The incidence of leptomeningeal disease in HNSCC is about 1–2% versus 5–10% in solid tumor SCC. Perineural invasion is the predominant route of spread to the meninges [80]. Leptomeningeal spread in head and neck cancer is rare and has a poor prognosis [81]. Unlike SCC of solid tumors, HNSCC rarely involves spinal cord and spinal nerve roots. Only one case of intramedullary spinal cord metastasis has been published [82]. The most sensitive imaging is currently MRI, which shows nodules or meningeal contrast enhancement [83]. Currently, treatment options include RT, intrathecal chemotherapy, or systemic therapy with CNS-penetrating agents. Epidermal growth factor receptor inhibitors and locally delivered chemotherapy may be effective in such cases [81].

Parenchymal brain metastases are very rare, and only a few case reports have been documented. The majority of these cases had long periods of time over which the patients had untreated primary disease [84, 85]. If brain metastasis appears in long-term survivors of HNSCC, there should also be high suspicion for a second primary malignancy. The origin of these brain metastases is either hematogenous (majority involving lung) or from CSF spread [86, 87]. In an autopsy of 2452 patients, 3% of all intracranial metastases were found in patients with HNSCC [87]. Over the past decade, there has been some rise in the incidence of brain metastasis from HNSCC. Some relate this rise to the increase in distant metastasis in patients with HNSCC who are HPV-positive [85]. In a study of 38 patients who underwent surgical excision of squamous cell carcinoma to the brain, 7 (18%) were from head and neck, and HPV-16 was detected in 4 (57%) of these HNSCC. In this study, invasive neurosurgical interventions, systemic chemotherapy, and RT were attempted to palliate symptoms in patients who presented with neurologic decline [85]. Hardee and colleagues recommend surveillance brain MRI for patients with long-standing untreated primary oral SCC [84].

Epidural spinal cord compression is also very rare in HNSCC compared with other solid tumors. In a study of 759 patients with head and neck cancer, 5 developed epidural compression (1%) [88]. In two large studies from Memorial Sloan Kettering Cancer Center, one showed 6% of cases of epidural metastasis originated from HNSCC [89, 90]. Another study of 337 patients with epidural spinal cord compression at the Mayo Clinic found HNSCC accounted for 1.5% of all cases [91]. Rades and colleagues developed a scoring system based on eleven factors including age, gender, performance status, tumor site, time from cancer diagnosis until epidural spinal cord compression, affected vertebrae, walking ability, further osseous lesions, organ metastases, time developing motor deficits, and radiation regimen to estimate 6-month survival probabilities of these patients [92]. In general, aggressive treatment of spinal epidural compression (surgical resection and RT) is recommended to achieve long-term survival [88]. Due to the rarity of epidural spinal cord compression of HNSCC tumors, if they are seen in patients without evidence of disease for more than 2 years, clinicians should suspect a second primary malignancy.

The brachial plexus is occasionally involved with advanced HNSCC. In a series of 75 patients at Memorial Sloan Kettering with brachial plexopathy due to neoplastic infiltration, only four patients had head and neck cancers [93]. These tumors will grow inferiorly, invading the superior plexus. The pattern of plexus involvement could be patchy due to irregular and random involvement of different areas of the plexus proximally and distally [94]. Contrary to radiation-induced plexopathy, neoplastic brachial plexopathy is painful and pain is the most common presenting symptom (75%) [93]. Prior neck dissection, concurrent chemotherapy, and maximum dose RT are significant risk factors for brachial plexopathy [95]. Treatment of metastatic plexopathy is palliative and includes RT to the tumor mass and chemotherapy [96].

