Millard-Gubler Syndrome

Etiology

Causes of Millard-Gubler syndrome (MGS) vary with age. In younger people, the leading causes are tumors, bacterial infections (eg, neurocysticercosis and tuberculosis),[3] viral infection (eg, rhombencephalitis), demyelinating disease (eg, multiple sclerosis), and other immune-mediated inflammatory disorders, such as neuro-Behçet's disease.[4]

In older patients, MGS is most frequently caused by vascular events, such as hemorrhagic or ischemic stroke in the posterior circulation; in MGS, the anatomic diagnosis is usually occlusion of the short circumferential branch of the basilar artery, a midline structure formed by the confluence of the vertebral arteries).[2] Compression of pontine arterial structures by prepontine subarachnoid hematoma or a space-occupying lesion can also give rise to MGS.[5][6][7]  Any other lesion of the basis pontis, such as a brainstem cavernous vascular malformation, may cause MGS, especially if it has bled recently.[8]

Epidemiology

Epidemiology varies according to the underlying cause of the MGS. Epidemiology related to brainstem stroke is available but somewhat limited. To date, nonvascular causes of MGS have primarily been described in case reports. 

Posterior circulation stroke, including ventral pontine syndromes such as MGS, is less common than events affecting the anterior circulation. Most recent epidemiological data are nearly a decade old now, but strokes in the posterior circulation reportedly account for up to 25% of cerebrovascular accidents.[9] According to one recent report, almost 20% of patients undergoing intravenous thrombolysis had presented with stroke arising in the posterior circulation. Compared to patients with anterior circulation strokes, those with posterior circulation strokes had significantly lower median scores on the National Institutes of Health Stroke Scale, fewer cardiovascular risk factors, much lower risk of post-thrombolytic bleeding, and similar functional outcomes; the paper reported a higher risk of death among those with posterior circulation stroke but did not demonstrate a statistically-significant difference between the two patient groups.[10]  More precisely, pontine strokes constitute 20% of all brainstem strokes and 7% of ischemic strokes.[11]

Pathophysiology

MGS is caused by a lesion in the ventral part of the pons (basis pontis) involving the infranuclear fascicular fibers of cranial nerve VII ipsilaterally and the corticospinal tract contralaterally. The result is ipsilateral peripheral facial paralysis and contralateral hemiplegia. CNVI is sometimes involved; however, as a medial structure, CNVI involvement was not described in the original case series of the eponymous syndrome reported by Millard and Gubler. Occlusion of the short circumferential branch of the basilar artery in the caudal portion produces ischemic MGS.

The corticospinal tract lies in the central region of the ventral pons. The nuclei of abducens (CNVI) and facial (CNVII) nerves lie in the pontine tegmentum near the pontomedullary junction, ventromedial to both the spinal nucleus and the spinal tract of the trigeminal nerve. The nerve fibers of CNVI (medially) and CNVII (laterally) pass through the pontine tegmentum and emerge anteriorly at the cerebellopontine angle. 

Two sensory tracts also pass through the anatomically dense pontine level of the brainstem. The spinothalamic tract, carrying sensory information about pain and temperature from the spine to the thalamus, lies in the anteromedial pontine tegmentum, medial to the descending tract, and the nucleus of the trigeminal (V) nerve.[8] The medial lemniscus, a medial structure lying posterior to the corticospinal tract, conveys sensory inputs about proprioception and vibration from the spine to the thalamus. Both sensory tracts are typically spared in this syndrome, thus explaining the usual absence of sensory symptoms; nonetheless, exceptions with positive sensory phenomena have been reported in the medical literature.[2]

History and Physical

A meticulous history, a careful and complete neurological examination, high clinical suspicion, and appropriate activation of magnetic resonance imaging are required for competent assessment of possible brainstem lesions, including stroke.[9] A comprehensive history of stroke risk factors and whether any previous similar episodes have occurred is a good starting place. Thorough medication reconciliation is mandatory. Finally, explicit details about the timing of symptom onset should be acquired against the possibility of intravenous thrombolysis or other interventional neuroradiology procedures (eg, embolectomy or thrombectomy). 

