A Fatal Case of Coxsackievirus B4 Meningoencephalitis

OBSERVATION A Fatal Case of Coxsackievirus B4 Meningoencephalitis

Bruce C. Cree, MD, PhD; Gary L. Bernardini, MD, PhD; Arthur P. Hays, MD; Gina Lowe, MD

Background: Coxsackieviruses and echoviruses are nervous system infection and myocarditis. Magnetic reso- common causes of aseptic meningitis, but they rarely cause nance imaging showed focal hyperintense lesions in the life-threatening illness. We report a fatal case of coxsack- substantia nigra that corresponded to the location of ievirus B4 meningoencephalitis in a woman who devel- pathological changes seen at autopsy. oped extrapyramidal symptoms suggestive of encephalitis lethargica. The exact causative agent of encephalitis Conclusions: This patient had a fulminant coxsackie- lethargica has rarely been found, but most cases of the virus B4 viral meningoencephalitis with a clinical pat- syndrome are assumed to be of viral origin. tern reminiscent of encephalitis lethargica and striking focal abnormalities in the substantia nigra identified on Case Description: A 33-year-old woman previously magnetic resonance imaging. The magnetic resonance im- treated with methylprednisolone and cyclophospha- aging findings correlated with pathological changes iden- mide for Henoch-Scho¨nlein purpura was transferred from tified at autopsy that were similar to the pathological find- a referring hospital because of sore throat, fever, and chills. ings observed in patients with encephalitis lethargica and Her neurologic findings progressed from headache with postencephalitic parkinsonism. It is likely that the pa- mild photophobia to lethargy, cogwheeling, increased tone tient’s immunocompromised state led to an overwhelm- in all 4 limbs, and brisk reflexes. The patient was diag- ing infection from an otherwise relatively innocuous vi- nosed as having coxsackievirus B4 meningoencephali- ral infection. tis and, despite treatment with the experimental antiviral agent pleconaril, died of an overwhelming central Arch Neurol. 2003;60:107-112

PPROXIMATELY 20000 cases ticularly in children, but are rarely life of acute encephalitis are threatening.2-6 We report a fatal case of me- reported each year in the ningoencephalitis and inflammatory myo- United States.1 In most carditis caused by coxsackievirus B4 likely cases, the causative infec- owing to susceptibility in an individual tiousA agent is viral, including Enteroviri- with a pharmacologically induced state of dae (eg, echovirus or coxsackievirus), ar- immunosuppression. bovirus (eg, West Nile, eastern or western equine, St Louis, Venezuelan equine, Cali- REPORT OF A CASE fornia, or LaCrosse virus), Herpesviridae (eg, herpesvirus type 1 or 2, varicella- A 33-year-old woman was admitted to a zoster virus, Epstein-Barr virus, and cy- community hospital because of 1 week of tomegalovirus), and parvovirus, and can malaise, sore throat, subjective fever, chills, be identified from the cerebrospinal fluid bilateral ear pain, and joint pain in her (CSF) and/or blood.1 However, determi- hands and feet. The patient had a history nation of the exact cause can be difficult, of Henoch-Scho¨nlein purpura, juvenile From the Neurological Institute often requiring repeated CSF sampling and rheumatoid arthritis treated with methyl- of New York, New York– polymerase chain reaction amplification prednisolone and cyclophosphamide, and Presbyterian Hospital, of the CSF. Abnormalities within the brain required hemodialysis for IgA nephropa- Columbia-Presbyterian Medical parenchyma (eg, medial temporal lobes or thy. On presentation, her temperature was Center, New York, NY brainstem) seen on magnetic resonance 39.8°C and a 2/6 systolic murmur was (Drs Cree, Hays, and Lowe), and Division of Stroke and (MR) imaging with T2- or T1-weighted im- heard at the left sternal border. Results of Neurocritical Care, Department ages after gadolinium contrast injection can general physical and neurologic examina- of Neurology, Albany Medical help to establish the diagnosis. tion were normal. Routine complete blood Center, Albany, NY Coxsackievirus and echovirus are fre- cell count showed a white blood cell (Dr Bernardini). quent causes of aseptic meningitis, par- (WBC) count of 1.7 ϫ103/µL, with a dif-

