25th June 2023

Cranial nerves associated with vision – II, III, IV, VI

CNII – Optic Nerve 

The optic nerve arises from the retina of each eye, passing through the optic canals and converging at the optic chiasm before continuing to the lateral geniculate body in the thalamus and into the cortex as optic radiations. There is bilateral innervation in that one half of each visual field is projected to the contralateral visual cortex, with the medial fibres of each optic nerve decussating at the optic chiasm to then travel to the contralateral cerebral hemisphere.

Relative Afferent Pupillary Defect – RAPD

Also known as a Marcus Gunn Pupil, a relative afferent pupillary defect (RAPD) is a condition where there is an asymmetric response to the same light stimuli as a result of unilateral damage to the optic afferent pathway involving the retina and optic nerve. This can be elicited by the swinging flashlight test (Marcus Gunn Test), where a pen torch is shone at one eye before moving to the other and alternating between the two to observe the pupils’ response. In RAPD, the affected optic afferent nerve would be less responsive to the light stimuli than the unaffected side and lead to a competition between the direct pupillary light reflex of that eye and the consensual pupillary light reflex of the contralateral eye. In the affected eye, the direct pupillary light reflex would be impaired by pathology, causing a paradoxical pupillary dilation in response to light stimuli.

Pathology that can cause RAPD can be divided into :

• Retinal causes
  • Vascular causes –Ischaemic retinal disease and ocular disease
  • Mechanical – Retinal detachment
  • Infection
  • Tumour

• Optic nerve causes
  • Demyelination – Multiple sclerosis, neuromyelitis optica spectrum disorder
  • Vascular –Ischaemia to the optic nerve, giant cell arteritis
  • Inflammatory – Sarcoidosis, SLE
  • Hereditary – Leber’s hereditary optic neuropathy
  • Pressure – Glaucoma, Tumours

Optic Neuritis

Optic neuritis is an umbrella term for inflammation of the optic nerve, which can have many different aetiologies. A hallmark of optic neuritis is the presence of pain. It should be distinguished from optic neuropathy, which is a general term for any damage to the optic nerves. Optic neuritis is characterised by a rapid onset, painful ophthalmic condition associated with visual symptoms of dyschromatopsia, visual field defect or pupillary reflex abnormality.

There are several different conditions that can cause an optic neuritis:

• Demyelination:
  • Multiple sclerosis
  • Neuromyelitis optica spectrum disorders, which are a large spectrum of conditions exhibiting optic neuritis with myelitis, including:
    • Anti-Aquaporin-4 IgG (Anti-AQP4) positive neuromyelitis optica
    • Anti-AQP4 negative, Anti Myelin Oligodendrocyte Glycoprotein (anti-MOG) positive neuromyelitis optica.
    • Anti-Glial Fibrillary Acidic protein positive neuromyelitis

• Autoimmune:
  • Systemic Lupus Erythematosus
  • Paraneoplastic
  • Sarcoidosis
  • Vasculitis, e.g. granulomatosis with polyangiitis

• Infective causes – Syphilis, Lyme disease

Treatment is with high dose IV methylprednisolone tapering onto oral prednisolone. As with all treatment with steroids, a PPI and bone protection should always be considered, and glycaemic control in patients with impaired glucose metabolism, e.g. diabetes, should also be considered. With antibody mediated optic neuritis, there is a role for plasma exchange (PLEX) or intravenous immunoglobulin (IVIg). Neuro-ophthalmology follow-up is essential.

Optic Neuropathy

Optic neuropathy is a very general term for any damage to the optic nerves, which also encompasses optic neuritis. The causes of optic neuropathy can broadly be divided into:

• Rapid onset – secondary to ischaemia, trauma, and autoimmune or inflammatory conditions.
• Gradual onset – secondary to toxins, e.g. lead toxicity-induced demyelination, drugs, e.g. ethambutol, compressive causes, e.g. glaucoma, metabolic, or mitochondrial causes.

Idiopathic Intracranial Hypertension – commonly affects the optic nerves

Idiopathic intracranial hypertension (IIH) commonly affects the optic nerves. IIH manifests as raised intracranial pressure without any obvious structural cause observed on imaging, with common associated clinical signs of vision loss and headache. Papilloedema can be found on fundoscopy.

