Isolated ipsilateral ptosis associated with ventral midbrain infarction: a case report and literature review

Abstract

Documented cases of ipsilateral ptosis caused by midbrain infarction remain rare. Herein, we present a patient with isolated ipsilateral ptosis that was initially considered to be a consequence of myasthenia gravis but was subsequently attributed to ventral midbrain infarction. We also discuss the possible underlying mechanisms; ipsilateral ptosis in our patient was attributed to selective damage of the levator palpebral muscle branch of the oculomotor nerve. The patient was started on aspirin (200 mg once daily) and atorvastatin (40 mg once daily). Improvement in ptosis occurred from day 5 of admission, and the patient was subsequently discharged. Ptosis disappeared 1 month after onset. This report describes an extremely rare case of ventral midbrain infarction presenting with isolated ipsilateral ptosis. Careful examination, including magnetic resonance imaging, is essential in such patients, especially in those with multiple cerebrovascular risk factors.

Introduction

Pure midbrain infarctions are rare, with prevalence rates ranging between 0.6% and 2.3%. ¹ In addition, reports of midbrain infarction-induced isolated unilateral ptosis without extraocular or intraocular muscle paresis remain extremely scarce. Herein, we report a case of midbrain infarction that presented with isolated ipsilateral ptosis.

Case report

A woman in her early 60s without hypertension or diabetes developed fluctuating right ptosis. The patient presented with isolated unilateral ptosis that worsened in the evening, along with fatigue. She visited our hospital on day 5 after onset, and a neurological examination revealed isolated right ptosis. Pupil sizes were equal, and eye movements and the lower lids of both eyes were unremarkable. The rest of the neurological examination was normal. The fatigue test, ice pack test (IPT) (Figure 1), and neostigmine test were all positive. The patient was tentatively diagnosed with myasthenia gravis. However, magnetic resonance imaging (MRI) revealed an acute infarction of the right ventral midbrain (Figure 2(a)). We did not suspect a posterior communicating artery aneurysm as a cause of ptosis because the patient presented with painless ptosis without extraocular muscle weakness or pupillary involvement. However, computerized tomography angiography of the brain vessels was performed as part of the stroke work-up and to rule out the remote possibility of a posterior communicating artery aneurysm. The outcome was normal (Figure 2(b)).

Figure 1.

Ice pack test in a patient with neurogenic ptosis on day 2 after admission. (a) Unilateral right ptosis and (b) improvement in ptosis.

Figure 2.

Imaging from the patient. (a) Acute infarct of the right ventral midbrain (white arrow) in a diffusion-weighted imaging sequence and (b) computerized tomography angiography image of brain vessels showing no aneurysm of the posterior communicating artery.

An experienced neurologist further examined the patient and agreed with the majority of our findings, but noted a subtle element of fatigability. Anti-acetylcholine receptor and muscle-specific tyrosine kinase antibodies were therefore tested, and were negative. Electromyography and repetitive electrical stimulation detected no obvious abnormalities. The etiological examination of cerebral infarction included cerebrovascular computerized tomography angiography, dynamic electrocardiogram, echocardiography, and right heart contrast echocardiography; these did not detect large vessel stenosis, atrial fibrillation, heart valve disease, or atrial septal defects. Based on her presentation, the patient was started on aspirin (200 mg once daily) and atorvastatin (40 mg once daily). The myasthenia gravis antibody test was negative on day 5 of admission. Improvement in ptosis was observed from day 5 of admission; the patient was subsequently discharged. Ptosis disappeared 1 month after onset. Using the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification system, the patient was finally diagnosed with small vessel occlusion infarction in the ventral midbrain.

The reporting of this study conforms to CARE guidelines (for CAse REports). ² We obtained written informed consent from the patient for her treatment and the publication of this case report. Ethics approval was not required because this was a report of a single patient.

Discussion

Fluctuating ptosis is considered a characteristic manifestation of myasthenia gravis, whereas isolated ptosis caused by cerebral infarction is extremely rare. We therefore performed IPT, a fatigue test, and a neostigmine test on our patient, all of which yielded positive results. Consequently, a preliminary diagnosis of myasthenia gravis was established.

Importantly, isolated unilateral ptosis needs to be differentiated from other conditions, including mononeuritis, Horner’s syndrome, and other muscle diseases such as Lambert–Eaton syndrome. In Horner’s syndrome, which results from sympathetic nerve dysfunction, there is a characteristic triad of ptosis, miosis, and anhidrosis. Ptosis associated with Horner’s syndrome is mild; it is caused by damage to Müller’s muscle (a small muscle that facilitates eyelid opening), causing inverse ptosis of the lower eyelid. Lambert–Eaton syndrome, also known as myasthenic syndrome, is characterized by the abnormal release of antibodies into presynaptic acetylcholine receptors, which results in clinical symptoms similar to those of myasthenia gravis. Lambert–Eaton syndrome frequently presents with proximal muscle weakness predominantly affecting the lower limbs; isolated involvement of the extraocular muscles is rare. In our patient, considering her advanced age, acute onset, and the presence of an acute cerebral infarction lesion in the lateral midbrain on MRI, antiplatelet and statin therapies were initiated. At the 1-month clinical follow-up, the ptosis symptoms had disappeared. The final diagnosis was midbrain infarction. Seronegative myasthenia gravis was not ruled out in the present case. The main supporting points for a diagnosis of myasthenia gravis included fluctuating upper eyelid ptosis, positive fatigue tests, and IPT; however, negative antibodies against myasthenia gravis and a newly diagnosed cerebral infarction on pontine MRI did not support the diagnosis. Nonetheless, the patient was not treated for myasthenia gravis, and the upper eyelid drooping symptoms completely disappeared. The patient therefore ultimately received a clinical diagnosis of cerebral infarction.