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Day of Hospitalization

Variable 4 6 17 22

Opening pressure, cm H2ONDNDND190 WBC count, cellsϫ103/µL 0.079 0.021 0.069 0.010 Differential count, % Neutrophils 86 79 6 ND Lymphocytes 14 21 94 88 Monocytes ND ND ND 12 Eosinophils ND ND ND ND RBC count, cellsϫ106/µL 0.000014 0.000009 0.000005 0.00010 Protein, g/dL 0.128 0.115 0.077 0.032 Glucose, mg/dL 68 68 78 68

Abbreviations: ND, not determined; RBC, red blood cell; WBC, white blood cell. SI conversion factor: To convert glucose to millimoles per liter, multiply by 0.0555.

ferential count of 34% polymorphonuclear leukocytes equivocal Babinski signs. Follow-up CSF examination on (PMNs), 4% bands, 38% lymphocytes, and 24% mono- the 17th hospital day yielded a protein level of 0.077 g/dL, cytes; a hemoglobin level of 11.9 g/dL; and a platelet count glucose level of 78 mg/dL (4.3 mmol/L), RBC count of of 262ϫ103/µL. Results of serum chemistry studies were 0.000005 ϫ106/µL, and WBC count of 0.069 ϫ103/µL, normal except for an elevated serum urea nitrogen level but now a lymphocytic predominance was observed: 6% of 71 mg/dL (25.3 mmol/L) and creatinine level of 4.6 mg/dL PMNs and 94% lymphocytes (Table). Serologic studies (407 µmol/L), consistent with her chronic renal failure. She sent for antibodies to Rickettsia, parvovirus B19, and Bru- was treated with intravenous antibiotics, stress-dosed cor- cella were negative; toxoplasmosis and Epstein-Barr vi- ticosteroids, and granulocyte colony-stimulating factor for rus antibody testing was positive for IgG but negative for empirical coverage of presumed bacterial infection in a set- IgM antibodies. Malaria organisms were not seen on ting of cyclophosphamide-induced leukopenia. blood smear, and multiple blood cultures yielded no On the fourth hospital day, the patient developed a growth. Polymerase chain reaction examination of CSF headache, mild photophobia, nuchal rigidity, and tem- did not amplify DNA for herpesvirus 1 or 2, cytomega- perature of 40.0°C but was otherwise neurologically in- lovirus, Mycobacterium tuberculosis,orBorrelia burgdor- tact. A lumbar puncture was performed, yielding clear, col- feri. Cytologic examination of the CSF was negative. Thy- orless CSF with a protein level of 0.128 g/dL, glucose level roid function test results and complement levels were of 68 mg/dL (3.8 mmol/L), red blood cell (RBC) count of normal. Other imaging studies including single-photon 0.00014 ϫ106/µL, and WBC count of 0.079 ϫ103/µL, with emission computed tomography of the brain, cerebral a differential count of 86% PMNs and 14% lymphocytes MR angiography, and total-body indium scan were (Table). An opening pressure was not recorded. The gram negative. stain and cultures did not show any organisms, but anti- The patient was transferred to New York– biotic therapy was broadened for empirical treatment of Presbyterian Hospital, New York, NY, on the 22nd day af- suspected bacterial meningitis. The patient’s neurologic ter the initial hospitalization. She was afebrile and her neck findings worsened 2 days later when she became stupor- was supple but she remained stuporous, responding only ous, responding only to painful stimuli. Brainstem re- to noxious stimulation with withdrawal of the limbs. Brain- flexes remained intact, with semipurposeful withdrawal stem reflexes were intact and deep tendon reflexes were of all 4 limbs and symmetrically brisk reflexes. A noncon- brisk, with bilateral ankle clonus and equivocal plantar re- trast computed tomographic scan of the head was nor- sponses. Laboratory studies at our institution showed a mal, and an electroencephalogram (EEG) showed diffuse serum WBC count elevated to 14.0 ϫ103/µL with a dif- slowing but no epileptiform activity. Repeated CSF sam- ferential count of 92% PMNs, 6% lymphocytes, and 2% pling yielded a protein level of 0.115 g/dL, glucose level monocytes. The elevated WBC count was presumed to be of 68 mg/dL (3.8 mmol/L), RBC count of 0.000009 ϫ106/ partly a consequence of treatment with granulocyte colony- µL, and WBC count of 0.021 ϫ103/µL, with continued poly- stimulating factor. The CSF examination showed an op- morphonuclear pleocytosis: 79% PMNs and 21% lympho- ening pressure of 190 cm H2O, protein level of 0.032 g/dL, cytes (Table). Cryptococcal antigen was not detected, and glucose level of 68 mg/dL (3.8 mmol/L), RBC count of no organisms were seen on gram stain. 0.0001 ϫ106/µL, and WBC count of 0.010 ϫ103/µL, with During the next 2 weeks the patient’s level of arousal a differential count of 88% lymphocytes and 12% mono- fluctuated between coma and lethargy. Periods of inter- cytes (Table). Repeat polymerase chain reaction studies mittent tachypnea were observed. She had marked dys- of the CSF did not amplify DNA for herpesvirus 1 or 2, arthria and roving eye movements in the horizontal plane Epstein-Barr virus, or cytomegalovirus, and CSF cultures and could occasionally follow some commands with hand did not grow bacteria or acid-fast bacilli; the VDRL test squeezing. There was marked increase in tone with cog- was nonreactive. An MR image of the brain showed focal, wheel rigidity in upper extremities and hyperactive deep linear, nonenhancing hyperintense lesions on T1- and T2- tendon reflexes; bilateral ankle clonus was noted but with weighted images in the region of the substantia nigra