Risk factors:

• Raised BMI
• Oral contraceptive pill use
• Tetracycline antibiotics
• Female

Treatment:

• Weight loss
• Acetazolamide
• Therapeutic lumbar puncture

Space occupying lesions can cause similar symptoms and should always be excluded before a diagnosis of IIH is made.

Leber’s hereditary optic neuropathy

Mitochondrially inherited defects in NADH-ubiquinone oxidoreductase chains interfere with glutamate transport and protection from reactive oxygen species, resulting in the loss of retinal ganglion cells and demyelination in the optic nerves, chiasm, and tracts. This manifests as acute progressive vision loss (both field and acuity) progressing from unilateral to bilateral, in young adults of 20 to 24 years old, with a preponderance for males. A key hallmark here is that it is painless and affects one eye before the other. It can be associated with extraocular neurological symptoms of dystonia and tremor and cardiac conduction defects, which if present, is termed LHON Plus.

Wolfram syndrome

Wolfram syndrome is a childhood onset autosomal-recessive genetic disorder that manifests as a combination of both diabetes insipidus and diabetes mellitus, with optic atrophy and deafness (the acronyms of which result in it being also known as DIDMOAD). It is caused by a mutation in the WFS-1 or WFS-2 gene which are responsible for the production of a protein called wolframin thought to regulate calcium metabolism. Not all the components of the syndrome may occur at once, but most sufferers of Wolfram syndrome will develop optic atrophy with diabetes mellitus.

CNIII – Oculomotor nerve

The oculomotor nerve extends from the ventral midbrain through the superior oblique fissure to travel to the extrinsic eye muscles. It has two nuclei in the midbrain, the motor nucleus which controls the extraocular muscles, and the parasympathetic nucleus, also known as the Edinger-Westphal nucleus, which controls the light reflex and accommodation reflex.

An oculomotor palsy consists of the following:

• Ptosis – paralysis of levator palpebrae superioris
• Lateral strabismus – unopposed CN 6 action
• Loss of pupillary light reflex
• Loss of accommodation

Care should be taken to distinguish the ptosis of an isolated CN 3 palsy from other causes of ptosis, including Horner’s Syndrome. The main differentiators are whether the ptosis is complete or partial, bilateral or unilateral, pupil size, along with other suggestive features.

In the presence of a painful ophthalmoplegia, always be aware of intracavernous carotid artery dissections, particularly if the history involves trauma to the neck or head, or any Valsalva manoeuvre action, e.g. weightlifting, straining against a load. In a painful isolated CN 3 palsy, a posterior communicating artery dissection or aneurysm should always be excluded.

Other causes of a painful ophthalmoplegia include vascular causes, e.g. cerebral venous sinus thrombosis, neoplastic causes, infective causes, e.g. aspergillosis, inflammatory causes, e.g. sarcoidosis, and Tolosa Hunt syndrome, which is an idiopathic inflammatory diagnosis of exclusion that manifests as periorbital headache, ipsilateral painful ophthalmoplegia, and often pain in the distribution of the trigeminal nerve.

CN IV – Trochlear nerve

The trochlear nerve is a motor nerve that innervates the superior oblique muscle of the eye, allowing the eye to look down and outwards.

Palsy of the trochlear nerve primarily causes diplopia when looking downwards, e.g. when going downstairs. The trochlear nerve decussates in the brainstem after originating from its nuclei in the midbrain. A unilateral lesion to the trochlear nucleus affects the contralateral nerve and superior oblique muscle, whereas a lesion to the trochlear nerve itself results in ipsilateral signs. If there is evidence of involvement of other ocular motor nerves, a lesion in the cavernous sinus or midbrain is likely implicated as these nerves are in close proximity in this space and share blood supply.

CN VI – Abducens nerve

The abducens nerve is a motor nerve that innervates the lateral rectus muscle of the eye. Due to its length and course, it is most vulnerable to damage from raised intracranial pressure, such as idiopathic intracranial hypertension and is prone to producing a false localising sign. Palsy of the abducens nerve causes loss of function of the lateral rectus resulting in the inability to look laterally. This nerve is associated with CN 3 and 4 at points of its course and can be associated with painful ophthalmoplegia.

Internuclear Ophthalmoplegia

Internuclear ophthalmoplegia (INO) is the failure of adduction of the ipsilateral eye towards the midline and nystagmus in the contralateral eye as it looks away from the midline.

Schematic of right internuclear ophthalmoplegia.