Glossopharyngeal neuralgia (GPN) is a rare complication of HNSCC [97, 98]. As in idiopathic cases, a brief severe stabbing pain felt in the ear, base of the tongue, tonsillar fossa, or beneath the angle of the jaw triggered by swallowing, talking, or coughing commonly exacerbates the pain. Syncope may accompany both idiopathic and tumor-related glossopharyngeal neuralgia in about 84% of cases [99]. In rare cases, GPN can present with syncope with no associated pain [100]. In nasopharyngeal carcinoma (NPC), syncope may be caused by parapharyngeal space extension, cervical lymph node involvement, and the invasion of the skull base causing lower cranial nerve palsies. This is mainly due to compression of the carotid sinus or glossopharyngeal nerve invasion [98]. During severe GPN pain, patients may experience pallor, followed by hypotension associated with bradycardia, which can lead to a loss of consciousness and associated tonic-clonic limb jerking movements [100]. Treatment for GPN includes anticonvulsant medications such as carbamazepine, gabapentin, phenytoin, oxcarbazepine, or pregabalin. For syncope, atropine should be used first, then RT with or without chemotherapy maybe effective [98, 100]. Rhizotomy and microvascular decompression of cranial nerves IX and X is the first surgical choice for pain relief [100].

HNSCC rarely accounts for neurologic paraneoplastic syndromes (PNS). Among head and neck tumors, paraneoplastic SIADH is most commonly associated with squamous cell oral cavity cancer. Two retrospective studies reported an incidence of 2% in a series of 260 cases, and an incidence of 3% in 1436 patients [101, 102]. The resulting hyponatremia may produce encephalopathy and seizures. Hormonal hypercalcemia (HH) is the most common PNS in patients with HNSCC with an incidence of 2.6–7.2% and has a poor prognostic significance. Most of the reported cases of paraneoplastic HH with oral cancer were diagnosed after RT and/or chemotherapy. Patients may experience confusion or fatigue. Dermatologic PNS is less common, but when they occur, they may precede the diagnosis of the oral tumor. Acrokeratosis paraneoplastica is a dermatologic PNS associated with HNSCC. The treatment of the skin lesions is directly related to the eradication of the underlying neoplasm by surgery, chemotherapy, or RT [103].

Resection of primary head and neck cancers often requires sacrifice of terminal branches of sensory nerves to the face, oral, and nasal cavity, the oropharynx and hypopharynx, or dermatomal branches of the upper cervical nerve roots. See Fig. 28.3. This typically causes severe side effects such as facial deformity, speech and swallowing difficulties, and chronic pain in the oral cavity, neck, face, or shoulder. The incidence of chronic pain approaches 40% at one year and 15% at five years. The accessory nerve and the nerves of the superficial cervical plexus are commonly injured and can cause typical and identifiable neuropathic pain syndromes [104]. Medications such as anticonvulsants (gabapentin, carbamazepine) are helpful in alleviating hyperalgesia and allodynia confined to a peripheral nerve in the acute postoperative setting [105]. Postoperative physical therapy techniques prevent chronic shoulder pain syndromes [106].

The most characteristic postoperative neurologic complications seen in patients with head and neck cancer are those related to neck dissection. The standard radical neck dissection involves removal of the sternocleidomastoid, digastric, and stylohyoid muscles, the internal and external jugular veins, the submaxillary gland, and the spinal accessory nerve. Swift examined 24 patients who underwent a total of 33 radical neck dissections in the years from 1951 to 1967. All had shoulder weakness, droop (accessory nerve), and scapular winging (cervical plexus). He also found lesions of the mandibular branch of the facial nerve in 67%, hypoglossal nerve in 39%, sympathetic nerve fibers in 33%, the vagus nerve in 15%, and phrenic nerves in 10%. Patients with involvement of the carotid sheath were at greater postoperative risk of Horner’s syndromes. Sensory loss was mostly limited to the ear, occiput, and supraclavicular regions [107]. However, recently there have been many attempts to spare the spinal accessory nerve, which has been shown to improve quality of life [108].

