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Rhomb- and Bickerstaff Encephalitis: Two Clinical Phenotypes?
Pediatric Neurology 48 (2013) 244e248
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Rhomb- and Bickerstaff Encephalitis: Two Clinical Phenotypes? Rebecca C. Gologorsky BA *, Jerome A. Barakos MD, Farhad Sahebkar MD Division of Pediatric Neurology, California Pacific Medical Center, San Francisco, California
article information
abstract
Article history: Received 10 April 2012 Accepted 12 November 2012
We report unusual cases of brainstem encephalitis in two young boys. Both presented with acute febrile illness, progressive encephalopathy, and marked cerebrospinal fluid pleocytosis. Case one shared some of the clinical features that have been seen in previously reported cases of brainstem encephalitis, such as ophthalmoplegia, ataxia, and progressive encephalopathy. Case two presented with similar clinical features, although without ophthalmoplegia and ataxia. A review of magnetic resonance imaging revealed mild differences with respect to anatomic lesion localization and confirmed a neuroanatomic basis for the variance in each patient’s symptoms. The features of these cases deviate from the classical symptoms described in the Miller-Fisher syndrome/Bickerstaff brainstem encephalitis/Guillain-Barré syndrome spectrum, although the cause for variability in clinical phenotypes is unknown. Ó 2013 Elsevier Inc. All rights reserved.
Introduction
Miller-Fisher syndrome, Guillain-Barré syndrome, and Bickerstaff brainstem encephalitis form a continuous spectrum of autoimmune, postinfectious diseases. Clinical features are often manifested as external ophthalmoplegia, ataxia, and reflex abnormality, and laboratory findings often include elevated anti-GQ1b antibodies and albuminocytologic dissociation. Miller-Fisher syndrome, Guillain-Barré syndrome, and Bickerstaff brainstem encephalitis are distinguished from one another by characteristic symptoms. Bickerstaff brainstem encephalitis is differentiated from Miller-Fisher syndrome and Guillain-Barré syndrome by disturbance of consciousness and pyramidal signs [1,2]. Patients often have development of ptosis and diplopia early in their illness, with elevated cerebrospinal fluid (CSF) protein and albuminocytologic dissociation frequently developing in the following weeks [3]. A triad of symptomsdexternal ophthalmoplegia, ataxia, and areflexiadcharacterizes Miller-Fisher syndrome. Limb weakness and albuminocytologic dissociation are also typical features (Table 1) [4].
* Communications should be addressed to: R. Gologorsky; 22 Monte Avenue; Piedmont; CA 94611. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2012.11.002
Guillain-Barré syndrome involves demyelination of the peripheral nervous system, resulting in progressive ascending limb weakness with bulbar involvement without ophthalmoplegia and ataxia. Altered mental status and abnormal magnetic resonance imaging (MRI) findings are unusual in Guillain-Barré syndrome and Miller-Fisher syndrome [4]. Bickerstaff brainstem encephalitis, MillerFisher syndrome, and Guillain-Barré syndrome are often treated with immune-modulating therapies, including intravenous immunoglobulin and plasmaphoresis; outcome is generally favorable with these three conditions. We describe two similar cases that share some of these features but do not meet previously established criteria for Miller-Fisher syndrome, Guillain-Barré syndrome, or Bickerstaff brainstem encephalitis. Both were young boys who presented with acute febrile illness, CSF pleocytosis, and progressive encephalopathy with abnormal MRI study results. Each responded to intravenous methylprednisolone administration. Case Reports Case One
A 12-year-old boy was admitted to the hospital after a 6-day history of fever, lethargy, headache, emesis, diplopia, and unsteady gait. On presentation, the patient was alert and oriented with fluent speech and was in no apparent distress. The patient displayed right ptosis with limited horizontal gaze and horizontal nystagmus, suggestive of bilateral
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Table 1. An overview of the laboratory and clinical findings of our cases, a similar case described in 1986,* and the presentation of BBE, GBS, and MFS as reported by case studies by Ito et al. [4], Uchino et al. [7], and Odaka et al. [3]
Age Sex CSF WBC week 1 CSF protein week 1 Anti-GQ1b antibodies CSF WBC week 2 CSF protein week 2 Initial symptoms Headache Emesis Fever Alteration of consciousness Upper respiratory infection Limb weakness Ptosis Diplopis Signs during illness Alteration of consciousness Limb weakness Ataxia Ptosis Diplopia Nystagmus Facial weakness Internal ophthalmoplegia External ophthalmoplegia Areflexia Hyperreflexia/normal reflex Imaging abnormality NCS (% abnormal)
Case 1
Case 2
Our Average
1986 Case
BBE (n ¼ 53)
GBS/BBE (n ¼ 37)
MFS (n ¼ 466)
12 M 1200 79 Negative 16 17
6 M 2910 148 Unknown 0 22
9 N/A 2055 114 N/A 8 20
7 M 409 35 Unknown 8 15
40 70% M 4 42 68% þ 3 81
37 54% M 3 34 70% þ 2 106
44 60% M 1 Unknown 83% þ 2 Unknown
Yes Yes Yes Yes No Yes Yes Yes
Yes Yes Yes Yes No Yes No No
Yes Yes Yes Yes No Yes Yes Yes
16% 16% 16% 9% 60% 0% 2% 32%
11% 11% 11% 5% 78% 19% 3% 51%
Yes Yes Yes Yes Yes Yes Yes Yes N Yes No Yes Normal
Yes Yes Yes No No No No No No No No Yes Unknown
Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Unknown
100% 49% 100% 34% Unknown 44% 42% 55% 100% 60% 40% 11% 75%
43% 32% 100% 27% Unknown 16% 57% 38% 100% 67% 33% 23% 58%
2% 2% 2% 0% 76% 2% 4% 65% 0% 25% 100% 37% Unknown Unknown 22% 35% 100% 100% 0% 1% 74%
Abbreviations: BBE ¼ Bickerstaff brainstem encephalitis CSF ¼ Cerebrospinal fluid GBS ¼ Guillain-Barré syndrome MFS ¼ Miller-Fisher syndrome NCS ¼ Nerve conduction study WBC ¼ White blood cell count Average values are presented for compiled reported cases of BBE, GBS, and MFS. * The 1986 case refers to a patient described by Tachi et al. [8].
