E v o k e d Po t e n t i a l s in Mu l t i p l e S c l e ro s i s George H. Kraft,
MD, MS
KEYWORDS Evoked potentials Visual evoked potentials Somatosensory evoked potentials Brain stem evoked responses KEY POINTS Evoked potentials still may be valuable in the diagnosis of and management of multiple schlerosis (MS). Evoked potentials provide a means of evaluating the type of neurologic abnormality: demyelination produces conduction slowing, whereas axonal degeneration causes attenuation of the potential amplitude. Evoked potentials are noninvasive and can be used to monitor changes in the central nervous system of a patient with MS. Evoked potentials are useful in identifying superimposed mechanical pathology (eg, cord stenosis) in MS patients.
INTRODUCTION
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), associated with neural degeneration. The diagnosis is based on the clinical history, physical examination, laboratory findings, imaging of the CNS (magnetic resonance imaging [MRI] and other neuroimaging techniques), spinal fluid analysis, and selected additional laboratory tests to eliminate other diseases. The diagnosis is confirmed when disease has been confirmed in at least 2 different locations of the CNS, occurring at 2 or more points in time, for which there is no alternative disease diagnosed. It can initially manifest itself in several distinct patterns: relapses followed by remissions (relapsing remitting or RR MS), progressive degeneration from onset (primary progressive or PP MS), and a progressive course with superimposed episodes of relapses and remissions (progressive relapsing MS). The fourth clinical type—second progressive MS—evolves from RR MS over time as the disease progresses.
Dr. Kraft has no relevant conflicts of interest. Department of Rehabilitation Medicine, University of Washington School of Medicine, University of Washington, Box 356490, Seattle, WA 98195, USA E-mail address: [email protected] Phys Med Rehabil Clin N Am 24 (2013) 717–720 http://dx.doi.org/10.1016/j.pmr.2013.07.001 1047-9651/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
pmr.theclinics.com
718
Kraft
There are 3 types of evoked potentials (EPs) used in MS diagnosis and management: (1) visual evoked potentials (VEPs), which assess neural conduction in the optic pathways. VEPs are most typically triggered by observing an illuminated, alternating checkerboard pattern of black and white squares (pattern reversal VEPs) or a flashing light. Recordings are made over the visual cortex. Prolongation of the latency indicates disease in that neural pathway; (2) somatosensory evoked potentials (SEPs) involve peripheral stimulation of the large 1 A afferent fibers in various mixed nerves in the extremities, with the ascending potentials measured at various points along the peripheral nerves, spinal cord, brainstem, and somatosensory cortex; (3) brainstem auditory evoked responses (BAERs), triggered by auditory clicks and recorded over the cortex. (Motor evoked potentials will not be covered in this review, as they are currently not Food and Drug Administration approved for clinical practice in the United States.) EPs represent a valuable adjunct to the diagnosis and management of MS because they measure physiology in the CNS. Indeed, it is the abnormal physiology of neural pathways caused by the inflammation and degeneration caused by MS that produces the motor weakness and sensory symptoms. Consequently, EPs are the only laboratory tools that directly measure the abnormal physiology resulting from the disease; all other tests are inferences of diseased pathways. USE OF EPS IN MANAGEMENT OF MS
Classically, the value of EPs is the identification of an additional region of the CNS that may be clinically “silent”—that is, not associated with clinical symptoms, which may provide the additional information necessary to satisfy the dissemination in space criterion required for a confirmed diagnosis of MS. Used for this purpose, the most sensitive of the several EPs is the VEP.1 Classically, the second most sensitive EP is the SEP, followed by the BAER. However, early studies evaluated only upper limb SEPs; they did not measure SEPs from the lower limbs. Subsequent research has demonstrated that with lower limb SEP testing (most commonly tibial nerve SEP), the sensitivity of SEPs may actually exceed VEP testing.2 The reason is that a tibial SEP evaluates the ascending afferent pathways through the entire length of the spinal cord, brainstem, and brain. As more neural tissue is traversed, there is a greater probability that areas of disease will be encountered. STEPS TO IDENTIFY ADDITIONAL SITES OF DISEASE
