidence of multifocal findings in our study may indicate that a prior demyelinating episode may have gone unrecognized. In LOMS patients, motor as well as cerebellar and brainstem symptoms have been found to be more prevalent than sensory symptoms and optic neuritis (Tremlett and Devonshire, 2006; Martinelli et al., 2004; Kis et al., 2008). We found that motor symptoms caused by transverse myelitis were more common in LOMS patients. Some studies have found that LOMS has a poor prognosis (Liguori et al., 2000; Runmarker et al., 1994; Weinshenker, 2000) while others report no difference between LOMS and AOMS (Tremlett and Devonshire, 2006; Moreau and Confavreux, 2000). A five-year follow up was available in nearly half of our patients. Surprisingly, more than half of the patients were reported to be stable. We suspect that this is because of the retrospective nature of the study; patients with a very slowly progressive disorder may report that they are stable. Most of the remainder had either continued to progress or had developed progressive disease, 10 patients continued with a relapsing course, and three patients with RRMS were clinically normal at follow up. It has been reported that LOMS patients progress more rapidly compared to their younger counterparts. Tremlett and Devonshire (2006) reported that those with LOMS took a median of 16.9 years to reach an expanded disability status scale (EDSS) score of 6 compared to younger patients with MS who took 27.7 years. The patients with LOMS were older when reaching EDSS score of 6 (58.4 in AOMS vs. 71.2 years in LOMS). The authors propose that disease prognosis is not determined by the presence of LOMS, rather it is determined by the disease course. This study does have some limitations. The referred patients may not be representative of all MS patients. Two of the centers were academic; however two were community neurology centers with a referral base not different from any other neurology community center. Also, the manner in which the history of a prior event suggestive of a demyelinating episode was obtained was not completely standardized; it was instead left to the judgment of the Neurologist. In the same way the manner in which MRI lesions were analyzed was not standardized and left to the judgment of the Neurologist. The nonstandardized approach may lead to results that are not reliable; however given that this is a clinical study the approach was deemed to be appropriate. A final limitation is that the history of our patients with prior episodes was not validated through record review. The history of prior episodes was solely based on patients report and the records were not available to determine the validity of our patient's reports. This creates an opportunity for recall bias. In conclusion, LOMS is rare but encompasses the same clinical courses as AOMS. VLOMS is even rarer and is more likely to be progressive in the later ages. The clinical
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
6
P. Roohani et al.
classification is based on historical and spontaneously reported data from the patient, which may not always be complete and accurate. Many patients initially diagnosed with PPMS and CIS report earlier neurological events, on further evaluation, suggestive of a previous episode of focal demyelination. The elucidation of a previous event indicates that clinicians need to be vigilant and careful when seeking a history of prior events at the time of initial evaluation. This information indicates that true onset after age of 50 is even less common than we thought, particularly with PPMS. In this age group, presentation with motor deficits, especially those associated with transverse myelitis, are more common than in AOMS while optic neuritis and pure sensory symptoms are less common.
Conflict of interest Pezhman Roohani, Tenbit Emir, Adam Carpenter, Christopher Luzzio, and Jerome Freeman have no conflict of interest or financial disclosure. Susan Scarberry has been on the speaker's bureau for NMSS, Teva Neuroscience and Genzyme. She has received research support from Teva Neuroscience, Biogen-Idec, and Novartis. She has been a speaker for Bayer and research for EMD Serono. Gary Beaver has received honoraria from Genzyme, Novartis, Biogen, Bayer, and Teva. Lisa Davidson has been on Allergan speaker's bureau and previously speaker for Pfizer and Teva. Gareth Parry has been on the speaker's bureau for bioCSL, Novartis, EMD-Serono, Sanofi-Genzyme and Teva Neuroscience in the last 5 years and has received research support from Biogen-Idec, EMD-Serono, Sanofi-Genzyme and Teva Neuroscience.
References Azzimondi G, Stracciari A, Rinaldi R, D’Alessandro R, Pazzaglia P. Multiple sclerosis with very late onset: report of six cases and review of the literature. Eur Neurol 1994;34(6):332–6. Bauer HJ, Hanefled FA. Multiple sclerosis: its impact from childhood to old age.London: W.B. Saunders; 1993. Bove R, Healy B, Augustine A, Musallam A, Gholipour T, Chitnis T. Effect of gender on later onset multiple sclerosis. Mult Scler 2012;18(10):1472–9. Cazzullo CL, Ghezzi A, Marforio S, Caputo D. Clinical picture of multiple sclerosis with late onset. Acta Neurol Scand 1978;58 (3):190–6. Compston A, Cole AJ. Multiple sclerosis. Lancet 2002;359(9313): 1221–1231. Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103(2):281–300. Crossburn M, Ingram G, Hirst C, Ben-Shlomo Y, Pickersgill TP, Robertson NP. Age at onset as a determinant of presenting phenotype and initial relapse and recovery in multiple sclerosis. Mult Scler 2012;18(1):45–54. Hooge JP, Redekop WK. Multiple sclerosis with very late onset. J Neurol 1992;42(10):1907–10.
