Questions:
1. What associated signs with lesions causing unilateral or bilateral ophthalmoplegia may help localize the lesion
2. What are the findings of the orbital apex syndrome?
3. What are the findings of the cavernous sinus syndrome?
4. Do brainstem lesions commonly produce multiple cranial nerve palsies?
5. What are 7 systemic disorders that affect the cranial nerves?
6. What condition should be considered in patients with unilateral or bilateral ophthalmoplegia and normal pupils presumed to result from multiple cranial neuropathies?
7.What should be presumed to be the cause of a painful orbital apex syndrome in a diabetic patient?
8. Do normal orbital imaging studies rule out an orbital apex lesion?
9. Does the orbital apex syndrome involve V2?
10. Which cranial nerves are enclosed in the lateral wall of the cavernous sinus?
11. Why do cavernous carotid artery aneurysms often present with an isolated sixth nerve palsy?
12. What diagnoses should be considered in all cases of new onset constant or transient ptosis and/or diplopia
13. What syndromes have ataxia, areflexia and ophthalmoplegia?
14. What is the Guillain-Barré syndrome?
15. What is the Miller Fisher syndrome?
16. What is the difference between the Miller Fisher and the Guillain-Barré syndromes?
17. When should the Wernicke encephalopathy be considered and what are its symptoms?
18. What is the cause and treatment of Wernicke encephalopathy?
19. What does botulism do to the pupils and what are its other symptoms?
20. What is the infectious agent of botulism?
21. What is the mechanism of the botulism toxin?
22. What is the treatment for botulism?
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Questions with answers:
1. What associated signs with lesions causing unilateral or bilateral ophthalmoplegia help localize the lesion?
Associated signs (such as Horner syndrome, optic neuropathy, chiasmal visual field defects, pain, skin lesions, and other neurologic findings) help localize the lesion.
2. What are the findings of the orbital apex syndrome?
Orbital apex syndrome involves combinations of third, fourth, sixth, and fifth (1st branch) nerve neuropathies with optic neuropathy, and sometimes Horner syndrome. Causes mostly include neoplasms and fungal infections (aspergillosis and mucormycosis).
3. What are the findings of the cavernous sinus syndrome?
The cavernous sinus syndrome involves combinations of ophthalmoplegia (multiple ocular motor cranial nerve palsies – third, fourth & sixth), Horner syndrome, pain and V1 (sometimes V2) sensory loss.
If there is venous hypertension (carotid-cavernous fistula or cavernous sinus thrombosis), there may be proptosis and periorbital edema from orbital venous congestion.
4. Do brainstem lesions commonly produce multiple cranial nerve palsies?
Brainstem lesions: can rarely produce multiple cranial nerve palsies (almost always associated with other neurologic symptoms and signs).
5. What are 7 systemic disorders that commonly affect the cranial nerves?
Miller Fisher syndrome
Guillain-Barré syndrome
Botulism
Wernicke encephalopathy
Myasthenia gravis
Other peripheral neuropathies (e.g., chronic inflammatory demyelinating peripheral neuropathy)
If over age 50, cranial arteritis
6. What condition should be considered in patients with unilateral or bilateral ophthalmoplegia and normal pupils presumed to result from multiple cranial neuropathies?
Always consider ocular myasthenia in patients with unilateral or bilateral ophthalmoplegia and normal pupils presumed to result from “multiple cranial neuropathies.”
7. What should be presumed to be the cause of a painful orbital apex syndrome in a diabetic patient?
A painful orbital apex syndrome in a diabetic patient should be presumed caused by a local infection by mucormycosis until proven otherwise.
8. Do normal orbital imaging studies rule out an orbital apex lesion?
Normal orbital imaging studies do not rule out an orbital apex lesion. Orbital apex lesions are usually very small and are difficult to see on imaging.
The adjacent sinuses are often abnormal, making it even more difficult to see a subtle enhancement on orbital CT or MRI. The appropriate imaging is either a CT scan of the orbits, the cavernous sinus, and the facial sinuses with contrast, or, preferably, a brain MRI scan with dedicated orbital views, fat suppression, and contrast.