Image Source: Wikimedia Commons (2006). Internuclear ophthalmoplegia, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Internuclear_ophthalmoplegia.jpg (Accessed on: 11 January 2023).

INO results from a lesion in the median longitudinal fasciculus (MLF) which coordinates the oculomotor nerve of the ipsilateral eye with the contralateral trochlear and abducens nerves via the paramedian pontine reticular formation (PPRF). The PPRF is a supranuclear centre close to the ipsilateral abducens nucleus which controls horizontal conjugate movements.

An INO manifests as an inability to adduct the eye ipsilateral to the lesion of the MLF. A right INO is a disorder of the right MLF leading to an inability to adduct the right eye. Midbrain and pontine demyelinating lesions can cause a unilateral or bilateral INO.

Bilateral INO is very characteristic of multiple sclerosis and causes an inability to adduct either eye with resultant bilateral abduction nystagmus. If the ipsilateral PPRF or abducens nuclei are affected in addition to the ipsilateral MLF, this can cause a ‘One and a Half’ spectrum of syndromes, where an ipsilateral conjugate horizontal gaze palsy with an ipsilateral INO results in the ipsilateral eye being incapable of horizontal movement with varying degrees of response to horizontal vestibular reflexes depending on where the lesion is, while the contralateral eye also experiences the conjugate horizontal gaze palsy resulting inability to adduct the contralateral eye.

Vertical gaze palsy

A vertical gaze palsy, also known as a supranuclear gaze palsy, is a bilateral inability to make voluntary eye movements in the vertical plane, i.e. upward or downward gaze movements. Involuntary vertical eye movements would still be preserved, e.g. in reflex conjugate eye movements such as the vestibulo-ocular reflex, which can be demonstrated when an examiner passively moves the patient’s head up and down, leading to correction of the vertical paresis. On moving the head up while the patient’s gaze is fixed on a point, the eyes would reflexively move down as the head is moved up, a movement they would not be able to voluntarily do in a vertical gaze palsy.

This is a classic symptom in progressive supranuclear palsy and corticobasal degeneration but can also result from a vascular or infective insult to the structures involved – the interstitial nucleus of Cajal, rostral interstitial nucleus of medial longitudinal fasciculus, and cranial nerve 3 and 4 nuclei, and from mechanical causes like hydrocephalus or tumour. A caveat to this is if there is a bilateral infranuclear lesion, e.g. a neuromuscular junction or muscle lesion such as in myasthenia gravis, which would result in a gaze palsy that cannot be overcome by conjugate gaze testing.

Parinaud Syndrome

Parinaud syndrome, also known as dorsal midbrain syndrome, is a combination of a vertical gaze palsy with an Argyll-Robertson pupil with bilateral lid retraction (Collier sign). An Argyll-Robertson pupil is the manifestation of bilaterally small pupils that are not reactive to light but have a preserved accommodation reflex – i.e. are able to constrict when looking at near objects but not to light.

This sign is suggestive of damage to the midbrain involving damage of the pretectal nucleus or Edinger-Westphal nuclei, which results in loss of parasympathetic innervation to the iris sphincter muscles and an inability to constrict the pupil in response to light and is associated with diabetic neuropathy and neurosyphilis. As a component of Parinaud syndrome, dorsal midbrain lesions can result from a variety of aetiologies, including:

• vascular lesions, e.g. infarction, haemorrhage, arteriovenous malformations
• mechanical, e.g. tumours, hydrocephalus, trauma
• demyelinating and inflammatory conditions, e.g. neurosyphilis, multiple sclerosis and infection

The most common causes are pineal region tumours, and brainstem haemorrhage or infarction.

Kearns-Sayre syndrome

Kearns-Sayre syndrome, also known as oculocraniosomatic neuromuscular disorder with ragged red fibres, is a rare syndrome caused by mitochondrial DNA deletions resulting in defective oxidative phosphorylation and subsequent mitochondrial myopathy.

It manifests as a tetrad of:

• Chronic progressive external ophthalmoplegia – weakness and paralysis of eye muscles
• Pigmentary retinopathy leading to vision loss and night blindness
• Cardiomyopathy and cardiac conduction defects
• Cerebral folate deficiency leading to ataxia, sensorineural hearing loss, and cognitive impairment.

It typically manifests before the age of 20 and has no specific gender predilection. Treatment is supportive, including Co-enzyme Q supplementation and consideration of prophylactic pacemaker implantation.