views & reviews Demyelinating after neurologically complicated primary Epstein-Barr virus

P.F. Bray, MD; K.W. Culp, BS; D.E. McFarlin, MD; H.S. Panitch, MD; R.D. Torkelson, MD; and J.P. Schlight, BS

Article abstract-This report describes five patients who, following a neurologically complicated primary Epstein- Barr virus infection, developed progressive or relapsing neurologic deficits. The sequelae in four patients followed 4 to 12 years led to the diagnosis of (MS). The fifth patient presented with acute disseminated sclerosis and exhibits diffuse neurologic deficits that have persisted for 2 years. We suggest that the diagnosis of an unexplained acute neurologic or psychiatric syndrome should raise the question of a primary EBV etiology. A precisely timed sero- logic and hematologic study of the blood is imperative to capture the essential evidence. The data presented represent a clinical association between a neurologically complicated primary EBV infection and both chronic and acute demyeli- nating disease. The evidence does not justify a conclusion that EBV virus causes MS. 1992;42:278-282

Antibodies to the ubiquitous Epstein-Barr virus The acute neurologic syndromes accompanying (EBV) are in the blood of patients wherever EBV take different clinical forms, includ- humans inhabit the planet. Almost all children in ing aseptic , , optic papillitis, the underdeveloped countries are infected, silently cranial (especially Bell’s palsy), brainstem for the most part, by age 4 years. Until recently, encephalitis, cerebellitis, acute psychosis, severe the virus has maintained a balanced and economic with and without increased relationship with its host. However, in northern (including Reye’s syndrome), Europe, United States, and Canada, where there is transverse , postinfectious polyneuritis less overcrowding and better sanitation, about (Guillain-Barre syndrome), brachial neuropathy one-half the population is not infected until the and, rarely, dysautonomia and movement disor- teen years or early adult life, when kissing ders. Although the pathogenesis remains unclear, becomes more habitual and the exchange of saliva almost all parts of the appear vul- allows the seeding of the uninfected person with nerable to involvement in IM.5-7There have been virus. Approximately one-half of these EBV- repeated descriptions of inflammatory infiltrates seronegative persons develop clinical, heterophile- and diffuse neuronal degenerative changes from positive, infectious mononucleosis (IM), and the brains of fatal cases, and similar pathologic other half experience a clinically unrecognized changes were present in one person convalescing EBV infection. from uncomplicated IM who died secondary to trau- A clinical association between glandular fever or ma.8 The virus has been recovered from CSF in two IM and concurrent acute neurologic complications documented cases of IM-associated encephaliti~,~J~ was documented over 50 years ago,1,2and when but fortunately, most patients with CNS complica- EBV was identified as the causal agent 25 years tions recover fully. late^-,^.^ the same association was ~onfirmed.~-~In Sumaya et all1 were among the first to publish exceptional cases, the disorder can be fatal for dif- serologic data that suggested a relationship ferent systemic reasons or be associated with acute between MS and EBV. Similar studies by us12J3 central or peripheral nervous system syndromes. showed that 100% of MS patients are seropositive Estimates of the frequency of neurologic complica- and that their blood antibody titers to the transfor- tions vary from 1 to 5%.536 mation EBV nuclear antigen (EBNA) and the lytic

From the Departments of Neurology and Pediatrics (Dr. Bray, and K.W. Culp and J.P. Schlight), University of Utah, Salt Lake City, UT; the Section on Neuroimmunology (Dr. McFarlin), National Institute of Neurologic Disease and , NIH, Bethesda, MD; the Department of Neurology (Dr. Panitch), University of Maryland, Baltimore, MD; and the Division of Pediatric Neurology (Dr. Torkelson), University of Nebraska, Omaha, NE. Supported in part by the Clipped Wings (flying personnel, United Airlines), Richard Uriarte, and the Utah Association of Life Underwriters Received May 13, 1991. Accepted for publication in final form July 29, 1991. Address correspondence and reprint requests to Dr. Patrick F. Bray, 50 No. Medical Drive, University Hospital, Salt Lake City, UT 84132

