The Multiple Facets of Multiple Sclerosis

Transcription

1 The Richard G. Scobee Memorial Lecture The Multiple Facets of Multiple Sclerosis Patricia Fagan Jenkins, C.O. ABSTRACT Introduction: Multiple sclerosis (MS) is an inflammatory and degenerative entity that may involve the brain, optic nerve, and/or the spinal cord. We reviewed 137 patients, aged 4 54 years old at the time of the diagnosis and will report on the vision, different motility disorders found, visual fields, optic neuritis and RAPD, return of vision following the neuritis, visual evoked potential, nerve fiber layer analysis, and systemic problems such as Uhthoff phenomenon, L Hermitte sign, urinary urgency, and constipation. Methods: One hundred thirty-seven patients were given full ophthalmologic and orthoptic evaluations. Particular attention was given to subtle relative afferent pupillary defects (RAPD), oscillopsia, pain with eye movement, and other specialty testing including visual evoked potentials and nerve fiber layer assessment. The immunology, pediatric MS, clinical courses, and treatment are also discussed. Treatment included medication, orthoptic modalities, strabismus procedures, and cooling devices. Results: Motiltiy disorders included exophoria, unilateral Internuclear Ophthalmoplegia (INO), esophoria, and various types of nystagmus. The majority of nonmotility ophthalmic entities included optic neuritis, RAPD, and abnormal nerve fiber layer studies. Most patients were diagnosed based on white matter lesions on the MRI and oligoclonal bands in the spinal fluid after lumbar puncture. The majority of systemic signs were numbness, Uhthoff sign, and balance difficulties. Thirty-four percent of the patients were helped with either convergence therapy, prisms for all kinds of diplopia, and field manipulation. Conclusions: MS is a multi-factorial entity. It is important to emphasize how important a few extra history questions are, including: any pain with eye movement, any bouncing of the images, and is vision or balance any worse in the heat? The Visual Evoked Potential (VEP) and nerve fiber layer studies are important in the diagnosis of MS. Seventy percent of patients with had eye complaints as their initial symptom. Finally, one-third of all patients were helped with some form of orthoptic therapy. From Neuro-Ophthalmology of Texas, Houston, Texas. Requests for reprints should be addressed to: Patricia Fagan Jenkins, C.O., 2617C W. Holcombe Blvd. #575, Houston, TX Presented as the 37th Richard G. Scobee lecture at the annual meeting of the American Association of Certified Orthoptists, Las Vegas, Nevada, November 13, INTRODUCTION It is a pleasure to give the Richard G. Scobee Memorial lecture this year. He is special to me for many reasons first he was a Texan and even had roots at the University of Texas Medical School in Houston 2007 Board of Regents of the University of Wisconsin System, American Orthoptic Journal, Volume 57, 2007, ISSN X, E-ISSN American Orthoptic Journal 69

