Clinical manifestations

Presentation and course

Some of the syndromes associated with tumors at the base of the skull are shown in Table 1.

Table 1. Multiple Cranial Nerve Syndromes Associated with Lesions at the Base of the Skull

Cavernous sinus syndrome is often used as a working diagnosis of signs and symptoms related to the four cranial nerves passing through the cavernous sinus. One study made an interesting observation that there was an approximately linear correlation between the number of cranial nerves affected by a lesion and the percentage of lesions located within the cavernous sinus (55). The likelihood of a lesion to be in the cavernous sinus increases to 77.8% with involvement of all four nerves, as compared to 17.7% if only one nerve is involved.

Prognosis and complications

Prognosis depends on the pathology of the primary lesions. Prognosis is poor with infiltration of the base of skull by malignant processes. Many of these tumors are inoperable and are treated with radiation therapy. Five-year survival of nasopharyngeal carcinoma with radiation therapy lies between 25% and 50%. Early detection of a tumor at the base of the skull in an operable stage may improve the prognosis.

Biological basis

Etiology and pathogenesis

Various causes of multiple cranial nerve palsies are shown in Table 2.

Table 2. Causes of Multiple Cranial Nerve Palsies

Cranial nerves pass through distinct passages at the base of the skull to innervate various structures in the head and the neck. They are vulnerable to lesions that involve the base of the skull. They are also liable to be involved after exit from the skull base to the structures in the neck. Other parts of the cranial nerves that are susceptible to discrete lesions are those between the brain and the base of the skull. In addition to lesions at the bony base of the skull, the nerves in this portion are liable to be involved in inflammatory processes involving the meninges, trauma and vascular malformations, and intracranial aneurysms. Giant intracranial aneurysms can involve multiple cranial nerves. Cranial nerves may also be affected due to vascular disturbances, such as those that result from vasculopathies involving the cerebral arteries and their branches.

Cranial nerve palsies due to cancer. The most frequent cause of cranial nerve palsies is malignant disease involving the base of the skull. Histology and primary location of the tumor do not play a decisive role in the causation of the cranial palsy. Damage to cranial nerves occurs during the infiltration by the tumor without intradural extension and rise of intracranial pressure. For example, malignant nasopharyngeal tumors expand in two directions: (1) through the foramen lacerum into the middle cranial fossa, then into the cavernous sinus and the superior orbital fissure with involvement of cranial nerves III to VI; and (2) to the lymph nodes behind the parotid gland with compression of the cranial nerves IX to XII.

A case of adenoid cystic carcinoma arising from the right salivary gland presented with right multiple cranial nerve palsies without any mass formation (39). The neurologic manifestations were attributed to the perineural spread of cancer. Leptomeningeal leukemic infiltration of basal meninges often presents with multiple cranial nerve palsies. A patient with multiple cranial nerve palsies was diagnosed with B-cell type acute lymphoblastic leukemia, and the presence of leukemic blast cells in CSF confirmed the diagnosis of leukemic meningitis (26). A patient with diffuse large B-cell lymphoma, which was in remission following chemotherapy, presented with dysphagia due to vagus nerve palsy, and later developed rapidly progressing bilateral seventh and eighth cranial nerve palsies, which was diagnosed as leptomeningeal recurrence of lymphoma (27). Cerebrospinal fluid analysis and flow cytometry, revealing markedly atypical monotypic CD19 positive B cells, confirmed the diagnosis.

Cranial nerve palsies as a sequel of radiotherapy for cancer. Although cranial nerves are relatively resistant to radiotherapy, late radiation-associated dysphagia is a rare delayed toxicity after radiotherapy and/or chemotherapy for oropharyngeal cancer, and a study reported that lower cranial neuropathies were present in 10 of 12 cases (11). Mean dose delivered to superior pharyngeal constrictor, but not the regions of interest containing cranial nerve paths, significantly predicted late-radiation-associated dysphagia and related cranial neuropathies.

Cranial nerve palsies as a complication of surgical procedures. Injuries to the auditory and facial nerves are well-known complications of removal of acoustic neuroma. Procedures involving cavernous sinus are associated with cranial nerve injuries. Internal carotid artery injury during endoscopic endonasal surgery, particularly if it involves the cavernous segment, can be associated with multiple cranial nerve palsies (18).

