Disorders That Mimic Multiple Sclerosis
David H. Mattson, MD, PhD, Department of Neurology, Indiana University Medical Center, Indianapolis, IN; Albert C. Lo, MD, PhD, CPH, Department of Clinical Neuroscience, Engineering and Neuroscience, Brown University, Providence, RI; Elizabeth Auld, PA, Departments of Primary Care and Neurology, VA Connecticut Healthcare System, West Haven, CT
If you have multiple sclerosis (MS)––or you know someone who does––you probably remember how long it took to make the diagnosis. You also may remember a lot of blood tests, a lumbar puncture, at least one magnetic resonance imaging (MRI) scan, as well as many visits and examinations by various doctors. You may wonder why it still takes so long to make the diagnosis in this modern age of MRIs and other sophisticated tests. We are going to try to explain why it can be so difficult for even the most expert MS neurologist to determine that someone has MS. You have to live with the diagnosis and face the disease and the treatments. You should understand and have confidence in the diagnosis. Also, if your case of MS does not fit the typical pattern, you need to be aware of the other disorders that can mimic MS. This is important because the treatments may be very different and, just as in most cases of MS, treatment begun early in the course of the disease is the best way to prevent or slow further neurologic damage.
MRI and new laboratory tests have definitely helped speed the diagnosis, but it still takes longer than anyone would wish, even in easy cases. This is partly because of the variable nature of the disease in its many signs and symptoms. But it is also because a rather long list of other medical disorders can cause neurologic symptoms and signs that resemble MS. Furthermore, the “white spots” on brain MRI can be caused by a number of other conditions that also need to be ruled out.
The diagnosis of clinically definite MS requires that a person experience at least two neurologic symptoms of the type seen in MS, in two different areas of the central nervous system (CNS), at two different times (‘disseminated in space and time’). Most typically, the symptoms are optic neuritis plus either an abnormal sensation or a problem with movement. It can also be numbness in one part of the body and weakness or lack of coordination in another. But in every case, there can be no other explanation for the symptoms, the changes seen on the MRI, and the abnormalities in the spinal fluid. Many “mimics” need to be ruled out in order to make the diagnosis of MS.
Potential Mimicking Diseases
The list of disorders that can be confused with MS is very long and includes some that are rather uncommon. The more important and more common disorders include other autoimmune disease, abnormal blood vessels of the brain, CNS tumors, conditions that lead to degeneration of the nervous system, certain infections including Lyme disease, and even some psychiatric diagnoses.
In autoimmune diseases (including MS), a person’s immune system attacks parts of his/her own body. In MS, the target is the myelin that wraps, insulates, and protects the nerves in the CNS.
In acute disseminated encephalomyelitis (ADEM), myelin is also injured in a manner similar to that in MS. ADEM is a diagnosis that falls, along with MS, under the category of inflammatory autoimmune disease of the CNS. Therefore, its signs and symptoms may appear very similar to, if not indistinguishable from, MS. However, classically, ADEM is often associated with a recent viral infection or immunization, and in comparison to MS, neurologic symptoms develop and progress rapidly, affecting many parts of the nervous system at once. What is important about distinguishing ADEM from MS is not so much the immediate medical management, since ADEM is also treated using intravenous steroids, but in the prognosis. ADEM is only a single neurologic event without progressive and recurrent symptoms and, therefore, can have a much more favorable long-term prognosis. Approximately 25% of the ADEM cases, however, are actually the beginning of MS.
Other autoimmune diseases that attack various parts of the body can produce symptoms that look like MS. One such group includes diseases of connective tissue, especially systemic lupus erythematosus (SLE) and Sjögren’s syndrome. People with these diseases can have CNS changes and relapses during the active phase of the disease. Eventually, they go on to develop symptoms that look more like those diseases than MS. In one case report (Pender & Chalk, 1989), the diagnosis of SLE was not made until after the person developed arthritis in more than one joint and high levels of antibodies that are commonly seen with SLE (low levels of this antibody can be seen in MS and many other diseases). Meanwhile, the patient ultimately diagnosed with Sjögren’s syndrome developed dry eyes and mouth, arthritis, and other symptoms specific to Sjögren’s. In addition, both patients had several first-trimester miscarriages, something that is quite common in persons with SLE, but not in persons with MS.