2 MULTIPLE SCLEROSIS as have I for many years. In his young life, he managed to accomplish many things including being in the Air Force, as my own father was also. He wrote many ophthalmology texts including the Oculorotary Muscles in 1947, which was in the American Encyclopedia and dictionary of ophthalmology. He also wrote A Child s Eyes and Vision Testing of School Children which is the orthoptist s national project in which I have actively participated for many years. Dr. Scobee also organized many strabismus meetings that would eventually have national and world-wide acclamation; he helped organize what would eventually be the AACO and helped start an orthoptic program. I could not find out if our Dr. Scobee was related to the astronaut, Richard Scobee, but I like to think he was related since my father was also at NASA and that was why my parents moved to the Houston area. This is, indeed an honor and a tribute to a wonderful man and a career that has been very rewarding to me! Multiple sclerosis (MS) is an inflammatory and degenerative entity that may involve the brain, optic nerve, and/or the spinal cord, and possibly all these areas in the same person. This neurological disease is thought to be the most common debilitating disease process of young people in the United States today. 1 PATIENTS AND METHODS Two hundred eighty-six charts with MS as the tentative or confirmed diagnosis, at the Neuro-Ophthalmology of Texas clinic, were studied. One hundred forty-nine patients were eliminated due to insufficient data or not having MS as the final diagnosis, leaving a total of 137 patients included in this study. Vision, pupils, including the presence of a relative afferent pupillary defect, orthoptic evaluation, color vision, visual fields, Amsler grid, Visual Evoked Potentials, nerve fiber layer analysis, and fundus exam were studied. There were 98 females and 39 males in this study. The ages ranged from 4 to 54 years old at the time of the diagnosis, with an average age of 31 years old. RESULTS The various motility disorders noted in this study included: exophoria, convergence insufficiency, intermittent exotropia/ exotropia [X(T)/XT], IVth nerve paresis, skew deviation, unilateral INO, bilateral INO, cogwheel pursuit, esophoria, VIth nerve paresis unilateral and bilateral, nystagmus and oscillopsia. Some patients had more than one of these entities (Table 1). Nystagmus was noted as abducting, jerk, rotary and right or left beating. The other nonmotility/ophthalmic signs (Table 2) included: optic neuritis and the following return of vision, relative afferent TABLE 1 MOTILITY DIAGNOSES Exophoria 39 Convergence insufficiency 8 X(T)/XT 4 Fourth CN 2 Skew deviation 7 Unilateral INO 14 Bilateral INO 4 Cogwheel pursuit 13 Esophoria 19 Sixth CN (1 bilateral) 7 Nystagmus 27 TABLE 2 NONMOTILITY/OPHTHALMIC SIGNS Optic neuritis 67 RAPD 79 Optic atrophy 6 Vision return following neuritis 41 Pain with eye mvmt 15 VF defect 54 VEP delay 46 NFL decrease Volume 57, 2007

3 JENKINS pupillary defect (RAPD), optic atrophy, pain with eye movement, visual field (VF) defects, abnormal Visual Evoked Potential (VEP) and nerve fiber layer (NFL) testing. The diagnosis was usually made with the MRI scan and some with a positive lumbar puncture (LP). Some patients were positive on one test and negative on the other. There were two cases where the MRI was not done due to financial reasons and still other patients that did not have this information in the chart. Note the white matter lesions on the MRI in Figure 1 (2006 personal communication from J.S. Schiffman, M.D., neuro-ophthalmologist, Anderson Cancer Institute, Houston, TX) and oligoclonal bands on the LP in Figure 2 (2006 personal communication from V. Rivera, M.D., neurologist, Houston, TX). The systemic characteristics are noted on Table 3, again with some patients having one or more of these complaints. The large majority of the patients had numbness or tingling somewhere in their bodies and difficulty in the heat (Uhthoff sign). Fourteen of fifteen patients with a recent onset of optic neuritis, had pain with eye movement. Pain is a predicting sign of optic neuritis due to inflammation of the sheath around the optic nerve where the inflammation extends to the extraocular FIGURE 1: This is an MRI showing a normal brain on the left and the typical white matter lesions with MS on the right. FIGURE 2: This is testing for MS in the cerebro spinal fluid. The normal is on the left and the typical oligoclonal bands seen in MS on the right. TABLE 3 SYSTEMIC CHARACTERISTICS Numbness/tingling 74 Balance 30 Memory 26 Urinary urgency or constipation 7 Uhthoff sign 68 L Hermitte sign 35 muscles, thereby causing the pain with eye movement (2006 personal communication from R. A. Tang, M.D., neuroophthalmologist, Neuro-Ophthalmology of Texas, Houston, TX). Visual field (VF) defects including ceco central suppression areas, central depressed areas, constriction of the field, and hemianopsias were present in 54/137 patients. VEP testing is an important diagnostic modality in MS. Forty-six of 137 had a delay. (Some of our patients had a multi-focal VEP, which is a more sensitive and lengthy test to look for a delayed response. There are smaller responses made from multiple locations that allow the clinician to note changes even in asymptomatic patients with this multi-focal VEP [2006 personal communication from N. Rangaswamy, M.D., University of Houston, Houston, TX].) Studying the nerve fiber layer (NFL) was American Orthoptic Journal 71