Focusing specifically on the brainstem, the patient should be assessed for any localizing symptoms: visual acuity and clarity, presence of diplopia, new visual impairment (eg, blind spots), trouble chewing, facial asymmetry, hearing changes, vertigo, incoordination or tremor, trouble swallowing, slurred speech, alterations in tongue mobility, tremor, and changes in gait or balance. The history of any headaches proximal to presentation should be explored. 

The diagnosis of Millard-Gubler syndrome (MGS) is suggested when clinical findings of ipsilateral lower motor neuron facial paresis (CN VII) along with contralateral hemiparesis of the upper and lower extremities are encountered. An abducens palsy may be present. 

Non-ischemic etiologies should also be considered when acquiring the history of the presenting illness. Basic inquiries should be made about systemic symptoms (eg, fever or malaise suggestive of infection), a pattern of relapsing and remitting symptoms that could suggest demyelinating disease, or slowly progressive changes that could suggest underlying neoplasm. 

Clinical Examination

Ipsilateral peripheral facial nerve involvement causes flaccid paralysis of the muscles of facial expression and loss of the corneal reflex.[12] The patient may be unable to close the eye on the affected side of the face. 

If present, a palsy of CN VI is heralded by complaints of diplopia and findings of restricted abduction ipsilateral to the lesion. Hemiparesis of the arms and legs contralateral to the lesion is present. A Babinski sign may be present on the affected side. Typically, but not invariably,[2] sensation in the face and the extremities is unaffected in MGS. 

Evaluation

MGS is most likely to present as a cerebrovascular accident, and acute stroke protocols should be activated until a stroke has been conclusively ruled out, following the adage that "time is brain." Intravenous thrombolysis or embolectomy should be considered for eligible patients, including elapsed time since symptom onset. 

Structural Neuroimaging

Structural neuroimaging should be obtained emergently, as is the case for all possible acute strokes.

A head CT is often available on a hyperacute basis in the Emergency Department. Such a scan is not likely to have sufficient sensitivity to identify the causal lesion. The scan performs 2 critical functions: (1) identify acute blood products if the MGS was caused by hemorrhage and (2) assist in the decision-making of risk-stratification for possible intravenous thrombolysis or other interventional neuroradiology procedures, ie, thrombectomy or embolectomy.

Brain MRI is more sensitive and specific than CT in virtually all brainstem lesions.[13] As with all acute strokes, brain MRI will demonstrate diffusion restriction on diffusion-weighted imaging (DWI), where the lesion will resemble bright white paint, accompanied by dark voids on the apparent diffusion coefficient (ADC) sequences, where the dark voids will appear corresponding precisely to the lesion seen on DWI.[14] The infarct will appear hypointense on T1 sequences and hyperintense on T2/FLAIR sequences, although these sequences are less sensitive than DWI and ADC in identifying acute stroke. Brainstem infarcts can be quite small compared to the devastation they can cause. In some cases, an infarct will evade diagnosis by neuroimaging unless thin cuts are requested. Indeed, cases of MGS have been reported in which initial imaging was negative.[15] 

Other associated lesions, such as tuberculomas and cysticercus granulomas, infections, or other mass lesions,[3] can frequently be identified using MRI imaging; in these cases, gadolinium contrast is often required. 

Angiography

Angiography of the posterior circulation (CT angiogram, MR angiogram, or digital subtraction angiography) is helpful in cases where the lesion is caused by stenosis or occlusion of the basilar artery.

Treatment / Management

Treatment mainly depends on the etiology of the disease. In some cases, patients presenting with multiple deficits require early conservative measures together with multidisciplinary rehabilitation.