9. Does the orbital apex syndrome involve V2?
No, the orbital apex syndrome involves and V1 sensory loss not V2. The orbital apex syndrome consists of ophthalmoplegia (multiple cranial nerve palsies), Horner syndrome, pain and V1 sensory loss (trigeminal nerve), and visual loss (optic neuropathy). The Cavernous sinus syndrome involves pain and V1 (sometimes also V2) sensory loss.
10. Which cranial nerves are enclosed in the lateral wall of the cavernous sinus?
The third, fourth, and fifth nerves (V1 and V2) are enclosed in the lateral wall of the cavernous sinus (made of dura).
11. Why do cavernous carotid artery aneurysms often present with an isolated sixth nerve palsy?
The sixth nerve is free within the cavernous sinus, in close relation with the internal carotid artery and not protected by the dura.
12. What diagnoses should be considered in all cases of new onset constant or transient ptosis and/or diplopia?Myasthenia, Wernicke syndrome, and if over age 50 cranial arteritis.
13. What syndromes have ataxia, areflexia and ophthalmoplegia?
The Miller Fisher and the Guillain-Barré syndromes are demyelinating polyradiculopathies that can be associated with multiple cranial nerve palsies and bilateral ophthalmoplegia.
14.What is the Guillain-Barré syndrome?
A demyelinating polyradiculopathy. Findings include:
1. Ataxia
2. Areflexia
3. Ophthalmoplegia (bilateral third, fourth, and 6th nerve palsies)
4. The pupils are often involved
5. Bilateral facial weakness is common
6. Progressive ascending symmetric limb weakness without sensory loss
7. May be complicated by respiratory paralysis.
8. Serum antibodies for Campylobacter jejuni or anti-GQ1b gangliosides may be positive.
The treatment for the Guillain-Barré and Miller Fisher syndromes is the same: intravenous immunoglobulin (IVIg) or plasmapheresis, and supportive care. Prognosis is usually good.
15. What is the Miller Fisher syndrome?
A variant of the Guillain-Barré syndrome. It is a demyelinating polyradiculopathy that presents with a classic triad of:
1. ataxia
2. areflexia
3. ophthalmoplegia (bilateral third, fourth, and 6th nerve palsies)
In addition: the pupils are often involved, bilateral facial weakness is common, and may be complicated by respiratory paralysis, but there is No limb weakness as is seen with the Guillain-Barré syndrome.
Serum antibodies for Campylobacter jejuni or anti-GQ1b gangliosides may be positive.
The treatment for the Guillain-Barré and Miller Fisher syndromes is the same: intravenous immunoglobulin (IVIg) or plasmapheresis, and supportive care. Prognosis is usually good.
16. What is the difference between the Miller Fisher and the Guillain-Barré syndromes?
The Guillain-Barré syndrome has progressive ascending limb weakness but the Miller Fisher syndrome does not. They both are demyelinating polyradiculopathies that can be associated with multiple cranial nerve palsies and bilateral ophthalmoplegia, pupillary dysfunction, bilateral facial weakness and respiratory paralysis. Both are associated with the serum anti-GQ1b IgG antibody.
17. When should the Wernicke encephalopathy be considered and what are its symptoms?
It should be suspected in any patient presenting with: confusion, ataxia, ophthalmoplegia (any pattern is possible, including 6th nerve palsy, horizontal or vertical gaze palsy, and internuclear ophthalmoplegia), nystagmus. Like myasthenia gravis, Wernicke encephalopathy can mimic any extraocular movement disorder with normal pupils.
18. What is the cause and treatment of Wernicke encephalopathy?
It is caused by a vitamin B1 (thiamine) deficiency that usually occurs as a result of chronic alcoholism and severe chronic malnutrition. It should be suspected in any patient presenting with: confusion, ataxia, ophthalmoplegia of any pattern. Treatment with vitamin B1, hydration, and appropriate nutrition is urgent to prevent irreversible dementia.
19. How are the pupils affected in botulism, and what are its other symptoms?
There is bilateral mydriasis associated bilateral diffuse ophthalmoplegia, ptosis and systemic signs (nausea, vomiting, dysphagia, proximal extremity weakness).
