Multiple Cranial Nerve Palsies: Analysis of 979 Cases

Background  To my knowledge, no large series of multiple cranial neuropathies is available.

Objectives  To examine the seats and causes of multiple cranial neuropathies in a large group of inpatients.

Design  Personal case series.

Setting  Wards of a large municipal hospital and affiliated rehabilitation hospital.

Patients  A consecutive series of 979 unselected inpatients with simultaneous or serial involvement of 2 or more different cranial nerves.

Results  Cranial nerves VI (565 cases), VII (466 cases), V (353 cases), and III (339 cases) were most commonly affected. The locations and causes were diverse, with cavernous sinus (252 cases), brainstem (217 cases), and individual nerves (182 cases) being the most frequent sites, and tumor (305 cases), vascular disease (128 cases), trauma (128 cases), infection (102 cases), and the Guillain-Barré and Fisher syndromes (91 cases total) being the most frequent causes. Recurrent cranial neuropathy was uncommon (43 cases, 106 episodes, 136 nerves), with diabetes mellitus (14 cases), self-limited unknown causes (14 cases), and idiopathic cavernous sinusitis (10 cases) being the usual causes.

Conclusion  While the locations and causes of multiple cranial neuropathy are highly diverse, the fact that tumor composes more than one quarter of cases places a premium on prompt diagnosis.

Most studies of multiple cranial neuropathy (MCN) address specific causes in small groups of cases, with emphasis on benign recurrent cranial neuropathy. To obtain an overview in a large inpatient population, I reviewed my experience with MCN.

Records of inpatients whom I personally examined over the past 34 years in the wards of the Los Angeles County/University of Southern California Medical Center, Los Angeles, and the Rancho Los Amigos National Rehabilitation Center, Downey, Calif, were studied. Patients with MCN are routinely admitted for evaluation at the Los Angeles County/University of Southern California Medical Center, making the inpatient basis for this study reasonably inclusive. Personal notes on all of the patients were reviewed, along with patient photographs (as 430 still photographs, 67 video segments, 57 motion picture clips, and 39 ocular fundus photographs were available) and selected radiographs and hospital records.

Patients who were selected had simultaneous or serial involvement of 2 or more different cranial nerves. Previously described patients^1-8 were included. Patients with botulism, but not those with myasthenia, were included. Neither postpapilledema optic atrophy nor chiasmal damage was tallied as second-nerve involvement. The first and ninth cranial nerves were not examined systematically and were not tabulated. Diagnoses were based on extensive inpatient evaluation using contemporary contrast studies and computed scans, spinal fluid examination, electrophysiological studies, and biopsies, as clinically indicated. Probable diagnoses were favored over no diagnosis.

Multiple cranial neuropathy is uncommon but not rare; these 979 cases compose 7.3% of the patients in my files.

Tumor was responsible for 305 (30%) of the 1028 cases (Table 1), with none of the 22 types of tumor constituting more than 18% of the total (Table 2). Schwannomas (53 cases: 46 cases from the eighth nerve, 4 cases from the fifth nerve, and 1 case each arising from the seventh, ninth, and tenth nerves) were most common, followed by metastases (49 cases) and meningiomas (41 cases). Lymphoma (29 cases) was more common than nasopharyngeal carcinoma (26 cases), but 4 cases of lymphoma and 2 cases of plasmacytoma appeared to originate in the nasopharynx. Of 33 intramedullary brainstem tumors, 28 were gliomas, 3 were metastases, 1 was ependymoma, and 1 was primary lymphoma. (The tuberculoma and histiocytoma also were located within the brainstem.) An apoplectic onset characterized 7 of the 16 pituitary adenomas. Less common tumors included chordoma (14 cases), leukemia (8 cases), epidermoid (7 cases), and glomus tumors (6 cases). Of 22 miscellaneous tumors, 4 were plasmacytomas, 4 were primitive neuroectodermal tumors, 3 were fibrosarcomas, 2 were rhabdomyosarcomas, 2 were cholesteatomas, and there was 1 case each of chondroma, myeloma, ependymoma, craniopharyngioma, hemangioblastoma, Ewing tumor, and endolymphatic sac tumor. The 40 leptomeningeal tumors comprised 20 cases of solid tumor metastases (6 cases of lung cancer, 6 cases of breast cancer, 2 cases of gastric cancer, and 6 cases of unknown primary origin), 10 cases of lymphoma, 7 cases of leukemia, and 1 case each of sarcoma, myeloma, and inflammation associated with an epidermoid.