4 MULTIPLE SCLEROSIS also an important tool in the diagnosis of MS in this study. The GDX or OCT instruments were used with some patients having both of these tests. The nerve fiber layer studies help in determining if there had been a prior incident of optic neuritis. We had 73/137 with decreased NFL with one or both of the tests used. Furthermore, it is felt that the more episodes of optic neuritis one has (eventually demonstrating decreased NFL) the higher chance of the patient being diagnosed with MS. Tang states (2006 personal communication) that glaucoma patients also have a decreased nerve fiber layer, but they additionally have the cupping of the disc that MS patients do not. Seventy percent (100/137) of patients had some type of visual complaint either blurring, blind spots/vf defects, pain with movement, fuzzy patches, or diplopia as their main concern to take them to either their ophthalmologist or neurologist to eventually make the MS diagnosis. There were several patients who noted much earlier problems in their lives prior to MS being diagnosed. Most had funny numbness or tingling, balance problems, and/or physical clumsiness. Some as young as four years old recalled having severe headaches, eye movement pain or migraines, and still others had unusual complaints and were considered hypochondriacs. Since the eye problem was the impetus that led many patients to their physician for the diagnosis, it is critical for the ophthalmologist and orthoptist to look for signs of multiple sclerosis. One systemic sign of this entity is the Uhthoff phenomenon, which was first described in the early 1900s when patients noted that heat and/or exercise made them have extreme fatigue, decreased vision, or dragging of their legs. All the problems would improve after cooling down their bodies. It was found that the heating of the body caused the blurred vision or balance difficulty, not another exacerbation of their MS. 2 Sixty-eight patients had this complaint. The L Hermitte sign is pain or an electrical jolt down the arms or legs with neck flexion. 3 We had 35 patients with this symptom. In our study, there were twenty pediatric patients with neurological impairment that were studied. Seven children were eliminated due to not having MS as the final diagnosis leaving 13 patients in this category. The children s age of onset was between 4 18 years old. Results of Pediatric Multiple Sclerosis Table 4 shows there were 8/13 who noted a visual problem (two diplopia and six blurred) that was the first complaint or the one that took them into the physician, four with decreased NFL, four with delayed VEP, four with optic neuritis, two with return of vision following the neuritis, five with pain with movement, one with optic TABLE 4 PEDIATRIC MS Vision Blurred 6 Vision Diplopia 2 NFL decrease 4 VEP delay 4 Optic neuritis 4 Return of VA after neuritis 2 Pain with eye movement 5 Optic atrophy 1 VF defect 3 RAPD 5 Convergence insufficiency 2 X(T)/XT 3 Nystagmus 3 INO 1 X 3 Numbness/tingling 7 Uhthoff 4 L Hermitte 5 HA 5 Balance problems 6 Memory problems 2 Urinary urgency 3 Hearing loss 1 72 Volume 57, 2007

5 JENKINS atrophy, three with VF defects, and five with a RAPD. There were two with convergence insufficiency (including one with combined accommodative insufficiency), three with X(T)/XT, three with nystagmus, one with INO, and three with exophoria. Table 4 also shows seven with numbness or tingling, four with Uhthoff, five with L Hermitte, five with HA, six with balance problems, two with memory problems, three with urinary urgency, and one with hearing loss. Some of these patients had more than one symptom. DISCUSSION Clinical Course FIGURE 3: This is the relapsing remitting type of MS where the patient has definite episodes of attacks with either diplopia, optic neuritis, numbness, balance problems or many other problems and/or combinations of any of these. Then, they usually completely recover. FIGURE 4: This is the primary progressive type of MS where the patient slowly decreases with neurological deficits with only small improvements. This is a rather rare type of multiple sclerosis. With MS, there are many different ways a person can be affected and many different ways each individual s disease can progress: either slowly or at a more rapid pace. It IS necessary to categorize the variances. There are four clinical courses of MS: 1) relapsing remitting; 2) primary progressive; 3) secondary progressive; and 4) progressive relapsing. Relapsing remitting is when the attacks are clearly defined: there can be specific worsening of neurological symptoms, and they may have partial or full recovery. There is also a specific disease-free time. This is the most common form of MS with a 85% frequency from the time of the first diagnosis (Figure 3). Primary progressive is when there is slow and gradual worsening of symptoms, and there are only minor improvements. There are no distinct remissions and there are usually some variations in the amount of progression. According to the National Society of MS, there is a 10% frequency of this type which makes it rather uncommon, (Figure 4). 4 Secondary progressive has characteristics of relapsing remitting with clearly marked and defined exacerbations and recoveries, then there is a gradual worsening with flare-ups and perhaps a plateau with recovery. This type has approximately 50% of patients first being diagnosed with relapsing remitting, then, ten years later, decompensating to secondary progressive. Drugs have not been effectively proven to delay the deterioration with this type (Figure 5). Finally, the most rare type is progressive relapsing, which has a continual worsening from the initial onset of symptoms to acute episodes, without recovery, and increased exacerbations (Figure 6). 4 American Orthoptic Journal 73

