Journal of Neuro-Ophthalmology, December 1985, Volume 5, Issue 4

Neuromyelitis optica: two new cases and review of the literature.

The clinical features of two recent cases of neuromyelitis optica are reviewed, along with 43 cases from the literature. Severe bilateral visual impairment, thoracic myelitis, prodromal symptoms suggesting a viral syndrome, and moderate pleocytosis of the cerebrospinal fluid (CSF) were characteristic. Respiratory failure developed in 22% of the cases. Seventy percent of patients improved neurologically, 14% had a poor neurological outcome, and 16% died in the acute stages. Predictors of a poor outcome were older age, marked CSF pleocytosis, and severe myelitis. Forty-two percent of patients had a recurrence of demyelinating disease after initial recovery, suggesting a diagnosis of multiple sclerosis. Fifty-eight percent of patients had a self-limited monophasic illness, consistent with a post-infectious encephalomyelitis. No clear predictors of patients at risk for recurrence were identified. CSF oligoclonal bands were absent in three patients with information available.

J. elin. Neurcrophth4mol. 5:263-269, 1985 © 1985 Raven Press, New York Neuromyelitis Optica: Two New Cases and Review of the Literature RUTH H. WHITHAM, M.D. ROBIN L. BREY, M.D. Abstract The clinical feahues of two recent cases of neuro­myelitis optica are reviewed, along with 43 cases from the literature. Severe bilater.al visual impair­ment, thoracic myelitis, prodromal symptoms sug­gesting a viral syndrome, and moderate pleocytosis of the cerebrospinal fluid (CSF) were characteristic. Respiratory f.ailure developed in 22'70 of the c.ases. Seventy percent of patients improved neurologi­cally, 14~ h.ad .a poor neurologic.al outcome, and 16~ died in the .acute st.Jges. Predictors of a poor outcome were older .age, marked CSF pleocytosis, and severe myelitis. Forty-two percent of patients had .a recurrence of demyelinating dise.ase .after initial recovery, suggesting .a di.agnosis of multiple sderosis. Fifty-eight percent of patients h.ad a self­limited monophasic illness, consistent with a post­infectious encephalomyelitis. No dear predictors of patients at risk for recurrence were identified. CSF oligoclonal bands were absent in three p.a­tients with infonnation .available. Neuromyelitis optica is a clinical syndrome characterized by the acute onset of optic nerve and spinal cord demyelination. Allbuttl recog­nized an association of optic nerve disease with inflammatory disease of the spinal cord in 1870, but it was not formally recognized as a clinical entity until 1894. Femand Gault and his teacher Eugene Devic described 17 patients presenting with optic neuritis and transverse myelitis, and proposed the name neuroptico-myelite to de­scribe the syndrome.2 Over 300 cases have been reported since that time, but the relationship of neuromyelitis optica to the other demyelinating diseases remains uncertain. Originally, neuro­myelitis optica was felt to be distinct clinically and pathologically from multiple sclerosis, Schilder's disease, and acute disseminated en­cephalomyelitis. 3- s More recently, neuromyeli- From the Department of Neurology, Oregon Health Sci­ences University, Portland, OR, U.S.A. Write for reprints to: R. H. Whith.Jm, M.D., Department of Neurology, Oregon Health Sciences University. 3181 S.W. Sam Jackson Park Road. Portland, OR 97201. U.S.A. December 1985 tis optica has been assumed to represent a vari­ant of multiple sderosis.6- 8 Two cases of neuromyelitis optica recently en­countered by the authors seemed atypical for multiple sclerosis and prompted a reexamina· tion of the literature. We reviewed the case re­ports of 80 patients with a diagnosis of neuro­myelitis optica from the English languare liter­ature since 1900. Of these, 43 patients3•S• -32 met the clinical criteria of unilateral or bilateral optic neuritis and transverse myelitis, occurring within an interval of less than 8 weeks. This definition, although somewhat arbitrary, pro­vided a more homogeneous group for evalua­tion and is similar to criteria used in previous reports. 