The majority of the vascular cases (85 of 128 cases) resulted from infarcts in the lateral pons or medulla—3 cases of which were associated with meningitis, 3 with trauma, and 1 each with surgical complication, mixed connective tissue disease, and syphilis. Of 28 hemorrhages, 24 were pontine, 2 were pontomesencephalic, 1 was cerebellar with brainstem compression, and 1 was cerebral with transtentorial herniation; 21 hemorrhages were attributed to hypertension (1 to eclampsia), 3 to arteriovenous malformations, 3 to cavernous and complex angiomas, and 1 to trauma. Aneurysms (8 carotid cavernous aneurysms, including 1 traumatic aneurysm,⁵ and 1 midbasilar aneurysm) were responsible for 9 cases, and carotid-cavernous fistulae were responsible for 6 cases.

Of 92 cases with blunt trauma, there were 46 cases of automobile accidents, 22 cases of falls and beatings, 13 cases of motorcycle accidents,⁶ 7 cases of pedestrians hit by vehicles, 2 cases of automobiles falling from jacks (twice in 1 case!), and 1 case each of bicycle and horse accidents. Penetrating injury (36 cases) was less than half as common as blunt trauma, was dominated by gunshot wounds (33 cases), and was joined by single instances of stabbings with a cleaver, a pencil, and a ballpoint pen refill. One automobile accident victim sustained a cervical fracture with vertebral artery injury and delayed pontine infarction.⁷

Infection composed 102 (10%) of the 979 cases, with 48 cases of meningitis (22 acute bacterial, 9 tuberculous [Figure], 9 cryptococcal, 3 unknown, and 2 herpes zoster cases, and 1 case each of coccidioides, histoplasmosis, and viral cause, with 3 cases acting through brainstem infarcts), 10 cases of botulism (6 of which were wound-related), 8 cases of mucormycosis, 6 of cysticercosis, 8 of viral encephalitis, 4 of syphilis, 3 of osteomyelitis, 3 of bacterial sphenoid sinusitis, 3 that were hepatitis-related, 2 of otitis, 2 of cavernous sinus aspergillus, 2 of bacterial abscesses, 1 of tuberculoma, 1 of geniculate zoster, and 1 infectious mononucleosis-related case. Of 22 patients with AIDS (tallied under specific causes), 10 had lymphoma and 12 had infections that included 5 cryptococcal infections, 1 each of histoplasmosis, zoster meningitis, and cytomegalovirus encephalitis infections, and 4 probable viral brainstem encephalitis infections. (One patient had human immunodeficiency virus–related Bell palsy with functional overlay.)

Cases of Fisher syndrome (29 cases) blended seamlessly with those of Guillain-Barré syndrome (62 cases) and, when combined, formed the fifth most common cause of MCN, with 91 cases. Idiopathic cavernous sinusitis (Tolosa-Hunt syndrome) was the next most common (56 cases), and it was a common cause (10 cases [23%]) among the 43 cases of recurrent MCN. Surgical complications in 54 patients involved procedures for 16 cases of meningiomas, 9 of schwannomas, 9 of aneurysms, 5 of epidermoids, 4 of pituitary adenomas, 2 of chordomas, and 1 each of glomus tumor, pineoblastoma, hemangioblastoma, tumor of unknown type, arteriovenous malformation, fibrous dysplasia, carotid-cavernous fistula (balloon repair), carotid endarterectomy, and tonsillectomy. Demyelinating disease (54 cases) included cases of proven and probable multiple sclerosis as well as acute demyelinating encephalomyelitis. The 26 cases with functional cranial nerve signs represented various combinations of hysterical loss of smell, sight, facial sensation, and hearing, and, less frequently, face and tongue paralysis, ipsilateral to functional hemiplegia or, in 6 instances, to Bell palsy.²

Diabetes mellitus (25 cases) and benign self-limited cases (23 cases) were uncommon. The 21 miscellaneous cases comprised 3 cases of benign intracranial hypertension variants (2 cases with sixth- and seventh-nerve palsies and 1 case with gunshot occlusion of the lateral sinus with pressure-related ophthalmoplegia⁹), 3 cases with various combinations of Chiari malformation, syringes, and platybasia, 2 cases each of Wernicke encephalopathy, sarcoidosis, chronic demyelinating inflammatory polyneuropathy, and undefined degenerative diseases, and 1 case each of brainstem histiocytosis, systemic lupus erythematosis with generalized neuropathy, an adult with previously undiagnosed Moebius syndrome, radiation necrosis, basilar ectasia, neurofibromatosis with unexplained hydrocephalus, and an undiagnosed case with aqueductal stenosis.

