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Brain stem encephalitis and the syndrome of Miller Fisher. A clinical study. By Amir Najim Al-Din, Milne Anderson, Edwin R. Bickerstaff and Ian Harvey (From the Midland Centre for Neurosurgery, Smethwick, West Midlands, UK). Brain 1982: 105; 481—495; and Bickerstaff's brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. By Masaaki Odaka, Nobuhiro Yuki, Mitsunori Yamada, Michiaki Koga, Toshihiko Takemi, Koichi Harata and Satoshi Kuwabara (From the University School of Medicine, Tochigi; Brain Research Institute, Niigata University; St Luke's International Hospital, Toyko; and Chiba University School of Medicine, Chiba, Japan) Brain 2003: 126; 2279–2290.
Cambridge
In 1957, Edwin Bickerstaff (1920–2007) followed up on three cases of mesencephalitis and rhomboencephalitis he had reported 6 years earlier with Philip Cloake (1890–1969), describing as a definitive syndrome eight patients with acute symmetrical ophthalmoplegia, other cranial nerve palsies and ataxia (Br Med J 1957: 1; 1384–1387). The team from Birmingham opens their new analysis of this disorder by stating unambiguously that ‘brainstem encephalitis includes the syndrome of ophthalmoplegia, ataxia and hyporeflexia’. The typical form is characterized by acute progressive ophthalmoplegia, involvement of other cranial nerves, ataxia and hyporeflexia, no significant motor or sensory deficit in the limbs and usually with full recovery. After the appearance of Charles Miller Fisher's paper in 1956 (New Engl J Med 1956: 255; 57–65) in which, reporting three cases and building on the suggestion by James Collier (1870–1935) that the Guillain–Barré syndrome may show external ophthalmoplegia with or without limb paralysis and in which Dr Fisher emphasizes the increase in cerebrospinal fluid protein without pleocytosis, the style of case series has been to designate this syndrome as a variant of acute post-infectious polyneuritis. With Edwin Bickerstaff as co-author, Amir Al-Din and colleagues now aim to show that the syndrome of acute ophthalmoplegia, ataxia and areflexia is distinct from the Guillain–Barré syndrome and the pathology does indeed affect the brainstem.
Eighteen cases are reported. Five children, eight young adults and five older subjects all developed drowsiness and acute progressive ophthalmoplegia, often both external and internal, and associated with facial and bulbar weakness. Each has ataxia with cerebellar incoordination of the limbs. Although 11 patients are areflexic, three have normal tendon reflexes and, in four others, these are pathologically brisk with one or both plantar responses extensor. The cerebrospinal fluid is often normal but half show either a rise in cell count or protein content. Involvement of respiratory muscles is rare but recovery usually complete so it is important to ventilate all patients. ‘After ophthalmoplegia, facial weakness is most common, then bulbar palsy. Rarely are all motor cranial nerves involved. This gives rise to a striking clinical picture of an apparently moribund patient who can use his limbs to operate suction apparatus to remove secretions accumulated in his throat’.
Two weeks after having an upper respiratory tract infection, a 59-year-old man becomes forgetful and drowsy but remains rousable: he develops complete ophthalmoplegia, bilateral facial and bulbar weakness, and has generalized areflexia and extensor plantar responses. Death occurs 1 month after onset from pulmonary embolism. Autopsy shows softening in the right occipital lobe and brainstem corresponding to an area of low density in the midbrain extending into the thalamus on the right, demonstrated by computerized brain scanning during life. Limited histological examination shows changes consistent with ‘encephalitis’: focal lesions with large areas of central necrosis, perivascular round cell cuffing with macrophage infiltration, occasional activated microglia (rod cells) and reactive astrocytosis (Fig. 1). In addition to the imaging abnormalities seen in this individual, case 14 had developed bilateral facial and bulbar weakness with areflexia following left mastoidectomy for cholesteatoma and with a low-density lesion in the midbrain; and case 18, who survived, also had a low density lesion in the medullary region on brain imaging (Fig. 2).
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Have these cases resolved the issue of a central or peripheral basis for Bickerstaff's brainstem encephalitis and the Miller Fisher syndrome? Since ophthalmoplegia is rare in acute idiopathic polyneuritis, and encephalitis commonly involves the brainstem ‘we believe that the constellation of signs presented in this series constitutes a distinct clinical entity’. The authors argue that rather few pathological processes other than encephalitis can explain the presence of bilateral internal and external ophthalmoplegia in a conscious patient with little or no evidence for pyramidal disturbance and with spontaneous recovery. The assertion by Miller Fisher that the pathological process is located in the peripheral nerves is considered inconsistent with the evidence: brain imaging in this series has shown that the oculomotor cranial nerve nuclei and their central connections are involved; the histological abnormalities demonstrated in the brain of case 17 and one of those described by Dr Bickerstaff in 1957 clearly implicate brain stem pathology; drowsiness is a prominent feature that can be attributed to involvement of the rostral part of the reticular formation with associated abnormalities of the electroencephalogram; the relative sparing of downgaze is better explained on the basis of a central (pre-rubral) than peripheral abnormality of eye movement; the march of cranial nerve involvement is usually rostral-caudal with respect to brainstem anatomy; and a minority of patients have significant sensory disturbance that cannot be accommodated by peripheral nerve disease. ‘We do not agree with Miller Fisher's suggestion that [the ataxia] is due to a unique widespread and selective attack on the sensory neurones underlying postural adjustments’. In support of this formulation, areflexia occurs in the absence of significant motor involvement and with normal F wave latencies in the present series (cases 13, 14 and 16) and most other case reports, further undermining Miller Fisher's claim that the tendon reflexes are lost as a manifestation of radicular involvement. ‘The clinical, neurophysiological, radiological and pathological findings ... suggest that this syndrome constitutes a recognisable ... abnormality within the brainstem. and in none of our cases is there evidence that the manifestations result from involvement of the peripheral nervous system’.