6- 8 These 43 patients and the two new cases are analyzed in detail, to provide an up­dated clinical profile of neuromyelitis optiea and to examine the prognostic implications of a single bout of neuromyelitis optica. Case Reports Patient 1 A 21-year-old white female was well until the two months prior to admission, during which she developed general fatigue, dizziness, fever, chills, and a tooth abscess. On the morning of admission, the vision in her right eye became blurry and progressed over several hours to complete blindness in that eye. The left eye be­came similarly affected later in the day. During the evening, she developed progressive leg weakness and inability to urinate. She was on no medications except for a nonprescription diet pill. Her past medical history and family history were unremarkable. Physical examination revealed a slightly le­thargic but fully oriented young woman. Tem­perature was 102°F. She had no light perception in either eye. Both pupils were dilated and non­reactive to light but reacted briskly to accom· modation. Funduscopic examination showed blurring of both optic disc margins with venous engorgement bilaterally and two small flame hemorrhages on the right. The remainder of the cranial nerve examination was normal. Upper 263 Neuromyelitis Optica Results The clinical features of the 43 cases from the literature and the two new cases are summa­rized in Tables 1-5 and Figure 1. The age at onset ranged from 5 to 66, with an average age of 27.3 years and a median of 27 years (Fig. 1). There were 26 females (58%) and 19 males (42%), a ratio of 1.4 to 1. Three of the patients were black (7%), and seven were oriental (16%). On physical examination she was afebiJe, alert, and oriented. She complained of poor vi­sion in the right eye but could read newsprint equally well with both eyes. Pupils were 5 mm and normally reactive to light bilaterally. Fun­doscopic examination was normal without evi­dence of papillitis. The remainder of the cranial nerve examination was normal. She had a spastic paraparesis and was non-ambulatory. Upper extremity strength was normal. Reflexes were diffusely hyperactive, with ankle clonus and Babinski responses bilaterally. Sensory ex­amination showed a T-2 sensory level. There were no cerebellar deficits, and sphincter tone was normal. CSF examination showed a normal opening pressure, a protein level of 67 mgldl, a glucose level of 50 mgldJ, and 44 white blood ceUs/mm3 with 75% lymphocytes. IgG index was 0.67, and oligoclonal banding studies were negative. cr scan of the brain was normal with and without contrast infusion. She received methylprednisolone, 50 mg in­travenously every 8 h for 24 h, followed by oral prednisone, 50 mg twice daily. She steadily im­proved, and by the ninth hospital day was am­bulatory with a mild paraparesis. She was with­drawn from steroids over the next 2 months, and her neurological examination was normal at a 3-month follow-up visit. She has had no recurrence of neurological disease and remains well 1 year after the onset of her symptoms. Age Figure 1. Age al onset of neuromyelitis optica. "41 2211 2211 2Zl' SolO 11-20 21-30 31.40 41-50 51-10 ~ r-- ,.......:.. ~ -la n Zl' 11 10 t (No.) Patients i 5 Patient 2 A 12-year-old white female was well until 3 weeks prior to admission, when she developed fever and headache. CSF examination showed 92 white cells/mm3 and a protein of 55 mgldl. Cultures were negative and a diagnosis of viral meningitis was made. Her symptoms abated until 3 days prior to admission, when she de­veloped progressive lower extremity weakness with associated numbness. She became unable to walk, and on the day before admission awoke with right-sided visual loss. She was on no medications and had received no recent im­munizations. Family history was positive only for myasthenia gravis in her maternal grand­mother. extremity strength and tone were normal, but there was mild bilateral pronator drift. She could stand with assistance only and was un­able to walk because of lower extremity weak­ness. Deep-tendon reflexes were normal in the upper extremities and absent in the lower ex­tremities. No Babinski response was elicited. Sensory examination suggested a T-lD sensory level. There were no cerebellar deficits. Cerebrospinal fluid (CSF) examination showed an opening lumbar pressure of 18 em of H20, protein level of 250 mg/dl, glucose level of 84 mgldl, and 93 white blood cells/mm3 with 