To the best of our knowledge, this is the first case report of isolated ipsilateral ptosis associated with ventral midbrain infarction. Chen et al. reported a 38-year-old man who presented with unilateral ptosis and mydriasis owing to a ventral midbrain infarction. ³ In addition, Cheong et al. reported an 88-year-old woman with isolated complete unilateral ptosis and intact extraocular eye movements that were caused by an acute infarct of the red nucleus. ⁴ Kumawat et al. reported a 60-year-old woman who complained of sudden-onset vertigo followed by drooping of the left eyelid as the result of paramedian midbrain infarction. ⁵ These series of isolated ptosis cases provide information regarding the innervation of the levator muscle of the eyelid, and indicate its midbrain distribution.

The distribution of the oculomotor nucleus within the midbrain is illustrated in Figure 3. ⁶ The superior division of the third nerve innervates the levator palpebrae superioris and superior rectus muscles, whereas the inferior division innervates the medial and inferior rectus muscles, inferior oblique muscle, and pupillary constrictor. Isolated involvement of the oculomotor nerve bundle that only innervates the levator palpebrae superioris is uncommon, likely because these nuclei and nerve bundles are closely arranged within a small area. Partial decussation of the superior rectus subnucleus within the oculomotor nucleus leads to contralateral innervation of the levator palpebrae superioris. Nuclear ptosis is therefore bilateral. When oculomotor nerve paralysis occurs at the level of the cavernous sinus, it is typically accompanied by paralysis of the fourth and sixth nerves. The oculomotor nerve bundle originates from the oculomotor nucleus and extends ventrally and laterally, passing through the red nucleus before innervating the levator palpebrae superioris and superior rectus muscles. In the current case, we believe that isolated ipsilateral ptosis occurred as the result of oculomotor nerve bundle damage within the midbrain. Although the patient did not complain of visual impairments, we conducted visual and field-of-view examinations, which elicited normal results. Despite the tightly arranged neural fiber bundles, the nerve bundle governing the levator muscle of the eyelid may be situated relatively ventrally. We therefore hypothesize that, in the current patient, the isolated unilateral ptosis on the same side as the infarction may be attributed to damage of the oculomotor nerve bundle supplying the levator muscle of the eyelid. In addition, the possibility of cerebral ptosis arising from a cortical stroke without any pathological impact on the brainstem, oculomotor nerve, or oculosympathetic fibers was considered. Nonetheless, this scenario seems improbable given that the presentation included complete bilateral ptosis accompanied by hemiparesis.

Figure 3.

Expanded view of the topographical arrangement of fibers within the oculomotor nerve in the midbrain.

In the current case, the positive IPT result was another intriguing observation. The IPT is a rapid, simple, non-invasive, safe, and cost-effective diagnostic method for suspected myasthenia gravis. For ocular myasthenia gravis, the diagnostic accuracy of the IPT is similar to that of single-fiber electromyography, with high sensitivity and specificity for diagnosing myasthenic ptosis. However, the reported sensitivity and specificity of the IPT vary across different studies. For example, Natarajan et al. ⁷ reported a sensitivity of 96% and a specificity of 100%, whereas Giannacoccaro and Liguori ⁸ reported a sensitivity of 86% and a specificity of just 79%.

Typically, the IPT is used primarily in patients exhibiting ptosis possibly linked to ocular myasthenia gravis. This is because a thorough neurological examination is typically adequate to differentiate between neuromuscular conditions and peripheral nerve or muscle disorders that can lead to ptosis. Interestingly, however, some studies have indicated that the IPT can yield positive results in cases of neurogenic ptosis. Nevertheless, the precise reason for notable improvements in neurogenic ptosis following the IPT remains uncertain. A mild enhancement in ptosis associated with oculomotor nerve palsy has also been observed after IPT, albeit resulting in a considerably larger marginal reflex distance than in patients with myasthenia gravis. Exposure to cold may augment sympathetic activity and prompt contraction of Müller’s muscle, thereby contributing to a 2-mm elevation of the eyelid. ⁹ Moreover, even in healthy individuals, cold exposure reduces acetylcholinesterase activity at the neuromuscular junction, thus leading to increased acetylcholine concentrations within the junction, which subsequently stimulates muscle contraction.

Although we cannot definitively assert that this explanation completely accounts for the positive IPT result in our patient, the favorable response of the levator muscle of the eyelid may suggest that the functionality of her third cranial nerve was not entirely compromised.

Conclusions

We have reported a very rare case of ventral midbrain infarction presenting as isolated ipsilateral ptosis, which emphasizes the course of the oculomotor nerve bundle within the midbrain. In patients with cerebrovascular risk factors, a thorough MRI to rule out acute cerebrovascular disease is of paramount importance despite the presence of fluctuating ptosis, susceptibility to fatigue, or even a positive IPT. On the basis of our findings in the present patient, we note the following important points: 1) it is easier to locate an underlying lesion if you are aware of the fascicular organization of the oculomotor nerve; 2) patients with pupil-sparing unilateral ptosis and intact extraocular movements should be evaluated for stroke detection; and 3) the IPT can yield positive results in cases of neurogenic ptosis.