internuclear ophthalmoplegia. Pertinent negatives included pupil abnormalities, petechiae, rash, focal motor deficits, clonus, Babinski signs, ataxia, dysmetria, and hyperreflexia or hyporeflexia. He was started on ceftriaxone therapy. A brain MRI scan showed abnormal T2 hyperintensity along the posterior pons extending to the periependymal surface of the rhomboid fossa of the fourth ventricle (Figure 1; day 1). Diagnoses of neoplasm, ventriculitis, tuberculosis, and botulism were eliminated on the basis of laboratory findings. A lumbar puncture yielded cloudy CSF with a white blood cell count of 1200 cells/uL, red blood cell count of 4 cells/uL, with 85% polymorphonuclear neutrophils, 9% lymphocytes, and 6% monocytes. CSF protein was 79 mg/dL, and glucose was 49 mg/dL. The results of CSF stains and cultures were negative. The patient tested negative for mycoplasma pneumoniae, Epstein-Barr virus immunoglobulin M antibodies, cryptococcal antigen, influenza A/B, enterovirus, Lyme antibodies, acid-fast bacilli stain, and tuberculosis culture. Anti-GQ1b antibodies were absent. A repeat lumbar puncture on day 14 showed elevated immunoglobulin G index. No oligoclonal bands were found. Within 48 hours, the patient’s mental and physical conditions deteriorated further; new symptoms included encephalopathy manifested as disorientation with waxing and waning mental status. The patient had development of left seventh nerve palsy with complete absence of horizontal gaze. Vertical eye movements remained normal. MRI showed progression of abnormal T2 hyperintensity involving the pontine tegmentum and contiguous portions of the midbrain, medulla,
brachium pontis, and the roof of the fourth ventricle (Figure 1; Day 3). The result of chest radiography was normal. Electromyography/nerve conduction studies ruled out underlying peripheral nervous system degeneration. A 2-day course of intravenous immunoglobulin therapy was initiated. On day 3, the patient’s neurologic condition and mental status continued to deteriorate, with progression to bilateral seventh nerve palsy, slurred speech, delusions, areflexia, bilateral lower extremity weakness, and bilateral 1 1/2 syndrome. He was intubated and started on 5 days of methylprednisolone (20 mg/kg) followed by 5 days tapered to 60 mg and decreasing by 5 mg every 4 days. Repeat CSF and imaging studies were obtained on day 14 because of minimal recovery. The CSF white blood cell count dropped to 16 cells/uL with 100% lymphocytes, and one red blood cell. CSF protein was 17 mg/ dL, and glucose was 66 mg/dL. MRI showed mild reduction in the extent and confluence of the abnormal T2 hyperintensity. The patient’s condition gradually improved, and he was extubated by day 24; improvement seen on MRI on day 14 corresponded with the patient’s improvement of mental status and partial resolution of abduction eye movement bilaterally. The patient’s mental status and deep tendon reflexes returned to baseline. Physical rehabilitation for severe lack of balance and truncal ataxia commenced on day 25, and the patient’s condition continued to improve. Six days later, the patient was discharged to a rehabilitation facility. At this point, he was able to ambulate with some assistance because of unsteady gait. The patient denied diplopia, and his ptosis had
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Figure 1. Case 1: MRI (Three time points: days 1, 3, and 14. Top and middle row: coronal FLAIR sequences, Lower row: axial FSE-T2 sequences) reveal abnormal T2 hyperintensity along the posterior pons extending to the periependymal surface of the rhomboid fossa of the fourth ventricle (floor of the fourth ventricle). These findings are noted on day 1, with progress by day 3, and improvement by day 14. On the axial images of days 1 and 3, involvement is also noted in the left brachium pontis. FLAIR, fluid-attenuated inversion recovery; FSE, fast spin echo. resolved. Bilateral abduction paresis persisted for a few weeks before complete recovery. Case Two
A 6-year-old boy with a 5-day history of fever, headache, emesis, and weakness was admitted to the hospital. On presentation, the patient was alert and oriented with fluent speech and was in no apparent distress. The patient’s neurologic examination result was within normal limits; he displayed no pupillary abnormalities, and extraocular movements were intact. Strength was observed to be 5/5 and symmetric in all four limbs with negative clonus, Babinski signs, focal motor deficit, dysmetria, and ataxia. A lumbar puncture yielded cloudy CSF with a white blood cell count of 2910, a red blood cell count of 25, and 91% neutrophils; CSF glucose was 60 mg/dL, and protein was 148 mg/dL. The patient was negative for herpes simplex virus, Epstein-Barr virus, IgG antibodies, influenza A/B, adenovirus, and Mycoplasma pneumoniae. CSF stains and cultures ruled out bacterial meningitis. The patient was started on ceftriaxone, vancomycin, acyclovir, and dexamethasone. A lumbar puncture on day 2 showed marked improvement, with a white blood cell count of 61, red blood cell count of 12, with 58% polymorphonuclear neutrophils, 22% lymphocytes, and 20% monocytes. CSF glucose was 57 mg/dL, and protein was 36 mg/dL. The result of a brain computed tomography scan was normal. Between days 2 and 3, the patient’s mental status declined, and he became difficult to arouse and slow to respond, with slurred speech. Electromyography/nerve conduction studies ruled out underlying peripheral nervous system degeneration.
By day 4, the patient was unresponsive and disoriented and was wheezing; methylprednisolone was initiated (20 mg/kg for 5 days) with a 4-week taper. Brain MRI revealed abnormal T2 hyperintensity within the posterior pons but not extending to the periependymal surface of the rhomboid fossa of the fourth ventricle. There was no significant involvement of the central pons or brachium pontis (Figure 2). The following day, the patient was intubated. Radiography showed haziness in the patient’s right lower lung; suctioned secretions tested positive for respiratory syncytial virus. A brain MRI on day 7 showed persistent but improved abnormal T2 signal within the medulla and pontomedullary junction, but with development of mild ventriculomegaly (Figure 2). The following day, the patient was extubated. He demonstrated improved awareness but was unable to speak or cough. On day 8, the patient regained his ability to speak, although not clearly. Over the next 24 hours, he began to sit and walk with assistance. On day 14, physical therapy was commenced. The patient was discharged on day 15, with referrals for outpatient physical and occupational therapy. A follow-up lumbar puncture 1 week after discharge showed a CSF white blood cell count of 0, and a red blood cell count of 1. CSF glucose was 52 mg/dL, and protein was 22 mg/dL. MRI showed interval improvement of the previously described T2 hyperintensity within the brainstem.
Discussion
Rhombencephalitis is a rare central nervous system (CNS) disorder in childhood. The underlying mechanism includes
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Figure 2. Case 2: MRI (Three time points: days 1, 7, and 24. Top and middle row: coronal FLAIR sequences, Lower row: axial FSE-T2 sequences) reveal abnormal T2 hyperintensity within the posterior pons but not extending to the periependymal surface of the rhomboid fossa of the fourth ventricle (floor of the fourth ventricle). These findings are most prominent on day 1 and demonstrate serial improvement on each of the follow-up MRI scans, day 7 and day 24, respectively. There is no significant involvement of the central pons or brachium pontis. FLAIR, fluid-attenuated inversion recovery; FSE, fast spin echo.