20. What is the infectious agent of botulism?
Clostridium botulinum (from contaminated canned food or contaminated wounds).
22. What is the mechanism of the botulism toxin?
It interferes with the release of acetylcholine vesicles in the synapse and blocks neuromuscular transmission.
23. What is the treatment for botulism?
This life-threatening disorder requires immediate life-support measures and treatment with specific antitoxins.
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The information below is from: Neuro-ophthalmology Illustrated-2nd Edition. Biousse V and Newman NJ. 2012. Theme
13.5.3 The Lesion Involves a Cranial Nerve
The diagnosis and management of ocular motor cranial nerve dysfunction vary according to the age of the patient, characteristics of the cranial nerve palsy, and presence of associated symptoms and signs.
Third Cranial Nerve (Oculomotor Nerve) Palsies
A third nerve palsy results in ipsilateral paresis of the following:
● Adduction (medial rectus)
● Elevation (superior rectus and inferior oblique)
● Depression (inferior rectus)
The following also occure:
● Ptosis (levator palpebrae)
● Pupillary dilation (parasympathics)
● Accommodation paralysis (parasympathics)
The classic presenting symptoms of a patient with a third nerve palsy are binocular vertical and horizontal diplopia, droopy lid, or, less frequently, awareness of an enlarged pupil or blurred monocular vision at near. Associated symptoms are of extreme importance in the evaluation of the third cranial nerve (▶Fig. 13.85).
Anatomy of the Third Cranial Nerve
The third nerve originates in the midbrain and is in close relationship with the internal carotid artery in its subarachnoid course (▶Fig. 13.86); an acute third nerve palsy always raises the possibility of an intracranial aneurysm.
● The nucleus is a cluster of subnuclei in the dorsal midbrain (see Anatomy of the Third Nerve Nucleus for description).
● From the third nerve nucleus and motor and parasympathetic neuron axons traverse anteriorly within the third nerve fascicle.
● The third nerve then exits the midbrain near the medial aspect of the cerebral peduncle.
● It enters the subarachnoid space, where it travels between the superior cerebellar artery and the posterior cerebral artery next to the tip of the basilar artery, then travels medially along the posterior communicating artery and lateral to the internal carotid artery.
● It enters the cavernous sinus where it is enclosed within the lateral wall, superior to the fourth nerve.
● It then enters the orbit through the superior orbital fissure and annulus of Zinn, at which point it divides into the following:
○ Superior division (innervates levator, superior rectus)
○ Inferior division (innervates the ciliary ganglion in the orbit (parasympathetics), medial rectus, inferior rectus, inferior oblique)
Anatomy of the Third Nerve Nucleus (▶Fig. 13.87)
The third nerve nucleus is a complex of small subnuclei: each muscle innervated by the third nerve is subserved by an individual subnucleus. Exceptionally, individual nuclei can be affected by a lesion, explaining the rare central partial third nerve palsies (in which not all extraocular muscles innervated by the third nerve are affected).
Each extraocular muscle innervated by the third nerve is subserved by an individual subnucleus located in the midbrain third nerve nuclear complex.
● The inferior oblique, inferior rectus, and medial rectus muscles are subserved by their ipsilateral subnuclei.
● The superior rectus muscle is subserved by the contralateral subnucleus (fibers cross the midline).
● Both levator palpebrae muscles are subserved by one single subnucleus (the central caudal nucleus).
● The pupillary constrictor and accommodation muscles are under the control of a parasympathetic pathway subserved by an ipsilateral subnucleus (Edinger–Westphal nucleus).
Because of these anatomical characteristics of the third nerve nuclear complex, specific clinical syndromes can be observed when there is a lesion at the level of the midbrain (▶Fig. 13.88, ▶Fig. 13.89, ▶Fig. 13.90, ▶Fig. 13.91, and ▶Fig. 13.92).
Partial lesions of one or both third nerve nuclei are possible and may produce a unilateral or bilateral incomplete (partial) third nerve palsy (▶Fig. 13.93). For example, the pupils may be spared and there may be no ptosis. However, an isolated unilateral mydriasis or isolated unilateral or bilateral adduction deficit (medial rectus palsy) is almost never related to a third nerve palsy.