Unlike a traumatically produced disease, MS does not suddenly appear in its fully manifested state. There is no single point in time whereby a completely healthy individual suddenly has MS. Rather, it occurs over time—often many years. The diagnosis of MS requires satisfaction of the criteria of CNS disease “disseminated in time and space.” Thus, by definition, MS is not a disease of sudden onset. Pathologically, RR MS starts in some portion of the CNS, producing symptoms that typically subside in weeks (remission). Somewhat later, another symptom might occur in a similar manner, or the initial symptom may return (exacerbation). By the time of diagnosis (sufficient symptomatology and pathology to produce the criteria of dissemination in time and space) many years may have transpired. It is not uncommon to see patients with moderately extensive brain and spinal cord disease at the time of definite diagnosis of MS. It is now clear that it is extremely important to diagnose RR MS as early as possible, as it is well established that treatment of RR MS in the earliest stages offers the best opportunity to control the disease,3 whichis the classic role of VEPs and SEPs in the
Evoked Potentials in Multiple Sclerosis
diagnosis of MS. In addition, SEPs also offer an excellent way to quantify spinal cord disease,2 which can be useful in monitoring the effect of a particular disease modifying treatment (DMT). This is an especially important benefit because MS lesions in the spinal cord—unlike those in the brain—are often not clearly demarcated on imaging (secondary to movement artifact produced by vascular pulsation and respiratory movement as well as the characteristics of the lesions themselves). STEPS TO GUIDE TREATMENT BY SUGGESTING TYPES OF MS
Now it seems that MS is not one disease, but consists of at least 4 distinct pathologic types4; all may manifest the same clinical symptoms and signs. As previously mentioned, it is well established that there are also 4 clinical types of MS.5 The available DMTs are indicated for RR MS or early second progressive MS, not PP MS, with the possible exception of glatiramer acetate in men with PP MS.6 Consequently, research on differentiating the various types of MS is expanding. This is an important effort as differentiation of clinical type is not possible based on examination and often very difficult based on the clinical course. Because PP MS is associated with relatively more neural degeneration and relatively less inflammatory demyelination than RR MS, it is possible that EPs may offer assistance in differentiating the clinical types. Demyelination is associated with relatively more conduction slowing and degeneration is more associated with attenuation of signal. Preliminary studies suggest that SEPs may provide helpful additional information to make such a differentiation.7 There is a strong economic argument to be made that testing to differentiate types of MS can have a profound fiscal impact, as it is estimated that use of a DMT may result on over $1 million lifetime cost. Avoidance of treatment of the wrong type of MS with the wrong drug justifies the small cost of additional testing. Because it is accepted that the best response from DMTs occurs in patients treated in the earliest stages of the disease,3 much effort has been put into the diagnosis of MS in its earliest stages. The “McDonald criteria” recognizes the importance of EPs in diagnosis.8 There is also evidence that VEP abnormalities correlate with those changes seen in MRI spectroscopy associated with neural degeneration (reduced N-acetylaspartate, a surrogate for axonal loss).9,10 Laboratory studies in experimental allergic encephalomyelitis, the animal model of MS, also suggest that they may become abnormal even before clinical symptomatology.11 Further discussion of EPs and other neurophysiologic assessments can be found in texts.12,13 SUMMARY
EPs are the only laboratory tools that actually evaluate the physiology of the neurologic changes that occur during the course of MS, and physiology is related to function. Utilization of EPs can help establish a second locus of disease, may help in assessing the type of MS, and can be especially useful in monitoring changes in physiology, representing lesion load, in the spinal cord. RECOMMENDATIONS
1. It is recommended that VEPs and SEPs be incorporated in the early assessment of patients with clinically isolated syndrome to facilitate an early diagnosis of MS so that DMTs can be started as early as possible in the disease course. 2. It is recommended that selected EPs be done at the time of MS diagnosis to determine the physiologic status and periodically repeated, as appropriate, to monitor disease changes.