278 NEUROLOGY 42 February 1992 viral capsid antigen (VCA) are significantly elevat- Results. A narrative description of the five ed. patients is given below. Over the past 6 years, we have watched for Patient 1. In 1977, a 30-year-old woman devel- patients with definite laboratory evidence of a pri- oped IM complicated by cerebellitis and brainstem mary EBV infection and in whom other encephalitis. Two positive HA tests were demon- that might mimic a primary EBV infection have strated within 1 month after the onset of her sys- been excluded. Over this observation period, we temic IM symptoms. Over the ensuing 10 months found five patients with laboratory evidence of pri- the disease ran a relapsing-remitting course. CSF mary EBV infection whose courses were complicat- electrophoresis performed after her third relapse ed by acute neurologic syndromes and in whom showed four OCB. An EM1 CT head scan revealed progressive or relapsing neurologic deficits have bilateral frontal lobe white matter lesions. This been observed. patient was reported in abstract form in 1977.20 She was followed and treated in an outpatient MS Methods. The five patients to be reported all exhibited clinic at the National Institutes of Health for 10 hematologic or serologic evidence of a primary EBV years. At age 41 years, her disability had pro- infection, and were included only if an acute neurologic gressed markedly and she was placed in a nursing or psychiatric syndrome was documented, the cause was home. She died at the age of 42 years without otherwise obscure, and neurologic complications persist- autopsy. ed. All patients exhibited CSF evidence of and quantitative or qualitative immunoglobulin abnor- Patient 2. An ll-year-old girl presented with a malities. Patients with postinfectious polyneuritis were severe acute illness and neurologic findings sug- excluded. gesting brainstem and cerebellar deficits. A serum In making the clinical diagnosis of MS, we adhered to HA test was positive, and CSF examination dis- the standard riter ria.'^^'^ Clinicians have used the terms closed 48 mononuclear cells, a total protein of 38 “remitt i n g- re 1a p s i n g ” and “chronic pro gre s s i v e ” to mg/dl, and OCB on electrophoresis. Bilateral visual describe most cases, but differentiation of these two clini- and brainstem auditory evoked responses were cal types may be difficult and our patients had features abnormal, revealing delayed latencies. For 7 years of both. after the acute illness, she had a relapsing-remit- Three laboratory methods were used to identify a pri- ting course; serial head MRIs showed an increasing mary EBV infection. A standard heterophile antibody (HA) test was used. Manual differential white blood cell number and size of patchy, bilateral, cerebral white counts were performed and special attention was given matter lesions. She is now seriously incapacitated to the presence and percentage of large atypical lympho- and carries the clinical diagnosis of MS. cytes. A complete EBV antibody profile was performed, Patient 3. Within 1 month after making two sui- including an indirect immunofluorescence study of titers cide attempts and being treated with an antide- to VCA (IgG, IgA+IgM), early antibody-diffuse pressant, this 16-year-old girl gradually developed (IgG+IgA), early antibody-restricted (IgG), and EBNA alteration of mood and cognition, and impaired (IgG), and to a negative control. To insure reproducibili- vision. Her first examination revealed bilateral ty, assays were performed in both our laboratory and pyramidal signs, and her CSF exhibited 25 that of Werner and Gertrude HenleI6 at the University of mononuclear cells, increased CNS IgG synthesis, Pennsylvania. Even in patients who exhibit typical clini- cal, hematologic, or HA evidence of primary EBV infec- and OCB in the IgG zone. After treatment for pre- tion, our experience and that of the Henles (personal sumed herpes encephalitis without benefit, she communication) indicate that EBV-specific IgM may be showed progressive deterioration in cognitive func- difficult to demonstrate. This probably results from the tion and diffuse EEG slowing along with a fourfold large molecular size of IgM, which may impede the entry rise in serum anti-EBVCA IgG. A differential of the IgM antibody through the cell membrane, and the leukocyte count at the time of symptom onset difficulty of obtaining commercial fluorescein-labeled showed 12% “atypical lymphocytes.” A brain biopsy IgM that is not contaminated with VCA IgG; the latter performed 2% months after disease onset showed may lead to competition for antigenic binding sites to inflammation and marked loss of , and the IgM molecules within the cell.’? No patient was included pathologist considered the findings most consistent in the study who did not fulfill the serologic or hemato- logic criteria for a primary EBV infection. Other causes with acute MS; an EBV DNA probe study was not for acute neurologic syndromes, including infectious carried out. A heterophile “monospot” performed 3 agents, were not found. months after disease onset, and repeated twice, Three quantitative assays of CSF IgG were performed was negative. Head CT and MRI showed progres- to measure the amount of IgG: the IgWalbumin ratio, sive multifocal, large and small white matter IgG index, and IgG synthesis. All these formulas are lesions in the periventricular and subcortical areas; intended to measure the same abnormality, ie, de novo the internal capsule and bioccipital white matter synthesis of IgG within the CNS. Special attention was also showed areas of demyelination. Because of devoted to the blood-brain barrier (BBB),calculated from progressive , incoordination, pyramidal the ratio of CSF albumin quantity to serum albumin tract weakness, and visual loss she attends a quantity, and only patients whose BBB was intact were included. Standard agarose gel electrophoresis was per- school for the blind in a wheelchair. She carries the formed on all CSF samples, concentrated 70 times, and a diagnosis of progressive MS 5 years after disease protein stain was applied to identify oligoclonal bands onset. (OCB)in the IgG z~ne.~~.’~ Patient 4. A 26-year-old woman had the acute