A case of multiple cranial nerve palsies, manifested by facial palsy and sensorineural hearing loss, has been reported after gamma knife surgery for vestibular schwannoma likely due to acute radiation necrosis in the tumor (44).

Multiple cranial nerve palsies as a sequel of neonatal hypoxia/ischemia. A newborn delivered by Cesarian section, who needed to be resuscitated, showed features of multiple right-sided lower motor neuron type of cranial nerve palsies (cranial nerves V, VII, IX, X) due to hypoxic-ischemic encephalopathy involving the brainstem (89).

Cranial neuropathies due to infections. Although involvement of skull base producing multiple cranial nerve palsies is usually from a malignant process, infections may also involve the base of skull. There are geographical variations in etiology. In a report from India, infections (40.7%) were the most common cause and only in only four patients the syndrome was described as neoplastic and idiopathic (64). Four cases of infective skull-base lesions causing multiple lower cranial nerve palsies in elderly patients have been described (77).

Epidemiology

Of the 20 cases of Garcin syndrome published between 1970 and 1988, 16 were due to malignant disease, one was due to compression from a benign intracranial tumor, and three were due to an infectious process (30). If one drops the definition of multiple cranial nerve lesions to involvement of two or more nerves, the number of cases may be impossible to record. In a hospital-based prospective observational study from 2015 to 2017 on 54 consecutive patients with multiple cranial palsies, the most frequently involved nerve was the abducens (75.9%) among all nerve combinations, whereas the cavernous sinus syndrome (37%), orbital apex syndrome (22.2%), and jugular foramen syndrome (11.1%) were the most frequent anatomical patterns (64).

Differential diagnosis

Confusing conditions

The differential diagnosis of multiple cranial nerve palsies involves two important steps:

(1) Localization of the cranial nerves involved and the allocation of an eponym, if it fits.
(2) Determination of the pathology of the lesion.

Various pathological processes that can be identified are as follows:

Primary malignancies at the base of skull. These include tumors of the nasopharynx, cylindromas, and osteosarcomas.

Metastatic tumors involving the base of the skull. A case of Garcin syndrome due to metastasis to the skull from breast carcinoma has been described (14). The patient presented with a unilateral abducent paralysis 12 years after mastectomy for breast carcinoma. Multiple unilateral cranial nerve involvement (V to XII) developed over a period of six months. CT scan showed the unilateral destructive lesion at the base of the skull on one side. A patient with metastatic breast carcinoma who presented with nausea, anorexia, vertigo, apraxia of lid closing, and dysphagia due to multiple cranial nerve palsies had improvement of cranial nerve symptoms after one week of palliative irradiation to the skull base (12).

In another case of Garcin syndrome with progressive cranial nerve palsies, MRI revealed an intracranial extension of a tumor from the skull base, which had metastasized from carcinoma of the lung (23). Cranial nerve palsies in metastatic prostate carcinoma usually occur late in the course of the disease, but a case is reported where diagnosis of prostate cancer was made following investigation of multiple cranial nerve palsies (65).

Benign tumors at the base of the skull. Acoustic neurinomas, and sphenoid ridge meningiomas may present with multiple cranial nerve palsies. Often, with large tumors, there will be signs of raised intracranial pressure as well as other localizing signs. Diagnosis of these treatable lesions can be made both clinically and radiologically. Parapharyngeal branchial cleft cyst can manifest as multiple, lower cranial nerve palsies (93).

Pituitary carcinoma. Pituitary carcinomas usually originate by transformation of benign invasive macroadenomas. A pituitary macroadenoma that invaded into the right cavernous sinus presented with abducent nerve palsy that resolved following transsphenoidal surgery plus Gamma Knife® radiation, but tumor recurred with malignant change producing right lower cranial nerve palsies, which resolved following repeat Gamma Knife radiation (75). Multiple cranial nerve palsies in this patient indicated malignant transformation of the tumor.

Giant cell tumor. This is a primary bone tumor rarely affecting the skull base. There is a case report of an 8-year-old child who presented with unilateral cranial nerve palsies of the 5th cranial nerve to the 12th cranial nerve and fulfills the criteria of Garcin syndrome (15).