719
720
Kraft
3. This is especially important for monitoring cord disease, as MRI may be less quantifiable in measuring changes in MS lesion load in the spinal cord. 4. It is recommended that SEPs be considered in clinical situations whereby additional information about the physiology and disease type may be required. REFERENCES
1. Purves SJ, Low MD, Galloway J, et al. A comparison of visual, brainstem auditory and somatosensory evoked potentials in multiple sclerosis. Can J Neurol Sci 1981;8(1):15–9. 2. Slimp JC, Janczakowski J, Seed LJ, et al. Comparison of median and posterior tibial nerve somatosensory evoked potentials in ambulatory patients with definite multiple sclerosis. Am J Phys Med Rehabil 1990;69(6):293–6. 3. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon Beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007; 370(9585):389–97. 4. Lassmann H, Bruck W, Lucchinetti C. Heterogenicity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001;7(3): 115–21. 5. Lublin FD, Reingold SC. 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. 6. Wolinsky JS, Narayana PA, O’Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007;61(1):14–24. 7. Shah A, Brown TR, Wadhwani R, et al. SEP testing to categorize multiple sclerosis subtypes. Int J MS Care 2005;7(2):70. 8. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;59(4):727–8. 9. Heide AC, Kraft GH, Slimp JC, et al. Cerebral N-acetylaspartate is low in patients with multiple sclerosis and abnormal visual evoked potentials. AJNR Am J Neuroradiol 1998;19:1047–54. 10. Kraft GH, Richards TL, Heide AC. Correlations of evoked potentials with MS imaging and MR spectroscopy in multiple sclerosis. Phys Med Rehabil Clin N Am 1998;9(3):561–7. 11. Kraft GH, Slimp JC. Electrophysiological monitoring of experimental allergic neuritis and experimental allergic encephalomyelitis. In: Alvord EC, Lies MW, Suckling AJ, editors. Experimental allergic encephalomyelitis: a useful for multiple sclerosis. New York: Model Alan R Liss, Inc; 1984. p. 449–53. 12. Kraft GH, Brown T. Comprehensive management of multiple sclerosis. In: Braddom RL, editor. Physical medicine and rehabilitation. 3rd edition. Philadelphia: Saunders Elsevier; 2007. p. 1223–42. 13. Kraft GH, Cui JY. Multiple Sclerosis. In: DeLisa J, Gans B, Walsh N, editors. Physical medicine and rehabilitation: principles and practice, vol. 2, 4th edition. Philadelphia: Lippincot Williams & Wilkins; 2005. p. 1753–69.
MD, MS
KEYWORDS Evoked potentials Visual evoked potentials Somatosensory evoked potentials Brain stem evoked responses KEY POINTS Evoked potentials still may be valuable in the diagnosis of and management of multiple schlerosis (MS). Evoked potentials provide a means of evaluating the type of neurologic abnormality: demyelination produces conduction slowing, whereas axonal degeneration causes attenuation of the potential amplitude. Evoked potentials are noninvasive and can be used to monitor changes in the central nervous system of a patient with MS. Evoked potentials are useful in identifying superimposed mechanical pathology (eg, cord stenosis) in MS patients.
INTRODUCTION
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), associated with neural degeneration. The diagnosis is based on the clinical history, physical examination, laboratory findings, imaging of the CNS (magnetic resonance imaging [MRI] and other neuroimaging techniques), spinal fluid analysis, and selected additional laboratory tests to eliminate other diseases. The diagnosis is confirmed when disease has been confirmed in at least 2 different locations of the CNS, occurring at 2 or more points in time, for which there is no alternative disease diagnosed. It can initially manifest itself in several distinct patterns: relapses followed by remissions (relapsing remitting or RR MS), progressive degeneration from onset (primary progressive or PP MS), and a progressive course with superimposed episodes of relapses and remissions (progressive relapsing MS). The fourth clinical type—second progressive MS—evolves from RR MS over time as the disease progresses.