79% lymphocytes. Myelin basic protein was 7.2 ng/ml (normal <4 ng/ml) and oligoclonal banding studies were negative. Computed to­mography (CT) scan of the brain was normal with and without contrast infusion. Visual evoked potentials were absent after stimulation of either eye. Brainstem auditory evoked poten­tials were normal. Functional vital capacity was 2.9 L (76% of predicted capacity). Collagen vas­cular serologies were negative. She was treated with methylprednisolone, 125 mg IV every 6 h for 48 h, followed by oral prednisone, 100 mg daily for 2 weeks. She made steady improvement, and steroids were gradu­ally withdrawn over 2 months. At a 3-month follow-up visit, she was ambulatory with a slightly spastic gait, and visual acuity was 20/70 in the left eye and 20/200 in the right eye. She had bilateral optic atrophy, lower extremity re­flexes were brisk, and Babinski responses were present bilaterally. Five months after her initial presentation, she developed recurrent bilateral optic neuritis fol­lOWing a flu like illness. Her symptoms remitted after 2 weeks, during which time she received a course of oral corticosteroids. At an 8-month follow-up visit, visual acuity was 20/100 bilat­erally and gait was normal. 264 Journal of Clinical Neuro-ophthalmology TABLE 1. PmdJomal Fe.hues of Neuromyelitis Opticoll PatillOts Whitham, Brey TABLE 2. MolIximum NeurologicolIl Deficit Patients A prodrome, often suggesting a viral syndrome, preceded the onset of neuromyelitis optica in 68% of patients (Table 1). Three patients had specific viral syndromes 1 to 4 weeks preceding onset: these were mumps,17 varicella, 10 and in­fectious mononudeosis.32 One patient devel­oped neuromyelitis optica 11 days after atten­uated live rubella virus vaccination. 18 The presenting symptom was bilateral optic neuritis in 36%, unilateral optic neuritis in 40%, transverse myelitis in 13%, and simultaneous optic neuritis and transverse myelitis in 11% of patients. The interval between development of optic neuritis and transverse myelitis ranged from simultaneous onset to 7 weeks, but was 1 week or less in 60% of patients. The maximum neurological deficit usually developed within 2 weeks, but progression could continue for as long as 10 weeks or be completed within hours. The maximum deficit (Table 2) included bilateral visual impairment in 91%, and unilateral or bi­lateral blindness in 58% of cases. A sensory level, most commonly thoracic, was present in 90% of patients. Paraplegia or paraparesis without upper extremity involvement occurred in 47% of cases, and 37% had upper and lower extremity weakness. Sphincter disturbance was present in 87% of patients, and 22% developed respiratory failure. The severity of the optic neuritis and transverse myelitis tended to cor­relate, but could be dissociated. A CSF sample obtained during the acute phase of illness was abnormal in 84% of cases. Sixty-two percent had an elevated CSF protein, and 61% had a CSF pleocytosis (Table 3). Neurological outcome after a single bout of neuromyelitis optica is summarized in Table 4. Seven patients (16%) died during the acute phases of their illness after a progressive down­hill course. Death occurred 8 days to 2.5 months after the onset of illness, usually from respira­tory failure. Six additional patients survived (14%) but had a poor neurological outcome, with two patients blind and paraplegic, three patients paraplegic, and one patient blind at TABLE 3. CSF Enminillion follow-up. Fifteen patients (34%) had a good outcome, with eight patients completely normal at follow-up and seven patients having rela­tively mild deficits (ambulatory with functional vision or better). In all, 31 patients (70%) im­proved neurologically, generally over a 2-6 month recovery period. Thirty-five percent ul­timately had normal vision, 46% had normal sensation, 50% had normal strength, 59% had normal sphincter function, and all had normal respiratory function at follow-up. The number of patients with a favorable outcome may ac­tually be higher, but patients reported as "im­proved" could not be classified further. Younger patients and males were more likely to have a good neurological outcome. Patients Specific virus Postvaccination Headache Upper respiratory Gastrointestinal Postsurgical Nonspecific No