Meningeal carcinomatosis. The cranial nerves involved are usually II, III, IV, VI, and VII. The involvement may be bilateral. There are headache and signs of raised intracranial pressure. Malignant cells can be demonstrated in the cerebrospinal fluid. Rarely, multiple cranial nerve palsies present as a manifestation of leptomeningeal involvement by glioblastoma multiforme (102).

An extramedullary anaplastic ependymoma has been reported that presented with bone metastases and intracranial leptomeningeal carcinomatosis (80). MRI scan revealed leptomeningeal carcinomatosis in the brainstem, the cerebellum, and along the whole spinal cord.

Orbital apex syndrome. It can result from multiple causes, including neoplasia, trauma, inflammation, and infection. The syndrome manifests as visual impairment from optic nerve dysfunction combined with extraocular muscle palsy (16).

Paraneoplastic syndrome with multiple cranial nerve palsies. One patient with small-cell lung cancer developed multiple cranial nerve palsies, including palsies of the left 5th nerve through 10th nerve and both 12th nerves as a manifestation of paraneoplastic sensory neuronopathy (24). There were no metastasis or direct invasion of malignancy, but there was gliosis and perivascular inflammation throughout the brainstem, indicating paraneoplastic encephalomyelitis. A paraneoplastic syndrome with involvement of multiple cranial nerves has been reported and may precede diagnosis of testicular cancer (68).

Multiple cranial nerve palsies may result from paraneoplastic effect of a tumor rather than local compression. There is a case report of an immunocompetent patient who presented with facial palsy, and then progressively developed other cranial nerve palsies over several months and was later diagnosed with diffuse large B cell lymphoma originating from the frontal sinus (49).

A patient developed cranial nerve palsies as of a paraneoplastic neurologic syndrome associated with gallbladder cancer starting with diplopia and progressing to bilateral paresis of oculomotor, abducens, and facial nerves (43). Gall bladder cancer was discovered on imaging studies and resected followed by radiotherapy. All cranial nerve palsies resolved within two months after the operation, and both cancer and neuropathies have shown no recurrence for over five years.

Inflammatory lesions at the base of the skull. Inflammatory myofibroblastic tumor of the orbit has been reported to manifest as multiple progressive cranial nerve palsies involving II, V1 to V3, and X with orbital and infraorbital masses and diffuse dural enhancement demonstrated on MRI (63). Diagnosis of inflammatory myofibroblastic tumor was confirmed by biopsies of the orbital lesion; the manifestations quickly improved with steroid administration. A case of isolated sphenoiditis presented with unilateral multiple cranial nerve palsies and was treated successfully with functional endoscopic sinus surgical drainage, and histological confirmation of diagnosis was obtained by biopsy (94).

Fractures of the base of skull. Fractures of the base of the skull can damage cranial nerves on one side. Diagnosis can be made by history or by radiological demonstration of fracture. There may be cerebrospinal fluid rhinorrhea. Unilateral IX, X, XI, and XII cranial nerve palsies (Collet-Sicard syndrome) have been reported after sustaining a closed head injury with linear fractures of the occipital bone traversing through the right occipital condyle (111). A case of Collet-Sicard syndrome presented following a traumatic atlas fracture in a patient with congenital basilar invagination. Such a fracture can compromise the space and make cranial nerves IX through XII more vulnerable to compression injury (38). Delayed glossopharyngeal nerve, vagus nerve, and facial nerve palsies have been reported after a head injury with fracture of the petrous part of the temporal bone (114).

Mild head injuries without fracture of the base of the skull may be associated with multiple cranial nerve palsies. In one series of head injuries with Glasgow Coma Scale scores of 14 to 15, multiple nerve injuries were observed in 22.4% of cases; the most frequent association was between cranial nerves VII and VIII (20). After one year, cranial nerve deficit was present in only 30% of mild head injury cases without CT abnormalities as compared to 81.2% of the cases with a skull base fracture.

Complications of surgery and other procedures at base of skull. Multiple cranial nerve palsies are recognized as complications of surgery on tumors around skull base, some of which already present with cranial nerve involvement. A patient developed multiple cranial nerve palsies following radiofrequency ablation for trigeminal neuralgia and improved over a period of four months (56).

Vascular diseases. Giant aneurysms of the circle of Willis can cause pressure on cranial nerves. Jugular bulb diverticulum, a rare condition, has been reported in association with lower cranial nerve palsies and multiple intracranial aneurysms in a patient who presented with dysphagia and hoarseness (52). The patient recovered after repair of the aneurysms.