postinfectious demyelination, autoimmune-mediated cytotoxic edema, or primary infection. Bickerstaff brainstem encephalitis, Miller-Fisher syndrome, and Guillain-Barré syndrome are closely related disorders with an underlying postinfectious autoimmune mechanism that involves the CNS and peripheral nervous system. Bickerstaff brainstem encephalitis involves demyelination of the CNS, whereas Guillain-Barré syndrome affects the peripheral nervous system. The presence of limb weakness in patients with Bickerstaff brainstem encephalitis has been linked to a demyelinating peripheral nerve process, referred to as Bickerstaff brainstem encephalitis with overlapping Guillain-Barré syndrome. Miller-Fisher syndrome is manifested by external ophthalmoplegia, ataxia, and areflexia caused by underlying peripheral and CNS involvement [3]. This spectrum of disorders is often associated with a history of prodromal illness, presence of anti-GQ1b IgG, CSF albuminocytologic dissociation, and normal imaging results [5]. We present two cases of acute rhombencephalitis with different clinical phenotypes. The first had encephalopathy with distinct bulbar paralysis, and the second had encephalopathy without bulbar paralysis. Our patients presented with similar laboratory findings and imaging study results that corresponded with their deficits. Our patient with bulbar paralysis had a slightly more protracted course with near-complete recovery, whereas the patient with an absence of bulbar paralysis had a faster, complete recovery. The first case demonstrated brainstem involvement on MRI centered along the periependymal surface of the posterior pons, contiguous with the floor of the fourth ventricle. This lesional distribution served to involve the medial longitudinal fasciculus, abducens nucleus (CN VI), as
well as the medial vestibulospinal tract and paramedian pontine reticular formation. As such, a variety of neurologic structures were involved that play a crucial role in coordinating eye movement and would account for the patient’s ophthalmoplegia. Involvement of the brachium pontis was noted, in keeping with the patient’s ataxia. In contrast, the MRI result in case two revealed brainstem involvement, which spared the most posterior aspect of the pons corresponding to the floor of the fourth ventricle. Therefore many of the neurologic structures involved with eye movement located in this areadincluding the medial longitudinal fasciculus, abducens nucleus, paramedian pontine reticular formation, and medial vestibulospinal tractdwere spared. Additionally, no lesions were identified involving the cerebellar peduncles or central pons corresponding to cortical spinal tracts and pontine nuclei. Therefore, although both patients demonstrated MRI features in keeping with a brainstem encephalitis, the varied anatomic localization of brainstem involvement between the two patients served to account for the contrasting neurologic symptoms. An acute clinical presentation of high fever, headache, emesis, and a concomitant decline in neurologic function with radiographic findings and marked pleocytosis in both of our cases suggest an underlying primary brainstem infection, rather than a postinfectious autoimmune-mediated process [6]. In patient two, a positive result for respiratory syncytial virus may suggest a direct viral invasion pathomechanism. Underlying peripheral nervous system involvement was ruled out by electromyography/nerve conduction studies (Table 1) [3,4,7,8]. Bickerstaff brainstem encephalitis, Miller-Fisher syndrome, and Guillain-Barré syndrome were further excluded on the basis of an absence of anti-GQ1b antibodies, and
