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The vascular supply of the midbrain is complex, though the majority is serviced via the basilar (paramedian perforators), superior cerebellar (SCA), and posterior cerebral (PCA) branches. Vascular supply zones may be roughly divided rostro-caudally into three levels: (1) pretectal, (2) superior col- liculus, and (3) inferior colliculus. Axially, the midbrain may be divided into medial and lateral zones. At the level of the pre- tectum, the paramedian branches of the basilar artery supply the medial zone. The more lateral zones are supplied primarily by the PCA. At the level of the superior colliculus, the lateral zones receive the majority of their vascular supply from the PCA, though the superior colliculi themselves are supplied principally by the SCA. The basilar artery supplies the medial zone. At the level of the inferior colliculi, the lateral zones are supplied by the SCA, whereas the medial zones are once again principally supplied by paramedian branches of the basilar artery (Fig. 4.10).

Fig. 4.10. Vascular distribution of the midbrain (see plate section for color image).

Case 4.1

52-year-old man comes to your office with a past medical history significant for diabetes, hypertension, coronary artery disease, and remote lymphoma treated and in remission. He is now reporting an approximate 2-week history of progressive left eye pain and double vision. In particular, he states that the diplopia is much more pronounced when looking to the right. Moreover, he reports blurred vision in his left eye even with his glasses on, though his acuity in the right eye remains sharp. In asking him to elaborate, he states that this problem has actually been going on for nearly a year, though historically it was intermittent and resolved spontaneously. For the headache, he took over-the- counter analgesics with good relief. For the past 2 weeks, his symptoms have not abated, and the eye pain persists despite taking 2400 mg of ibuprofen daily.

On examination, asymmetry with respect to his eyes is imme- diately apparent. Attempts at fixed primary gaze reveal a downward and laterally deviated left orbit. Moreover, he has moderate left lid ptosis with a raised eyebrow and wrinkled forehead on the left. Closer inspection reveals a dilated left pupil that is sluggishly reactive to light. Interestingly, the con- sensual response on the right is intact, though the opposite is not true (Fig. 4.11).

Based on the present exam, where would you localize the lesion? This patient’s history and physical exam are compatible with a palsy of the third cranial nerve. Given the longstanding symptoms with recent exacerbation, one would suspect a slow, insidious pro- cess such as a mass lesion, indolent infection, or metabolic derange- ment. To assist in localization, let’s review the anatomy of the third

cranial nerve.

Recall that the oculomotor nucleus is located in the midbrain at the level of the superior colliculus. Lower motor neurons course through the red nucleus and cerebral peduncles exiting ventrally into the interpeduncular fossa. Here, fibers from the parasympa- thetic Edinger–Westphal nucleus join superficially to form the oculomotor nerve (CN III). Its course immediately encounters a common site of pathology, as it is sandwiched between the poster- ior cerebral (PCA) and superior cerebellar (SCA) arteries. PCA aneurisms often present as third nerve palsies, and this gentle- man’s presentation is not entirely inconsistent with this. However, his complaint of eye pain is somewhat atypical for this pathology, though this is an important diagnosis and should be considered in the differential. After progressing anteriorly, CN III travels through the cavernous sinus, another common site of pathology (Fig. 4.9). However, recall that the cavernous sinus also contains branches of the trigeminal nerve (V1 and V2), as well as the trochlear (CN IV) and abducens (CN VI) nerves. It would be atypical for this man to have an isolated third nerve palsy referable to cavernous sinus pathology. Finally, the nerve travels through the superior orbital fissure and splits into superior and inferior divisions innervating the following structures:

Superior division

Superior rectus – elevation and intorsion Levator palpebrae superioris – elevates the eyelid Inferior division

Inferior rectus – depression and intorsion Inferior oblique – elevation and extorsion Medial rectus – adduction

The parasympathetic fibers of the Edinger–Westphal nucleus innervate the pupillary constrictor muscles. The fact that these fibers course on the periphery of CN III can provide important diagnostic clues. When a third nerve palsy involves the pupil, a

compressive/surface pathological process should be suspected immediately. When a third nerve palsy spares the pupil, a meta- bolic derangement such as diabetes becomes more likely.

MRI examination is presented above (Fig.4.12). What does the imaging reveal?

This man has diffuse, linear enhancement of his left CN III. This pathology is consistent with all of his presenting signs and symp- toms. Given his history of lymphoma, the most likely diagnosis is carcinomatous lymphomatosis of the third cranial nerve. A lum- bar puncture to evaluate cytology would be helpful in establish- ing this diagnosis.

a b

Fig. 4.12. Axial and coronal post-contrast fat-saturation images through the brainstem revealing enhancement of the left third nerve.