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RLRL

C D

350 µm 35 µm

A and B, Axial magnetic resonance images demonstrating bilateral, symmetric increased signal intensity within the substantia nigra. A, T1-weighted image. B, T2-weighted fast spin-echo image. C and D, Pathological sections. C, Midbrain lesions showing depigmentation and focal necrosis of the substantia nigra (arrow) (hematoxylin-eosin). D, Lesion within the substantia nigra containing many macrophages and small mineral deposits. These deposits are shown as thin spicules (arrowheads) and 1 aggregate (arrow) (hematoxylin-eosin).

(Figure, A and B). Subtle linear hyperintense lesions on stem reflexes and required intubation and mechanical ven- T2-weighted images in the posterior limb of the right in- tilation. Continuous EEG monitoring in the neurologic ternal capsule and superior lateral aspect of the right intensive care unit showed generalized background slow- thalamus were also identified (images not shown). An MR ing and frequent spike-and-wave activity. She was treated angiogram of the circle of Willis and neck vessels was for nonconvulsive seizures and given a continuous mid- normal. azolam infusion. Three days later, the patient became tachypneic with Approximately 1 week later an electrocardiogram bilateral hand jerking. An EEG showed moderate dif- showed conduction abnormalities. Cardiac enzyme fuse background slowing and frequent runs of frontally testing showed an elevated creatine kinase level of 906 predominant rhythmic delta waves consistent with sei- IU/L, with a 13.6% MB fraction. Transthoracic echo- zure activity. Phenytoin and valproic acid were begun. cardiogram showed mild global hypokinesis with She subsequently became comatose with sluggish brain- regional wall motion abnormalities. These results were