Cavernous sinus thrombosis can involve the cranial nerves traversing the sinus and can produce a cavernous sinus syndrome. Multiple cranial nerve palsies (III to VIII), without evidence of other signs and symptoms, have been documented in patients with thrombosis of the ipsilateral transverse and sigmoid sinus (53). The diagnosis was supported by MRI with the application of a newly developed subtraction technique.

The usual presentation of spontaneous internal carotid artery dissection includes ipsilateral hemicranial headache, oculosympathetic paresis, and contralateral focal cerebral ischemic deficits. Multiple cranial nerve palsies are reported in more than 10% of patients with spontaneous dissection of the internal carotid artery. Two cases with multiple cranial nerve involvement ipsilateral to the dissection as the principal feature have been described (76). One of these patients had involvement of the IX, X, XI, and XII cranial nerves, and the other showed abnormalities of the V, VII, IX, X, and XII cranial nerves. In both, MRI revealed a ring-like area of abnormal signal intensity surrounding the carotid artery at the skull base. Carotid angiography was consistent with the suggestion of dissection on the magnetic resonance studies in both cases. Another patient with right internal carotid artery dissection developed ipsilateral II, V, VII, VIII, IX, X, and XII cranial nerve deficits, which resolved as the internal carotid artery recanalized following conservative treatment (61). The acute onset of cranial nerve palsies IX through XII, mostly accompanied by pain in the head, neck, or ear, should prompt consideration of a diagnosis of internal carotid artery dissection (79). Internal carotid artery dissection, presenting multiple cranial nerve palsies, could be mistaken for an infiltrating tumor of the skull base, and MRI is useful in correctly identifying the condition.

Vertebrobasilar occlusive disease may produce multiple cranial nerve palsies but is easy to distinguish clinically because of the involvement of other structures in the brain stem.

Collet-Sicard syndrome with paralysis of cranial nerves IX to XII due to internal carotid artery dissection was observed (97).

Giant cell arteritis, a systemic vasculitis of medium and large arteries, often presents with ophthalmic involvement, including ischemic optic neuropathy, retinal artery occlusion, and ocular motor cranial nerve palsies (87).

Infections. Any subacute or chronic meningitis may involve the cranial nerves. Well-recognized causes are pneumococcal, tubercular, cryptococcal, mycoplasmal, and treponemal infections. Craniovertebral junction tuberculosis is a cause of multiple cranial nerve palsies, and diagnosis is confirmed on histopathological examination. A patient with skull base osteomyelitis due to septic pulmonary embolism who presented with multiple cranial nerve palsies was treated successfully with antibiotics and anticoagulants (54). One patient with AIDS who developed cryptococcal meningitis had involvement of five cranial nerves, resulting in the complete loss of vision and hearing as well palsies of cranial nerves III, VI, and VII, which improved following treatment with multiple antifungal medications (66). Scrub typhus has been reported to present as acute or subacute meningitis complicated by multiple cranial palsies and cerebellitis (37).

Another patient with AIDS presented with neurosyphilis as the initial manifestation of HIV infection with acute bilateral hearing loss and bilateral facial droop multiple cranial nerves palsies caused by direct invasion of the central nervous system by the spirochete Treponema pallidum (08). Basal meningoencephalitis resolved with recovery of cranial nerves after a course of treatment with penicillin, and antiretroviral therapy was started later. Another case of neurosyphilis that was also HIV positive presented with multiple cranial nerve palsies (81).

Multiple cranial nerve palsies may occur in viral infections. Unilateral IX, X, and XI have been reported in a rare case of laryngeal herpes zoster where the mucosal lesions were discovered during upper gastrointestinal endoscopy, and the patient recovered with antiviral therapy (108).