Kis B, Rumberg B, Berlit P. Clinical characteristics of patients with late-onset multiple sclerosis. J Neurol 2008;255(5):697–702. Liguori M, Marrosu MG, Pugliatti M, Giuliani F, De Robertis F, Cocco E, et al. Age at onset in multiple sclerosis. Neurol Sci 2000;21(4):825–9. Lublin F, Reingold S. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46(4):907–11. Martinelli V, Rodegher M, Moiola L, Comi G. Late onset multiple sclerosis: clinical characteristics, prognostic factors and differential diagnosis. Neurol Sci 2004;25(4):350–5. McDonald WI, Compston A, Edan G, Hartung HP, Lumlin FD, McFarland HF, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50(1):121–7. Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler 2008;14(9):1157–74. Moreau T, Confavreux C. Can the prognosis of multiple sclerosis be predicted? Pathol Biol 2000;48(2):132–8. Paolino E, Fainardi E, Ruppi P, Tola MR, Govoni V, Casetta I, et al. A prospective study on the predictive value of CSF oligoclonal bands and MRI in acute isolated neurological syndromes for subsequent progression to multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;60(5):572–5. Phadke JG. Clinical aspects of multiple sclerosis in north-east Scotland with particular reference to its course and prognosis. Brain 1990;113(Pt 6):1597–628. Polliack M, Barak Y, Achiron A. Late-onset multiple sclerosis. J Am Geriatr Soc 2001;49(2):168–71. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13(3):227–31. Pugliatti M, Rosati G, Carton H, Riise T, Drulovic J, Vecsei L, et al. The epidemiology of multiple sclerosis in Europe. Eur J Neurol 2006;13(7):700–22. Qiu W, Wu JS, Castley A, James I, Joseph J, Christiansen FT, et al. Clinical profile and HLA-DRB1 genotype of late onset multiple sclerosis in Western Australia. J Clin Neurosci 2010;17 (8):1009–13. Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci 2001;22:117–39. Runmarker B, Andersson C, Oden A, Andersen O. Prediction of outcome in multiple sclerosis based on multivariate models. J Neurol 1994;241(10):597–604. Sellner J, Luthi N, Buhler R, Gebhardt A, Findiling O, Greeve I, et al. Acute partial transverse myelitis: risk factors for conversion to multiple sclerosis. Eur J Neurol 2008;15(4):398–405. Shams PN, Plant GT. Optic neuritis: a review. Int MS J 2009;16(3):82–9. Steinman L. Autoimmune disease. Sci Am 1993;269(3):106–14. Thompson AJ, Polman CH, Miller DH, McDonald WI, Brochet B, Filippi M, et al. Primary progressive multiple sclerosis. Brain 1997;120(6):1085–96. Tremlett H, Devonshire V. Is later onset multiple sclerosis associated with a worse outcome? J Neurol 2006;67:954–9. Weinshenker BG, Bass B, Rice GPA, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographical based study. 1. Clinical course and disability. Brain 1989;112(1):133–46. Weinshenker BG. Progressive forms of MS: classification streamlined or consensus overturned? Lancet 2000;355(9199):162–3. White AD, Swingler RJ, Compston DA. Features of multiple sclerosis in older patients in South Wales. Gerontology 1990;36:159–64.