A 2001 study found that 10 of 60 patients with confirmed primary progressive MS actually had Sjögren’s syndrome (de Seze et al., 2001). Sjögren’s syndrome is an autoimmune disease in which the body’s immune system mistakenly attacks its own moisture producing glands (1%-5% of the general population develops Sjögren’s; most are women). Trying to distinguish SLE from MS is further confused by the fact that 25% of patients with typical MS will have a low level false positive titer of antinuclear antibodies (ANA), one of the tests used to screen for SLE.
Symptoms of SLE/Lupus: The autoantibodies and immune complexes of Lupus can affect many different body systems. The best known symptoms are fatigue, malaise, fever, joint and muscle pain, and skin rash. Other symptoms will vary depending upon which body organs are involved (i.e., blood cells, heart, lungs, gastrointestinal [GI] tract, kidneys). The neurologic symptoms can be varied and diffuse. They may include cognitive dysfunction, psychosis, stroke, seizures, cerebellar dysfunction (trouble with balance and tremor and coordination), other movement disorders, aseptic meningitis (causing headaches), optic neuritis, transverse myelitis (causing weakness, paralysis, and bowel and bladder problems), and cranial nerve or peripheral nerve abnormalities. Depression or anxiety is also frequently seen.
Symptoms of Sjögren’s Syndrome: the characteristic symptoms of Sjögren’s are related to impaired lacrimal (pertaining to tears) and salivary (pertaining to the oral cavity) gland function. Therefore, dry eyes, eye fatigue, dry mouth, difficulty swallowing, and difficulty in speaking are all common complaints. Less commonly, the disease may also cause decreased mucous secretion of other organs such as the upper and lower respiratory tract, the kidneys, GI tract, blood vessels, lung, liver, and pancreas. Persons with Sjögren’s syndrome can also develop neurologic complications. Most often, the peripheral nervous system is affected, causing decreased sensation or numbness or pain. At first, these symptoms can seem like MS, but nerve conduction velocity (NCV) tests can distinguish between the kind of damage in MS (central) and that in Sjögren’s. The damage in the latter affects the CNS and can cause impaired attention, memory and concentration, cerebellar dysfunction, or even spinal cord involvement in the form of transverse myelitis.
Sarcoidosis is yet another disorder that involves the immune system and can sometimes look just like MS. The neurologic symptoms of sarcoidosis can be just as varied as with MS, including decreased vision, numbness, weakness, and bowel and bladder changes. Sarcoidosis affects many different body organs. Almost all persons will have sarcoidosis in the lungs, while less than 10% will have sarcoidosis involving the nervous system. If someone with MS-like symptoms were found to have sarcoidosis in the lungs, it would be extremely unlikely for the neurologic problems to be due to anything else but neurosarcoid. The visual problems caused by sarcoidosis can appear at first a lot like optic neuritis, that is blurry vision or blind spots, but an ophthalmologic examination of the eyes shows very different changes from those seen in MS. When these are found, sarcoidosis becomes the most likely diagnosis. In other cases, however, the diagnosis is more difficult. A high level of blood enzyme called serum angiotensin converting enzyme (ACE) sometimes helps make the diagnosis, but it is not always abnormal. Adding to the diagnostic confusion, the results of tests on the cerebral spinal fluid (CSF) can look a lot like MS, including having positive oligoclonal bands. Occasionally, it is necessary to biopsy the brain, the brain lining (meninges), or the spinal cord to make the diagnosis.
A number of diseases that primarily affect the blood vessels of the brain or spinal cord can produce signs and symptoms similar to those seen in MS. Isolated CNS angitis is an inflammation of the blood vessels of the brain. Typical symptoms for this disease include headache and confusion. More specific neurologic deficits, which develop slowly and progressively, produce a variety of abnormalities in many parts of the nervous system.