Varicella zoster. Virus infections such as varicella zoster may rarely cause multiple cranial nerve palsies. These can be recognized by cerebrospinal fluid examination, serology, or molecular diagnostics. Unilateral cranial neuropathy involving cranial nerves VII to X has been associated with serological evidence of varicella zoster infection (62). A case of multiple cranial nerve palsies (left VIII, IX, X, XI and right VII, IX, X) has been reported to be due to varicella zoster infection (47). Multiple lower cranial nerve palsies due to the reactivation of varicella zoster virus may be present without skin lesions; this is known as zoster sine herpete. There is a case report of a patient with unilateral involvement of the cranial nerves VIII, IX, X, and XI without skin lesions and mononuclear pleocytosis in the cerebrospinal fluid with antibodies against Herpes zoster (101). Another patient with varicella zoster, who initially presented with Ramsay Hunt syndrome, later developed multiple cranial nerves palsies mimicking Garcin syndrome but improved following treatment with intravenous acyclovir and corticosteroids (71).

Chickenpox. Guillain-Barré syndrome is a rare complication of chickenpox. A case is reported with flaccid areflexic quadriparesis and bilateral seventh, ninth, tenth, and twelfth cranial nerve palsies 10 days after chickenpox (13). CSF analysis done in the second week showed marked lymphocytic pleocytosis, and electroneurographic studies were suggestive of acute inflammatory demyelinating polyradiculopathy.

Cranial neuropathies in COVID-19. Loss of smell due to involvement of olfactory nerves is a well-recognized symptom of involvement of the nervous system in COVID-19. Cases of isolated third and sixth cranial nerve palsies have also been reported in COVID-19 patients. There is a case report of a patient with Miller Fisher syndrome, a variant of Guillain-Barre syndrome, who presented with involvement of third, fourth, and sixth cranial nerves 20 days after testing positive for COVID-19 (92). Absence of intrathecal production of SARS-CoV-2 antibodies as disease-causing antibodies in CSF in this as well as 2 previously reported cases led the authors to suggest that different immune-mediated mechanisms were involved as compared to those of non-COVID-19 Miller Fisher syndrome (31; 84). All the reported patients recovered after intravenous immune globulin therapy.

Infectious mononucleosis. Multiple cranial nerve palsies can occur due to inflammatory lesion in the jugular foramen as a complication of infectious mononucleosis.

Malignant otitis externa. This syndrome consists of an antibiotic-resistant Pseudomonas aeruginosa infection of the external auditory meatus with osteomyelitis of the temporal bone. It usually affects patients with long-standing diabetes mellitus and a weakened immune system. The incidence of multiple cranial nerve palsy was reported to be 24% of one series of cases of malignant otitis externa (07). Malignant external otitis often spreads inferiorly from the external canal to involve the subtemporal area and progresses medically toward the petrous apex leading to multiple cranial nerve palsies. There is a case report of a 65-year old diabetic man who presented with progressing left otitis externa and developed ipsilateral proptosis, ophthalmoplegia, blindness, facial palsy, hearing loss, and contralateral evolvement of the temporal bone with hearing impairment (96). With history of otitis externa in an immunocompromised or diabetic patient presenting with multiple cranial nerve palsies, a diagnosis of osteomyelitis of base of the skull should be considered.

CT findings in malignant external otitis include obliteration of the normal fat planes in the subtemporal area as well as patchy destruction of the bony cortex of the mastoid. The point of exit of the various cranial nerves can be identified on CT scans, and the extent of the inflammatory mass correlates well with the clinical findings.

Fungal infections. Aspergillosis of the CNS should be considered in those with clinical features of headache, multiple cranial nerve palsies, and alteration of consciousness accompanied by sinusitis, especially in elderly and diabetic patients. Mucormycosis is a devastating fungal disease that occurs most commonly in immune-suppressed patients who have burns, are on long-term corticosteroid therapy, or present with diabetic acidosis. Cases of Garcin syndrome have been reported with unilateral palsy of all cranial nerves in patients with rhinocerebral mucormycosis (33; 69). The disease is often fatal when cerebral extension occurs with multiple cranial nerve involvement. One patient with malignant lymphoma was reported with an acute rhinocerebral infection after chemotherapy that manifested initially as a stuffy nose and intractable headache. Ptosis, proptosis, and multiple cranial nerve palsies appeared later (103). Rhinocerebral mucormycosis should be ruled out in patients with diabetes mellitus or immunosuppressed patients presenting with rapid onset of multiple cranial nerve palsies (46). A patient who presented with right-sided facial paralysis and paresthesias in the maxillary division of trigeminal nerve due to extensive fungal sinusitis with sphenoid sinus dehiscence and skull base osteitis underwent endoscopic sinus debridement and systemic antifungal therapy with full recovery of cranial neuropathies (34).