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Late onset multiple sclerosis: Is it really late onset? Pezhman Roohania,n, Tenbit Emirua, Adam Carpentera,1, Christopher Luzziob, Jerome Freemanc, Susan Scarberryd, Gary Beavera, Lisa Davidsone, Gareth Parrya a
Department of Neurology, University of Minnesota, 420 Delaware Street SE, MMC 295, Minneapolis, MN 55455, United States b Department of Neurology, University of Wisconsin, 20 South Park, Madison, WI 53715, United States c Sanford Clinic Neurology, School of Medicine of the University of South Dakota, 1210 W 18th Street, Suite 101, Sioux Falls, SD 57104, United States d Sanford Neuroscience Center, 700 1st Avenue S, Fargo, ND 58103, United States e Mankato Clinic, Department of Neurology, 1230 E Main, Mankato, MN 56002, United States Received 11 December 2013; received in revised form 10 February 2014; accepted 19 February 2014
KEYWORDS Late onset multiple sclerosis; Multiple sclerosis; Demyelinating disease in the elderly
Abstract Background: Multiple sclerosis (MS) is the most common demyelinating disease, and onset over the age of 50 years is referred to as late onset MS (LOMS). It has been thought that LOMS patients will be more likely to exhibit a primary progressive (PPMS) clinical course. Objective: To identify the clinical characteristics of demyelinating disease in patients over the age of 50 years from four different MS centers in the Northern Midwest USA. Methods: We reviewed medical records of all patients seen at the MS centers and identified those who were 50 years of age or more at the time of first spontaneously reported symptoms. We included those who were diagnosed with MS or clinically isolated syndrome (CIS) and excluded MS mimickers. Demographics, initial clinical course diagnosis, clinical characteristics, and any available five-year follow up data were collected. The clinical course was reevaluated in each patient with careful questioning regarding any prior focal neurological symptoms that had persisted for at least 48 h, not otherwise explained. Those with a prior event who were initially diagnosed with PPMS or CIS were reclassified as secondary-progressive MS (SPMS) and relapsing-remitting MS (RRMS) respectively. Results: We identified 124 patients from a total of 3700 patients, making LOMS 3.4% MS in our population. The initial clinical course was RRMS in 50 (40%), PPMS in 44 (36%), SPMS in 15 (12%), and CIS in 15 (12%) patients. After reclassification the clinical course was RRMS in 55 (44%),
n
Corresponding author. Tel.: +1 305 890 4913. E-mail addresses: [email protected] (P. Roohani), [email protected] (T. Emiru), [email protected] (A. Carpenter), [email protected] (C. Luzzio), [email protected] (J. Freeman), [email protected] (S. Scarberry), [email protected] (G. Parry). 1 Current address: Brain Sciences Center, 11B, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, United States. http://dx.doi.org/10.1016/j.msard.2014.02.004 2211-0348 & 2014 Published by Elsevier B.V.
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
2
P. Roohani et al. PPMS in 25 (20%), SPMS in 34 (28%), and CIS in 10 (8%) patients. The clinical syndrome was identified as acute for 77 patients (62%) with transverse myelitis (N= 25, 32%) as the most common type. The clinical syndrome was chronic for 47 patients (37%) and again transverse myelitis (N =24, 51%) was the most common type. Five-year follow up data was available for 44% of these patients. Discussion: LOMS is rare and RRMS is the most common clinical course. Reclassification of the clinical course, not done before in any other LOMS study, with careful questioning regarding a prior neurological event reveals that SPMS is the most common type of progressive MS and PPMS may be less common than previously thought. Transverse myelitis is the most common clinical presentation. & 2014 Published by Elsevier B.V.
1.
Introduction
Demyelinating disease initially presenting after the age of 50 years is not common. Multiple sclerosis (MS), the most common form of demyelinating disease, usually has onset in early adulthood. Late-onset MS (LOMS) has been defined as MS in which the first recognized manifestation of disease appears after the age of 50 years (Bauer and Hanefled, 1993; Polliack et al., 2001; White et al., 1990; Martinelli et al., 2004) while MS initially presenting after the age of 60 has been defined as very late onset MS (Azzimondi et al., 1994; Hooge and Redekop, 1992). The primary objective of this study was to identify the clinical characteristics of demyelinating disease in patients over the age of 50 years from four different MS centers in Northern Midwest USA. We postulated that LOMS would most often be of the progressive type, either primary progressive MS (PPMS) or secondary progressive MS (SPMS). In our clinics we have seen several patients whose MS was initially first recognized after the age of 50 years but in whom further questioning unearthed a history of prior neurological events suggestive of an earlier MS relapse. We, therefore, specifically questioned all subjects in this study to determine the proportion of LOMS patients with such a history.
2.