6 MULTIPLE SCLEROSIS FIGURE 5: This is the secondary progressive type of MS. These patients have distinct attacks, similar to relapsing remitting; however, there is a gradual worsening of their condition and may eventually reach a plateau of recovery. FIGURE 6: This is the very rare, progressive relapsing type of MS. The patient gradually declines in neurological symptoms without recovery. Immunology It is difficult to determine who is more likely to develop MS, since it is a multifactorial disease. However, there seems to be a greater chance to develop MS the farther away from the equator one lives, which may be attributed to an increased chance of vitamin D deficiency. It seems the more exposure to bright sunlight early in one s life, the more the body naturally produces more vitamin D, which has been shown to have a beneficial effect against autoimmune diseases, like MS (Figure 7). 4 It has been demonstrated that those born in high risk areas around the world yet move to a population of low risk before age 15 years old, then acquire the risk of the new area. 6 The MS society further states that certain infections/viruses could trigger MS, such as measles, Epstein-Barr virus, canine distemper, Chlamydia, pneumonia, herpes, and other viruses, but more research is needed. Some authors feel certain airborne exposure from the environment before puberty may trigger MS in certain individuals. 4 Karpatkin 5 reported a correlation between locations or tracks of the lesions and specific symptoms. He noted the different tracts as the following: 1) vestibular tracts where oscillopsia and nystagmus might be noted; 2) cerebellar tracts affecting balance and numbness or tingling; 3) cognitive tracts affecting memory; 4) motor tracts affecting the bladder and bowel; and 5) visual tracts affecting decreased VA, brainstem-diplopia, and visual field defects. Of note, the reason INO is a rather common finding with MS is that the pathologic lesions of MS tend to be in periventricular white matter. The medial longitudinal fisciculus (MLF) is a long white matter bundle that is located near the ventricular system, which is therefore affected easily, causing the INO. We felt the VEP test was an important diagnostic modality that tested the response of the visual stimulus measured from the visual cortex. The normal VEP averages the entire VF. The implicit time is one of the parameters on the VEP that demonstrates how much time it takes the signal to travel from the retina to the visual cortex. So, if there is plenty of myelin, the impulse will be fast; however, if there is demyelination and reduced myelin, then the impulse time of the VEP will be slower or delayed. 74 Volume 57, 2007

7 JENKINS FIGURE 7: Here is the world distribution of multiple sclerosis. As you can see, the dark areas are the most at risk for the disease, lighter colors indicate lower risk areas (areas that have longer periods of sunshine). PEDIATRIC MULTIPLE SCLEROSIS There are approximately 10,000 children under the age of 18 years old with demyelinating disease and another 15,000 with symptoms that could lead to an MS diagnosis, according to the statistics at the National Society of Multiple Sclerosis. 4 While there has not been much written involving children with this entity in the United States, it has been reported that youngsters with MS have decreased abilities with memory, cognition, and language as compared to the normal population of the same age group. 7, 8 Two studies abroad found that treatment with Rebif (interferon beta la) and Betaseron (interferon beta lb) had fair-moderate results 9, 10 in children and adolescents with MS. Adams stressed the importance of using the MRI with children as well as adults, even though there is still not an exact correlation, with pediatric MS to adult. Differential diagnoses of childhood multiple sclerosis include acute disseminating encephalomyelitis (ADEM), and Devic disease or neuromyelitis optica (NMO). Most authors readily admit it is difficult to distinguish among these neurological problems. First, ADEM has encephalopathy, a preceding illness and pleocytosis (cells in the spinal cord, like inflammation). ADEM is typically polysymptomatic just as MS also has many symptoms. With ADEM, there is usually early onset ataxia and gray matter lesions 12 as well as white matter lesions 17 on the MRI. Other characteristics include acute neurological deficits and no evidence of pre-existing demyelinating disease. Typically, ADEM can be associated with vaccinations and infectious causes. 13 Devic disease, or neuromyelitis optica (NMO), is considered a variant of MS. This is an inflammatory disorder especially involving the optic nerve and spinal cord. The inflammation is usually more acute and severe than the optic neuritis in MS. There American Orthoptic Journal 75