Intracranial hypertension. Multiple cranial nerve palsies have been described as a complication of pseudotumor cerebri, presumably due to stretching of the cranial nerves due to raised intracranial pressure. These usually recover following measures to reduce intracranial pressure. A 13-year-old boy who presented with papilledema as well as an acute-onset paresis of the left abducens and facial and vagus nerves was diagnosed with pseudotumor cerebri and recovered following acetazolamide therapy (09). Intracranial hypertension due to venous sinus thrombosis has been reported to be associated with multiple cranial nerve palsies (82).

Granulomatous diseases. Granulomas can be due to diverse causes such as infections and vasculitis, or due to unknown causes.

Granulomatous infections. There is a case report of a patient with multiple cranial nerve palsies of V, VII, VIII, IX, X, XI and spastic paraparesis due to hypertrophic cranial pachymeningitis extending into the spinal epidural space and originating from a bacterial infection secondary to the secretory otitis media (03). MRI revealed hypertrophy of the dura of the posterior fossa and a spinal epidural mass that showed chronic granulomatous change on biopsy.

Sarcoidosis. Sarcoidosis is a multisystem granulomatous disorder of unknown cause. There is a predilection for the lungs, with up to 90% of cases displaying pulmonary sarcoidosis. Neurosarcoidosis is relatively rare and accounts for approximately 5% to 15% of cases. Sarcoidosis typically produces unilateral or bilateral facial palsies and less commonly involves the II and VIII nerves. In a series of patients with neurosarcoidosis, 72% of the patients presented with cranial nerve palsies (115). One case of neurosarcoidosis presented with multiple cranial nerve palsy manifested by hyposmia, visual loss, facial hypoesthesia, facial weakness, dysphagia, and gustatory disturbance (107). A case has been reported with the involvement of cranial nerves V, VII, VIII, IX, and X following a viral-like illness (86). Biopsy of lymph nodes showed granulomatous lymphadenopathy, and the diagnosis was made on combined clinical, radiological, and histological findings. The patient recovered following corticosteroid therapy. A review of 64 patients in Japanese literature with multiple cranial nerve palsy due to sarcoidosis showed that the most commonly affected cranial nerves were the facial and glossopharyngeal/vagus nerves, and most of the patients received systemic steroid therapy with total or partial remission in 96.5% of the patients (73).

Wegener granulomatosis. This is a systemic granulomatous vasculitis involving multiple organs. The neurologic complications are due to vasculitis, but it may encroach on the base of the skull and involve cranial nerves (45). Palsies affecting cranial nerves VII to XII were manifestations of a case of Wegener granulomatosis due to refractory sinus disease, and it was successfully treated with immunosuppressive therapy (51).

Hyperostosis of the skull. Paget disease of the bone may narrow the exit foramina of the skull and affect any of the cranial nerves. The VIII nerve is affected with progressive loss of hearing. Involvement of the V and VI nerves are associated with trigeminal neuralgia and hemifacial spasm respectively. Lower cranial nerves are involved if there is associated platybasia. Diagnosis can be established by plain x-rays of the skull and CT of the skull base. Serum alkaline phosphatase is elevated.

Hyperostosis cranialis interna. This is a genetic bone disorder with intracranial hyperostosis and otosclerosis of the calvaria and the base of the skull. The rest of the skeleton is normal. A case has been described where this disorder led to variable involvement of cranial nerves I, II, VII, and VIII from late childhood onward (59). The diagnosis was based on appearance of the skull on x-rays. Among the eight members of the family who had this lesion of the skull, only a single member has remained asymptomatic on follow-up. The age of onset ranged from nine years to 32 years.

Osteopetrosis of skull. Osteopetrosis, a rare inherited disorder characterized by increased bone density, is caused by reduced activity of osteoclasts, which results in defective remodeling of bone. Complications can include compression of cranial nerves. A 6-year old girl presented with strabismus, impaired hearing, loss of vision, frontal bossing, and diffusely thickened bones of the skull on CT (113).

Multiple sclerosis. The multiplicity of neurologic signs in multiple sclerosis include those due to lesions of visual pathways, disturbances of eye movements, and brainstem manifestations, including facial palsy. These patients may also present with trigeminal neuralgia that may resemble the idiopathic form. History, clinical neurologic examination, and MRI of the brain help to distinguish this disease from most of the other pathologies mentioned in the differential diagnosis.