February 1992 NEUROLOGY 42 279 ’able. Literature review

Acute Residual neurologic deficit Evidence of Reference signs/ or primary CSF Case Age number symptoms autopsy EBV abnormalities

6 31 21 Cranial neuritis + Cranial nerve deficit, HA = 896, Total protein = 91 brainstem upgaze palsy 76% lymphocytes encephalitis 7 19 22 , Degeneration cranial nerves HA = 14,336 50 WBC, , stiff 111 + IV, reticular normal total neck, “legs nucleus, “hemorrhasc protein weak” encephalomyelopathy” (autopsy) 8 21 23 , stiff Brain swelling; diffuse HA = 114,688 Total protein = 102 neck, neuronal degeneration decerebrate I autopsy) state, death

9 18 24 Coma, Mild spastic HA = 512, Total protein = 50 herniplegxi, 78‘V lymphocytes aphasia ( 15-mo follow-up)

10 17 25 Hemianopia; Persistent hemianopia HA = 1,200 Total protein = 160, brain pressure = 310 mm biopsy = inflammatory demyelination

11 19 26 Aseptic Seven episodes aseptic HA positive, Cell count ( x 71, meningitis meningitis 68% lymphocytes 128 to 1,250 mononuclears

onset of severe , “dizziness,” blurred nation again showed OCB, and an MRI of her cervi- vision, and . Persistence of head cal spine was normal. A clinical diagnosis of left and photophobia were associated with neck stiff- was made. The constellation of poste- ness, nausea, and vomiting. Initial examination rior column sensory , recurrent aseptic showed only diffuse lymphadenopathy and mild meningitis, and the later development of optic neu- nuchal rigidity. Twenty-five percent of her total ritis suggested the probable diagnosis of MS. lymphocytes were “large and atypical” and her HA Patient 5. This 19-year-old woman developed a test was positive. CSF examination revealed 10 severe acute encephalopathy in March 1989. This mononuclear cells, four dense OCB, and increased led to spastic weakness in all four extremities, de novo CNS synthesis of IgG. An extensive search incontinence, emotional lability, and markedly for causes of her CSF IgG abnormalities, other than impaired cognition. Her blood EBV profile disclosed MS, was unproductive. Essentially identical CSF EBV IgM antibody. CSF examination revealed an IgG findings were noted on three subsequent CSF elevated total protein (135 mg/dl), nine mononucle- examinations performed over the following 14 ar cells/dl, and increased de novo synthesis of IgG months. Over a 3-year follow-up period the patient without OCB. Three head MRIs over 4 months continued to complain of severe headache, which revealed extensive foci of white matter loss in the benefited substantially but only temporarily from periventricular areas and deep white matter loss in courses of prednisone therapy. She developed pares- the cerebrum, cerebellum, and brainstem, consis- thesias and a positive Lhermitte’s sign. Neurologic tent with demyelination. The patient’s neurologic examination showed persistent mild ataxia of both deficits persist after more than 2 years of follow-up. trunk and extremities, associated with mild loss of Initially, the clinical diagnosis was acute dissemi- proprioception. Two head MRIs done 1 month apart nated , or acute MS, but a longer at the onset of illness were normal. One and one- temporal profile is needed to define her diagnosis half years later, 4 years after her initial illness and with precision. The patient’s father is said to have while continuing to have sensory symptoms, ataxia, MS but the authors were unable to interview or and headache, the patient abruptly developed examine this man. painful loss of vision in her left eye and an afferent pupillary defect, associated with prolonged visual Discussion. The world literature was searched for evoked responses on the left. A repeat CSF exami- other patients who had documented heterophile-