8 MULTIPLE SCLEROSIS are no or few white matter lesions on the MRI of the brain; however, there are lesions on the spinal cord MRI that are distinctive of neuromyelitis optica syndrome. They are longitudinal and extensive lesions over 3 4 vertical segments. There is pleocytosis of the CSF, with more than fifty leukocytes. The optic neuritis and myelitis can have several years between episodes. Following the first episode of optic neuritis, 40% of these cases become completely blind. NMO can also have either unilateral or bilateral optic neuritis. 14 TREATMENT I was honored to meet Dr. Maldovan, a neurologist who started the Houston Chapter of MS in the 1960s (2006 personal communication with Dr. Maldovan). He has been impressed over the years that there is much more hope for MS patients now, with early diagnosis and, consequently, early treatment. Additionally, there are new treatment methods for multiple sclerosis. The treatment for MS has varied throughout the years, including orthoptics, medications, specific strabismic surgery, exercises, cooling devices, etc. ORTHOPTICS Some form of orthoptics helped 34% of these patients: the eight CI patients with various convergence therapies, all seven vertical deviations were helped with prism, ten of the unilateral INOs were helped with convergence therapy, two unilateral INO patients needed prism, two bilateral INO were helped with convergence therapy, one bilateral INO needed prism, one bilateral INO had prism to manipulate the VF, three esophoric patients needed prism, eight with sixth CN palsies needed prism, one with bilateral sixth CN palsies needed prism, three X(T)/XT patients were helped with prism. Additionally, there were two people (one 16 years old and the other 46 years old) who were given safety glasses with unilateral poor vision from optic atrophy. MEDICATIONS In a report by the CHAMPS Study Group, it was stated that Avonex (or interferon beta 1a), given at the first episode of optic neuritis could decrease exacerbations in the future. 15 Consequently, many of our patients who had MS diagnosed a few years ago, began their treatment on Avonex. Also, IV steroids is a common treatment for patients with decreased vision and optic neuritis. It is important to note that these patients do not always acquire the label of MS. It has been shown that oral steroids are contraindicated in the first episode of optic neuritis as they may increase the incidence of optic neuritis in patients with idiopathic optic neuritis. 13 In this present study, Copaxone seems to be the treatment of choice as most people either began with Copaxone or were eventually changed to this medicine. Personally interviewing many of these patients, I was told this medicine actually enabled them to do many activities that had been part of their lifestyles prior to the limiting condition or were able to do again things that the other medicines had not made possible (no financial interest). Rebif, Betaseron, and chemotherapy were also used to help the different types of demyelinating disease. SURGERY To improve oscillopsia, null point strabismus surgery has been advocated and may be used in combination with an oral medication, Memantine, typically used to treat Alzheimer disease. 16 Treatment of pendular nystagmus and oscillopsia has been reported to improve with Neurontin, as some of our patients experienced. 76 Volume 57, 2007