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internal ophthalmoplegia; it remains unclear whether the first dose of intravenous immunoglobulin could have masked the presence of anti-GQ1b antibodies in patient one. Although symptoms in patient two may have been masked by decreased consciousness, the patient’s initial presentation did not include oculomotor disturbances or ataxia, contributing to our determination of this case as distinct from typical features of Bickerstaff brainstem encephalitis. Other key differences include average age of presentation, MRI abnormalities, electromyography/nerve conduction study results, and presentation of illness (Table 1) [3,4,7,8].Tachi et al. [8] reported a case of a young boy presenting with a nearly identical set of symptoms, laboratory results, and imaging workup results. The authors concluded that, despite the absence of brainstem abnormality on CT scanning, this was brainstem encephalitis, rather than a variant of Guillain-Barré syndrome [8]. In these patients, MRI and lumbar puncture are important diagnostic tools. Although no specific treatment exists, immunomodulation, including empiric use of steroids, intravenous immunoglobulin, and plasmaphoresis, has been successful [3,5,9,10]. Placing our conditions within the Miller-Fisher syndrome/Bickerstaff brainstem encephalitis/ Guillain-Barré syndrome spectrum without distinguishing their unique features would erroneously imply the presence of a shared pathomechanism. The lack of characteristics classic to the spectrum suggests that these two cases are brainstem encephalitis with a unique cause and may represent a subset of the Miller-Fisher syndrome/Bickerstaff
brainstem encephalitis/Guillain-Barré syndrome spectrum. Clearly delineating each of these syndromes will aid the investigation of their particular pathomechanisms, causes, and therapies. References [1] Bickerstaff E. Brain-stem encephalitis. Br Med J 1957;1:1384e7. [2] Bickerstaff E, Cloake P. Mesencephalitis and rhombencephalitis. Br Med J 1951;2:77e81. [3] Odaka M, Yuki N, Yamada M, et al. Bickerstaff’s brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. Brain 2003;126:2279e90. [4] Ito M, Kuwabara S, Odaka M, et al. Bickerstaff’s brainstem encephalitis and Fisher syndrome form a continuous spectrum. J Neurol 2007;255:674e82. [5] Ogawara K, Kuwabara S, Yuki N. Fisher syndrome or Bickerstaff brainstem encephalitis? Anti-GQ1b IgG antibody syndrome involving both the peripheral and central nervous systems. Muscle Nerve 2002;26:845e9. [6] Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: Clinical and immunological range. J Neurol Neurosurg Psychiatry 2001;104:50e5. [7] Uchino M, Haga D, Nomoto J, Mito T, Kuramitsu T. Brainstem involvement in hypertensive encephalopathy: A report of two cases and literature review. Eur Neurol 2007;57:223e6. [8] Tachi N, Tsuzuki Y, Minami R. A case of brainstem encephalitis with CT scan abnormality mimicking Fisher syndrome. Brain Dev 1986;8:538e41. [9] Chikakiyo H, Kunishige M, Yoshino H, et al. Delayed motor and sensory neuropathy in a patient with brainstem encephalitis. J Neurolog Sci 2005;234:105e8. [10] Mori M, Koga M, Yuki N, Hattori T, Kuwabara S. Bickerstaff’s brainstem encephalitis after an outbreak of Campylobacter jejuni enteritis. J Neuroimmunol 2008;196:143e6.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Rhomb- and Bickerstaff Encephalitis: Two Clinical Phenotypes? Rebecca C. Gologorsky BA *, Jerome A. Barakos MD, Farhad Sahebkar MD Division of Pediatric Neurology, California Pacific Medical Center, San Francisco, California
article information
abstract
Article history: Received 10 April 2012 Accepted 12 November 2012
We report unusual cases of brainstem encephalitis in two young boys. Both presented with acute febrile illness, progressive encephalopathy, and marked cerebrospinal fluid pleocytosis. Case one shared some of the clinical features that have been seen in previously reported cases of brainstem encephalitis, such as ophthalmoplegia, ataxia, and progressive encephalopathy. Case two presented with similar clinical features, although without ophthalmoplegia and ataxia. A review of magnetic resonance imaging revealed mild differences with respect to anatomic lesion localization and confirmed a neuroanatomic basis for the variance in each patient’s symptoms. The features of these cases deviate from the classical symptoms described in the Miller-Fisher syndrome/Bickerstaff brainstem encephalitis/Guillain-Barré syndrome spectrum, although the cause for variability in clinical phenotypes is unknown. Ó 2013 Elsevier Inc. All rights reserved.
