Late Onset MS
Denise I. Campagnolo MD, MS––Barrow Neurological Institute, Phoenix, Arizona
Multiple sclerosis (MS) has typically been considered a disease of young adults. It actually occurs in people of all ages, but affects far fewer children and older adults than people in their 20’s and 30’s. Studies describing MS that is diagnosed after age 50 (late-onset MS; LOMS) have provided conflicting information about LOMS patients’ prognosis, compared with that of individuals whose MS symptoms start before age 40 (young-onset MS; YOMS). More-recent investigations have led to a better understanding of LOMS and its differences from YOMS, as described in brief below.
Clinical Features and Age of Onset for Typical MS
Types of MS at Onset and Disease Course. The vast majority of people with MS (approximately 80%) experience their first symptoms by age 40, and most––by a ratio of 2:1––are women. Of these, about 85% have the familiar relapsing-remitting (RR) form of the disease. RRMS is characterized by acute episodes (also called ‘attacks,’ ‘exacerbations,’ or ‘relapses’) of neurologic problems, such as numbness, visual disturbances, loss of voluntary movement of some part of the body, lack of coordination, or dizziness, which are followed by periods with little disease activity. During the periods of remission, patients usually regain most or all of the functionality lost during the previous attack. Most people with RRMS eventually enter a phase called “secondary progressive” (SP) MS, which is marked by a progressive accumulation of neurologic deficits, with or without acute attacks. It is in this later phase that the cumulative damage to the central nervous system (CNS) begins to result in permanent disability.
Approximately 10 to 15% of patients with YOMS patients do not have RRMS at disease onset. Instead, they have the “primary progressive” (PP) form of the disease. This form of MS has an unremitting course of increasing disability, usually without the acute attacks that characterize RRMS.
Events in the CNS. The symptoms caused by RRMS generally result from lesions in the CNS that are visible on magnetic resonance (MR) images. These lesions appear when nerve fibers are stripped of their protective wrapping, a fatty substance called ‘myelin,’ which insulates the fibers and improves nerve signaling, much like insulation does for electrical wires. Although the cause of MS is unknown, it is widely accepted that inflammation in confined areas of the CNS destroys the myelin, and that neurons that have lost their myelin may subsequently be damaged and lost.
When MS lesions occur in the brain or spinal cord, the patient usually experiences problems with movement (motor symptoms) and/or sensation (sensory symptoms). Symptoms such as dizziness or poor coordination can reflect lesions in the brain stem or the cerebellum, areas that integrate many different CNS functions. As the disease progresses, the presence of inflammatory lesions correlates less well with the kinds of neurologic problems the patients experience or how quickly they become disabled. This loss of direct effect between lesion location and disability is most likely owing to the long-term effects of inflammation and demyelination, including nerve fiber destruction, which lead to the widespread death of nerve cells and to brain shrinkage (atrophy).
There is some controversy about the role and frequency of inflammatory lesions in patients with PPMS but, on balance, current information suggests that demyelinating lesions are present at similar levels at the onset of both RRMS and PPMS (see Kis, Rumberg, & Berlit 2008).
Disease Symptoms at Onset. When MS occurs in people under 40, about 70% experience sensory difficulties as the first (‘presenting’) symptom. The most frequent sensory symptom is a difficulty with vision, although numbness and tingling in various areas of the body are also common. Symptoms in which voluntary movement is affected (‘motor symptoms’) occur in fewer than 30% of YOMS patients as the presenting symptom, and problems with dizziness or coordination are relatively rare. It is fairly common for patients to have multiple symptoms at the time of disease onset. As RRMS progresses, it affects various CNS functions.
Approximately 20% of people who develop MS are diagnosed after age 40. To allow direct comparison among investigations, LOMS has been defined as MS with onset after age 50. The oldest reported age of MS diagnosis is 82. The percentage of people with MS who have LOMS is 4 to 10%. (Martinelli, Rodegher, Moiola, & Comi 2004).
Clinical Course and Patient Characteristics of LOMS. One of the notable differences between LOMS and YOMS is that many more patients with LOMS have the PP form of the disease: 32 to 83%, depending on the study (Martinelli et al., 2004). The ratio of women to men among patients with LOMS also appears to be slightly lower than in the younger-onset population (1.4:1 in one study; Kis et al., 2008), with men being over-represented among patients with PPMS. In addition, it seems that the older the age at onset, the more likely the patient will have PPMS. One study of 30 patients in Israel with LOMS found that those whose MS was diagnosed at age 54 or later had the PP form (Polliack, Barak, & Achiron, 2001).
Individuals with LOMS tend to have a motor deficit as their presenting symptom (63-80%), although sensory symptoms are also frequent (30-45%) (Kis et al., 2008; Polliack et al., 2001). Most have only one symptom at the time of onset, and visual disturbances as the presenting symptom are rare. One study also strongly linked depression with the onset of LOMS (Polliack et al., 2001). PPMS most often involves a worsening of the symptoms present at onset (Kis et al., 2008).
Diagnostic Testing: Differences Between LOMS and YOMS
Physicians can perform a variety of tests to help diagnose MS, and it is important to understand whether the results of these tests look similar in patients with YOMS and LOMS.