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 interpreted as consistent with myocardial inflam- ative agent of von Economo disease was never isolated, mation. clinical diagnostic criteria were developed to identify spo- The viral cultures sent on CSF obtained at our in- radic cases of encephalitis lethargica.14,18 Indeed, the pres- stitution yielded coxsackievirus B4 enterovirus. In ad- ence of impaired level of consciousness, central respira- dition, a rectal swab yielded coxsackievirus B4 entero- tory disturbance, and rigidity observed in our patient with virus, suggesting actively shedding virus in our patient. encephalitis fit the proposed diagnostic criteria for en- A research laboratory (ViroPharma, Exton, Pa) was con- cephalitis lethargica.14 However, our patient did not ex- tacted and arrangements were made for compassionate perience ophthalmoplegia or oculogyric crises, nor was use of pleconaril, an antipicornavirus agent.7,8 The pa- there observable sleep disorder and abnormal behaviors tient received a 7-day course of pleconaril without overt during the acute phase of illness that are characteristic side effects; however, she remained comatose. The pa- of the von Economo somnolent-ophthalmoplegic type of tient’s hospital course was further complicated by pneu- encephalitis lethargica.14,18,19,20 monia, anasarca, thrombocytopenia, deep venous throm- A diagnosis of encephalitis lethargica is based on bosis, and gastrointestinal tract bleeding. Fifty-three days clinical presentation, cerebrospinal findings, EEG, and after the onset of symptoms, she developed a fatal ven- pathological features. von Economo19 described 3 clini- tricular fibrillation. cal forms of the disease: the most common, the somnolent- A complete autopsy was performed that showed ophthalmoplegic form, begins with an influenzalike ill- grossly normal brain, spinal cord, and meninges except ness followed by drowsiness and confusion progressing for depigmentation of the substantia nigra bilaterally. Mi- to coma associated with external ophthalmoplegia, ocu- croscopic examination showed necrosis of the substan- logyric crises, and nystagmus as early features; the other tia nigra with near-complete loss of pigmented neurons 2 forms are bradykinesia-cataplexy-mutism and hyper- and numerous macrophages, some containing a typical kinesis, the latter of which is associated with extreme mo- appearance of melanin (Figure, C and D). Basophilic spic- tor restlessness, visual hallucinations, and dyskinesias. ules with a beaded appearance were scattered through- Clinical features considered major criteria supporting the out the lesions, consistent with mineralized material. Simi- diagnosis of encephalitis lethargica include an acute or lar but smaller lesions were located symmetrically in the subacute encephalitis associated with at least 3 of the fol- lateral and superior aspects of the tegmentum. There were lowing major criteria: signs of basal ganglia involve- also sparse microglial nodules in the thalamus, inferior ment, oculogyric crises, ophthalmoplegia, obsessive- olivary nucleus, dentate nucleus, and cerebellar cortex. compulsive behavior, akinetic mutism, central respiratory In particular, the dentate nucleus of the cerebellum was irregularities, or somnolence and/or sleep inversion.14 The hypercellular with astrocytosis and neuronal loss. The CSF is frequently abnormal, with signs of meningeal ir- macrophages and microglia were accompanied by a few ritation, ie, increased pressure and protein content and scattered lymphocytes. No neurofibrillary tangles were mild or moderate predominantly lymphocytic pleocyto- specifically identified. The remainder of the brain and spi- sis that can be seen in the early stages. The CSF glucose nal cord were histologically normal. Examination of the level is invariably normal, but oligoclonal band positiv- heart showed extensive active myocarditis with moder- ity has been reported.21 An EEG during the acute phase ate dilated cardiomyopathy. Additional pathological find- of the illness often shows diffuse unilateral or bilateral ings included vascular congestion and macrophages in slowing in the delta or theta frequencies and focal sharp- the lungs, a bone marrow embolus in a small pulmo- wave activity.14 Pathological findings of von Economo dis- nary artery, and near–end-stage chronic nephropathy. ease typically consist of a nonhemorrhagic involvement of the gray matter, preferentially in the midbrain. Al- COMMENT though the most severe involvement is usually isolated to the brainstem and basal ganglia, cerebral cortex and This is the first reported case, to our knowledge, of docu- spinal cord can be affected as well.14,22 The pathological mented coxsackievirus B4 infection presenting as encepha- hallmark of the disease is cytoplasmic inclusions of neu- litis lethargica; however, we are cautious about overinter- rofibrillary tangles within the substantia nigra, often preting this finding. It seems unlikely that coxsackievirus associated with severe neuronal loss.22 B4 is a causative agent of von Economo disease, since out- The MR imaging studies in our patient showed breaks of coxsackievirus B4 meningitis are not associated unusual hyperintense signals on both T1- and T2- with encephalitis lethargica. We believe that the unusual weighted imaging in the substantia nigra bilaterally (Fig- pattern of illness in our patient was due to preexisting im- ure, A and B). The basis for these signal changes is un- munosuppression resulting in enhanced susceptibility to certain. However, pathological changes seen at autopsy severe viral infection. Nevertheless, this case extends correlate anatomically with the MR imaging findings. the pattern of illness attributable to coxsackievirus B4 Thus, the T1- and T2- hyperintense signals on MR im- infection. aging seen in our patient may be due to tissue necrosis The anteceding prodrome with signs of meningis- and mineralization of the lesions. Microhemorrhages mus, fluctuating level of consciousness, increased tone, could give rise to hyperintense T1- and T2-weighted sig- extrapyramidal signs, and respiratory disorder seen in our nals, although there was no histological evidence to sup- patient are reminiscent of encephalitis lethargica. Rare port this suggestion at autopsy. Identical MR imaging find- sporadic cases of encephalitis that bear striking similar- ings were recently reported in a case of encephalitis ity to von Economo disease have been reported since the lethargica.17 In that report, both T1- and T2-weighted hy- time of the epidemic of 1915 to 1930.9-17 Because the caus- perintensity was also seen in the substantia nigra, and