The cavernous sinus was the most frequent site of involvement (252 cases) (Table 3), particularly by tumors (81 cases) and trauma (66 cases). Brainstem involvement (217 cases) was dominated by vascular causes (113 cases); nonlocalized neuropathy (182 cases) was dominated by the Guillain-Barré and Fisher syndromes (91 cases total); clivus-skull base (128 cases) was dominated by tumors (66 cases); and subarachnoid space (101 cases) was dominated by meningeal infection and tumor (97 cases).

Reflecting frequent involvement in cavernous sinus lesions and meningeal processes, the sixth cranial nerve (565 cases) was most commonly involved by a wide margin (Table 4). The seventh cranial nerve (466 cases) was implicated in the Guillain-Barré and Fisher syndromes as well as in benign causes and skull base lesions. Cranial nerves III (466 cases) and V (353 cases) were most commonly damaged within the cavernous sinus. Recurrent cranial neuropathy frequently involved cranial nerves VII (48 cases), III (36 cases), and VI (26 cases) (Table 4).

No patient had involvement of all of the cranial nerves, and only 1 patient (with nasopharyngeal carcinoma) had damage to all of the unilateral nerves. The average number of impaired cranial nerves per patient was 2.7, but 3 patients had 12 nerves involved, 1 patient had 11 nerves involved, 9 patients had 10 nerves involved, 8 patients had 9 nerves involved, and 29 patients had 8 nerves involved. Of the 50 patients with 8 or more impaired cranial nerves, 26 had Guillain-Barré or Fisher syndromes, 15 had tumors, 3 had botulism, 3 had other infections, and 3 had other causes. The most common combinations of involved cranial nerves were III and VI (285 cases), V and VI (214 cases), and V and VII (209 cases) (Table 5). By comparison, 222 patients had nystagmus, 91 had Horner syndrome (54 had first-neuron involvement), 57 had skew deviation, and 20 had internuclear ophthalmoplegia.

The French pioneered brainstem localization in the 19th century and localization of cranial nerve combinations in the early 20th century.¹⁰ A recent study¹¹ of idiopathic cranial polyneuropathy seen over 18 years in Lyon, France, is one of the few that addresses the overall causes of MCN: of 43 patients, 22 had tumor, 15 were idiopathic, 1 had trauma, 1 had brainstem infarct, 1 had Chiari malformation, 1 had paraneoplastic syndrome, 1 had cluster headache, and 1 had probable herpes zoster.

Most descriptions of MCN focus on the fascinating entity of benign recurrent cranial neuropathy, first characterized by Symonds.¹² It is relatively common in several countries in Southeast Asia, being seen 4 to13 times per year in large series,^13,14 but it occurs only about once per year in large US tertiary medical centers¹⁵ and less than once every 2 years in the present study. A relationship to other self-limited cranial neuropathies in idiopathic cavernous sinusitis¹⁶ and idiopathic cranial pachymeningitis¹⁷ has been posited.

Otherwise, most descriptions of MCN concern 1 or a few cases of unusual entities. Of particular interest are presentations that may elude the unfocused magnetic resonance image or its interpreter, such as osseous infection¹⁸ and metastasis,¹⁹ or intraneural spread of cutaneous malignancies.²⁰

In the present study, only 22% of MCN cases originated in the brainstem. Central signs were absent in just 1 case that had a lateral pontomedullary infarct similar to another in the literature.²¹ Nearly all of the brainstem cases of MCN will have telltale clues such as long track signs, gaze palsies, internuclear ophthalmoplegia, and complex spontaneous eye movement abnormalities. Because an origin of cranial nerve signs in the neck is rare (3% in this study) and may be overlooked on radiologic studies, a careful examination of the neck is indicated when lower cranial nerves are involved.

In summary, MCN affects a wide variety of cranial nerve combinations in diverse locations, resulting from a multitude of causes with varying prognoses. Since tumor is the most common cause by a wide margin, the appearance of MCN should be regarded as ominous. Prompt diagnosis is aided by careful clinical localization prior to a workup—usually centered on focused magnetic resonance imaging and spinal fluid analysis.

Correspondence: James R Keane, MD, Los Angeles County/University of Southern California Medical Center, Room 5641, 1200 N State St, Los Angeles, CA 90033.

Accepted for Publication: December 30, 2004.

Author Contributions:Study concept and design: Keane. Acquisition of data: Keane. Analysis and interpretation of data: Keane. Drafting of the manuscript: Keane. Critical revision of the manuscript for important intellectual content: Keane. Study supervision: Keane.

Acknowledgment: Frances C. Keane, RN, MPH, helped to organize and retrieve patient files.