Patient with pontine warning syndrome and bilateral posterior internuclear ophthalmoplegia: case report

Capsular warning syndrome was first described by Donnan et al, denotes a burst of stereotyped transient ischemic attacks (TIAs), clustered within a brief period of time, with motor and/or sensory dysfunction and no cortical signs, and associated with a high risk of internal capsule infarction [1, 2]. However, clinically typical capsular warning syndrome can be linked to a pontine infarct [3–6]. Recently Saposnik and Caplan et al coined the term "Pontine warning syndrome" to characterize recurrent stereotyped episodes resembling those of capsular warning syndrome associated with a high risk of imminent basilar artery branch infarction and a permanent deficit [7]. In this article, we reported a case of a 54-year-old woman admitted to our stroke center a few months ago, who experienced three stereotyped episodes of left-sided hemiplegia within 7 hours and developed an acute pontine infarct eventually.

The vascular risk factors in our patient included hypertension, diabetes mellitus and dyslipidemia, in concordance with previously published reports [2, 3, 5–8]. As a consequence of these risk factors, intracranial artery stenosis or occlusion was speculated to be the main pathological basis for those "warning syndrome" by most authors [1, 2, 6, 7]. The atheroma in a large intracranial artery may occlude the origin of a penetrating branch and lead to hypoperfusion, which was demonstrated to be a major mechanism of ischemic stroke [9]. It has been demonstrated a high prevalence of intracranial artery stenosis among Asian, Black and Hispanic population [10, 11]. Furthermore, in a population-based study in southern China, we found 30 person with asymptomatic basilar artery stenosis among 1005 participants with transcranial Doppler, demonstrating a prevalence of 2.90% (data unpublished), considerably higher compared to that of 1.41% in patients from United Kingdom with ischemic stroke of non-POCI (posterior circulation infarction) subtype reported by Mead et al [12]. Accordingly, a recent article by some colleagues from our stroke center reported pontine infarction accounted for up to 10.2% of the first-ever ischemic stroke [13]. Given to the relatively poor clinical outcome, pontine warning syndrome may be underestimated and understudied, especially in populations with high prevalence of intracranial artery stenosis.

These "warning syndromes" are characterized by the identifiably stereotyped and crescendo nature of repetitive ischemic episodes. Although the hypothesis has not been verified in any experimental models, it is widely accepted that the repetitive episodes of neurologic deficit were associated with intermittent hypoperfusion of the vascular territory of terminal arteries with insufficient collateral flow, due to penetrating branch disease rather than lipohyalinosis. An anecdotal report may provide further evidence for this hypothesis. Six patients presented with intermittently decreased blood pressure, coinciding with clinical worsening and leading to definite stroke in 4 of them. One patient received noradrenalin, which allowed stabilization of the blood pressure values and complete resolution of the neurological symptoms [14]. Our patient had a history of nifedipine-treated hypertension, and the blood pressure level was "normal" on admission. We presumed lowered blood pressure may involve in the pathogenesis of her pontine infarct. Although recently some reports showed that blood pressure lowing in acute stage might favor the clinical outcome of ischemic stroke [15], blood pressure lowing administration may be improper for patients with pontine warning syndrome.

The 64-year-old patient by Saposnik et al had had 2 episodes of complete bilateral horizontal conjugate gaze palsy with unimpaired consciousness lasting for 5 minutes each [7]. Similarly, our patient demonstrated bilateral posterior internuclear ophthalmoplegia on admission. Bilateral abduction palsy were seen when she tried to remain horizontal lateral gaze-holding. However, the rim of the corneal could transiently reach the outer canthus in voluntary saccades, pursuit movements or vestibulo-ocular responses. In general, posterior internuclear ophthalmoplegia is caused by lesions interrupting the connection between the paramedian pontine reticular formation (PPRF) and the ipsilateral abducens nucleus. A patient with multiple myeloma who developed left posterior internuclear ophthalmoplegia was reported by Bogousslavsky et al [16]. At autopsy multiple small infarcts were found in the left PPRF extending towards the abducens nucleus, which was involved only in its inferior pole [16]. Posterior internuclear ophthalmoplegia is a clinically rare sign in cerebrovascular disease and may be of great value indicating a pontine lesion rather than other possible locations that could also associate with motor and/or sensory dysfunction. However, the mechanism that a unilateral pontine infarct could cause such a symmetric sign of bilateral posterior internuclear ophthalmoplegia should be further clarified.

Capsular warning syndrome had been proposed to be ideal to formally test various therapies because of the clinically well recognized features and the relatively high incidence of subsequent ischemic stroke [2]. However, this form of TIA seems to be resistant to classical therapies, including anticoagulation, aspirin and hemodilution [2, 6]. A combination of aspirin and clopidogrel of loading dose was reported to be effective in 2 cases of capsular warning syndrome [8], but further evidence from randomized controlled trials has not been found to date. Intravenous thrombosis may be a promising therapy for preventing the permanent deficit [17, 18]. Unfortunately, the nature of dramatical recovery may impede some patients arriving at hospital within therapeutic window, especially in developing countries. Our patient took for granted that the episode of neurological deficit might resolve spontaneously, such that she chose to wait and stay at home until 6 hours passed. Therefore, propagation that "TIA is an emergency requiring urgent interventions [19]" should take an important part in public heath education.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.