Dr. Kraft has no relevant conflicts of interest. Department of Rehabilitation Medicine, University of Washington School of Medicine, University of Washington, Box 356490, Seattle, WA 98195, USA E-mail address: [email protected] Phys Med Rehabil Clin N Am 24 (2013) 717–720 http://dx.doi.org/10.1016/j.pmr.2013.07.001 1047-9651/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
pmr.theclinics.com
718
Kraft
There are 3 types of evoked potentials (EPs) used in MS diagnosis and management: (1) visual evoked potentials (VEPs), which assess neural conduction in the optic pathways. VEPs are most typically triggered by observing an illuminated, alternating checkerboard pattern of black and white squares (pattern reversal VEPs) or a flashing light. Recordings are made over the visual cortex. Prolongation of the latency indicates disease in that neural pathway; (2) somatosensory evoked potentials (SEPs) involve peripheral stimulation of the large 1 A afferent fibers in various mixed nerves in the extremities, with the ascending potentials measured at various points along the peripheral nerves, spinal cord, brainstem, and somatosensory cortex; (3) brainstem auditory evoked responses (BAERs), triggered by auditory clicks and recorded over the cortex. (Motor evoked potentials will not be covered in this review, as they are currently not Food and Drug Administration approved for clinical practice in the United States.) EPs represent a valuable adjunct to the diagnosis and management of MS because they measure physiology in the CNS. Indeed, it is the abnormal physiology of neural pathways caused by the inflammation and degeneration caused by MS that produces the motor weakness and sensory symptoms. Consequently, EPs are the only laboratory tools that directly measure the abnormal physiology resulting from the disease; all other tests are inferences of diseased pathways. USE OF EPS IN MANAGEMENT OF MS
Classically, the value of EPs is the identification of an additional region of the CNS that may be clinically “silent”—that is, not associated with clinical symptoms, which may provide the additional information necessary to satisfy the dissemination in space criterion required for a confirmed diagnosis of MS. Used for this purpose, the most sensitive of the several EPs is the VEP.1 Classically, the second most sensitive EP is the SEP, followed by the BAER. However, early studies evaluated only upper limb SEPs; they did not measure SEPs from the lower limbs. Subsequent research has demonstrated that with lower limb SEP testing (most commonly tibial nerve SEP), the sensitivity of SEPs may actually exceed VEP testing.2 The reason is that a tibial SEP evaluates the ascending afferent pathways through the entire length of the spinal cord, brainstem, and brain. As more neural tissue is traversed, there is a greater probability that areas of disease will be encountered. STEPS TO IDENTIFY ADDITIONAL SITES OF DISEASE
Unlike a traumatically produced disease, MS does not suddenly appear in its fully manifested state. There is no single point in time whereby a completely healthy individual suddenly has MS. Rather, it occurs over time—often many years. The diagnosis of MS requires satisfaction of the criteria of CNS disease “disseminated in time and space.” Thus, by definition, MS is not a disease of sudden onset. Pathologically, RR MS starts in some portion of the CNS, producing symptoms that typically subside in weeks (remission). Somewhat later, another symptom might occur in a similar manner, or the initial symptom may return (exacerbation). By the time of diagnosis (sufficient symptomatology and pathology to produce the criteria of dissemination in time and space) many years may have transpired. It is not uncommon to see patients with moderately extensive brain and spinal cord disease at the time of definite diagnosis of MS. It is now clear that it is extremely important to diagnose RR MS as early as possible, as it is well established that treatment of RR MS in the earliest stages offers the best opportunity to control the disease,3 whichis the classic role of VEPs and SEPs in the
Evoked Potentials in Multiple Sclerosis
diagnosis of MS. In addition, SEPs also offer an excellent way to quantify spinal cord disease,2 which can be useful in monitoring the effect of a particular disease modifying treatment (DMT). This is an especially important benefit because MS lesions in the spinal cord—unlike those in the brain—are often not clearly demarcated on imaging (secondary to movement artifact produced by vascular pulsation and respiratory movement as well as the characteristics of the lesions themselves). STEPS TO GUIDE TREATMENT BY SUGGESTING TYPES OF MS