Classification of Third Cranial Nerve Palsies
Third nerve palsies may be classified as follows:
● Partial: when not all muscles innervated by the third nerve are involved or when there is only moderate paresis of the muscles
● Complete: when all the muscles innervated by the third nerve are involved and when the paresis is complete
○ With pupil involvement: when there is anisocoria, with the larger pupil being on the side of the third nerve palsy and when the larger pupil does not react well to light
○ Pupil-sparing: when the pupils are symmetric and briskly reactive to light
Third Nerve Palsy with Pupillary Involvement
Because of the dorsal and peripheral location of the pupillary fibers, a dilated pupil associated with a third nerve palsy may be the first sign of a compressive lesion in the subarachnoid space (▶Fig. 13.94).
In the subarachnoid space, the pupillary fibers are located at the surface of the third nerve, whereas the fibers subserving the extraocular muscles are located deeper in the nerve.
Isolated oculomotor nerve palsy with pupillary involvement in adults is usually related to compression of the third nerve either by an intracranial aneurysm, typically originating at the junction of the posterior communicating and the internal carotid arteries, or by a pituitary tumor (such as in pituitary apoplexy). Both disorders are life-threatening conditions.
Pupil-Sparing Third Nerve Palsy
Ischemia of the nerve usually involves only the very central part of the nerve itself, at the most distal end of the circulation. Therefore, occlusion of these small vessels (vasa-nervorum), as seen in diabetic patients, will present with abnormal eye movements but often normal pupils.
Pupil-sparing third nerve palsy refers only to complete third nerve palsies in which the pupil remains of normal size and reactivity. Third nerve palsies without dysfunction of all of the muscles innervated by the third nerve that also do not involve the pupil are not pupillary sparing. The distinction becomes very important in management (to be discussed). The cause of most isolated pupil-sparing third nerve palsies is believed to be microvascular ischemia, frequently associated with diabetes mellitus or other vascular risk factors. Microvascular third nerve palsies may be quite painful but usually resolve after 3 to 4 months.
Pearls
Microvascular third nerve palsies are most often nonarteritic, but giant cell arteritis should always be considered. Very subtle anisocoria (< 1 mm) is sometimes seen with microvascular third nerve palsy.
Evaluation of the Patient with Suspected Third Nerve Palsy (▶Fig. 13.95)
Fig.13.95 Evaluation of a third nerve palsy (in adults). MRI: magnetic resonance imaging; CTA: computed tomography angiogram; ESR: erythrocyte sedimentation rate; CRP: c-reactive protein.
● Based on other illnesses and age
● Neurological evaluation looking for other symptoms or signs
● Ophthalmological evaluation looking for orbital syndrome, optic neuropathy, papilledema, other ocular motor cranial nerve involvement
● Systemic evaluation looking for giant cell arteritis (if over 50), fever, systemic inflammatory disorder, atheromatous vascular risk factors
● Could it be myasthenia? (definitely not if the pupil is involved)
● Is the third nerve palsy
○ isolated, or not?
○ painful, or not?
○ complete, or not?
○ pupil-sparing, or not (only relevant if complete third nerve palsy)?
Causes of Third Nerve Palsy
Localization of the lesion producing a third nerve palsy is the first step of the diagnosis (▶Table 13.5).
The sudden onset of a painful third nerve palsy with associated meningeal signs suggests subarachnoid hemorrhage from aneurysmal rupture. Pituitary apoplexy may also present similarly but is usually easily diagnosed on brain imaging.
These are a life-threatening emergency requiring immediate workup:
● Head CT without intravenous contrast (looking for blood in the subarachnoid space)and with contrast (looking for an intracranial aneurysm or alternate cause of oculomotor nerve palsy) and/or MRI of the brain with contrast is obtained.
● If a subarachnoid hemorrhage is diagnosed, a CT angiogram (CTA) and usually an emergent catheter angiogram are obtained.
● If there is no subarachnoid hemorrhage on imaging, and the patient has severe headaches, then a lumbar puncture should be performed looking for blood or xanthochromia (in cases of subarachnoid hemorrhage of more than 8 hours).