Introduction
Miller-Fisher syndrome, Guillain-Barré syndrome, and Bickerstaff brainstem encephalitis form a continuous spectrum of autoimmune, postinfectious diseases. Clinical features are often manifested as external ophthalmoplegia, ataxia, and reflex abnormality, and laboratory findings often include elevated anti-GQ1b antibodies and albuminocytologic dissociation. Miller-Fisher syndrome, Guillain-Barré syndrome, and Bickerstaff brainstem encephalitis are distinguished from one another by characteristic symptoms. Bickerstaff brainstem encephalitis is differentiated from Miller-Fisher syndrome and Guillain-Barré syndrome by disturbance of consciousness and pyramidal signs [1,2]. Patients often have development of ptosis and diplopia early in their illness, with elevated cerebrospinal fluid (CSF) protein and albuminocytologic dissociation frequently developing in the following weeks [3]. A triad of symptomsdexternal ophthalmoplegia, ataxia, and areflexiadcharacterizes Miller-Fisher syndrome. Limb weakness and albuminocytologic dissociation are also typical features (Table 1) [4].
* Communications should be addressed to: R. Gologorsky; 22 Monte Avenue; Piedmont; CA 94611. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2012.11.002
Guillain-Barré syndrome involves demyelination of the peripheral nervous system, resulting in progressive ascending limb weakness with bulbar involvement without ophthalmoplegia and ataxia. Altered mental status and abnormal magnetic resonance imaging (MRI) findings are unusual in Guillain-Barré syndrome and Miller-Fisher syndrome [4]. Bickerstaff brainstem encephalitis, MillerFisher syndrome, and Guillain-Barré syndrome are often treated with immune-modulating therapies, including intravenous immunoglobulin and plasmaphoresis; outcome is generally favorable with these three conditions. We describe two similar cases that share some of these features but do not meet previously established criteria for Miller-Fisher syndrome, Guillain-Barré syndrome, or Bickerstaff brainstem encephalitis. Both were young boys who presented with acute febrile illness, CSF pleocytosis, and progressive encephalopathy with abnormal MRI study results. Each responded to intravenous methylprednisolone administration. Case Reports Case One
A 12-year-old boy was admitted to the hospital after a 6-day history of fever, lethargy, headache, emesis, diplopia, and unsteady gait. On presentation, the patient was alert and oriented with fluent speech and was in no apparent distress. The patient displayed right ptosis with limited horizontal gaze and horizontal nystagmus, suggestive of bilateral
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Table 1. An overview of the laboratory and clinical findings of our cases, a similar case described in 1986,* and the presentation of BBE, GBS, and MFS as reported by case studies by Ito et al. [4], Uchino et al. [7], and Odaka et al. [3]
Age Sex CSF WBC week 1 CSF protein week 1 Anti-GQ1b antibodies CSF WBC week 2 CSF protein week 2 Initial symptoms Headache Emesis Fever Alteration of consciousness Upper respiratory infection Limb weakness Ptosis Diplopis Signs during illness Alteration of consciousness Limb weakness Ataxia Ptosis Diplopia Nystagmus Facial weakness Internal ophthalmoplegia External ophthalmoplegia Areflexia Hyperreflexia/normal reflex Imaging abnormality NCS (% abnormal)
Case 1
Case 2
Our Average
1986 Case
BBE (n ¼ 53)
GBS/BBE (n ¼ 37)
MFS (n ¼ 466)
12 M 1200 79 Negative 16 17
6 M 2910 148 Unknown 0 22
9 N/A 2055 114 N/A 8 20
7 M 409 35 Unknown 8 15
40 70% M 4 42 68% þ 3 81
37 54% M 3 34 70% þ 2 106
44 60% M 1 Unknown 83% þ 2 Unknown
Yes Yes Yes Yes No Yes Yes Yes
Yes Yes Yes Yes No Yes No No
Yes Yes Yes Yes No Yes Yes Yes
16% 16% 16% 9% 60% 0% 2% 32%
11% 11% 11% 5% 78% 19% 3% 51%
Yes Yes Yes Yes Yes Yes Yes Yes N Yes No Yes Normal
Yes Yes Yes No No No No No No No No Yes Unknown
Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Unknown
100% 49% 100% 34% Unknown 44% 42% 55% 100% 60% 40% 11% 75%
43% 32% 100% 27% Unknown 16% 57% 38% 100% 67% 33% 23% 58%
2% 2% 2% 0% 76% 2% 4% 65% 0% 25% 100% 37% Unknown Unknown 22% 35% 100% 100% 0% 1% 74%
Abbreviations: BBE ¼ Bickerstaff brainstem encephalitis CSF ¼ Cerebrospinal fluid GBS ¼ Guillain-Barré syndrome MFS ¼ Miller-Fisher syndrome NCS ¼ Nerve conduction study WBC ¼ White blood cell count Average values are presented for compiled reported cases of BBE, GBS, and MFS. * The 1986 case refers to a patient described by Tachi et al. [8].
