An Elderly Patient with Bickerstaff Brainstem Encephalitis and Transient Episodes of Brainstem Dysfunction

OBSERVATION An Elderly Patient With Bickerstaff Brainstem Encephalitis and Transient Episodes of Brainstem Dysfunction

Raymond P. Roos, MD; Betty Soliven, MD; Fernando Goldenberg, MD; Aamir Badruddin, MD; Joseph M. Baron, MD

Background: Bickerstaff brainstem encephalitis (BBE) sodes of brainstem dysfunction during the recovery phase. is a rare inflammatory, demyelinating disease that generally has a good prognosis. Main Outcome Measures: Clinical and biochemical evaluation with magnetic resonance imaging. Objective: To describe the course of a patient with se- vere BBE and multiple medical complications. Conclusions: Bickerstaff brainstem encephalitis is a po- tentially reversible syndrome that needs early diagnosis (fa- Design: Case report. cilitated by magnetic resonance imaging) and prompt aggressive and supportive treatment. Frequent episodes of Setting: Academic medical center. transient brainstem dysfunction occurred in our patient during recovery, possibly due to ephaptic transmission. Patient: An 81-year-old woman with BBE who fully re- covered. The patient had transient and very frequent epi- Arch Neurol. 2008;65(6):821-824

ICKERSTAFF AND CLOAKE slurred speech, diplopia, clumsiness, and first described the entity unsteady walking. One month before ad- known as Bickerstaff brain- mission, the patient had developed a se- stem encephalitis (BBE)1; vere nonproductive cough that was diag- however, the definition of nosed as interstitial pneumonitis and BBE has evolved. In a recent review, Odaka treated with moxifloxacin hydrochlo- B2 et al defined BBE as a disorder with pro- ride. The respiratory problems initially im- gressive ophthalmoplegia and ataxia and proved, but then the cough significantly with features suggesting a central ner- worsened before the onset of neurologi- vous system process, such as disturbed cal problems. Three days before admis- consciousness or hyperreflexia. In this re- sion, the patient developed dysarthria fol- port, we describe a patient who had BBE lowed by diplopia, clumsiness, and ataxia. with a number of remarkable features. The On admission, the patient was afebrile diagnosis was made quickly, partly with a mildly disturbed mental state and through the use of magnetic resonance dysarthria. She exhibited incomplete hori- imaging (MRI) studies. Methylpredniso- zontal eye movements with no ptosis or lone sodium succinate and prednisone pupillary abnormalities. Results of the mo- were used as the only BBE treatment and tor examination were unremarkable ex- led to a complete recovery, stressing the cept for a questionable right Babinski sign importance of early disease recognition and and unsteady gait. The patient had dys- aggressive treatment—even in elderly pa- metria and slowed rapid alternating move- tients such as ours. Of special interest was ments in the upper extremities. Results of the development of very brief transient epi- the sensory examination were normal. sodes of brainstem dysfunction that oc- A chest radiograph showed an in- curred hundreds of times a day during the crease in interstitial markings and small Author Affiliations: recovery phase. right-sided effusion. A brain MRI showed Departments of Neurology (Drs Roos, Soliven, Goldenberg, increased signal on fluid-attenuated in- and Badruddin) and Medicine REPORT OF A CASE version recovery image sequences, with (Dr Baron), University of gadolinium enhancement in the brain- Chicago Medical Center, An 81-year-old woman was admitted on stem (Figure). A magnetic resonance an- Chicago, Illinois. April 2, 2006, because of progressively giogram showed no abnormalities. Analy-

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D E

Figure. Magnetic resonance imaging in an 81-year-old patient on admission (A-C) showing increased signal in the midbrain on fluid-attenuated inversion recovery (FLAIR) images (A and B), with gadolinium enhancement on a T1-weighted image (C), and 5 weeks later (D and E) showing significant resolution on FLAIR images.