Case 4.2

65-year-old woman with past medical history significant for poorly controlled hypertension, diabetes, and coronary artery disease, was brought into the emergency department after fall- ing and striking her face. In obtaining more details, it is discov- ered that she fell after becoming markedly weak on her left side. On your examination, she is able to lift her left arm off the gurney, but remains unable to support her weight with her left leg. She has a contusion on the left side of her face, though careful inspection reveals facial weakness on that side includ- ing drooping of the mouth and flattening of the left nasolabial fold.

On further testing, it becomes obvious that, in addition to her facial weakness, initially masked by the contusion, she is having difficulty moving her right eye, and is reporting double vision on attempts to gaze to the left. Careful inspection reveals a down and out deviation of the right eye, drooping of the eyelid, and a dilated, non-responsive right pupil.

Based on the present exam, where would you localize the lesion? This case is interesting in that it presents with clear involvement of cranial nerves in conjunction with upper motor neuron plegia. This clinical condition is often referred to as the ‘‘Syndrome of Weber,’’ after Sir Herman David Weber, a German–English physician who first described it in 1863 (Fig. 4.13). Thoughtful consideration of midbrain anatomy is

invaluable in localizing the lesion. Involvement of CN III or its nucleus on the right side would explain the eye deviation, diplopia, ptosis, and afferent pupillary defect. Given the addi- tional pathology you find on exam, it is extremely unlikely to be a CN III nerve lesion, and more likely involves the nucleus or fibers as they course through the midbrain. Further, you know that the nucleus of CN III lies very proximal to the red nucleus. If a lesion involved this area, you may expect a tremor as part of the presentation. However, you can explain the contralateral weakness by involvement of the corticosp- inal tracts, as they pass through the midbrain (Kim and Kim, 2005). In fact, at this level of the midbrain, the dorsal aspect consists of the cerebral peduncles, which, among other tracts, contain the corticospinal tracts serving the face, arm, and leg (Fig. 4.13).

The pattern of weakness you observed in the face is referred to as lower facial weakness. That her forehead is relatively spared is a consequence of the bilateral cortical innervation of the upper

face. When you observe a ‘‘peripheral’’ facial palsy involving both the lower and upper face, a lesion of the facial nerve (CN VII) is usually the culprit.

MRI imaging is presented above (Fig.4.14). What does the imaging reveal?

These three images reveal an acute infarct involving the mid- brain. The pattern of hyperintensity is consistent with dysfunc- tion of corticospinal tracts coursing through the left cerebral peduncle, as well as rootlets of cranial nerve three as they exit the midbrain ventrally. The vascular distribution of this acute infarct likely involves the posterior cerebral and/or posterior communicating artery.

Reference

Kim, J. S. and Kim, J. Pure midbrain infarction: clinical, radiologic, and pathophysiologic findings. Neurology 2005; 64(7): 1227–1232.

a b

Fig. 4.14. (a) Axial T2 and (b) DWI images revealing a subacute infarct involving the left cerebral peduncle.

Case 4.3

52-year-old woman with diabetes and hypertension presented to your office after several months of progressively worsening blurred vision and difficulty in walking. She describes an indo- lent course and cannot recall with precision the exact onset. However, she can recall an event approximately 2 to 3 months ago when she was stepping onto a curb with her left leg, mis- judged the height, and fell. Following that incident, she feels as if her vision has not been ‘‘right,’’ and notes occasional double vision. She admits to poor dietary discretion and diabetes control and has felt that her symptoms were due to this. However, she is now barely able to ambulate independently, has developed a significant tremor, and continues to have difficulty with her vision.

At examination, the patient was found to have dense, pupillary- involving palsy with an inferolateral deviation of the globe and a dense ptosis. The patient was also mildly dysarthric, with some slurred speech. Cerebellar function testing with finger-to-nose and heel-to-shin exercises was intact on the right but

compromised by significant tremor on the left. Moreover, the patient showed disturbances in gait with unsteadiness, broad- based stance, swaying, short, irregular steps with variable ampli- tude and occasional high-stepping (especially with the left leg), and difficulty initiating locomotion. The patient was unable to attempt tandem gait. Sensory testing revealed markedly dimin- ished vibratory and proprioception in the left arm and leg, as well as some diminution of temperature and pin-prick sensation. You observe no evidence of truncal ataxia while the patient was sitting. No stooping or shuffling was seen during the patient’s gait, and no evidence of masked facies or resting tremor was present.