Design and methods
We reviewed medical records of patients seen at University of Minnesota in Minneapolis, University of Wisconsin in Madison, Sanford Clinic Neurology in Sioux Falls, South Dakota and Fargo, North Dakota. Patients who were 50 years of age or more at time of first recognized symptom thought to be due to MS were included. Patient over the age of 50 years were identified to have LOMS (Bauer and Hanefled, 1993; Polliack et al., 2001; White et al., 1990; Martinelli et al., 2004) and those over the age of 60 years were identified as having VLOMS (Azzimondi et al., 1994; Hooge and Redekop, 1992). Because this was a retrospective study and many patients were first seen more than 10 years ago, MS diagnosis was based on Poser criteria or the original McDonald criteria (Poser et al., 1983; McDonald et al., 2001). In reviewing the records we tried to ensure that a more plausible diagnosis could not explain the clinical presentation. Specifically, we sought clinical, imaging or
laboratory evidence of neuromyelitis optica, cerebrovascular disease, connective tissue disease, Lyme disease, CADASIL, sarcoidosis, fragile X syndrome, vitamin B12 deficiency, or copper deficiency. Gender, date of symptom onset, and age at symptom onset were recorded. The initial MS clinical course was identified as relapsing remitting (RRMS), primary progressive (PPMS), or secondary progressive (SPMS) (Lublin and Reingold, 1996). Some patients had isolated events and were identified as clinically isolated syndrome (CIS) (Miller et al., 2008). The percentage of patients who presented with each clinical course was calculated and reported. Patients presenting with the clinical course of PPMS and CIS were carefully questioned to determine if a previous episode of neurological dysfunction, highly suggestive of demyelinating disease, had occurred. To be included as an episode suggestive of an earlier MS relapse, prior symptoms had to be focal in distribution and must have persisted for at least 48 h. Subjects were questioned by the evaluating neurologist either at the time of the initial presentation, at a subsequent clinic visit or by way of a follow up telephone call. The nature of the questioning was at the discretion of the evaluating neurologist but patients were specifically questioned regarding transient monocular visual loss, diplopia, vertigo and focal weakness, numbness or paresthesias. Vague and nonspecific symptoms such as fatigue, isolated sphincter disturbances, dizziness without vertigo and nonfocal weakness or sensory symptoms were not regarded as evidence suggestive of prior relapse. The age at which any prior symptom had occurred was recorded as accurately as possible. Those patients from whom the stated history was identified were then reclassified. Patients who were initially diagnosed with PPMS were reclassified as SPMS and similarly, patients who were initially diagnosed with CIS were reclassified as RRMS. After reclassification, the percentage of individuals with each clinical course was then calculated again. Also, given that the mean age of onset was now different, the mean age of onset after reclassification was calculated and reported. The clinical syndrome at the time that MS was initially recognized was defined as an acute relapse if symptoms developed over a period of days, or as chronic, if symptoms began insidiously. The exact nature of the clinical syndrome was categorized based on the neurological examination and MRI appearance as transverse myelitis, optic neuritis, brainstem or cerebellar disease, subcortical motor, subcortical sensory,
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
Late onset multiple sclerosis
3
multifocal, or cerebral, such as cognitive impairment, seizure or fatigue. The percentage or proportion of patients with each clinical syndrome was calculated and reported. Magnetic resonance imaging (MRI) and laboratory data obtained during the initial presentation and any available five-year follow up information obtained through chart review were also recorded. The initial MRI's were personally reviewed by the evaluating neurologists in the course of their routine clinical assessments of the patient; no standardized approach to lesion assessment was used. The percentage or proportion of specific lesion types were calculated and reported. Lumbar puncture was not routinely performed; therefore insufficient data was available to permit analysis.
common (Table 1) while SPMS and CIS were much less common. This was true regardless of gender. Based on reporting of a prior focal neurological event on specific questioning, some patients initially diagnosed with PPMS and CIS were reclassified (Table 2). 43% of the PPMS patients and 33% of CIS patients recalled a prior focal neurological event and were reclassified as SPMS or RRMS respectively. The final classification of patients was, therefore, RRMS in 55 (44%), PPMS in 25 (20%), SPMS in 34 (28%),
Table 2 Clinical course classification before and after reclassification based on careful questioning regarding a prior focal neurological deficit. Clinical course Initial diagnosis Reclassified diagnosis
3.
