29.5Cranial Nerve III, IV, and VI Palsies due to Head and Neck Cancers

Head and neck cancers may cause cranial nerve deficits either by direct extension into the orbit, cavernous sinus, or skull base or by perineural spread (see Chapter 30).

Direct extension of head and neck tumors into the orbit, cavernous sinus, or skull base may result in cranial nerve deficits. The head and neck tumor that most commonly causes cranial neuropathies is squamous cell carcinoma, which accounts for greater than 90% of head and neck cancers. Squamous cell carcinoma commonly affects the maxillary sinus, nasal cavity and ethmoid sinus as well as nasopharynx. Nasopharyngeal carcinoma, may invade the sphenoid sinus, cavernous sinus, clivus and orbit to cause and middle cranial fossa to cause palsies of cranial nerves II–VI [7]. The frequency of cranial nerve involvement in nasopharyngeal carcinoma is 8–29% and is an important prognostic factor [8–10]. Adenocarcinoma, sarcoma, melanoma, lymphoma, and adenoid cystic carcinoma are other head and neck tumors that can extend into the orbit or skull base and cause cranial neuropathies. Not infrequently the entire central skull base may be involved, including the cavernous sinus, sphenoid, and clivus, leading to these multiple nerve palsies.

Perineural spread from head and neck tumors is well documented and most commonly occurs with squamous cell carcinoma and adenoid cystic carcinoma [7, 11, 12]. Perineural spread most commonly involves cranial nerve V (all three divisions may be involved) and may be retrograde (toward the brain) or anterograde (toward the orbit) [1, 7, 12]. Most often the tumors that infiltrate small branches of V1 and V2 go retrograde and involve the cavernous sinus and therefore will present with cavernous sinus signs of III, IV, and VI and any combination of these. Tumors on V3 go retrograde to Meckels cave and continue on to the brain stem where CN VI paresis may occur most commonly. On the other hand, tumors on V3 once they reach Meckels cave may travel anterograde to involve the cavernous sinus. Cranial nerve VII is the second most common cranial nerve affected by perineural invasion [1]. Perineural spread of cutaneous neoplasms such as squamous cell carcinoma and desmoplastic melanoma may affect any branch of cranial nerve V, depending on the location of the malignancy. Perineural spread from mucosal tumors such as squamous cell carcinoma and adenoid cystic carcinoma of the salivary glands often affects the second (maxillary) and third (mandibular) branches of cranial nerve V [1, 7, 11, 12]. Nasopharyngeal tumors may spread via the pterygopalatine fossa to the maxillary branch of cranial nerve V [9] and from there go into the cavernous sinus and cause CN III, IV, or VI. Malignant primary and secondary parotid gland tumors may be associated with perineural spread along cranial nerve VII and the mandibular branch of cranial nerve V, the latter getting into Meckel’s cave and leading to either brain stem or cavernous sinus involvement [1]. Perineural tumor extension is also seen in lymphoma, melanoma rhabdomyosarcoma, and malignant nerve sheath tumors [1].

29.6Cranial Nerve III, IV, and VI Palsies due to Leptomeningeal Disease

Leptomeningeal disease is a common cause of deficits of cranial nerves III, IV and VI. These palsies may be extremely subtle such that one does not see a restriction in ductions, therefore they can only be measured in extremes of gaze. Other cranial neuropathies are common including II, V, VII, VIII as well as the lower CN. Leptomeningeal disease may occur with solid tumors, hematogenous tumors, or primary central nervous system tumors. Please see Chapter 32 for a more detailed discussion of the causes and management of leptomeningeal disease.

29.7Other Causes of CN III, IV, and VI Palsies in Cancer Patients

Other causes of cranial III, IV and VI palsies in cancer patients include those related to intracranial pressure, medications due to various mechanisms, radiation/ chemotherapy effects, infections of orbit and CNS as well as paraneoplastic and hypercoagulable states see Table 29.1 for more detail.

