Answers

Short answers:

1 The figure shows a unilateral partial ptosis, miosis, and apparent enophthalmos of the patient’s right eye, consistent with Horner’s syndrome. The sudden onset of the symptoms, the vascular risk factors, and the findings of the examination make Wallenberg (lateral medullary) syndrome the most likely diagnosis.

2 Horner’s syndrome is caused by interruption of the sympathetic nervous system and it can originate anywhere along the pathway. Lesions can be central: (brainstem stroke, demyelination, syringomyelia, or spinal cord tumour), preganglionic (Pancoast’s tumour, cervical rib, mediastinal mass, thyroid mass, or surgery), or postganglionic (carotid artery aneurysm or carotid dissection).

3 A thorough history (checking for weight loss, neck pain, and vascular risk factors) and examination (for example, checking the neck for masses and scars, examining the supraclavicular area for evidence of consolidation, and performing a thorough neurological examination for associated signs) may help localise the lesion. Investigations depend on the likely underlying cause but include magnetic resonance imaging (MRI) of the brain or spine and computed tomography of the chest.

Long answer 1: Likely diagnosis
The figure shows a unilateral partial ptosis, miosis and apparent enophthalmos. Causes of unilateral ptosis include lesions of the third cranial nerve, myasthenia gravis, congenital or idiopathic ptosis, and Horner’s syndrome. Causes of miosis include Horner’s syndrome, Argyll Robertson pupils (bilateral), anisocoria (20% of normal population), and senile miosis.

The combination of a partial ptosis and miosis makes Horner’s syndrome the most likely cause. Horner’s syndrome is caused by interruption of the sympathetic chain and is characterised by miosis, partial ptosis, and anhydrosis. Horner’s syndrome in itself is not a diagnosis, and underlying causes need to be investigated. In this case the sudden onset of the history, coupled with the patient’s vascular risk factors and the examination findings, are consistent with a diagnosis of lateral medullary syndrome.

Miosis results from paralysis of the radial (dilator) smooth muscle of the iris, which is under sympathetic control.¹ Levator palpebrae, which is supplied by parasympathetic fibres of the third cranial nerve, are mostly responsible for upper eyelid retraction, although it is partially helped by Müller’s muscle, which has sympathetic innervation. Because only Müller’s muscle is affected in Horner’s syndrome, ptosis is mild, usually 1-2 mm.² The apparent enophthalmos results from the weakness of Müller’s muscle causing the lower eyelid to elevate, which together with the upper eyelid ptosis causes narrowing of the palpebral fissure. This creates an illusion that the eye is displaced backwards in the orbit.

Anhydrosis is a feature of lesions that occur before the superior cervical ganglion. Because the sympathetic fibres responsible for facial sweating and vasodilation branch off from the rest of the oculosympathetic pathway at the superior cervical ganglion, anhydrosis is a feature of preganglionic lesions.³

Lateral medullary syndrome
Lateral medullary syndrome, also known as Wallenberg’s syndrome, was first described in 1895. It is the most common brainstem stroke and occurs in the vertebral or posterior inferior cerebellar artery of the brain stem.⁴ This syndrome seems to be the most common of the posterior circulation strokes, which account for 10-15% of all strokes.^{5 6}

Lateral medullary syndrome and other brainstem syndromes have a mixed presentation and are difficult to diagnose.⁷ One study found that the most common symptoms are ataxia (70%), numbness of the ipsilateral face or of the contralateral body (64%), vertigo (51%), and dysphagia (51%). Horner’s syndrome was found in 91% of patients. Other features include ocular symptoms (diplopia or blurred vision), contralateral hypalgesia, nystagmus (61%), and facial weakness (42%).