Results
After excluding all patients for whom there was a more plausible explanation of symptoms we identified 124 MS patients (Table 1) whose first spontaneously reported symptom developed after the age of 50 years from a total of 3700 patients seen in our four MS centers. LOMS, therefore, constituted 3.4% of this MS population. Twenty six (21%) of LOMS patients experienced the first symptom at the age of 60 years or more and nine (7%) at age 70 years or more. Patients with onset after the age of 60 years were classified as very late-onset MS (VLOMS) (Hooge and Redekop, 1992; Azzimondi et al., 1994). The median age was 55 years for females (range 50–72) and 55.5 years for males (range 50– 77). Table 1 shows the demographics, clinical course, and clinical syndrome of the patients. Based on the initial clinical impression, that is, before closer questioning regarding earlier symptoms suggestive of prior relapses, RRMS and PPMS were approximately equally Table 1
RRMS PPMS SPMS CIS
40% 36 12 12
(N =50) (N =44) (N =15) (N =15)
44% 20 28 8
(N =55) (N =25) (N =34) (N =10)
Table 3 Age of onset stratified by clinical course before and after reclassification. Mean age (years)
Clinical course
Before reclassification RRMS PPMS SPMS CIS
56.8 56.7 56.8 56.2
(s =5.4) (5.6) (6.2) (6.1)
After reclassification 55.4 56.2 49.4 54.5
(s =7.3) (5.5) (8.9) (5.9)
Clinical course diagnosis and clinical syndrome sub analyzed by gender.
Demographics Median age (range)
Female 64% (N =79) 55 (50–72)
Male 36% (N =45) 55.5 (50–77)
Total (N =124) 55.2 (50–77)
Clinical course RRMS PPMS SPMS CIS
42% 34 13 11
(N =33) (N =27) (N =10) (N =9)
38% 38 11 13
(N= 17) (N= 17) (N= 5) (N= 6)
40% 36 12 12
(N =50) (N =44) (N =15) (N =15)
Clinical syndrome – acute Transverse myelitis Multifocal Optic neuritis Subcortical sensory Subcortical motor Cerebral Brainstem/cerebellar
29 23 12 14 8 8 6
(N =15) (N =12) (N =6) (N =7) (N =4) (N =4) (N =3)
38 15 12 4 7 12 12
(N= 10) (N= 4) (N= 3) (N= 1) (N= 2) (N= 3) (N= 3)
32 21 12 10 8 9 8
(N =25) (N =16) (N =9) (N =8) (N =6) (N =7) (N =6)
Clinical syndrome – chronic Transverse myelitis Subcortical motor Other
50 (N =14) 18 (N =5) 32 (N =9)
53 (N= 10) 10 (N= 2) 37 (N= 7)
51 (N =24) 15 (N =7) 34 (N =16)
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
4
P. Roohani et al.
Table 4
Clinical course classification by age groups.
Clinical course
Age 50–59 (N =89)
RRMS PPMS SPMS CIS
40% 34 14 12
VLOMS 60–77 (N= 35)
(N =36) (N =30) (N =12) (N =11)
40% 40 9 11
(N =14) (N =14) (N =3) (N =4)
MRI brain MRI spine
72 60
41 39
Lesion distribution (%) Periventricular Corpus callosum Juxtacortical Brainstem Cerebellar Spinal
83 39 29 26 17 22
88 44 24 15 22 21
and CIS in 10 (8%) patients. Table 2 shows the reclassified clinical course. For those with CIS reclassified as RRMS the mean and median age of onset is 41. For those with PPMS reclassified as SPMS the mean age of onset is 44 and median age of onset is 43. Age of onset by clinical course, before and after reclassification, is shown in Table 3. Thirty five patients presented with VLOMS. In those whose first symptom occurred between age 60 and 69 years (N =26) the clinical course was RRMS in 12 (46%), PPMS in 10 (38%), SPMS in one (4%), and CIS in three (12%) patients. In those whose first symptom occurred after the age of 70 years (N = 9) the clinical course was: RRMS in two (22%), PPMS in four (45%), SPMS in two (22%), and CIS in one (11%) patient. Table 4 shows the clinical course divided by age group, including for VLOMS. Seventy seven (62%) patients presented with an acute focal neurological syndrome. The most common type of acute clinical syndrome was transverse myelitis (N= 25, 32%). Other clinical patterns included multifocal deficits, optic neuritis, subcortical sensory, subcortical motor, brainstem or cerebellar deficits, and other cortical deficits (Table 1). Forty seven (38%) patients presented with a chronic neurological syndrome. The most common type of chronic clinical presentation was transverse myelitis (51%). Seven (15%) patients had subcortical motor deficits (Table 1). Brain MRI results were available in 113 (91%) patients, 72 (64%) of whom had the acute onset and 41 (36%) who had the chronic onset. Spinal MRI was obtained in 99 (80%) patients, 60 (60%) of whom had acute onset and 39 (40%) who had chronic onset. The number of available MRI results
Number of patients
Chronic
(N =12) (N =10) (N =1) (N =3)
22% 45 22 11
(N =2) (N =4) (N =2) (N =1)
25 20 15 10 5 0 A
B
C
D
Figure 1 (A) No difficulty with ambulation, (B) ambulation impaired but can walk without assistance, (C) uses a cane, walker, wheelchair or scooter and (D) confined to wheelchair. Disease course status at 5 year follow up Number of patients
Acute
46% 38 4 12
VLOMS470 (N=9)
Ambulation at 5 year follow up
Table 5 Number of patients with MRI imaging available and the proportion of images (in %) with localized lesions in different areas. Imaging modality
VLOMS 60–69 (N= 26)
25 20 15 10 5 0 A
B
C
D
Figure 2 (A) neurologically normal, (B) static residual deficit, (C) recurrent relapse and (D) progressive deficits.