internuclear ophthalmoplegia. Pertinent negatives included pupil abnormalities, petechiae, rash, focal motor deficits, clonus, Babinski signs, ataxia, dysmetria, and hyperreflexia or hyporeflexia. He was started on ceftriaxone therapy. A brain MRI scan showed abnormal T2 hyperintensity along the posterior pons extending to the periependymal surface of the rhomboid fossa of the fourth ventricle (Figure 1; day 1). Diagnoses of neoplasm, ventriculitis, tuberculosis, and botulism were eliminated on the basis of laboratory findings. A lumbar puncture yielded cloudy CSF with a white blood cell count of 1200 cells/uL, red blood cell count of 4 cells/uL, with 85% polymorphonuclear neutrophils, 9% lymphocytes, and 6% monocytes. CSF protein was 79 mg/dL, and glucose was 49 mg/dL. The results of CSF stains and cultures were negative. The patient tested negative for mycoplasma pneumoniae, Epstein-Barr virus immunoglobulin M antibodies, cryptococcal antigen, influenza A/B, enterovirus, Lyme antibodies, acid-fast bacilli stain, and tuberculosis culture. Anti-GQ1b antibodies were absent. A repeat lumbar puncture on day 14 showed elevated immunoglobulin G index. No oligoclonal bands were found. Within 48 hours, the patient’s mental and physical conditions deteriorated further; new symptoms included encephalopathy manifested as disorientation with waxing and waning mental status. The patient had development of left seventh nerve palsy with complete absence of horizontal gaze. Vertical eye movements remained normal. MRI showed progression of abnormal T2 hyperintensity involving the pontine tegmentum and contiguous portions of the midbrain, medulla,
brachium pontis, and the roof of the fourth ventricle (Figure 1; Day 3). The result of chest radiography was normal. Electromyography/nerve conduction studies ruled out underlying peripheral nervous system degeneration. A 2-day course of intravenous immunoglobulin therapy was initiated. On day 3, the patient’s neurologic condition and mental status continued to deteriorate, with progression to bilateral seventh nerve palsy, slurred speech, delusions, areflexia, bilateral lower extremity weakness, and bilateral 1 1/2 syndrome. He was intubated and started on 5 days of methylprednisolone (20 mg/kg) followed by 5 days tapered to 60 mg and decreasing by 5 mg every 4 days. Repeat CSF and imaging studies were obtained on day 14 because of minimal recovery. The CSF white blood cell count dropped to 16 cells/uL with 100% lymphocytes, and one red blood cell. CSF protein was 17 mg/ dL, and glucose was 66 mg/dL. MRI showed mild reduction in the extent and confluence of the abnormal T2 hyperintensity. The patient’s condition gradually improved, and he was extubated by day 24; improvement seen on MRI on day 14 corresponded with the patient’s improvement of mental status and partial resolution of abduction eye movement bilaterally. The patient’s mental status and deep tendon reflexes returned to baseline. Physical rehabilitation for severe lack of balance and truncal ataxia commenced on day 25, and the patient’s condition continued to improve. Six days later, the patient was discharged to a rehabilitation facility. At this point, he was able to ambulate with some assistance because of unsteady gait. The patient denied diplopia, and his ptosis had
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Figure 1. Case 1: MRI (Three time points: days 1, 3, and 14. Top and middle row: coronal FLAIR sequences, Lower row: axial FSE-T2 sequences) reveal abnormal T2 hyperintensity along the posterior pons extending to the periependymal surface of the rhomboid fossa of the fourth ventricle (floor of the fourth ventricle). These findings are noted on day 1, with progress by day 3, and improvement by day 14. On the axial images of days 1 and 3, involvement is also noted in the left brachium pontis. FLAIR, fluid-attenuated inversion recovery; FSE, fast spin echo. resolved. Bilateral abduction paresis persisted for a few weeks before complete recovery. Case Two
A 6-year-old boy with a 5-day history of fever, headache, emesis, and weakness was admitted to the hospital. On presentation, the patient was alert and oriented with fluent speech and was in no apparent distress. The patient’s neurologic examination result was within normal limits; he displayed no pupillary abnormalities, and extraocular movements were intact. Strength was observed to be 5/5 and symmetric in all four limbs with negative clonus, Babinski signs, focal motor deficit, dysmetria, and ataxia. A lumbar puncture yielded cloudy CSF with a white blood cell count of 2910, a red blood cell count of 25, and 91% neutrophils; CSF glucose was 60 mg/dL, and protein was 148 mg/dL. The patient was negative for herpes simplex virus, Epstein-Barr virus, IgG antibodies, influenza A/B, adenovirus, and Mycoplasma pneumoniae. CSF stains and cultures ruled out bacterial meningitis. The patient was started on ceftriaxone, vancomycin, acyclovir, and dexamethasone. A lumbar puncture on day 2 showed marked improvement, with a white blood cell count of 61, red blood cell count of 12, with 58% polymorphonuclear neutrophils, 22% lymphocytes, and 20% monocytes. CSF glucose was 57 mg/dL, and protein was 36 mg/dL. The result of a brain computed tomography scan was normal. Between days 2 and 3, the patient’s mental status declined, and he became difficult to arouse and slow to respond, with slurred speech. Electromyography/nerve conduction studies ruled out underlying peripheral nervous system degeneration.