Based on the present exam, where would you localize the lesion?

The overall clinical picture for this patient is very interesting, and includes pathology involving the oculomotor nucleus or nerve, locomotor systems, posterior column sensation, and cere- bellum or red nucleus (tremor). The most likely localization

placing all of these pathways in proximity is the tegmentum of the mesencephalon at the level of the superior colliculus. Recalling the anatomy of this location, one can assign oculomotor pathology to the rootlets of CN III, the hemianesthesia to the fibers of the medial lemniscus and to a lesser extent the spinothalamic tracts, and the tremor to the red nucleus (Fig. 4.15).

Taken alone, these symptoms are described as the ‘‘Syndrome of Benedikt,’’ after Moritz Benedikt, an Austrian physician who described it as a vascular syndrome in 1889.

However, this case is more interesting in that it was not an abrupt onset (as would be expected in a vascular syndrome), and the difficulties with ambulation seem to be disproportionate with what would be expected for the above listed systems. Recollection of other key structures in the immediate vicinity reveals a nuclear group known as the pedunculopontine nucleus, which has been described as important in locomotion (Bhidayasiri et al., 2003; Hathout and Bhidayasiri,2005). At the level of the inferior colliculus, this lies in close proximity to the spinothalamic tract and medial lemniscus, further clarifying this woman’s symp- tomatology (Fig. 4.16).

Because of the slow but relentless progression of her disease course, a mass lesion at the level of the superior colliculus, with caudal extension to the level of the inferior colliculus, may be expected.

MRI images are presented below (Fig.4.17). What does the imaging reveal?

Other common clinical pathologies involving midbrain nucleus extra ocular movements not illustrated in these cases include the following.

CN III – Vascular

(a) Aneurysms of the posterior cerebral or superior cerebellar artery may compress the oculomotor nerve

(b) Infarction in the basal midbrain may damage either the nucleus or axons of the oculomotor nerve.

– Inflammation

Any inflammatory processes (especially tuberculous meningi- tis) located in or around the optic chiasm, temporal lobes, or pons, may specifically affect the oculomotor nerve.

– Temporal lobe herniation

Any condition effecting downward herniation may cause the tentorial notch to displace the cerebral peduncle and com- press the oculomotor nerve.

– Cavernous sinus pathology

Multiple pathologies of the cavernous sinus, including infec- tion, venous thrombosis, and mass lesions may affect the oculomotor nerve as it passes through the sinus.

Clinical correlates

– Lower motor neuron lesions of the oculomotor nerve may effect any or all of the following clinical symptoms (a) divergent gaze resulting in diplopia

(b) ptosis (c) midriasis

(d) down and out deviation of the eye (e) inability to accommodate

CN IV – Vascular

Aneurysms of the posterior cerebral or superior cerebellar artery may compress the trochlear nerve.

– Inflammation

Inflammatory processes may affect the trochlear nerve. – Cavernous sinus pathology

Multiple pathologies of the cavernous sinus, including infec- tion, venous thrombosis, and mass lesions may affect the oculomotor nerve as it passes through the sinus.

Clinical correlates

– Lower motor neuron lesions of the trochlear nerve may effect vertical diplopia which is most pronounced on contralateral downward gaze. Patients may present with a head tilt towards the non-paretic nerve to compensate for the action of the paralyzed superior oblique.

Reference

Bhidayasiri, R., Hathout, G., Cohen, S. N., and Tourtellotte, W. W. Midbrain ataxia: possible role of the pedunculopontine nucleus in human locomo- tion. Cerebrovascular Diseases 2003; 16(1): 95–96.

Hathout, G. M., and Bhidayasiri, R. Midbrain ataxia: an introduction to the mesencephalic locomotor region and the pedunculopontine nucleus. American Journal of Roentgenology 2005; 184(3): 953–956. Fig. 4.16. The location of the pedunculopontine nucleus in relation to

the spinothalamic tract and medial lemniscus.

a b

c

d

Fig. 4.17. (a) T1 axial, (b) FLAIR axial, (c) GRE T2 coronal, and (d) T2 axial images through the midbrain are provided. There is an ovoid lesion, isointense on T1, slightly hypointense on T2, and blooming on the GRE sequence, consistent with an unusual cavernous hemangioma in the right midbrain.

Case 4.4

You are called to evaluate Mr. M in the emergency department. The patient is a 66-year-old man with a past medical history of Type-II diabetes, coronary artery disease, peripheral vascular dis- ease, and chronic myelogenous leukemia with complaints of visual problems and incoordination. The ED physician reports to you that he has gait difficulties and restricted eye movements.