● Emergent noninvasive vascular imaging should be obtained in all patients with a third nerve palsy. When interpreted by experienced neuroradiologists, CTA and magnetic resonance angiography (MRA) are very sensitive, especially for aneurysms measuring at least 3 to 5mm. However, smaller aneurysms can also rupture, and the consequences of missing an intracranial aneurysm are potentially grave; interpretation of CTA and MRA is difficult, and the clinician must make sure that the interpreting radiologist knows that the test is obtained to look for an aneurysm in a patient with a third nerve palsy. A catheter angiogram is sometimes obtained if there is still a high suspicion of aneurysm, or if there is doubt concerning the CTA or MRA results.
Although most aneurysms responsible for a third nerve palsy involve the ipsilateral carotid circulation, the basilar circulation must also be studied to exclude a more posterior location. The contralateral carotid circulation should also be evaluated because ~20% of patients have more than one aneurysm.
All patients under the age of 50 who present with an isolated third nerve palsy of any extent should also have complete neurologic evaluation, including brain MRI, MRA, and CTA (if MRI and MRA are normal). A catheter angiogram may also be obtained in selected patients with normal noninvasive imaging (▶Fig. 13.96 and ▶Fig. 13.97).
Patients over the age of 50 who present with an isolated, pupil-sparing, but otherwise complete third nerve palsy, even in the presence of pain, can usually be assumed to have a microvascular third nerve palsy. However, brain imaging with noninvasive vascular imaging (CTA or MRA) is always obtained in patients with third nerve palsies. These patients must be observed closely for the next week for evidence of pupillary involvement.
The patient over age 50 with an isolated complete oculomotor nerve palsy with some pupillary involvement or a partial third nerve palsy should have at least MRI, MRA, and CTA scans.
Pearls
Although aneurysms are life threatening and need to be ruled out by vascular imaging, it is very important to obtain an MRI scan with contrast to rule out a mass or an infiltrative process as the cause of the third nerve palsy when vascular imaging is normal.
Third nerve palsies sometimes precede aneurysmal rupture and subarachnoid hemorrhage. Prompt recognition allows emergent diagnosis and treatment before the aneurysm ruptures. In these cases, the aneurysm is either treated by endovascular approach or surgically clipped, and the prognosis is usually excellent. On the other hand, the prognosis of ruptured aneurysms is poor, with a high, acute mortality rate. Devastating neurologic sequelae are common in survivors (▶Fig. 13.98).
Pearls
Intracranial aneurysms may be missed on noninvasive imaging such as CTA or MRA. Interpretation of these tests is difficult; the clinician must communicate with the interpreting radiologist, who should know that an aneurysm is suspected, and who should be aware of the patient’s clinical presentation.
Causes of Third Nerve Palsies in Children
Causes of third nerve palsies in children are different from those classically observed in adults:
● Congenital
● Acquired, most commonly due to the following:
○ Trauma
○ Posterior fossa tumors
○ Meningitis
Children with an isolated third nerve palsy should be evaluated with brain MRI (with contrast). A lumbar puncture is usually performed only in children with acquired, acute third nerve palsies with normal imaging. Vascular imaging is usually not obtained in children younger than 10 years.
Congenital Third Nerve Palsies
Most have pupillary involvement, aberrant regeneration, and amblyopia.
Aberrant Regeneration of the Third Nerve
Aberrant regeneration of the third nerve (synkinesis) occurs after trauma or with compression of the third nerve. Branches of the third nerve originally destined for one muscle aberrantly regenerate to innervate a different muscle, including even the pupillary sphincter (▶Fig. 13.99).
Pearls
In the absence of trauma, the presence of aberrant regeneration of the third nerve makes a compressive cause of the third nerve palsy very likely.
The majority of third nerve palsies of ischemic etiology resolve within 3 months.
Compressive or traumatic oculomotor nerve palsies may take longer to improve, and incomplete recovery with or without aberrant regeneration is more likely.
Reference: 1. Neuro-ophthalmology Illustrated-2nd Edition. Biousse V and Newman NJ. 2012. Theme
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