By day 4, the patient was unresponsive and disoriented and was wheezing; methylprednisolone was initiated (20 mg/kg for 5 days) with a 4-week taper. Brain MRI revealed abnormal T2 hyperintensity within the posterior pons but not extending to the periependymal surface of the rhomboid fossa of the fourth ventricle. There was no significant involvement of the central pons or brachium pontis (Figure 2). The following day, the patient was intubated. Radiography showed haziness in the patient’s right lower lung; suctioned secretions tested positive for respiratory syncytial virus. A brain MRI on day 7 showed persistent but improved abnormal T2 signal within the medulla and pontomedullary junction, but with development of mild ventriculomegaly (Figure 2). The following day, the patient was extubated. He demonstrated improved awareness but was unable to speak or cough. On day 8, the patient regained his ability to speak, although not clearly. Over the next 24 hours, he began to sit and walk with assistance. On day 14, physical therapy was commenced. The patient was discharged on day 15, with referrals for outpatient physical and occupational therapy. A follow-up lumbar puncture 1 week after discharge showed a CSF white blood cell count of 0, and a red blood cell count of 1. CSF glucose was 52 mg/dL, and protein was 22 mg/dL. MRI showed interval improvement of the previously described T2 hyperintensity within the brainstem.
Discussion
Rhombencephalitis is a rare central nervous system (CNS) disorder in childhood. The underlying mechanism includes
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Figure 2. Case 2: MRI (Three time points: days 1, 7, and 24. Top and middle row: coronal FLAIR sequences, Lower row: axial FSE-T2 sequences) reveal abnormal T2 hyperintensity within the posterior pons but not extending to the periependymal surface of the rhomboid fossa of the fourth ventricle (floor of the fourth ventricle). These findings are most prominent on day 1 and demonstrate serial improvement on each of the follow-up MRI scans, day 7 and day 24, respectively. There is no significant involvement of the central pons or brachium pontis. FLAIR, fluid-attenuated inversion recovery; FSE, fast spin echo.
postinfectious demyelination, autoimmune-mediated cytotoxic edema, or primary infection. Bickerstaff brainstem encephalitis, Miller-Fisher syndrome, and Guillain-Barré syndrome are closely related disorders with an underlying postinfectious autoimmune mechanism that involves the CNS and peripheral nervous system. Bickerstaff brainstem encephalitis involves demyelination of the CNS, whereas Guillain-Barré syndrome affects the peripheral nervous system. The presence of limb weakness in patients with Bickerstaff brainstem encephalitis has been linked to a demyelinating peripheral nerve process, referred to as Bickerstaff brainstem encephalitis with overlapping Guillain-Barré syndrome. Miller-Fisher syndrome is manifested by external ophthalmoplegia, ataxia, and areflexia caused by underlying peripheral and CNS involvement [3]. This spectrum of disorders is often associated with a history of prodromal illness, presence of anti-GQ1b IgG, CSF albuminocytologic dissociation, and normal imaging results [5]. We present two cases of acute rhombencephalitis with different clinical phenotypes. The first had encephalopathy with distinct bulbar paralysis, and the second had encephalopathy without bulbar paralysis. Our patients presented with similar laboratory findings and imaging study results that corresponded with their deficits. Our patient with bulbar paralysis had a slightly more protracted course with near-complete recovery, whereas the patient with an absence of bulbar paralysis had a faster, complete recovery. The first case demonstrated brainstem involvement on MRI centered along the periependymal surface of the posterior pons, contiguous with the floor of the fourth ventricle. This lesional distribution served to involve the medial longitudinal fasciculus, abducens nucleus (CN VI), as