Now it seems that MS is not one disease, but consists of at least 4 distinct pathologic types4; all may manifest the same clinical symptoms and signs. As previously mentioned, it is well established that there are also 4 clinical types of MS.5 The available DMTs are indicated for RR MS or early second progressive MS, not PP MS, with the possible exception of glatiramer acetate in men with PP MS.6 Consequently, research on differentiating the various types of MS is expanding. This is an important effort as differentiation of clinical type is not possible based on examination and often very difficult based on the clinical course. Because PP MS is associated with relatively more neural degeneration and relatively less inflammatory demyelination than RR MS, it is possible that EPs may offer assistance in differentiating the clinical types. Demyelination is associated with relatively more conduction slowing and degeneration is more associated with attenuation of signal. Preliminary studies suggest that SEPs may provide helpful additional information to make such a differentiation.7 There is a strong economic argument to be made that testing to differentiate types of MS can have a profound fiscal impact, as it is estimated that use of a DMT may result on over $1 million lifetime cost. Avoidance of treatment of the wrong type of MS with the wrong drug justifies the small cost of additional testing. Because it is accepted that the best response from DMTs occurs in patients treated in the earliest stages of the disease,3 much effort has been put into the diagnosis of MS in its earliest stages. The “McDonald criteria” recognizes the importance of EPs in diagnosis.8 There is also evidence that VEP abnormalities correlate with those changes seen in MRI spectroscopy associated with neural degeneration (reduced N-acetylaspartate, a surrogate for axonal loss).9,10 Laboratory studies in experimental allergic encephalomyelitis, the animal model of MS, also suggest that they may become abnormal even before clinical symptomatology.11 Further discussion of EPs and other neurophysiologic assessments can be found in texts.12,13 SUMMARY
EPs are the only laboratory tools that actually evaluate the physiology of the neurologic changes that occur during the course of MS, and physiology is related to function. Utilization of EPs can help establish a second locus of disease, may help in assessing the type of MS, and can be especially useful in monitoring changes in physiology, representing lesion load, in the spinal cord. RECOMMENDATIONS
1. It is recommended that VEPs and SEPs be incorporated in the early assessment of patients with clinically isolated syndrome to facilitate an early diagnosis of MS so that DMTs can be started as early as possible in the disease course. 2. It is recommended that selected EPs be done at the time of MS diagnosis to determine the physiologic status and periodically repeated, as appropriate, to monitor disease changes.
719
720
Kraft
3. This is especially important for monitoring cord disease, as MRI may be less quantifiable in measuring changes in MS lesion load in the spinal cord. 4. It is recommended that SEPs be considered in clinical situations whereby additional information about the physiology and disease type may be required. REFERENCES
1. Purves SJ, Low MD, Galloway J, et al. A comparison of visual, brainstem auditory and somatosensory evoked potentials in multiple sclerosis. Can J Neurol Sci 1981;8(1):15–9. 2. Slimp JC, Janczakowski J, Seed LJ, et al. Comparison of median and posterior tibial nerve somatosensory evoked potentials in ambulatory patients with definite multiple sclerosis. Am J Phys Med Rehabil 1990;69(6):293–6. 3. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon Beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007; 370(9585):389–97. 4. Lassmann H, Bruck W, Lucchinetti C. Heterogenicity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001;7(3): 115–21. 5. Lublin FD, Reingold SC. 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. 6. Wolinsky JS, Narayana PA, O’Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007;61(1):14–24. 7. Shah A, Brown TR, Wadhwani R, et al. SEP testing to categorize multiple sclerosis subtypes. Int J MS Care 2005;7(2):70. 8. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;59(4):727–8. 9. Heide AC, Kraft GH, Slimp JC, et al. Cerebral N-acetylaspartate is low in patients with multiple sclerosis and abnormal visual evoked potentials. AJNR Am J Neuroradiol 1998;19:1047–54. 10. Kraft GH, Richards TL, Heide AC. Correlations of evoked potentials with MS imaging and MR spectroscopy in multiple sclerosis. Phys Med Rehabil Clin N Am 1998;9(3):561–7. 11. Kraft GH, Slimp JC. Electrophysiological monitoring of experimental allergic neuritis and experimental allergic encephalomyelitis. In: Alvord EC, Lies MW, Suckling AJ, editors. Experimental allergic encephalomyelitis: a useful for multiple sclerosis. New York: Model Alan R Liss, Inc; 1984. p. 449–53. 12. Kraft GH, Brown T. Comprehensive management of multiple sclerosis. In: Braddom RL, editor. Physical medicine and rehabilitation. 3rd edition. Philadelphia: Saunders Elsevier; 2007. p. 1223–42. 13. Kraft GH, Cui JY. Multiple Sclerosis. In: DeLisa J, Gans B, Walsh N, editors. Physical medicine and rehabilitation: principles and practice, vol. 2, 4th edition. Philadelphia: Lippincot Williams & Wilkins; 2005. p. 1753–69.