These difficulties began abruptly, and were noticed immediately, as the gentleman was driving during symptom onset. He was suddenly aware of diplopia and restricted gaze in attempting to navigate traffic.

In the ED, your exam reveals dysmetria on finger-to nose testing with the right arm. The arm ataxia is accompanied by a

slight tremor that worsens when the gentleman approaches your finger and his nose. This incoordination is also seen in the right leg, both when you request that he perform heel-to-shin exercise, and on attempts to walk. His natural gait shows poor foot place- ment and cadence limited to the right leg. He is unable to tandem walk without assistance, again due to difficulties involving his right leg.

Mr. M states that part of his problem with walking is due to his double vision. On careful oculomotor exam, you detect an inabil- ity to adduct the left eye when instructed to look rightward. He reports that this attempt exacerbates his diplopia. In addition, he

has difficulty looking superiorly with his left eye. Downgaze is intact and pupillary movements to direct and consensual light, and convergence are intact bilaterally.

Based on the present exam, where would you localize the lesion? The constellation of symptoms presented is known as Claude syndrome (Asakawa et al.,2003) and includes pathology referable to the left oculomotor nerve or nuclei and coordination centers involving the right hemibody (Fong,2005). Given the acute and simultaneous onset of his symptoms, one would predict a single lesion as causative, and suspect stroke as the etiology. The most likely site of localization is the rostral midbrain (Seo et al.,2001). The affected anatomical structures may be seen inFig. 4.18.

A stroke in this area may involve the neuroanatomic structures including cranial nerve III, explaining the eye findings, and the red nucleus, and/or brachium conjunctivum, explaining the incoordi- nation. It is likely that the brachium conjunctivum is involved given the description of the tremor. Tremors that worsen when the target is approached, known as intention tremor, are often referable to cerebellar pathology.

MRI images are presented (Fig. 4.19). What does the imaging reveal?

Recall the neuroanatomy of the midbrain at the level of the oculomotor nucleus (Figs. 4.8, 4.10, and 4.20).

Importantly, recognize that, though the oculomotor nucleus itself lies close to the midline, the fibers of CN III run through the red nucleus and proximal to the brachium conjunctivum (superior cerebellar peduncle). It is notable, on exam, that the patient exhibits no pathology regarding nuclei governing other extra ocular move- ments, and especially pupillary defects. Remember that the para- sympathetic fibers from the Edinger–Westphal nucleus do not join the nerve proper until their exit from the midbrain. Therefore, an infarct involving the territory of the proximal posterior cerebral

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Fig. 4.19. (a) Axial T2 and (b) DWI images through the midbrain, with significant motion artifact. There is a subacute infarct in the left midbrain tegmentum, extending from the aqueduct of Sylvius through the red nucleus.

artery, or alternatively, paramedian branches of the top of the basilar artery, would affect the anatomical structures implicated in this gentleman’s clinical pathology.

References

Asakawa, H., Yanaka, K., and Nose, T. MRI of Claude’s syndrome. Neurology 2003; 61(4): 575.

Fong, C. S. Claude’s syndrome associated with supranuclear horizontal gaze palsy caused by dorsomedial midbrain infarction. Acta Neurologia Taiwan 2005; 14(3): 147–150.

Seo, S. W., Heo, J. H., Lee, K. Y. et al. Localization of Claude’s syndrome. Neurology 2001; 57(12): 2304–2307.

Fig. 4.20. The location of the fibers exiting the oculomotor nuclear complex and the structures they innervate.

Case 4.5

50-year-old engineer, previously in good health, reports incoor- dination, difficulties with vision, and ataxia slowly progressing over the past several months. Approximately 1 week ago he had presented to a local clinic with an acute onset of vertigo and vomiting (lasting 1 to 2 hours), after which he was rela- tively unresponsive and remained so for about 24 hours. Initially, it was thought that he had contracted a severe gastro- enteritis with fluid loss. However, upon regaining conscious- ness, he was unable to open his eyes or keep his balance while walking. Vomiting and vertigo did not recur. There was no history of fever, trauma, or headache. Plain non-contrast CT of the head was unremarkable, though his failure to return to his baseline prompted a transfer to your hospital.

On your examination, his speech was slurred but he had no evidence of aphasia. Both eyes were infra and abducted suggest- ing bilateral third nerve (or nuclei) lesions. There was sustained horizontal nystagmus when he attempted to look at an object at the extreme right or left. His pupils were round, unequal, and not