sis of the cerebrospinal fluid showed a white blood cell tection and hemodynamic stabilization was started. Epi- count of 2/µL, a glucose level of 58 mg/dL, and a protein sodes of agitation prompted treatment with haloperidol level of 26 mg/dL; no oligoclonal bands or elevation of and midazolam and a decrease in methylprednisolone so- IgG, IgG index, or IgG synthesis; and negative polymer- dium succinate to 500 mg/d. On April 6, the patient was ase chain reaction results for herpes simplex virus and noted to have bilateral Babinski signs with unsustained varicella-zoster virus genome. Blood study results showed ankle clonus; she became more difficult to arouse, with no elevation of antibodies to neurotropic viruses, Bru- extensor posturing on the right side. A second MRI cella,orMycobacterium tuberculosis. Results of other blood showed extension of the brainstem involvement with- studies, including SSA (Ro) and SSB (La) antibodies, DNA out new lesions. A cervical spine MRI showed no abnor- double-stranded antibody, antinuclear antibody, and para- malities. An electroencephalogram showed marked gen- neoplastic antibody panel, were unremarkable. Results eralized slowing in the theta range, suggestive of an of serological studies on a variety of respiratory patho- encephalopathy. Results of a second lumbar puncture on gens showed no elevations that would suggest a recent April 7 were normal. On April 9, an MRI showed no infection. change and no gadolinium enhancement, and the meth- A tentative diagnosis of BBE was made, and the pa- ylprednisolone sodium succinate dosage was lowered to tient was transferred to the neurological intensive care 60 mg/d given intravenously. On April 10, the patient unit. A regimen of acyclovir, doxycycline, a combina- was more responsive and a tetraparesis became appar- tion of sulfamethoxazole and trimethoprim, and meth- ent. The examination on April 11 showed horizontal gaze ylprednisolone sodium succinate, 1 g/d, was begun. The abnormalities, ptosis, seventh nerve palsies, and in- patient quickly developed dysphagia and hyperactive re- creased strength. Over the next several days, the patient flexes, as well as cardiac arrhythmias and signs of acute improved in mental state, ptosis, eye movements, and re- kidney injury. On April 5, acyclovir administration was nal function and was therefore extubated. Prednisone discontinued and mechanical ventilation for airway pro- therapy was begun. The patient’s speech became clearer