prodrome No information 3 ( 7%) 1 ( 2%) 6 (15%) 8(19%) 2 ( 5%) 2 ( 5%) 6 (15%) 13 (32%) 4 Vision Bilateral blindness Bilateral partial visual loss Unilateral blindness plus unilateral partial visual loss Unilateral partial visual loss Se,rsory level Cervical Thoracic Lumbar No level No information Motor !lInction invotvtment Paraplegia Paraparesis Paraplegia and upper extremities Paraparesis and upper extremities Normal strength Sphinctt.'r disturbance No information Respiratory involvement Protein (mg/dl) 0;;45 46-100 >100 No information Whitt.' cdls/mm2 0;;5 6-50 51-100 >100 No information Patients 12 (38%) 14 (43%) 6 (19%) 13 15 (39%) 11 (28%) 6 (15%) 7 (18%) 6 21 (47%) 15 (33%) 5 (11%) 4 (9%) 10 (24%) 27 (66%) O( 0%) 4 (10%) 4 16 (36%) 5 (11%) 11 (24%) 6 (13%) 7 (16%) 34 (87%) 6 10 (22%) December 1985 265 Neuromyelitis Optica TABLE 5. Recurrent Neurological Disease TABLE 4. Neurological Outcome after Neuromyelitis Optica with severe neurological deficits acutely were more likely to remain disabled. A marked CSF pleocytosis (>100 cells) was associated with se­vere myelitis and a poor outcome. Deaths were more common in older patients. Steroid therapy (10 patients) did not appear to influence out­come. Assessment of risk of recurrent neurological disease after stabilization or recovery from a single bout of neuromyelitis optica was limited by the short follow-up in many of the cases. Twelve patients had essentially no follow-up beyond the immediate recovery phase. If these patients and the seven patients who died are excluded, there are 26 patients at risk to develop recurrent demyelinating disease (Table 5). Fif­teen patients (58%) with a minimum of 1 year of follow-up had no recurrence of neurological illness. Four patients (15%) had recurrent mul­tifocal demyelination, four patients (15%) had recurrent bilateral optic neuritis, and three pa­tients (12%) had recurrent optic neuritis and transverse myelitis. Fifty-five percent of the re­currences were within the first 6 months, but 18% occurred more than 5 years after the initial bout of neuromyelitis optica (Table 5). Of 17 pa­tients followed for 10 years or more, 11 had re­current disease and six had no recurrence of dis­ease. Assuming the nine patients lost to follow- Death after downhill course Poor neurological outcome Neurological improvement Good neurological outcome No information No recurrence Relapse of bilateral optic neuritis Relapse of optic neuritis and transverse myelitis Relapse of multifocal disease FoUow-up <1 year When Recurrence Occurred ,,;;;6 months 7-12 months 18 months 6 years 9 years 266 Patients 7 (16%) 6 (14%) 16 (36%) 15 (34%) 1 Patients IS (58%) 4 (15%) 3 (12'70) 4 (15%) 12 6 (55%) 1 ( 9%) 2 (18%) 1 ( 9%) I ( 9'70) up after one year were without recurrence, there is a minimum recurrence rate of 42% at 10 years. Those with recurrent demyelinating dis­ease often fared poorly: two of the three pa­tients with recurrent optic neuritis and trans­verse myelitis and two of th~ fo~r pa~ents with recurrent multifocal demyelination died of re­spiratory failure or sepsis within 2 years.of their initial disease onset. Though follow-up m some was short, those with only optic neuritis recur­ring made acceptable recoveries, as did those with late recurrences. There were no clear pre­dictors of recurrent neurological disease, except that females had a somewhat higher rate of re­currence (7/13 females vs. 4/13 males). Steroid therapy did not appear to prevent recurrent dis­ease. Discussion The clinical features of neuromyelitis optica in the current report are similar to those noted previously, but the prognosis for ~eurological recovery is better than formerly rea~ed. Se~e.re bilateral visual impairment, a thoraac myelitis, prodromal symptoms suggesting a viral syn­drome, and moderate CSF pleocytosis are con­sistent with previous reports. ].25,26,28.33 There is a wide range of susceptible ages, but onset after age 50 is rare. 25•28.33 We found a slight female predominance, as did Stansbury,28 ~ut others have either found no sex preference25 or found tha t males are more frequently aff~cted.IS.26 Onset with optic neuritis may be more frequent than with transverse myelitis, 15,23,25 but this has not been substantiated in all series. 