Abnormal structure of the blood vessels along the spinal cord, known as dural arteriovenous fistulas, rob the spinal cord of blood and cause weakness, sensory symptoms, and bowel and bladder changes, often in a progressive or a relapsing manner. MRIs of the spinal cord, done in a special way (called MRAs), are useful in identifying these spinal vascular malformations. Sometimes spinal angiography, a much more invasive test, is required (Jellema, 2003).
Strokes can be caused by bleeding in the brain or by blood clots that cut off the blood supply to an area of the brain. The result is that neurons in the brain die. Major strokes cause very obvious losses in function and are very unlikely to be confused with MS. However, smaller strokes can produce changes or loss in function that can look like an MS attack. Accordingly, multiple small strokes can cause a variety of stepwise and progressive neurologic deficits.
Binswanger’s disease is a particular form of cerebrovascular disease seen in older patients with a history of high blood pressure. It is characterized by progressive dementia along with brief neurologic abnormalities. These individuals develop demyelination of the white matter tracts around the ventricles of the brain, which on brain MRI generates the appearance of diffuse white matter lesions similar, but in general not identical, to that seen in patients with MS.
Organisms that infect the nervous system can produce symptoms that mimic MS. For instance, Lyme disease, an illness caused by an infection from the tick-borne bacterium Borrelia burgdorferi, can enter the CNS. Symptoms of CNS Lyme disease include headache, stiff neck, and sometimes weakness or paralysis of various cranial nerves (nerves that send and receive messages from the skin, muscles and glands of the head/face), most commonly the facial nerve. This type of paralysis is known as Bell’s palsy. Early descriptions of Lyme disease also included changes in memory, concentration, and ataxia. The clinical course of CNS Lyme disease may be either relapsing or progressive in nature.
The bacterium Treponema pallidum causes syphilis and can infect the meninges, brain, and spinal cord resulting in neurosyphilis. Tertiary syphilis may produce a large number of progressive symptoms including cognitive changes, visual problems, and dysfunction along the sensory and motor tracts of the spinal cord. In either case, the production of antibodies against Treponema pallidum (for syphilis) or Borrelia burgdorferi (for Lyme) within the CSF is an important diagnostic test to identify these infectious agents rather than MS as the cause of a person’s symptoms.
The human T-cell lymphotrophic virus-1 (HTLV-1) has been associated with progressive thoracic spinal cord dysfunction, causing spastic paraparesis (weakness and stiffness of both legs), in addition to bladder and bowel incontinence as well as impotence (inability or difficulty in having an erection). Accordingly, HTLV-1 titers should be performed, particularly when evaluating a patient with a primary progressive myelopathy.
Other diseases complicate the diagnostic process. Some, including familial spastic paraparesis, chronic fatigue syndrome, factitious MS, degenerative spine disease, and brain and spinal cord tumors, are relatively easily distinguished from MS. In all cases, however, it is essential that both the patient and clinician work to establish an accurate history of the course of the symptoms. This, combined with a healthy amount of skepticism when the pieces of the puzzle do not fit perfectly, will guide the diagnostic evaluation. The goal is that patients and clinicians both have confidence that the diagnosis of MS (or of one of the ‘mimics’) is accurate.
Strategies to Minimize Misdiagnosis
Rudick, Schiffer, Schwertz, and Herndon (1986) described 10 patients whose symptoms were originally diagnosed as MS or suspected MS, but who were later found to be suffering from something else. Most had neurologic disorders, including nervous system degeneration, tumors, or a disorder of the blood vessels in the brain. One had depression––the symptoms reported by this patient turned out to be largely a manifestation of the emotional disorder. The authors analyzed these cases to find the features that alerted them to an incorrect diagnosis and came up with “red flags.” The following list is based on their red flags plus some additions we consider important.