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 and her reflexes more normal. On April 20, the patient gest a motor axonal neuropathy, presumably represent- was discharged to a rehabilitation facility while receiving an acute motor axonal neuropathy variant of GBS.7 One ing prednisone, 40 mg/d, with a tapering regimen. could also envision BBE as a brainstem-localized variant The patient noted continuing improvement at the re- of ADEM, an immune-mediated inflammatory disease that habilitation facility and was discharged on May 17 while usually affects the white matter of the brain and spinal cord receiving prednisone, 10 mg/d. A few days later, she no- and is often preceded by an infection. The similarities in ticed very frequent, stereotypic episodes lasting 1 to 10 BBE, MFS, GBS, and ADEM suggest their classification in seconds and occurring throughout the day; these epi- a spectrum of autoimmune disorders that sometimes over- sodes consisted of transient diplopia accompanied by dys- lap.2 A number of different viral and bacterial infections arthria (if talking) and gait imbalance (if walking). The have been implicated in the prodromal illness, including episodes increased in frequency so that they occurred up Campylobacter jejuni,8,9 raising the possibility that BBE can to hundreds of times a day. The patient was witnessed result from an autoimmune response to a number of dif- to have multiple episodes of paroxysmal worsening of ferent pathogens. slurred speech and ataxia with diplopia. Between epi- In our case, the presence of Babinski signs, a dis- sodes, results of an examination showed minimal dys- turbed state of consciousness, and the dramatic MRI sig- arthria, full eye movements, no ptosis, a questionable right nal abnormalities in the brainstem indicated a diagnosis Babinski sign, slight clumsiness, and a slow gait with a of BBE. The patient’s weakness presumably resulted from negative Romberg sign. Electroencephalograms and elec- the extensive brainstem lesion involving the corticospi- trocardiograms showed no abnormalities during the epi- nal tracts and was not related to an associated GBS. The sodes. Magnetic resonance imaging showed a decrease age of the patient was not at all typical for patients with in the abnormal signal in the brainstem with no evi- BBE and contrasts with previously presented cases.2 dence of recent stroke (Figure, D and E). Prednisone was A remarkable feature of our patient was the presence increased to 15 mg/d and then slowly tapered over more of brief paroxysmal episodes of brainstem dysfunction than a month. When seen by one of us (R.P.R.) on June that appeared after recovery of much of her neurologi- 14, the patient continued to have these episodes on a very cal function. During these episodes, the patient exhib- frequent basis although they no longer involved diplo- ited transient ataxia, diplopia, and dysarthria—deficits pia. On June 28, the episodes decreased in frequency to that had been seen on a continuous basis earlier in the approximately only2 per day. In addition to the epi- disease course. For several weeks, the episodes oc- sodes, the patient had minimal slurring of words when curred hundreds of times a day, lasting 1 to 10 seconds. she first began to speak and a slight imbalance when she They were not related to a seizure phenomenon or car- began to walk. Over the next few weeks, the episodes dis- diovascular abnormality. appeared and the patient returned to her normal base- Episodes of sensory disturbance are not infrequent in line condition. An anti-GQ1b antibody level measured demyelinating processes such as multiple sclerosis. Epi- months after admission was normal (Ͻ1:100). sodes that involve more complex abnormalities are not common but have been described. The episodes of brain- COMMENT stem dysfunction in our patient resembled similar events reported by Andermann et al10 and Espir et al.11 One of The definition of BBE has evolved since the original de- the 2 patients described by Andermann et al had as many scription, partly as a result of a classification of similar and, as 200 attacks a day that lasted 10 to 15 seconds and sub- at times, overlapping disease entities such as the Miller sided over months; these episodes were thought to re- Fisher syndrome (MFS) (see Lo3 for a review), Guillain- sult from a disturbance in the excitability of demyelin- Barre´ syndrome (GBS) (see Griffin and Sheikh4 for a re- ated axons. Our patient’s episodes exhibited several view), and acute demyelinating encephalomyelitis (ADEM) brainstem abnormalities suggesting mass synchronous (see Tenembaum et al5 for a review), and partly because firing as a result of ephaptic transmission (see Smith and of the availability of new diagnostic tools, including MRI McDonald12 for a review). In this condition, neuronal ex- and anti-GQ1b antibody testing. There are a number of fea- citability can spread laterally to adjacent axons that may tures shared by BBE and MFS, a variant of GBS, including have an abnormally lowered threshold for firing as a re- a prodromal infection, ophthalmoplegia, decreased result of demyelination. Interestingly, axons that are ex- flexes, and albuminocytological dissociation in the cere- perimentally demyelinated develop spontaneous activ- brospinal fluid; the close relationship between BBE and MFS ity with a lowered threshold for firing 1 week or more is supported by the presence in some patients with BBE of after the insult, possibly explaining the onset of these epi- anti-GQ1b antibody, a frequent feature of MFS.2,6 How- sodes during the patient’s recovery. ever, in contrast to BBE, most cases of MFS show few if any The dramatic MRI abnormalities in our patient as- signs of central nervous system involvement. Therefore, pa- sisted us in making an early diagnosis, which allowed tients are generally classified as having BBE rather than MFS prompt treatment of BBE. Various treatments of BBE have if there is evidence of corticospinal tract abnormalities, a been used in the past, including corticosteroids, intra- disturbed state of consciousness, or a significant brain- venous immunoglobulin, and plasmapheresis. Our pa- stem lesion on MRI or at autopsy. At times, there is an over- tient was treated with corticosteroids, which seemed to lap between BBE and GBS, which prompted Odaka et al2 have a positive therapeutic effect. Additional treatment to classify some patients with BBE who had symmetrical with intravenous immunoglobulin and plasmapheresis flaccid limb weakness as having BBE associated with GBS; was not used because of concerns about our patient’s re- electrophysiological study results of these patients can sug- nal and hemodynamic status. Despite the fact that this