Intracranial hypertension may result from many mechanisms (see 29.3 above and Chapter 35.2). In the setting of raised ICP without an associated mass, this may cause a unilateral or bilateral cranial nerve VI palsy, leading to diplopia. In this scenario, cranial nerve VI palsy may be a false localization sign. Intracranial hypotension can also result in unilateral or bilateral CN VI paresis most commonly. This can be a result of spinal taps, skull base tumor repairs or spinal tumor repairs with CSF leaks.

Medications can cause CN III, IV, VI paresis by its effect on ICP, direct effects, evoking PRES. Medication effects may result in diplopia but not do to CN issues but rather neuromuscular blockade effects and other mechanisms described in Table 29.1.

Radiation therapy can cause cranial nerve palsies. Although optic nerve enhancement on T1-weighted MR imaging from radiation necrosis may occur, enhancement of cranial nerves III, IV, and VI is not described as a common finding from radiation necrosis [1, 13, 14]. A few cases of isolated cranial nerve deficits following radiation therapy have been reported. These include deficits of cranial nerves VI and XII. One study evaluating tolerance of cranial nerves III, IV, V, and VI following stereotactic radiosurgery for lesions within or near the cavernous sinus demonstrated new cranial neuropathies in 12 of 62 patients [15]. We have seen enhancement of CN III in a patient with radiation necrosis of adjacent temporal lobe after treatment of an aggressive pituitary adenoma. We have also seen a patient with a temporal lobe glioma treated with radiation and gliadel wafers plus develop CN III paresis and enhancement of this nerve. Both of these patients also developed concomitant neuromyotonia of CN III.

Cranial nerve III enhancement due to radiation necrosis along with evidence of cranial nerve palsy with or without ocular neuromyotonia [16]. Ocular

neuromyotonia is characterized by brief episodes of diplopia secondary to persistent spasm of one or more extraocular muscles induced by sustained gaze in the field of action of the affected muscle. This condition has clearly been demonstrated following radiation therapy. It most commonly involves cranial nerve III but has also been reported to involve cranial nerve VI [17]. Most cases involve radiation therapy for parasellar and sellar tumors affecting cranial nerve III; cases may occur years after irradiation. In the cases reported to involve cranial nerve VI, radiation therapy was applied to tumors in areas other than the parasellar or sellar area [17]. A related syndrome of acquired oculomotor nerve paresis with cyclic spasms also occurs postradiation [16]. Herein patients present with spasms of hyperactivity and hypoactivity of CN III.

Infections can also cause cranial neuropathies. Infections are common in patients with cancer because the cancer and its treatment can lead to immunodeficiency. Infections of the orbit, with or without cavernous sinus thrombosis, meningitis, abscesses, epidural or subdural empyema are all potential types of infections that may cause CN III, IV and VI paresis depending on the site of the lesion and mass effect. A number of these can occur endogenously, relate to sinus infections or relate to prior, surgical procedures on the brain, brainstem or skull base.

Paraneoplastic syndrome refers to dysfunction of the nervous system secondary to a neoplasm via mechanisms other than metastasis, infection, treatment side effects, or vascular consequence. Paraneoplastic syndromes may present with nystagmus, horizontal or vertical gaze palsies, skew deviation, cranial neuropathy, or other neurologic signs. Paraneoplastic cerebellar degeneration is most frequently associated with Hodgkin disease and cancers of the lung, ovary, and breast and has been associated with nystagmus, ocular dysmetria, saccadic pursuit, saccadic intrusions and oscillation, skew deviation, and cranial nerve VI palsies [18]. In paraneoplastic brain stem encephalitis, the patient may complain of diplopia and may have findings of vertical nystagmus, horizontal gaze paresis, internuclear ophthalmoplegia, skew deviation, and cranial nerve III, V, and VI palsies [18]. Paraneoplastic syndrome associated with testicular carcinoma may cause oculomotility defects that mimic CN III, IV, and VI paresis.

29.8 Conclusion

New onset of a cranial nerve III, IV, and VI paresis in a cancer patient demands particular attention to the mechanism of the palsy in order to guide management. Direct tumor involvement, from both primary CNS vs metastatic tumors of the brain, brain stem, skull base direct or perineural spread from head and neck cancer, leptomeningeal disease, and other conditions may result in cranial neuropathies.

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