and the proportion of patients with different types of MRI lesions are reported in Table 5. Five-year follow up data was available for 54 patients (44%), the other patients were either lost to follow up or they had not yet reached the five years from initial evaluation. Fifty (93%) had difficulty with ambulation at that time (Figure 1). In 39 (31%) patients, whose course status was assessed; three (8%) were neurologically normal, 22 (56%) had static residual deficits, 10 (26%) experienced at least one relapse, and four (10%) patients had worsening of neurological deficits (Figure 2).
4.
Discussion
This study confirms that LOMS is uncommon; 3.4% of MS patients from the upper Midwest region of the US presented after the age of 50, consistent with previous findings (Phadke, 1990; Crossburn et al., 2012; Bove et al., 2012; Tremlett and Devonshire, 2006). Women were more commonly represented, with a female:male ratio of 1.7:1. We had anticipated that the most common clinical course would be a progressive disorder, but found that relapsing and progressive courses were nearly equally common. The most
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
Late onset multiple sclerosis common clinical course diagnosed at our centers were RRMS and PPMS, however, several patients with PPMS and CIS were subsequently reclassified as SPMS and RRMS, making SPMS and RRMS a more common diagnosis than initially recognized. VLOMS is present in about 1% of the total MS population in our centers. In VLOMS, PPMS and SPMS constitute two-thirds of the diagnoses over the age of 70 years. The most common clinical syndrome acutely and chronically was transverse myelitis and progressive paraperesis, respectively. Among patients for whom five year clinical outcome was available, the majority required assistance to walk or were confined to a wheelchair. The disease course that was most common was static disease with residual deficits. MS presenting before the age of 50 years is generally accepted to have a female predominance of 2–3:1 (Bove et al., 2012; Steinman, 1993; Confavreux et al., 1980; Rosati, 2001; Pugliatti et al., 2006). Studies of LOMS have also shown a female predominance (Bauer and Hanefled, 1993; Cazzullo et al., 1978; Compston and Cole, 2002). In our study a female predominance is present but males are relatively more common compared to younger patients, as the female to male ratio is 1.7:1. Other gender differences have been reported in the past and our study failed to reproduce the same significant differences. In some studies, PPMS was found to be more common in males (Crossburn et al., 2012; Martinelli et al., 2004; Bove et al., 2012). Polliack et al. (2001) reported a large difference in LOMS based on gender; while 63% of female patients had RRMS, 73% of their male counterparts had PPMS. Sub analysis based on gender in our study did not recapitulate these findings. Some studies have shown a marked predominance of PPMS in LOMS (Tremlett and Devonshire, 2006; Kis et al., 2008). Bove et al. (2012) on the other hand reported RRMS to be more common, as was seen in our study. It is clear though, that despite the predominance of RRMS, PPMS is more common in the late onset population in comparison to adult onset MS (AOMS) in whom it has been most frequently reported to be about 15% (Confavreux et al., 1980; Thompson et al., 1997; Weinshenker et al., 1989). In our study, we sought to determine if patients presenting after the age of 50 had experienced an event for which the most plausible explanation was a prior demyelinating lesion, but who had not sought medical attention or had been undiagnosed. Several patients with initial diagnosis of CIS and PPMS reported prior events, thus we were able to identify probable disease onset prior to the age of 50 years in these patients and reclassified those patients initially thought to have CIS to RRMS and those initially thought to have PPMS to SPMS. The reclassification demonstrates that RRMS is more common than initially thought and SPMS is the commonest progressive clinical course. We acknowledge that reclassification was based on subjective reporting of events that occurred, in some cases, many years earlier. VLOMS has been defined as MS with onset after the age of 60 years (Azzimondi et al., 1994; Hooge and Redekop, 1992). In our study several patients presented with VLOMS. We found that the clinical course shifted towards a progressive type in those aged 70 years and more, although the sample size was very small. Other studies have reported that VLOMS occurs in 0.8–1.33% of MS patients (Bove et al., 2012; Tremlett and Devonshire, 2006). In another study 80% of LOMS patients