Uncontrollable hiccups may also occur, and some people lose their sense of taste on one side of their tongue.⁸ Pain or unpleasant feelings in the face are sometimes the earliest and most prominent feature of the syndrome and are related to lesions of the spinal nucleus of V and the descending spinal tract of V.⁹ The signs result from damage to the structures in the lateral medulla, which include the sympathetic pathway, trigeminal nerve, vestibular nuclei, inferior cerebellar peduncle, and ninth and tenth cranial nerves. A triad of Horner’s syndrome, ipsilateral ataxia, and contralateral hypalgesia helps to identify patients with lateral medullary syndrome.⁸

Cardiac embolism causes 5% of these strokes, while dissection causes 15%.¹⁰ MRI with diffusion weighted imaging is the most sensitive test available to detect acute infarcts.¹¹ A study of 33 patients with lateral medullary syndrome investigated with MRI concluded that this is the most sensitive test available for detecting acute infarcts.¹² It allows localisation of anatomical-clinical correlations in patients but does not provide complete visualisation of the brain stem, owing to artefacts related to the skull.¹²

Long answer 2: Differential diagnosis of Horner’s syndrome
Horner’s syndrome results from the interruption of the sympathetic pathway anywhere from the sympathetic nucleus along its course through the brainstem and spinal cord to the level of C8/T2 to the sympathetic chain, stellate ganglion, and carotid sympathetic plexus. In one large case series, 40% of cases of Horner’s syndrome had an unknown diagnosis.¹³ In the remaining 270 patients, 13% of cases were related to a first order (central) lesion, 44% to a second order (preganglionic) lesion, and 43% to a third order (postganglionic) lesion.

Knowing the anatomy of the sympathetic cord is crucial to understanding Horner’s syndrome and possible causes (box). The sympathetic cord consists of a three neurone arc. Interruption at any location along this pathway (preganglionic or postganglionic) will induce an ipsilateral Horner’s syndrome.

First neurone (central)
The sympathetic pathway originates in the dorsolateral hypothalamus and travels through the reticular formation of the brainstem; it terminates in the grey matter of the spinal cord at C8/T1. Central Horner’s syndrome is usually caused by vascular disease—most commonly a lateral medullary infarction, which produces Horner’s syndrome as part of the Wallenberg syndrome.

Strokes, tumours, and demyelinating lesions affecting the sympathetic tracts in the hypothalamus, midbrain, pons, medulla, or cervicothoracic spinal cord can also cause central Horner’s syndrome, as can syringomyelia and cervical cord trauma when the intermediolateral columns are affected. These central lesions are usually associated with other neurological signs and symptoms, such as weakness, sensory deficit, homonymous hemianopia, diplopia, or ataxia. Similarly, myelopathic features (unilateral or bilateral long tract signs and sensory level signs) indicate a lesion in the cervical or thoracic spine.¹⁴

Second neurone (preganglionic)
The sympathetic pathway travels from C8/T1, through the brachial plexus, and over the lung apex. It then ascends to the superior cervical ganglion, located near the angle of the mandible and the bifurcation of the common carotid artery. Most preganglionic lesions are caused by trauma or malignancy. Second order Horner’s syndromes can occur with trauma or surgery to the spinal cord, thoracic outlet, or lung apex. Cases related to malignancy, which can be occult at the time of presentation with Horner’s syndrome,¹⁵ are often accompanied by ipsilateral axillary.¹¹ Lumbar epidural anaesthesia, usually for obstetric procedures, can also cause Horner’s syndrome by disrupting the preganglionic neurone as it exits the spinal cord.¹⁶

Third neurone (postganglionic)
The third order neurone then ascends within the adventitia of the internal carotid artery, through the cavernous sinus, where it is close to the sixth cranial nerve. The oculosympathetic pathway then joins the ophthalmic division of the fifth cranial nerve (trigeminal nerve). In the orbit and the eye, the oculosympathetic fibres innervate the iris dilator muscle as well as Müller’s muscle, a small smooth muscle in the eyelids responsible for a minor part of the upper lid elevation and lower lid retraction.

Third order Horner’s syndromes often indicate lesions of the internal carotid artery such as an arterial dissection, thrombosis, or cavernous sinus aneurysm. Carotid endarterectomy and carotid artery stenting can also produce Horner’s syndrome.¹⁷

Until shown to be otherwise, the cause of acute Horner’s syndrome with neck or facial pain is presumed to be carotid dissection.¹⁸ Between 40% and 60% of patients with internal carotid artery dissections present with isolated painful third order Horner’s syndrome.^{19 20} Patients often have a history of neck trauma, but this can be subtle, and some carotid dissections are spontaneous. Patients with acute carotid dissection are at high risk for cerebral infarction, which usually occurs within the first few weeks, often days, of onset of Horner’s syndrome.^{21 22}

Other causes of postganglionic Horner’s syndrome include neck masses, otitis media, and pathology of the cavernous sinus. In this last case, other oculomotor deficits, particularly palsy of the sixth nerve, are common.²³

Horner’s syndrome is common in cluster headache. It occurs with unilateral eye or temple pain and lacrimation, and it usually lasts no more than one or two hours.^{24 25}

Horner’s syndrome can be congenital; these patients have iris heterochromia, with the iris remaining a blue-grey colour on the affected side. Iris pigmentation is under sympathetic control during development, which is completed by age 2 years.