-No eye abnormalities: The authors state that although they may be subtle, abnormalities in visual evoked potentials or eye movement are so common in MS that their absence is worth noting. They recommended caution in accepting a verbal history of eye problems, if they cannot be verified by testing.
-Unremitting progression: Although primary progressive disease certainly occurs in patients with MS, the authors point out that this is unusual in younger patients and raises the possibility of a tumor or neural degeneration.
-Localized disease: MS is characterized by dissemination in space, and the lack of evidence of dissemination suggests an alternative diagnosis. The authors note, however, that in two of their patients with localized disease, the symptoms suggested the involvement of more than one nervous system region.
-Unusual clinical findings: Some findings are so common in MS (such as problems with sensation or bladder function) that their absence should be considered a hint that the disorder might be something else. Other features are rare, such as progressive dementia and seizures, and their presence might trigger a re-evaluation. Also, the presence of joint swelling or aches, rashes, fevers, relentless headaches, dry eyes, dry mouth (apart from those caused by medication), or prominent family history should raise concern regarding another illness and not MS.
-Lack of abnormal CSF findings: Abnormal oligoclonal IgG antibodies are found in the CSF of up to 95% of patients with MS. Thus, a normal CSF result could be reason in and of itself to re-evaluate the diagnosis.
-Symptoms of MS associated with negative brain MRI: In early disease, only 16% of patients with symptoms suggestive of MS but with normal brain MRI go on to be diagnosed with MS over the next 5 years. Therefore, a normal brain MRI in a patient suspected of having MS is an important red flag that the person may not have MS.
The Trouble with Brain and Spinal MRI in MS
In recent years, MRI has been used extensively in the diagnosis of MS. MS lesions have a characteristic appearance and distribution in the brain. For example, there tend to be many lesions near the ventricles––the large fluid-filled spaces inside the brain. An unusual distribution of lesions might be a hint that the disorder is something besides MS. In that situation, MRI can help distinguish between MS and the other disorders. However, a number of disorders cause MRI changes that are similar to those in MS, and in that case, MRI does not help much (see Falini et al., 2001).
According to Poser and Brinar (2001), as many as one-third of cases in which MRI is used as the sole or primary tool, are misdiagnosed. In addition, different MRI machines and techniques complicate the use of even this wonderful technology. This problem emphasizes the importance of gathering information from different sources before making a diagnosis, including other laboratory tests, physical examination, and a complete history.
Making a certain diagnosis of MS continues to be difficult and challenging. New disorders that mimic MS continue to be identified. It is hoped that future research will identify reliable features of MS that can be used for accurate and rapid diagnosis. In the meantime, for persons whose symptoms, history, clinical course, or laboratory tests are not classic for MS, they and their physicians need to maintain a healthy level of skepticism and be willing to re-evaluate the diagnosis when appropriate.
de Seze, J., Devos, D., Castelnovo, G., Labauge, P., Dubucquoi, S., Stojkovic, T., et al. (2001). The Prevalence of Sjögren Syndrome in Patients with Primary Progressive Multiple Sclerosis. Neurology, 57, 1359-1363.
Falini, F., Kesavadas, C., Pontesilli, S., Rovaris, M., & Scotti, G. (2001). Differential Diagnosis of Posterior Fossa Multiple Sclerosis Lesions – Neuroradiological Aspects. Neurological Sciences, 22 (Suppl. 2), S79-S83.
Jellema, K., Canta, L. R., Tijssen, C.C. et al. (2003). Spinal dural arteriovenous fistulas:
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Pender, M. P., & Chalk, J. B. (1989). Connective tissue disease mimicking multiple sclerosis. Australia and New Zealand Journal of Medicine, 19, 469-472.
Poser, C. M., & Brinar, V. V. (2001). Diagnostic criteria for multiple sclerosis. Clinical Neurology and Neurosurgery, 103, 1-11.
Rudick, R. A., Schiffer, F. B., Schwetz, K. M., & Herndon, R. M. (1986). Multiple sclerosis: The problem of incorrect diagnosis. Archives of Neurology, 43, 578-583.