28.34 The cur­rent review suggests a relatively low incidence of respiratory failure and a good neurological outcome in a higher proportion of patients than previously reported, and all acute deaths oc­curred prior to 1943. Advances in supportive care and the recognition of milder cases have undoubtedly contributed to this trend. Goulden reported that recovery from neuromyelitis op­tica was rare, 15 and Stansbury noted a 50% mor­tality rate in the acute phases and an additional 30% mortality secondary to complications of prolonged severe deficits. 28 Scott was one of the first to document that patients with milder my­elitis have a substantially better prognosis.25 More recently, Cloys and Netsky reported that 20% of patients die in the acute stages, and 30% die with complications after many months.33 The current report suggests a more optimistic outlook for the patient who survives the acute phase of illness. Young age and male sex were variables associated with a better outcome in the present series, whereas older age, severe my­elitis, and marked CSF pleocytosis often indi­cated a poor outcome. Journal of Clinical Neuro-ophthalmology Historically, the relationship of neuromyelitis optica to multiple sclerosis is an area of contro­versy, 3,4,5,22.35,36 and the risk of recurrent de-myelinating disease after an attack of neuro­myelitis optica is not well addressed in the lit­erature. The current review used for selection clinical criteria that excluded patients with prior neurological disease and those with prominent symptoms and signs in addition to optic neuritis and transverse myelitis at the time of presen­tation. Previous reports tended to include a broader spectrum of patients and were often predicated upon finding demyelination of optic nerves and spinal cord at autopsy, regardless of the clinical setting or the extent of demyelin­ation in other areas of the central nervous system. This may have led to an over-represen­tation of patients with multiple sclerosis. The clinical histories of the patients reviewed in the current report suggest that the syndrome of neuromyelitis optica represents at least two major groups of patients: those with a postin­fectious (or postvaccinial) encephalomyelitis and those having their first attack of multiple sclerosis. It is often not possible to classify pa­tients into one or the other group at the outset, and even with careful follow-up differentiation can be difficult. Postinfectious encephalomy­elitis, though classically monophasic, has been reported to relapse,22 and its relationship to multiple sclerosis then becomes unclear, partic­ularly if relapse is confined to the optic nerves and spinal cord. Other patients may have neu­romyelitis optica as a manifestation of collagen vascular disease37.38 or as a paraneoplastic syn­drome, although these patients tend to present less acutely and are less likely to meet the cri­teria outlined for this report. The histopathology of neuromyelitis optica reported in the literature has included a wide spectrum of changes,3-5,28,33.34.35 and does not provide a clear separation of multiple sclerosis from postinfectious encephalomyelitis. At one extreme are cases that show widespread ne­crosis of gray and white matter, often associated with diffuse inflammation and hemorrhage. At the other extreme are cases with chronic de­myelinating plaques characteristic of multiple sclerosis. Other cases show perivenous infiltra­tion of gray and white matter by mononuclear cells and perivascular zones of demyelination, typical of a postinfectious or postvaccinial en­cephalomyelitis. Finally, cases that seem to be transitional between these patterns have also been described. The most prominent changes are in the spinal cord and optic nerves, but other areas of the central nervous system may show similar changes to a variable degree. The spectrum of pathologic changes may well reflect December 1985 Whitham, Brey the acuteness or chronicity of the disease fro­cess, rather than a specific etiology.33,35.36.3 There were no clear clinical variables predic­tive of recurrent demyelinating disease in the current review, though females may have been at slightly higher risk. Idiopathic optic neuritis and acute transverse myelitis are related de­myelinating syndromes which have been re­ported following viral