Long answer 3: Localisation of the lesion
Once the diagnosis of Horner’s syndrome has been confirmed clinically, the lesion should be localised and the aetiology sought. Important examinations include:

Looking for cranial nerve abnormalities (seen in brainstem lesions) and ipsilateral ataxia, which are seen if the cerebellum or its connections are affected

Examining the neck for scars or distended neck veins to identify superior vena cava obstruction. Palpating for masses and tenderness, feeling the pulse, and auscultating for carotid bruits. Percussing and auscultating the supraclavicular area for signs of consolidation

Looking at the ipsilateral arm for wasting or weakness of the small muscle of the hand, which suggests that the lower plexus is affected. Looking for confirmatory signs of sensory loss and hyporeflexia or hyper-reflexia and also for signs of clubbing.

Important features from the history can also help to localise a lesion. Most patients with a first order lesion have other neurological signs or symptoms that help to localise the lesion to the hypothalamus, brainstem, or spinal cord. Patients with second order Horner’s syndrome often have a history of surgery of the chest, great vessels, neck, or thyroid. Neck pain, local neck trauma, or both suggest internal carotid artery dissection.²⁰ A history of cigarette smoking and arm pain suggest a Pancoast’s tumour.⁸

The level of the lesion can be determined by the distribution of the loss of sweating, with a central lesion resulting in the loss of sweating over the entire half of the head, arm, and upper trunk, whereas a preganglionic lesion reduces sweating on the face. Postganglionic lesions have no affect on sweating.²⁶

Investigations to help localise the lesion
Textbooks mention pharmacological testing to identify the level of the lesion, but these tests are rarely used in clinical practice. Topically applied 10% cocaine dilates the normally innervated pupil by inhibiting the reuptake of norepinephrine at the nerve ending. The pupils of patients with Horner’s syndrome dilate poorly compared with normal pupils because of the absence of norepinephrine at the nerve endings.²⁷ The lesion can then be localised to the preganglionic or postganglionic neurones by using topical hydroxyamphetamine. This stimulates the release of norepinephrine from the postganglionic neurone. But in patients with damage to the third order (postganglionic) neurone, the pupil will not dilate.²⁸

Cases of Horner’s syndrome must be investigated thoroughly because the cause may be life threatening; however, the underlying aetiology is often never found. Important features from the patient’s history and examination will dictate which part of the body should be imaged. If cerebrovascular disease is suspected, urgent imaging is required—usually MRI of the brain unless this is not practical. Horner’s syndrome in association with acute stroke is usually a feature of dissection of the internal carotid artery or lateral medullary syndrome.

Computerised tomography of the brain usually cannot identify the lesion in the brain stem. In one study of 33 patients with lateral medullary syndrome, the computed tomography scan was abnormal in only three patients, whereas an MRI scan of the brain was abnormal in 20 of the 22 patients who underwent this test.⁸ Therefore a brain MRI is indicated in patients with brainstem symptoms or signs (such as lateralised weakness or sensory deficit, diplopia, and ataxia). Acute Horner’s syndrome with pain of the neck or face should prompt an evaluation for carotid artery dissection.²⁰ An axial MRI of the neck and ideally magnetic resonance angiography will detect most internal carotid artery dissections. However, conventional angiography remains the gold standard.²⁰

Neuroimaging (usually MRI) should focus on the cavernous sinus in Horner’s syndrome with ophthalmoparesis, particularly if the sixth cranial nerve is affected. Myelopathic features (ipsilateral or bilateral long track signs) or a sensory level defect typically accompany cervicothoracic lesions.⁷ When these features are present, an MRI of the cervical spinal cord is needed. Patients with preganglionic Horner’s syndrome without neurological symptoms should have an MRI or computed tomography scan of the chest to evaluate the lung apex and paravertebral area.²⁹

Cite this as: BMJ 2009;338:a3111