Carotid rupture is another significant neurologic complication from neck dissection or advanced HNSCC. Invasion of the carotid artery could also be seen by recurrent HNSCC. Many surgeons remove the affected carotid artery along with the tumor and do reconstruction of the vessel. Carotid artery rupture (carotid blowout) may occur either as a surgical complication in 3–5% of aggressive HNSCC resections, or in the setting of post-RT tumor resection [109, 110]. Ligation of the common carotid or internal carotid artery was standard therapy; however, it led to major strokes. One study showed major neurologic complications with carotid ligation in an emergency setting of about 60% with mortality rates of 40% [110]. In a retrospective study of 28 patients with advanced head and neck malignancy who underwent carotid resection, 12 patients underwent immediate carotid artery resection and ligation, one patient died of severe neurologic deficits, two patients experienced neurologic deficits with good recovery, and one patient was moderately disabled [111]. This poor outcome has been significantly improved by endovascular techniques (e.g., coils, balloons, stents) [112].

Sacrifice of the internal jugular vein(IJV) can also produce major neurologic deficits such as increased intracranial pressure (ICP) [113]. This may be associated with headache, facial swelling, and cerebral edema resulting in seizures and obtundation. The symptoms may worsen in a supine patient due to the effects of impaired venous drainage upon ICP. Attempts have being made to spare the IJV; however, IJV preservation is associated with an increased risk of neck failure and a worse outcome mainly in patients with extracapsular node involvement [114]. Benign intracranial hypertension has also been documented in either bilateral or unilateral RND due to resection of the dominant IJV in the presence of a hypoplastic or aplastic contralateral IJV or transverse sinus. In some cases, this can result in permanent visual loss. MRA is an effective technique to diagnose and follow these patients [115].

Radiotherapy for head and neck cancers typically involves the administration of 7000 cGy over six to seven weeks with a dose of 5600 cGy delivered to the areas of likely microscopic disease involvement, and 5000–5250 cGy delivered to areas at very low risk for presence of tumor [116]. Some patients with radiation injury to the cervical spinal cord experience Lhermitte’s sign (LS) , which is an electric shock-like sensation, spreading along the spine in a cervico-caudal direction and also into both arms and legs upon forward flexion of the neck. Radiation can produce spinal cord toxicity in a transient form or reversible myelopathy characterized by LS, which appears soon after or within six months of RT with duration of weeks to six months [117]. The toxicity is due to demyelination of the ascending sensory axons. The incidence of LS developing in the context of transient radiation myelopathy was reported to be between 3.6 and 13% in large patient groups receiving RT for head and neck and thoracic malignancies [118]. At present, the maximum dose considered safe for spinal cord tolerance and the prevention of delayed radiation myelopathy is 45–50 Gy delivered in 1.8–2 Gy daily fractions. When the spinal cord dose is kept below 50 Gy, the incidence of delayed radiation myelitis is very low [119]. In transient cases, MRI may be normal even if the patient has a severe neurologic deficit, as positive MRI findings appear only in delayed radiation myelitis [120]. In the absence of pain or other signs of myelopathy, close follow-up is all that is needed. However, occasionally patients with HNSCC develop serious late-delayed radiation myelopathy (incidence of 0.5–5%). The incidence increases with doses above 5500 cGy, high dose fractions, and longer length spinal cord in the radiation field [121]. Time of onset of symptoms following RT is variable and ranges from 12 months to eight years. Typical symptoms are those of a slowly progressive ascending sensorimotor disturbance. MRI has enabled both an early and specific diagnosis of radiation myelitis. Imaging reveals central cord swelling confined to the irradiated field and, in some cases, cord atrophy [122]. Clinical features of radiation myelopathy are discussed in Chap. 14. See Fig. 28.4a, b.

Patients with treated head and neck cancer may have focal neurologic symptoms and personality changes due to delayed cerebral radionecrosis. These lesions are usually in the frontal and temporal regions and on imaging may resemble high-grade gliomas or metastatic tumors. Histopathologic changes include fibrotic response of the meninges with pleomorphic and vacuolated fibroblasts, capillary hyperplasia, reactive astrocytes, and fibrosis of the blood vessels. Craniotomy is the recommended course of treatment [123] for symptoms unresponsive to corticosteroids or bevacizumab.