infections or vaccina­tion40- 44 and are similar clinically to neuromy­elitis optica.45-49 The risk of developing a course suggestive of multiple sclerosis after idiopathic optic neuritis has varied from 8% to 85%,46.47.50 but it has been highest in females and in pa­tients aged 20-40. Similar risk factors and re­currence rates might be expected for neuromye­litis optica. Acute transverse myelitis has a lower risk of recurrent demyelinating disease­3- 13% in published series_45,48.49 and the pre­dictors of recurrence are not as well docu­mented. CSF immunoglobulin abnormalities may prove to be useful predictors of recurrent dis­ease. CSF oligoclonal bands have been detected in 85-95% of clinically definite multiple scle­rosis patients5l and are often present early in the disease course. CSF electrophoresis on the two patients presented in the current report showed no oligoclonal bands. A 56-year-old woman with neuromyelitis optica following a flulike illness was recently reported, and CSF electroEhoresis again showed no oligoclonal bands. 2 Other patients reported in the litera­ture to date have not had CSF analysis for oli­goclonal bands. Forty to fifty percent of patients with idiopathic optic neuritis have been re­ported to have CSF oligoclonal bands50·53.54 and 28% of patients with acute transverse myelitis have also had oligoclonal bands. 55 In patients with idiopathic optic neuritis, the presence of oligoclonal bands has been associated with a higher risk of developing multiple sclerosis. 50.54 Further studies of oligoclonal bands in neuro­myelitis optica and other demyelinating syn­dromes may allow earlier identification of pa­tients at risk for chronic recurrent disease. The treatment of neuromyelitis optica has been primarily supportive, but there are anec­dotal reports supporting the use of steroids, particularly in cases of neuromyelitis optica that seem to clearly follow a viral prodrome.18.32 Re­cent reports of the dramatic reversal of a pro­gressive downhill course when steroids were in­stituted for treatment of acute disseminated encephalomyeLitis56 suggest that a trial of ste­roids may be warranted in certain cases of neu­romyelitis optica. The etiology of neuromyelitis optica is un­known. As for the other demyelinating dis- 267 Neuromyelitis Optica eases an immunopathologic process is sus­pected. The syndrome of neuromyelitis optica probably reflects a selective vulnerab~lity of the optic nerves and spinal cord to a. variety of de­myelinating insults, and speculatlO.n.s about the anatomic basis for this vulnerablhty are nu­merous. 15.28.3'1.57.511 Of interest in this regard is the relatively high frequency of neuromyeli.tis optica in countries such as Japan and lndl~, where the overall incidence of multiple sclerOSIS is low. In these countries, an opticospinal form of multiple sclerosis predominates, with a high incidence of bilateral visual impairment and spinal cord involvement at presentatio~:6-8.27 Patients fulfilling criteria for neuromyelitis op­tica comprise 6-9% of large series of multiple sclerosis patients in Japan and India.6-8Pre~um­ably genetic (including LAH type), environ­mental, and other undetermined factors are in­volved in determining this topographic pattern of involvement. Magnetic resonance imaging of the brain may be a helpful new modality in studying patients with neuromyelitis optica, but this modality was not available in the cases here reported. The syndrome of neuromyelitis optica is an important link between the opticospinal form of multiple sclerosis, classical Western multiple sclerosis, and the postinfectious en­cephalomyelitides. The existence and character­istics of this syndrome support the likelihood of a common pathophysiology in many of the de­myelinating diseases. Acknowledgments The authors thank Dr. David Siegel and Dr. James Schimschock for providing clinical folJow-up on the patients presented, Dr. Fredrick Seil and Dr. Bruce Coull for reviewing the manuscript, and Ms. Eliza­beth Hoffman for preparing the manuscript. References 1. Allbuu, T. c.: On the ophthalmoscopic signs of spinal disease. Lancet 1: 76-78, 1870. 2. Gault, F.: De la neuromyelite optique aigue. These de Lyon. Serre 1, No. 981, 1894. 3. Balser, B. 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