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 the patient survived the acute encephalitis but devel- phropathy. Therefore, it is likely that immune suppres- oped postencephalitic parkinsonism. No causative agent sion or possibly abnormalities intrinsic to her immune sys- was identified. tem made the patient susceptible to a more fulminant The substantia nigra was selectively involved in our course of infection. There are similarities in the patho- patient and is reminiscent of the pathological changes seen logical changes in our patient to those seen in infantile cox- in cases of postinfectious parkinsonism and encephali- sackievirus encephalitis41,42 and the enteroviral chronic tis lethargica.23,24 Although pathological involvement of meningoencephalitis of agammaglobulinemia39; how- the basal ganglia and thalamus frequently occurs in post- ever, in our patient there was less lymphocytic infiltra- encephalitic parkinsonism and encephalitis lethargica, tion. Furthermore, severe changes in the substantia nigra these structures appear less frequently and severely af- seen in our patient are not seen in infantile coxsackievi- fected than the preferential involvement of the substan- rus encephalitis or the enteroviral chronic meningoen- tia nigra. Indeed, pathological findings in our case are cephalitis of agammaglobulinemia, which spare this strikingly similar to those in 4 patients with postencepha- nucleus. There are no reports of postencephalitic par- litis parkinsonism reported by Bojinov,23 one of whom kinsonism in infantile enteroviral meningoencephalitis had died of concurrent myocarditis. In this patient a vi- or in agammaglobulinemia. rus was isolated but not identified. It is possible that cox- Newer treatments such as pleconaril7,8 may pro- sackievirus B4 may be another causative agent of this syn- vide benefit in the treatment of life-threatening entero- drome, since, as in our case, viral infection of the central viral infections.43 However, early identification of the caus- nervous system was associated with destruction of the ative agent is vital for potential effectiveness of these substantia nigra. However, it is speculative to say whether therapies. Repeated viral cultures of the oral mucosa, rec- our patient would have had delayed onset of parkinson- tal mucosa, and CSF are recommended in all patients sus- ism had she survived. pected of having meningoencephalitis, and serologic test- While the coxsackievirus B4 might be implicated in ing is now available for most enteroviruses. This latter the evolution of parkinsonian symptoms, it is less clear how method may be a more practical assay for detection of it caused profound coma in our patient. The diffuse slow- infection, since standard viral cultures require rapid de- ing seen on EEG and seizure activity suggest that cerebral livery to a virology laboratory for incubation. Polymer- cortex was affected by the meningoencephalitis. Similar ob- ase chain reaction–based assays on CSF may eventually servations were described in cases of postencephalitic par- replace these other methods of enteroviral detection.40 kinsonism.14,23 It is curious that there was no extensive injury to the reticular activating system or cerebral cortex that Accepted for publication April 5, 2002. could account for the coma. The diffuse subcortical white- Author contributions: Study concept and design (Drs matter astrogliosis in a case of von Economo encephalitis Cree and Bernardini); acquisition of data (Drs Cree, Hays, lethargica and in another case of postencephalitic parkin- and Bernardini); analysis and interpretation of data (Drs sonism described by Elizan and Casals25 was not seen in Cree, Bernardini, Hays, and Lowe); drafting of the manu- our case. Perhaps these structures were involved earlier in script (Drs Cree and Bernardini); critical revision of the the course of the infection and were no longer compro- manuscript for important intellectual content (Drs Cree, mised at the time of the patient’s death, or the viral infec- Hays, Bernadini, and Lowe); administrative, technical, or tion produced diffuse cerebral dysfunction by mecha- material support (Drs Cree, Bernardini, Hays, and Lowe); nisms other than tissue destruction. study supervision (Dr Bernardini). Although the causative agent of von Economo Corresponding author and reprints: Gary L. Bernar- encephalitis was never identified,26 a viral agent is impli- dini, MD, PhD, Division of Stroke and Neurocritical Care, cated by pathological study.25 Subsequently, several vi- Department of Neurology, 47 New Scotland Ave, MC-70, ruses have been causally linked to postencephalitic par- Albany, NY 12208-3479 (e-mail: [email protected]). kinsonism. 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