Cranial nerve palsy (CNP) is a rare complication of RT. In a study of 328 patients with nasopharyngeal carcinoma who received RT, 72 were found to have CNP after a mean follow-up of 11.2 years. The latency of palsy ranged from 0.6 to 16 years. Most patients develop CNP after two years. In those who received first course RT, CN IX and CNX were mostly affected (85%). In patients with reradiation, most had multiple upper cranial nerve injuries. Patients with facial–cervical field radiation had a significantly longer latency compared with patients who developed facial–cervical split fields [124]. In other studies, CNXII nerve has been shown to be most commonly affected [125].

Vasculopathy from RT for head and neck cancers may cause neurologic symptoms. The damage to small vessels and the endothelium can produce cerebral radionecrosis [123]. The injury to large vessels, such as the carotid artery, leads to stroke. The key mechanism of accelerated carotid atherosclerosis, endothelial damage, and fibrosis are due to tissue necrosis and inflammation caused by radiation. These mechanisms resemble morphologic features of spontaneous atherosclerosis [126]. Radiation-induced carotid disease is limited to the irradiated area and is less likely associated with atherogenic risk factors [127]. In a meta-analysis of 34 papers on radiation-induced carotid atherosclerosis, the authors found relative risk of stroke to be 5.6 in patients treated for head and neck cancer. The prevalence of carotid artery stenosis was increased by 16–55%, and carotid intima medial thickness was increased by 18–40% [128]. Carotid Doppler is recommended for long-term follow-up of these patients.

Cisplatin produces dose-related ototoxicity and peripheral neuropathy. It occasionally causes LS, which indicates the involvement of the centripetal branch of the sensory pathway within the spinal cord [129]. Chemotherapy protocols for head and neck cancers using cisplatin (commonly 100 mg/m² for every 3 weeks with concurrent radiation) rarely achieve the cumulative dose of cisplatin sufficient to produce a high incidence of peripheral neuropathy (cumulative dose ≥ 300 mg/m²). Peripheral sensory neurotoxicities with platinum agents vary from paresthesias in fingers, loss of vibration, and ankle jerks to ataxic gait (loss of proprioception), which might be transient or irreversible. It damages peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways which mediate apoptosis [130]. However, severe neuropathy is seen in <1% of patients treated for head and neck cancer. Ototoxicity is another progressive and irreversible adverse effect of platinum chemotherapy with a high frequency of almost 88%; it usually presents bilaterally and may occur during or years after treatment [131]. Cisplatin accumulates in the cochlear tissue, forms DNA adducts, and causes inefficient and dysfunctional protein and enzyme synthesis leading to apoptosis of auditory sensory cells [132]. However, severe ototoxicity is seen in fewer than 5% of treated HNSCC patients. Cisplatin is almost always given in combination with other chemotherapy drugs and/or radiation, which could also be neurotoxic. However, the concurrent use of cisplatin/5-FU in moderate doses with radiation resulted in no instances of myelopathy or other CNS complications [133].

Other chemotherapeutic agents, including paclitaxel and docetaxel, are used in combination with cisplatin for treatment of head and neck cancer. This increases the risk of peripheral neuropathy. Paclitaxel-induced peripheral neuropathy is also associated with proximal muscle weakness [134]. The combination of paclitaxel, ifosfamide, and cisplatin (TIP regimen) is sometimes used for recurrent head and neck cancer, which can cause a higher incidence of peripheral neuropathy and fatigue. When cisplatin was replaced with carboplatin in the regimen (TIC), the side effects decreased significantly [39]. Other new chemotherapy agents, such as cetuximab, can cause peripheral neuropathy, fatigue, and weakness. However, there are not many cases reported in the literature.