5 presented between the ages of 50 and 59 (Qiu et al., 2010). These studies are consistent with our findings. The clinical syndrome at presentation in our study is different from MS presenting earlier in life. In the acute onset patients 32% presented with TM and 21% presented with multifocal findings while only 12% presented with ON. In contrast ON is the initial diagnosis in 20–38% of MS patients presenting at the more typical younger age (Shams and Plant, 2009; Sellner et al., 2008) while TM has been reported as the initial event in o14% of patients (Paolino et al., 1996). The high incidence of multifocal findings in our study may indicate that a prior demyelinating episode may have gone unrecognized. In LOMS patients, motor as well as cerebellar and brainstem symptoms have been found to be more prevalent than sensory symptoms and optic neuritis (Tremlett and Devonshire, 2006; Martinelli et al., 2004; Kis et al., 2008). We found that motor symptoms caused by transverse myelitis were more common in LOMS patients. Some studies have found that LOMS has a poor prognosis (Liguori et al., 2000; Runmarker et al., 1994; Weinshenker, 2000) while others report no difference between LOMS and AOMS (Tremlett and Devonshire, 2006; Moreau and Confavreux, 2000). A five-year follow up was available in nearly half of our patients. Surprisingly, more than half of the patients were reported to be stable. We suspect that this is because of the retrospective nature of the study; patients with a very slowly progressive disorder may report that they are stable. Most of the remainder had either continued to progress or had developed progressive disease, 10 patients continued with a relapsing course, and three patients with RRMS were clinically normal at follow up. It has been reported that LOMS patients progress more rapidly compared to their younger counterparts. Tremlett and Devonshire (2006) reported that those with LOMS took a median of 16.9 years to reach an expanded disability status scale (EDSS) score of 6 compared to younger patients with MS who took 27.7 years. The patients with LOMS were older when reaching EDSS score of 6 (58.4 in AOMS vs. 71.2 years in LOMS). The authors propose that disease prognosis is not determined by the presence of LOMS, rather it is determined by the disease course. This study does have some limitations. The referred patients may not be representative of all MS patients. Two of the centers were academic; however two were community neurology centers with a referral base not different from any other neurology community center. Also, the manner in which the history of a prior event suggestive of a demyelinating episode was obtained was not completely standardized; it was instead left to the judgment of the Neurologist. In the same way the manner in which MRI lesions were analyzed was not standardized and left to the judgment of the Neurologist. The nonstandardized approach may lead to results that are not reliable; however given that this is a clinical study the approach was deemed to be appropriate. A final limitation is that the history of our patients with prior episodes was not validated through record review. The history of prior episodes was solely based on patients report and the records were not available to determine the validity of our patient's reports. This creates an opportunity for recall bias. In conclusion, LOMS is rare but encompasses the same clinical courses as AOMS. VLOMS is even rarer and is more likely to be progressive in the later ages. The clinical
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
6
P. Roohani et al.
classification is based on historical and spontaneously reported data from the patient, which may not always be complete and accurate. Many patients initially diagnosed with PPMS and CIS report earlier neurological events, on further evaluation, suggestive of a previous episode of focal demyelination. The elucidation of a previous event indicates that clinicians need to be vigilant and careful when seeking a history of prior events at the time of initial evaluation. This information indicates that true onset after age of 50 is even less common than we thought, particularly with PPMS. In this age group, presentation with motor deficits, especially those associated with transverse myelitis, are more common than in AOMS while optic neuritis and pure sensory symptoms are less common.
Conflict of interest Pezhman Roohani, Tenbit Emir, Adam Carpenter, Christopher Luzzio, and Jerome Freeman have no conflict of interest or financial disclosure. Susan Scarberry has been on the speaker's bureau for NMSS, Teva Neuroscience and Genzyme. She has received research support from Teva Neuroscience, Biogen-Idec, and Novartis. She has been a speaker for Bayer and research for EMD Serono. Gary Beaver has received honoraria from Genzyme, Novartis, Biogen, Bayer, and Teva. Lisa Davidson has been on Allergan speaker's bureau and previously speaker for Pfizer and Teva. Gareth Parry has been on the speaker's bureau for bioCSL, Novartis, EMD-Serono, Sanofi-Genzyme and Teva Neuroscience in the last 5 years and has received research support from Biogen-Idec, EMD-Serono, Sanofi-Genzyme and Teva Neuroscience.