280 NEUROLOGY 42 February 1992 positive IM and who survived with neurologic and other observations by Kurtzke suggest that deficit or died of neurologic complications. We the age at the time of exposure to an environmen- found six cases similar in particular respects to tal factor, if such exists, may be an important fac- ours (table). Most reported patients presented with tor in the development of clinical disease.2x clinical signs of diffuse or focal encephalitis or Kilbourne,2Yamong others, has pointed out that brainstem-cerebellar encephalitis.2126 Most of the old viruses can cause “new” diseases. Paralytic patients with fatal IM had brainstem disease. poliomyelitis offers one of the best examples. Autopsy findings in these patients showed neu- When primary poliomyelitis infection occurs in ronal degeneration in the cranial nerve nuclei, infancy and early childhood, the disease is often including nerve cells in the region of the respirato- subclinical and usually does not cause paralysis. ry center. Three surviving patients had persistent However, with the advent of modern sanitation in cranial nerve deficits, spastic hemiparesis, and the first half of the 20th century, and when pri- hemianopia, respectively. The last of these present- mary poliomyelitis virus infection occurred in ed with a hemianopia and symptoms of increased older children and adults, the frequency of paraly- intracranial pressure; brain biopsy revealed sis was high enough to appear in epidemic form. A “inflammatory demyelination,” similar to patient 3 parallel epidemiologic situation may exist in the in our series, and the patient survived with a hemi- case of IM. As Rickinson has suggested, IM must anopia. be considered “a novelty, the product of millions of Capturing the necessary serologic and hemato- years of virus-host coevolution, which is now logic evidence to document a primary EBV infec- being disturbed in the materially privileged tion is complicated by three factors: the very nar- Western world where primary infection is fre- row window of time during which the primary diag- quently delayed until the 2nd decade or later.”g0 nostic data are demonstrable, the remarkable indi- Having made a point of a possible role of EBV in vidual diversity in the person’s antibody-making MS, the authors readily concede that a number of repertoire, and the inconsistent temporal correla- other environmental and genetic factors may play tion between the diagnostic laboratory evidence an equally or more important role in the many and the clinical symptoms and signs, both systemic patients with demyelination, a process that many and neurologic. Documentation of a primary EBV believe represents one of the limited and more obvi- infection is limited further in those cases where the ous ways for the CNS to react to diverse disease neurologic syndrome develops abruptly with no conditions. However, most such causes and their clinical evidence of systemic infection, including pathogeneses have not as yet been clearly elucidat- symptoms or signs of IM. In such instances, the ed. We also readily acknowledge that any environ- physician’s attention is often misdirected to other mental agent, including one or more viruses, may serious neurologic diseases. Such cases have been mediate its damaging effect upon myelin via documented.s Patients 3 and 4 in our series deserve “autoimmune” mechanisms. Similarly, OCB may particular comment because patient 3 had an atyp- appear in the CSF in a large number of microbe- ical lymphocytosis but the HA studies were nega- specific CNS infections, as well as in paraneoplas- tive. The first of the three HA tests was not per- tic syndromes and rarely in primary cerebral lym- formed until 3 months after the onset of disease phomas. These other causes for OCB in CSF were symptoms, so that the a positive HA test may have excluded from our cases by revie of the cases in been eclipsed by time. Furthermore, 10% of detail. patients with IM never develop a positive HA In conclusion, we believe that a new-onset neu- test. li Serial anti-EBVCA IgC; antibodies in patient rologic or psychiatric syndrome in a young or mid- 3 showed a fourfold rise in titers. This same patient dle-aged person, not otherwise readily explained, had evidence of demyelination, by both brain biop- should suggest the possibility of a primary expo- sy and brain imaging, in the acute and subacute sure to EBV. The report describes an association stages of her illness. Patient 4 experienced recur- between a neurologically complicated primary EBV rent bouts of aseptic meningitis, findings that infection and both chronic and acute demyelinating resemble those noted in our literature review of disease in five patients. The evidence presented in case 11 (table). this manuscript does not justify a conclusion that Speculatively, the epidemiologic similarities the EBV virus causes MS. between clinical IM and clinical MS are notewor- thy. Specifically, children who acquire their EBV infection in their early years are generally at low risk for clinical IM, and MS occurs only rarely in Acknowledgments childhood. In the case of MS, migration data show that when persons move from a high-incidence Special thanks go to Werner and Gertrude Henle and their area after the age of 15 years, they carry with laboratory staff for help with the development of the EBV them the risk of the country from which they have assays. We are also indebted to Sidney A. Houff, Edward S. Gratz, Kurt A. Jaeckle, and Michael K. Koerncr for contribut- migrated. Conversely, those who move from a ing to the clinical observations, and to Marjory B. McKinney high-incidence area before 15 years assume the and Mary M. Sheppard for their secretarial and technical risk of the country to which they move.2i These assistance.

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282 NEUROLOGY 42 February 1992 Demyelinating disease after neurologically complicated primary Epstein−Barr virus infection P. F. Bray, K. W. Culp, D. E. McFarlin, et al. Neurology 1992;42;278 DOI 10.1212/WNL.42.2.278

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