9 JENKINS EXERCISE In a study by White, 17 it was noted that resistance training exercise programs improved their patients ability to move and function comfortably and also decreased their fatigue. This is quite different from those who felt MS patients would benefit from little activity. Since exacerbations may occur at any time, it was emphasized that one must be flexible as this is an unpredictable disease and the exercise regimen may need to change quickly. 5 Cardiovascular function, fatigue, depression, and strength have all been reported to improve with a regular exercise program. 5 COOLING DEVICES In addition to the aerobics and resistance training, cool devices from the MS Society have been reported to help keep the body s temperature cool and thereby decreasing any reduced functioning in the heat. These include hats, scarves, car fans, and, fairly new to the market, cooling vests. 4 These devices improve the quality of life for children with MS, just as they have helped adults. This is also true of medications, including Copaxone, Avonex, IV steroids, and combinations of these with similar dosages to that of adults as well. It has been noted that there is a slower progression in children with MS. 18 CONCLUSION Multiple sclerosis is a disease that has multiple facets. We reported on the importance of specifically checking for a subtle RAPD, obtaining a complete orthoptic evaluation, checking visual fields, studying the nerve fiber layer, and obtaining a visual evoked potential as well as a complete ophthalmologic exam. Additionally, a few extra questions regarding the history could possibly steer the exam toward a faster di- agnosis, including whether there is any pain with eye movement, bouncing of objects in lateral gazes, or worse vision or balance in the heat? There were 70% of patients with eye complaints as the initial symptom that led to the MS diagnosis. In this study, it was noted that one-third of all patients were helped with some form of orthoptic management. From convergence therapy, to prisms for all kinds of diplopia and manipulation of field defects, to teaching the patient how to refocus by turning the head, to helping maintain a positive attitude, to being a contact/mediator/ intercessory for the patient and the MS Society... the orthoptist can make a difference! ACKNOWLEDGEMENT Many thanks to Fernando Alcocer, M.D., and Lourdes Lopez, M.D., for their help with this research. REFERENCES 1. Wolinsky JS: Promise Study Group. The diagnosis of primary progressive multiple sclerosis. J Neurol Sci 2003;206: Nelson DA, Jeffreys WH, McDowell F: Effects of induced hypothermia on some neurological diseases. Arch Neurol Psychiatry 1958;79: Wall M: Multiple sclerosis. Chapter 212 in Albert and Jakobiec, Principles and Practice of Ophthalmology. Boston: WB Saunders Co.; Vol. 4, pp National Multiple Sclerosis Society website: August 6, Karpatkin H: Improved walking endurance in 57- year-old man with multiple sclerosis after intermittent exercise: Case report. Int J MS Care 8: Maxner CE: Neuro-ophthalmology and multiple sclerosis (John Pratt-Johnson Lecture). Am Orthopt J 2006;56: Banwell B, Reder A, et al.: Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology 2005;66: McAllister WS, Belman AL: Cognitive functioning in children and adolescents with multiple sclerosis. Neurology 2005;64: American Orthoptic Journal 77

10 MULTIPLE SCLEROSIS 9. Pohl D, Rostasy K, et al.: Treatment of early onset multiple sclerosis with sub-cutaneous interferon beta-1a. Neurology 2005; 64: Tenembaum SN, Besura MJ: Interferon beta-1a in childhood and juvenile onset multiple sclerosis. Neurology 2006;67: Adams HP, Koziol JA: Progressive cerebral atrophy in multiple sclerosis: A serial study using registered, volumetric MRI. Neurology 2000;55: Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean MJ: Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology 2001;56: Kutlus VF: Ophthalmological manifestations in pediatric population with acute disseminating encephomyolitis. J AAPOS 2004; 9: Wingerchuk DM: Devics disease handout. Dept. of Neurology, Mayo Clinic, Scottsdale, AZ. 15. CHAMPS Study Group, Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343: Tomsask RL, Dell Osso LF, et al.: Treatment of pendular nystagmus from multiple sclerosis with eye muscle surgery followed by oral memantine. Digital J Ophthal 2006;6/9/ White LJ, McCoy SC, et al.: Resistance training improves strength and functional capacity in persons with multiple sclerosis. Mult Scler 2004;10: Cole GF, Stuart CA: A long perspective on childhood multiple sclerosis. Dev Med Child Neurol 1995;37: Key words: multiple sclerosis (MS), diplopia, INO, optic neuritis, pediatric demyelinating disease Continuing Education Credit Orthoptists wishing to earn American Orthoptic Council approved continuing education credits may earn 5 hours of credit by completing a self-study test based on the articles contained in the American Orthoptic Journal. Allied Health Personnel in Ophthalmology may earn 4 hours of JCAHPO approved continuing education credit upon successful completion of the self-test. Information regarding the test may be obtained by writing to: Thomas D. France, M.D., Editor, American Orthoptic Journal, 2870 University Ave., Suite 103, Madison, WI tdfrance@facstaff.wisc.edu 78 Volume 57, 2007