well as the medial vestibulospinal tract and paramedian pontine reticular formation. As such, a variety of neurologic structures were involved that play a crucial role in coordinating eye movement and would account for the patient’s ophthalmoplegia. Involvement of the brachium pontis was noted, in keeping with the patient’s ataxia. In contrast, the MRI result in case two revealed brainstem involvement, which spared the most posterior aspect of the pons corresponding to the floor of the fourth ventricle. Therefore many of the neurologic structures involved with eye movement located in this areadincluding the medial longitudinal fasciculus, abducens nucleus, paramedian pontine reticular formation, and medial vestibulospinal tractdwere spared. Additionally, no lesions were identified involving the cerebellar peduncles or central pons corresponding to cortical spinal tracts and pontine nuclei. Therefore, although both patients demonstrated MRI features in keeping with a brainstem encephalitis, the varied anatomic localization of brainstem involvement between the two patients served to account for the contrasting neurologic symptoms. An acute clinical presentation of high fever, headache, emesis, and a concomitant decline in neurologic function with radiographic findings and marked pleocytosis in both of our cases suggest an underlying primary brainstem infection, rather than a postinfectious autoimmune-mediated process [6]. In patient two, a positive result for respiratory syncytial virus may suggest a direct viral invasion pathomechanism. Underlying peripheral nervous system involvement was ruled out by electromyography/nerve conduction studies (Table 1) [3,4,7,8]. Bickerstaff brainstem encephalitis, Miller-Fisher syndrome, and Guillain-Barré syndrome were further excluded on the basis of an absence of anti-GQ1b antibodies, and
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internal ophthalmoplegia; it remains unclear whether the first dose of intravenous immunoglobulin could have masked the presence of anti-GQ1b antibodies in patient one. Although symptoms in patient two may have been masked by decreased consciousness, the patient’s initial presentation did not include oculomotor disturbances or ataxia, contributing to our determination of this case as distinct from typical features of Bickerstaff brainstem encephalitis. Other key differences include average age of presentation, MRI abnormalities, electromyography/nerve conduction study results, and presentation of illness (Table 1) [3,4,7,8].Tachi et al. [8] reported a case of a young boy presenting with a nearly identical set of symptoms, laboratory results, and imaging workup results. The authors concluded that, despite the absence of brainstem abnormality on CT scanning, this was brainstem encephalitis, rather than a variant of Guillain-Barré syndrome [8]. In these patients, MRI and lumbar puncture are important diagnostic tools. Although no specific treatment exists, immunomodulation, including empiric use of steroids, intravenous immunoglobulin, and plasmaphoresis, has been successful [3,5,9,10]. Placing our conditions within the Miller-Fisher syndrome/Bickerstaff brainstem encephalitis/ Guillain-Barré syndrome spectrum without distinguishing their unique features would erroneously imply the presence of a shared pathomechanism. The lack of characteristics classic to the spectrum suggests that these two cases are brainstem encephalitis with a unique cause and may represent a subset of the Miller-Fisher syndrome/Bickerstaff
brainstem encephalitis/Guillain-Barré syndrome spectrum. Clearly delineating each of these syndromes will aid the investigation of their particular pathomechanisms, causes, and therapies. References [1] Bickerstaff E. Brain-stem encephalitis. Br Med J 1957;1:1384e7. [2] Bickerstaff E, Cloake P. Mesencephalitis and rhombencephalitis. Br Med J 1951;2:77e81. [3] Odaka M, Yuki N, Yamada M, et al. Bickerstaff’s brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. Brain 2003;126:2279e90. [4] Ito M, Kuwabara S, Odaka M, et al. Bickerstaff’s brainstem encephalitis and Fisher syndrome form a continuous spectrum. J Neurol 2007;255:674e82. [5] Ogawara K, Kuwabara S, Yuki N. Fisher syndrome or Bickerstaff brainstem encephalitis? Anti-GQ1b IgG antibody syndrome involving both the peripheral and central nervous systems. Muscle Nerve 2002;26:845e9. [6] Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: Clinical and immunological range. J Neurol Neurosurg Psychiatry 2001;104:50e5. [7] Uchino M, Haga D, Nomoto J, Mito T, Kuramitsu T. Brainstem involvement in hypertensive encephalopathy: A report of two cases and literature review. Eur Neurol 2007;57:223e6. [8] Tachi N, Tsuzuki Y, Minami R. A case of brainstem encephalitis with CT scan abnormality mimicking Fisher syndrome. Brain Dev 1986;8:538e41. [9] Chikakiyo H, Kunishige M, Yoshino H, et al. Delayed motor and sensory neuropathy in a patient with brainstem encephalitis. J Neurolog Sci 2005;234:105e8. [10] Mori M, Koga M, Yuki N, Hattori T, Kuwabara S. Bickerstaff’s brainstem encephalitis after an outbreak of Campylobacter jejuni enteritis. J Neuroimmunol 2008;196:143e6.