Hypertrophic pachymeningitis. Multiple cranial nerve palsies can occur in intracranial hypertrophic pachymeningitis (fibrosclerosis of the meninges) with normal cerebrospinal fluid findings. Many of these cases are idiopathic. Gadolinium-enhanced MRI is essential in identifying meningeal inflammation and locating suitable sites for biopsy. The causes in reported cases, however, include tuberculosis, Lyme disease, and sarcoidosis. One case report is that of an old man who presented with multiple cranial nerve palsies, central diabetes insipidus, and had an elevated serum titer of perinuclear antineutrophil cytoplasmic antibody (99). MRI showed thickening of the dura and an intrasellar mass. The etiology could not be determined, but corticosteroid and oral cyclophosphamide therapy improved his neurologic symptoms. Another patient with hypertrophic pachymeningitis and multiple cranial nerve palsies of the left II and III, bilateral VI and VII, and right IX, X, and XII cranial nerves had hypopituitarism due to hypothalamic failure (58). The patient was seropositive for rheumatoid factor, but there were no symptoms of rheumatoid arthritis. In a patient with hypertrophic pachymeningitis, presenting features were bilateral loss of vision, left hearing loss, and right IX, X, and XI nerve palsies (104). Dural biopsy showed inflammatory thickening of the dura mater with infiltration by plasma cells that were immunoreactive to an anti-IgG4 antibody. There was some improvement following corticosteroid therapy.

A retrospective case series of patients with multiple cranial nerve palsies due to pachymeningitis in granulomatosis with polyangiitis has been reported from Latin America (36). Gadolinium-enhanced brain MRI showed dural thickening in 12 patients and leptomeningeal enhancement in one patient. They were treated with a combination of glucocorticoids plus immunosuppressants with improvement of the condition.

Melkersson-Rosenthal syndrome. This is complex neuromucocutaneous disorder with recurrent facial edema, facial palsy, and fissured tongue, which can be associated with multiple cranial nerve palsies in complete form (116).

Moebius syndrome. This is a rare congenital anomaly due to intrauterine hypoxia and is characterized by multiple cranial nerve palsies, orofacial malformations, and limb anomalies. Children with this syndrome also drool saliva.

Idiopathic cranial polyneuropathy. The diagnosis is usually made after exclusion of other causes. This term is also used for an unusual syndrome of pain in the face and head followed by the onset of multiple cranial nerve palsies occurring days to weeks later (42). Cranial nerves III to VII are involved in various degrees. Involvement of the lower cranial nerves (VIII to XII) is less common. Fifty percent of these patients have mild cerebrospinal fluid lymphocytosis or protein elevation.

Complication of Ramsay Hunt syndrome. Ramsay Hunt syndrome is associated with varicella zoster virus infection along the distribution of the sensory nerves innervating the ear, which usually includes the geniculate ganglion and is associated with facial paralysis unilaterally. Rarely, other cranial nerves may be affected. One case of Ramsay Hunt syndrome evolved into multiple cranial nerve palsies involving cranial nerves V, VII, VIII, IX, X, XI, and XII unilaterally (67). A retrospective study reviewed 11 patients with Ramsay Hunt syndrome who presented with cranial polyneuropathy between 1999 and 2009; all of these were treated with systemic steroids and antiviral agents resulting in improvement of cranial nerve functions except hearing loss in most patients (50). There is a case report of Ramsay Hunt syndrome with delayed-onset multiple cranial nerve involvement causing severe dysphagia and aspiration, and a clinical course that improved after more than one year of dysphagia rehabilitation and percutaneous endoscopic gastrostomy (48).

Guillain-Barré syndrome. About half of the patients with this syndrome develop cranial nerve palsies following the ascending limb weakness. Facial palsy is the most common; bulbar palsy and weakness of the muscles of mastication follow close behind in frequency. Ocular palsy occurs in 10% of the patients. In 80% of Guillain-Barré syndrome cases, spinal cord involvement, clinical course of the disease, and cerebrospinal fluid findings of protein elevation with normal cell count help to distinguish it from other cranial neuropathies. An atypical case of Guillain-Barré syndrome presented only with multiple cranial nerve palsies (74).