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 elderly woman had significant neurological deficits and 3. Lo YL. Clinical and immunological spectrum of the Miller Fisher syndrome. Muscle serious medical problems, she eventually returned to her Nerve. 2007;36(5):615-627. 4. Griffin JW, Sheikh K. The Guillain-Barre´ syndromes. In: Dyck P, Thomas PK, eds. baseline status, highlighting the importance of aggres- Peripheral Neuropathy. Vol 2. 4th ed. Philadelphia, PA: Elsevier Saunders; 2005: sive, supportive treatment in what can be a completely 2197-2219. 2,13 reversible process. 5. Tenembaum S, Chitnis T, Ness J, Hahn JS; International Pediatric MS Study Group. Acute disseminated encephalomyelitis. Neurology. 2007;68(16)(suppl 2):S23- Accepted for Publication: November 2, 2007. S36. Correspondence: Raymond P. Roos, MD, Department of 6. Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: clinical and immunological range. J Neurol Neurosurg Psychiatry. 2001;70(1):50-55. Neurology, Mail Code 2030, University of Chicago Medi- 7. Griffin JW, Li CY, Ho TW, et al. Guillain-Barre´ syndrome in northern China: the cal Center, 5841 S Maryland Ave, Chicago, IL 60637 (rroos spectrum of neuropathological changes in clinically defined cases. Brain. 1995; @neurology.bsd.uchicago.edu). 118(pt 3):577-595. Author Contributions: Study concept and design: Roos and 8. Hussain AM, Flint NJ, Livsey SA, Wong R, Spiers P, Bukhari SS. Bickerstaff’s Baron. Acquisition of data: Roos, Goldenberg, and Badrud- brainstem encephalitis related to Campylobacter jejuni gastroenteritis. J Clin Pathol. din. Analysis and interpretation of data: Roos, Soliven, and 2007;60(10):1161-1162. 9. Kamasaki A, Kinoshita I, Koga M, Yamaguchi T, Yuki N. A case of brainstem en- Baron. Drafting of the manuscript: Roos. Critical revision cephalitis associated with Epstein-Barr virus infection: differentiation of acute of the manuscript for important intellectual content: Roos, disseminated encephalomyelitis and Bickerstaff’s brainstem encephalitis [in Soliven, Goldenberg, Badruddin, and Baron. Study su- Japanese]. No To Shinkei. 2001;53(10):951-955. pervision: Roos and Goldenberg. 10. Andermann F, Cosgrove JB, Lloyd-Smith D, Walters AM. Paroxysmal dysarthria Financial Disclosure: None reported. and ataxia in multiple sclerosis; a report of 2 unusual cases. Neurology. 1959; 9(4):211-215. 11. Espir ML, Watkins SM, Smith HV. Paroxysmal dysarthria and other transient neu- REFERENCES rological disturbances in disseminated sclerosis. J Neurol Neurosurg Psychiatry. 1966;29(4):323-330. 1. Bickerstaff ER, Cloake PC. Mesencephalitis and rhombencephalitis. Br Med J. 12. Smith KJ, McDonald WI. The pathophysiology of multiple sclerosis: the mecha- 1951;2(4723):77-81. nisms underlying the production of symptoms and the natural history of the disease. 2. Odaka M, Yuki N, Yamada M, et al. Bickerstaff’s brainstem encephalitis: clinical Philos Trans R Soc Lond B Biol Sci. 1999;354(1390):1649-1673. features of 62 cases and a subgroup associated with Guillain-Barre´ syndrome. 13. Bickerstaff ER. Brain-stem encephalitis; further observations on a grave syn- Brain. 2003;126(pt 10):2279-2290. drome with benign prognosis. Br Med J. 1957;1(5032):1384-1387.

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