In most cases, MGS will be found secondary to an acute cerebrovascular accident. For this reason, MGS should be managed according to clinical guidelines and clinical best practices for acute stroke.[16] Patients presenting with strokes in the posterior circulation can be treated with multiple different stroke therapies, including intravenous thrombolysis. In one recent study, patients who underwent thrombolysis for posterior circulation events had a much lower risk of post-thrombolytic bleeding compared to anterior circulation stroke patients; functional outcomes between the two groups were similar. The paper reported a higher risk of death among those with posterior circulation stroke but did not demonstrate a statistically significant difference between the two patient groups.[10] (A1)

Patients with MGS present with lower motor neuron facial palsy. In this condition, the entire side of the face, ipsilateral to the lesion, is affected. The affected eye will be partially or fully unable to close. Thus, it is always essential to protect the eye, including with eye drops (eg, artificial tears or other lubricants) during the day and eye ointment at night to prevent dryness. An eye patch will also prevent irritants, injuries, and dryness. The feasibility of lid loading with gold-weight, autogenous temporalis fascia, and platinum chains has been recently reported for the treatment of lagophthalmos after facial palsy.[17] 

Differential Diagnosis

Other pontine syndromes with crossed hemiparesis or hemianaesthesia are Foville, Raymond, Raymond–Cestan syndrome, Gasperini syndrome, and Brissaud-Sicard syndrome. In all of these syndromes, the lesion involves the brainstem above the decussation of the pyramidal tracts. Therefore, the clinical signs of the cranial nerve are ipsilateral to the lesion, and the long tract signs contralateral, resulting in the classical crossed brainstem syndrome.

Foville syndrome is caused by a unilateral lesion involving the medial pontine tegmentum in the caudal third of the pons and manifests as ipsilateral facial palsy, horizontal gaze palsy, and contralateral hemiparesis. Foville syndrome is caused by occlusion of the paramedian branch of the basilar artery if the cause is an acute stroke. In contrast, MGS is caused by occlusion of the short circumferential branch of the basilar artery, sparing the medial dorsal structures.

Raymond syndrome (ventral pontine syndrome) is caused by a lesion involving the rostral ventral medial pons. Raymond syndrome usually presents as 2 subtypes—classical and common. Classical Raymond syndrome manifests as ipsilateral abducens palsy, contralateral central facial paresis, and contralateral hemiparesis. The common subtype of Raymond syndrome presents as ipsilateral lateral gaze paresis and contralateral hemiparesis sparing the face.[18]

Raymond-Cestan syndrome is caused by a lesion involving the upper dorsal pons. This syndrome manifests as ipsilateral ataxia and coarse intention tremor, ipsilateral paralysis of muscles of mastication and sensory loss in the face, contralateral sensory loss in the body, and contralateral hemiparesis of the face and the body.[19]

Marie-Foix (lateral pontine syndrome) is caused by occlusion of the perforating branches of the basilar artery or the anterior inferior cerebellar artery. This syndrome causes ipsilateral ataxia, facial sensory impairment, facial weakness, hearing loss, vertigo/nystagmus, contralateral hemiparesis, and hemianesthesia of the arms and legs.

Gasperini syndrome is a rare syndrome caused by a lesion of the caudal pons tegmentum. This syndrome mostly presents as ipsilateral impairment of the cranial nerves V, VI, VII, VIII and contralateral sensory loss.

Brissaud-Sicard syndrome is a very rare pontine syndrome caused by damage of the anterolateral and inferior pons involving the corticospinal tract and CN VII nucleus and nerve root. Classically this syndrome presents as ipsilateral facial cramps and contralateral hemiparesis.

Prognosis

The prognosis mainly depends on the extent and etiology of the disease. A vertebrobasilar stroke may leave a significant neurologic deficit. Isolated pontine infarction may have a good prognosis if diagnosed and managed early.[11] Patients with small lesions usually have a better prognosis. 

Complications

In patients with atypical facial or orbital pain (including the burning "salt and pepper" sensation) after stroke, the stroke lesions are typically located in the pons.[20] Emotional dysmetria can be a sequela of pontine stroke, particularly one with concomitant cerebellar involvement.[21] Restless leg syndrome can occur subsequent to a pontine infarct. All patients with pontine infarcts should be screened and surveilled for symptoms of restless leg syndrome.[22] 

A recent case report described paroxysmal sympathetic hyperactivity occurring approximately 3 months after a pontine infarct.[23] In short, pontine infarcts can lead to diverse possible complications. A low threshold of suspicion should be brought to bear when a patient with a prior pontine stroke demonstrates unusual or unexpected symptoms.