Among the three gold-standard tests, MRI, which most people are familiar with, is used to evaluate the presence of demyelinating lesions and brain atrophy. Another test, “evoked potential latency,” is a measurement of electrical conduction by the nerves in the brain or spinal cord. The time it takes the signal to reach the point of measurement is the “latency.” When nerves are damaged, more time is required for the transmission of the signal, resulting in a longer latency. Both the strength and latency of the signal can be affected by the state of the nerve fibers. The third test involves analysis of the cerebral spinal fluid (CSF), which bathes the CNS and is obtained by a lumbar puncture (also known as a ‘spinal tap’). Individuals with MS typically have antibodies in their CSF that will form a pattern of characteristic “bands” when analyzed by a technique called electrophoresis.
MRI. The results on MRIs, which are extremely helpful in diagnosing YOMS, are complicated by the effects of age and age-related illness in patients with LOMS. As people age, their brains tend to accumulate small lesions that can appear much like MS lesions on MR images, which can make it difficult to interpret MRIs for the diagnosis of LOMS. Furthermore, several conditions that disproportionately affect the aged, such as inflammation of the blood vessels, can give MRI results that are similar to MS lesions (Martinelli et al., 2004).
There are also differences in the locations of lesions between YOMS and LOMS. Kis and colleagues (2008) found that, although about the same number of people with LOMS and typical MS had lesions in the cerebrum and mid-brain, significantly more patients with LOMS had spinal cord lesions. In addition, fewer people with LOMS than YOMS had lesions in the brainstem and cerebellum, and patients with LOMS in general had many fewer “enhancing” lesions, in which a contrast agent brightly marks areas of fresh inflammation where the blood-brain barrier has broken down.
Overall, the changes on MRIs caused by age and the multiple health problems of older adults means that MRI is less useful for diagnosing LOMS than YOMS. If MRI is used to diagnose LOMS, the images should be interpreted carefully by physicians experienced in MRI of the CNS in older adults.
Evoked potentials. Unlike MRI, the results from evoked potential studies are largely identical for LOMS and YOMS patients (Kis et al., 2008), with the only really notable difference being in the strength of the signal from sensory-evoked potentials, which is worse in patients with YOMS. Although there are some conditions that can cause similar evoked potential latencies as MS, and these conditions are more frequent in older adults, evoked potentials appear useful for diagnosing LOMS (Martinelli et al., 2004).
CSF analysis. CSF analysis may be the least affected by the age of MS onset. Kis and colleagues (2008) found only that more YOMS patients than LOMS patients had increased numbers of white blood cells in the CSF. Otherwise, there were no differences among the groups. Therefore, results that show a difference in “banding” between the CSF and the blood serum strongly point to a diagnosis of MS, regardless of the patient’s age.
Misdiagnosis of LOMS
As suggested by the discussion above, misdiagnosis of LOMS is apparently far more common than misdiagnosis of YOMS. Kis and colleagues (2008) showed that 40% of their patients with LOMS had an average delay of 3 years between the onset of their first symptoms and a correct diagnosis of MS. By contrast, only 15% of their patients with LOMS were misdiagnosed at first.
The diseases that mimic MS are unspecified inflammation of the CNS, neuropathies, stroke, blood vessel inflammation, and tumor, with a total of 13 different incorrect diagnoses among 21 patients. This finding is consistent with the idea that the unusual presenting symptoms of LOMS, coupled with the complexity of determining which of an older patient’s multiple health conditions is responsible for which symptoms, leads to considerable difficulty in making an accurate diagnosis of LOMS. Details of possible conditions that can complicate the diagnosis, how they affect various tests, and recommendations for discriminating among them are described by Martinelli and colleagues (2004).
Prognosis and Treatment
Once LOMS has been diagnosed, an important issue for patients and their family members, is the likely outcome of the disease (its prognosis). Unfortunately, by almost every measure, patients with LOMS fare worse than those with YOMS. Still, as with YOMS, the disease course of each person in very individual , and some patients do very well (Martinelli et al., 2004).
As yet, little research has been done to determine the best therapeutic approaches for patients with LOMS. PPMS in particular is considered refractory to treatment, although it is unknown if the age of the patient at onset could affect this poor response. Finally, some data that show rapid deterioration and higher mortality rates among patients with LOMS probably reflect the general health condition of elderly people, not that MS is simply more aggressive in older adults. Therefore controlling other concomitant medical conditions that typically come on with age (primary hypertension for example) is very important. In the meantime, RRMS can be treated in patients with LOMS just as in patients with YOMS, with a strong focus on preventing future relapses with disease modifying therapies.
Kis, B., Rumberg, B., & Berlit, P. (2008). Clinical characteristics of patients with late-onset multiple sclerosis. Journal of Neurology, 255, 697-702.
Martinelli, V., Rodegher, M., Moiola, L., & Comi, G. (2004). Late onset multiple sclerosis: clinical characteristics, prognostic factors, and differential diagnosis. Neurologic Science, 25, S350-S355.
Polliack, M.L., Barak, Y., & Achiron, A. (2001). Late-onset multiple sclerosis. Journal of the American Geriatric Society, 49, 168-171.