It does not take long for the nosological status of Bickerstaff's brainstem encephalitis to excite criticism—Allan Ropper reclassifying the 1982 series as six typical cases of the Miller Fisher syndrome and 12 others with obscure brainstem lesions lacking neuropathy as a core feature (Arch Neurol 1983: 40; 397–398). And with the demonstration that anti-G1Qb autoantibody is typically present in cases of Miller Fisher syndrome and in those designated as having Bickerstaff brainstem encephalitis, it seems that these may not after all be separate entities.
Gradually, the position emerges that the term Bickerstaff brainstem encephalitis should only be used in the context of cases having coma, brisk reflexes and long tract sensory disturbances in addition to the triad of ophthalmoplegia, ataxia and areflexia. Masaaki Odaka and colleagues from Japan take cases with the triad, drowsiness and hyperreflexia, and no other apparent explanation for brainstem disease, as their working definition of Bickerstaff's brainstem encephalitis. They report 62 cases aged from 2 to 91 years at onset. Most have had an antecedent illness. Apart from limb weakness, no striking clinical differences are seen comparing cases with ophthalmoplegia, ataxia and areflexia and the two thirds showing additional features typical of the Guillain–Barré syndrome: high intensity T2-weighted abnormalities of the brainstem or other parts of the central nervous system are present in about one third; electrophysiological abnormalities of peripheral nerve, most usually axonal and mimicking the acute motor axonal neuropathy (AMAN) pattern of disease, are seen in half; a variety of cerebrospinal fluid abnormalities with albuminocytological dissociation occur in one third, or higher late in the illness; anti-GQ1b autoantibodies are present in two thirds and the antibodies associated with AMAN (anti-GM1, –GD1a and –Ga1NAc-GD1a) in a smaller proportion; about one quarter appear recently to have had campylobacter jejuni infection; and the prognosis is good with most making a full clinical recovery over 6 months.
One patient has died of asphyxia: autopsy shows perivascular infiltration with oedema and glial nodules: ‘the findings confirmed that Bickerstaff's brainstem encephalitis ... defined as a syndrome presenting with acute ophthalmoplegia, ataxia and disturbance of consciousness as its major manifestations, in association with certain symptoms and signs indicative of central involvement ... constitutes a clinical entity ... a considerable number of patients develop[ed] a flaccid tetraparesis which is presumed to be a sign of overlapping Guillain-Barré syndrome’. The Japanese commentators assess the accuracy of the original cases in the literature: 1 of the 3 described by Miller Fisher, 6 of 8 originally reported by Bickerstaff and 9 of 18 described by Al-Din can reasonably be said to have brainstem encephalitis not Miller Fisher syndrome and 5 others of the 29 cases have had Bickerstaff's brainstem encephalitis with overlapping Guillain-Barré syndrome. Clearly the high frequency of anti-GQ1b autoantibodies in Bickerstaff's brainstem encephalitis suggests a close mechanistic relationship between these disorders. But just because a central lesion explains the coma, extensor plantar responses and long tract sensory disturbances, this does not mean that the triad of ophthalmoplegia, ataxia and arflexia has also to be interpreted in that light.
The Birmingham team end with a compromise: ‘perhaps our cases represent one end of a spectrum in which the pathological process predominates in the central nervous system, while at the opposite end of the spectrum the brunt falls on the peripheral nerves and in between combined central and peripheral nervous system involvement occurs ... what seems most likely is that ... the CNS responds in a hypersensitive or allergic manner to some external and probably infective challenge’. And this view is endorsed by the later study from Japan: ‘the clinical, electrophysiological and immunological findings reported in our study support the original hypothesis of Bickerstaff and Cloake that Bickerstaff's brainstem encephalitis is closely related to Guillain-Barré syndrome and they form a continuous spectrum’.
Against this background, the inhibition of clinical and electrophysiological features in a model of the Miller Fisher syndrome that follows the prevention of membrane attack complex formation, reported by the group of Hugh Willison from Glasgow (page 1197), suggests a new option for treating the Miller Fisher syndrome and, therefore, cases of Bickerstaff's brainstem encephalitis.
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