Metabolic disorders. Renal injury impairs skeletal anabolism, decreasing the osteoblast compartment of the skeleton and consequent bone formation. There is a case report of bilateral deafness and recurrent episodes of bilateral facial nerve palsy that were caused by renal osteodystrophy, and it was suggested that this condition be considered in the differential diagnosis of multiple cranial nerve palsies (02).

Cranial diabetic neuropathy. Diabetes mellitus is usually associated with peripheral neuropathies and rarely with cranial nerve palsies. In a large series, cranial nerve palsies were identified in 0.75%, which were mostly isolated III, VII, or VI nerve palsies, and multiple palsies in only 0.04% of these (29). A case report shows the possible rare association between uncontrolled diabetes and the involvement of trigeminal, glossopharyngeal, and vagal nerves, which were managed by glycemic control (60). A 55-year-old diabetic woman developed simultaneous right VII and left III, IV, VI cranial nerve palsies that responded to treatment with intravenous immunoglobulin (106).

Hypothyroidism. A patient who presented with mild facial palsy on the left side, uvular deviation to the left with preserved gag reflex, tongue deviation to the left, and lingual dysarthria was diagnosed with hypothyroidism, which can rarely cause multiple cranial neuropathies, but the patient improved after levothyroxine substitution (35).

Diagnostic workup

The following diagnostic procedures are recommended in a patient who presents with multiple cranial nerve palsies:

Management

Treatment of the cause of nerve palsies. Cancer detected early may be amenable to surgery and radiotherapy. In one retrospective study, brain irradiation was found to be effective in reversing the cranial nerve palsies in leukemic patients with no radiological evidence of intracranial leukemic infiltration (32). Corticosteroids have been used with improvement of inflammatory lesions. Calcitonin may be used in Paget disease with cranial nerve compression; however, the response is not as good as in cases of spinal cord compression.

Some of the infectious granulomas are amenable to appropriate antibiotic therapy. Malignant otitis externa requires intensive management with antibiotics, surgery, and hyperbaric oxygen therapy (41). This condition should no longer be called malignant for most of the patients for whom the disease is diagnosed early and treated adequately. The mainstay of the treatment of rhinocerebral mucormycosis is surgery for eradication of the underlying cause, amphotericin B, and hyperbaric oxygen.

Management of cases in which cause is not known. In cases of idiopathic multiple cranial nerve palsy, where no cause is discovered despite extensive investigations, good response may be obtained by use of corticosteroids. A case of multiple cranial neuropathy with positive antinuclear antibody but no established diagnosis responded to steroids even though there was no change in titer of antinuclear antibody (72). Marked improvement was reported following two cycles of intravenous immunoglobulin therapy in a child with multiple palsies involving cranial nerves III, IV, V, VI, VII, IX, X, XI, and XII after initial, unsuccessful treatment with corticosteroids and acyclovir (78).

Surgical procedures. Although surgical procedures are performed for correction of sequelae of lesions of some of the individual cranial nerves, patients with multiple cranial nerve palsies are usually considered for surgical procedures only for removal of the causative lesions, such as skull base tumors. In a case of dysphagia due to palsies of cranial nerves V and VII after radiotherapy for nasopharyngeal carcinoma, anastomosis of the functioning XII nerve to the buccal branch of the VII nerve in an end-to-side fashion, and direct implantation of a nerve graft from the spinal XI to the masseter muscle, failed to restore masticatory function (06).

Outcomes

Outcome of treatment depends on the cause of nerve palsies and the method of treatment.

Special considerations

Pregnancy

None of the reported cases of multiple cranial nerve palsies have been associated with pregnancy.

Anesthesia

Transitional lower cranial nerve palsies may occur as an adverse effect of bupivacaine-fentanyl combination used in patients during and following spinal anesthesia (05). This complication may occur a few days after the procedure and resolves by conservative measures. Delayed onset is difficult to explain but may be possibly due to CSF loss from the lumbar puncture site causing descent of the brain and stretching of the nerves.

Problems can arise during anesthesia in children with Moebius syndrome. There is a high incidence of difficult or failed intubation with potential for problems with aspiration of oral secretions. Use of premedication to reduce salivary secretion is recommended. Children with Moebius syndrome have a high incidence of other anomalies, including congenital heart disease. A careful preoperative assessment should be done.