Pupil-sparing complete third nerve palsy from cryptogenic midbrain stroke in an otherwise-healthy young adult with patent foramen ovale.

Although pupil-sparing in acute unilateral complete third nerve palsy is often a sign of ischemic nerve injury, it is not specific for injury outside of the midbrain. This report documents acute pupil-sparing complete third nerve palsy in an otherwise healthy young adult with patent foramen ovale and associated atrial dilatation who suffered cryptogenic focal midbrain stroke, presumably from a paradoxical embolism. The patent foramen ovale was surgically closed. Over the next several months neurological recovery was complete except for diplopia and relatively comitant hypotropia, which responded well to conventional strabismus surgery.

INTRODUCTION

Although pupil-sparing in acute unilateral complete third nerve palsy is often a sign of ischemic nerve injury, it is not specific for injury outside of the midbrain.1–3 This report documents acute pupil-sparing complete third nerve palsy in an otherwise-healthy young adult with patent foramen ovale and associated atrial dilatation who suffered cryptogenic focal midbrain stroke, presumably from a paradoxical embolism.

CASE REPORT

A 23-year-old otherwise healthy female with a 2-day history of diplopia and right ptosis after awakening had right complete pupil-sparing third nerve palsy (complete ptosis, moderate hypotropia, large exotropia and no supraduction/infraduction/adduction). Ocular examination was otherwise unremarkable in both eyes. Directed questioning and physical exam also revealed left dysmetria of the upper and lower extremity, left partial upper motor facial nerve weakness and impaired touch sensation on the right anterior 2/3 of the tongue. Neurology and rheumatology consultations confirmed these as the only significant physical examination findings.

The patient underwent extensive medical questioning and investigation. A review of symptoms and history included questioning regarding any recent illnesses, skin rashes, ulcers or sores, insect bites, pains, respiratory symptoms, gastrointestinal symptoms, urinary symptoms, neurological symptoms, trauma, medication history, prior hospitalizations, intravenous needle use, trips abroad and illnesses in family members. The patient had suffered from occasional oral ulcers and minor pain in the left knee over the last few years. Laboratory studies included complete blood count, erythrocyte sedimentation rate, platelet count, prothrombin time, activated prothrombin time, bleeding time, lipid profile, plasma homocystine, fasting blood sugar, anticardiolipin (antiphospholipid) antibody, lipoprotein A, plasma fibrinogen, factor V Leiden, antithrombin III, protein S, protein C, antinuclear antibody, purified protein derivative standard testing, Treponema pallidum hemagglutination assay, Venereal Disease Research Laboratory assay, sickle cell testing, prothrombin (factor II) analysis for gene mutation at G20210A and acetylcholine antibody receptor testing. These investigations were significant only for sickle cell trait. Radiological studies included chest X-ray, trans-esophageal echocardiography, brain magnetic resonance imaging (MRI), carotid Doppler ultrasound and cerebral angiography. MRI was significant for a focal T2-weighted hyperintense focal midbrain lesion adjacent to the aqueduct of Sylvius and consistent with infarction [Figure 1]. Echochardiography revealed aneurismal atrial septum with relatively large (0.7 cm) patent foramen ovale. Cardiology and neurology consultants agreed that the patent foramen ovale in this setting led to paradoxical embolism and cryptogenic midbrain stroke. The foramen ovale was thus closed surgically via catheterization.

Figure 1

In this T2-weighted magnetic resonance image with contrast, an almond-shaped hyperintense lesion can be seen in the right midbrain adjacent to the aqueduct of Sylvius. The eyes are in right gaze

Over the next few months, all signs and symptoms resolved except for a residual right hypotropia and constant vertical diplopia in all positions of gaze. Repeated MRI scanning showed resolution of the prior lesion with no other abnormalities. Two years after the event, ophthalmic examination was significant for a stable relatively comitant right hypotropia of 25 prism diopters that was slightly greater in upgaze with minimal right supraduction limitation. Forced generation and forced duction testing of the right eye were normal. Following informed consent, the patient underwent right superior rectus muscle resection of 6 mm and right inferior rectus muscle recession of 6 mm via a fornix technique. Postoperatively, the patient was diplopia-free with a slight chin-up position. There was a minimal right hypotropia in the forced primary position, which increased to 10-15 prism diopters in upgaze. She has remained stable and satisfied one year following strabismus surgery.

DISCUSSION

Generally, sparing of the pupil in acute unilateral complete third nerve palsy suggests ischemic extraaxial (nerve) injury.1 However, this “rule of the pupil” is less applicable to younger patients without any ischemic risk factors.12 Pupil-sparing in unilateral complete third nerve palsy can occur secondary to focal midbrain injuries that affect third nerve fascicles responsible for extraocular and levator muscles without affecting topographically separated fascicules that carry pupillary fibers.1 Directed questioning and physical exam often reveal accompanying neurological signs and symptoms that were not initially volunteered by an affected patient, though very rarely a complete midbrain pupil-sparing complete third nerve palsy can be truly isolated.3

Third nerve fascicules maintain their topographical arrangement through and around the red nucleus before exiting the midbrain adjacent to the cerebral peduncle as the third nerve.4 Several named syndromes describe the possible neurological associations of midbrain third nerve fascicular injury.5 Fascicular injury in the area of the red nucleus can cause third nerve palsy with contralateral hemitremor via damage to cerebral afferents to the thalamus (Benedikt syndrome). Fascicular injury in the area of the cerebral peduncle can cause third nerve palsy with contralateral hemiparesis including the lower face and tongue (Weber syndrome). Other named syndromes include Nothnagel syndrome (midbrain third nerve palsy with ipsilateral cerebellar ataxia from injury to the superior cerebellar peduncle) and Claude syndrome (midbrain third nerve palsy plus contralateral ataxia, asynergy and dysdiadochokinesis due to involvement of the red nucleus and superior cerebellar peduncle). In practice, neurological signs and symptoms that accompany midbrain third nerve injury do not usually cleanly compartmentalize into an eponymous syndrome.6

Midbrain third nerve injury is typically ischemic in origin and rarely embolic.6 Although patent foramen ovale is a common congenital defect that by itself is often of no consequence, it confers a risk for stroke via paradoxical embolism when associated with atrial dilatation.67 A patent foramen ovale can allow particles in the circulation that are normally filtered by small capillaries in the lungs to be transmitted directly from the right to the left atrium and thus gain access to the cerebral small vessel circulation, which is particularly susceptible to embolic phenomena.

In the current patient, all signs of midbrain stroke resolved with time except for a relatively comitant hypertropia with associated vertical diplopia. The deviation responded well to conventional strabismus surgery. Both pre- and postoperatively, there was a slight right supraduction defect. In the setting of grossly normal forced duction and forced generation testing, the preoperative incomitance suggested a minimal residual superior rectus weakness from the midbrain insult.