References Azzimondi G, Stracciari A, Rinaldi R, D’Alessandro R, Pazzaglia P. Multiple sclerosis with very late onset: report of six cases and review of the literature. Eur Neurol 1994;34(6):332–6. Bauer HJ, Hanefled FA. Multiple sclerosis: its impact from childhood to old age.London: W.B. Saunders; 1993. Bove R, Healy B, Augustine A, Musallam A, Gholipour T, Chitnis T. Effect of gender on later onset multiple sclerosis. Mult Scler 2012;18(10):1472–9. Cazzullo CL, Ghezzi A, Marforio S, Caputo D. Clinical picture of multiple sclerosis with late onset. Acta Neurol Scand 1978;58 (3):190–6. Compston A, Cole AJ. Multiple sclerosis. Lancet 2002;359(9313): 1221–1231. Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103(2):281–300. Crossburn M, Ingram G, Hirst C, Ben-Shlomo Y, Pickersgill TP, Robertson NP. Age at onset as a determinant of presenting phenotype and initial relapse and recovery in multiple sclerosis. Mult Scler 2012;18(1):45–54. Hooge JP, Redekop WK. Multiple sclerosis with very late onset. J Neurol 1992;42(10):1907–10.
Kis B, Rumberg B, Berlit P. Clinical characteristics of patients with late-onset multiple sclerosis. J Neurol 2008;255(5):697–702. Liguori M, Marrosu MG, Pugliatti M, Giuliani F, De Robertis F, Cocco E, et al. Age at onset in multiple sclerosis. Neurol Sci 2000;21(4):825–9. Lublin F, Reingold S. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46(4):907–11. Martinelli V, Rodegher M, Moiola L, Comi G. Late onset multiple sclerosis: clinical characteristics, prognostic factors and differential diagnosis. Neurol Sci 2004;25(4):350–5. McDonald WI, Compston A, Edan G, Hartung HP, Lumlin FD, McFarland HF, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50(1):121–7. Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler 2008;14(9):1157–74. Moreau T, Confavreux C. Can the prognosis of multiple sclerosis be predicted? Pathol Biol 2000;48(2):132–8. Paolino E, Fainardi E, Ruppi P, Tola MR, Govoni V, Casetta I, et al. A prospective study on the predictive value of CSF oligoclonal bands and MRI in acute isolated neurological syndromes for subsequent progression to multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;60(5):572–5. Phadke JG. Clinical aspects of multiple sclerosis in north-east Scotland with particular reference to its course and prognosis. Brain 1990;113(Pt 6):1597–628. Polliack M, Barak Y, Achiron A. Late-onset multiple sclerosis. J Am Geriatr Soc 2001;49(2):168–71. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13(3):227–31. Pugliatti M, Rosati G, Carton H, Riise T, Drulovic J, Vecsei L, et al. The epidemiology of multiple sclerosis in Europe. Eur J Neurol 2006;13(7):700–22. Qiu W, Wu JS, Castley A, James I, Joseph J, Christiansen FT, et al. Clinical profile and HLA-DRB1 genotype of late onset multiple sclerosis in Western Australia. J Clin Neurosci 2010;17 (8):1009–13. Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci 2001;22:117–39. Runmarker B, Andersson C, Oden A, Andersen O. Prediction of outcome in multiple sclerosis based on multivariate models. J Neurol 1994;241(10):597–604. Sellner J, Luthi N, Buhler R, Gebhardt A, Findiling O, Greeve I, et al. Acute partial transverse myelitis: risk factors for conversion to multiple sclerosis. Eur J Neurol 2008;15(4):398–405. Shams PN, Plant GT. Optic neuritis: a review. Int MS J 2009;16(3):82–9. Steinman L. Autoimmune disease. Sci Am 1993;269(3):106–14. Thompson AJ, Polman CH, Miller DH, McDonald WI, Brochet B, Filippi M, et al. Primary progressive multiple sclerosis. Brain 1997;120(6):1085–96. Tremlett H, Devonshire V. Is later onset multiple sclerosis associated with a worse outcome? J Neurol 2006;67:954–9. Weinshenker BG, Bass B, Rice GPA, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographical based study. 1. Clinical course and disability. Brain 1989;112(1):133–46. Weinshenker BG. Progressive forms of MS: classification streamlined or consensus overturned? Lancet 2000;355(9199):162–3. White AD, Swingler RJ, Compston DA. Features of multiple sclerosis in older patients in South Wales. Gerontology 1990;36:159–64.
Please cite this article as: Roohani P, et al. Late onset multiple sclerosis: Is it really late onset? Multiple Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.02.004
