ORIGINAL CONTRIBUTION

Multiple Cranial Nerve Palsies

Analysis of 979 Cases
James R. Keane, MD

Background: To my knowledge, no large series of mul-
tiple cranial neuropathies is available.
Objectives: To examine the seats and causes of mul-
tiple cranial neuropathies in a large group of inpatients.
Design: Personal case series.
Setting: Wards of a large municipal hospital and affili-
ated rehabilitation hospital.
affected. The locations and causes were diverse, with cav-
ernous sinus (252 cases), brainstem (217 cases), and indi-
vidual 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 idio-
pathic cavernous sinusitis (10 cases) being the usual causes.

Patients: A consecutive series of 979 unselected inpa-
tients 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
Conclusion: While the locations and causes of mul-
tiple cranial neuropathy are highly diverse, the fact that
tumor composes more than one quarter of cases places
a premium on prompt diagnosis.
Arch Neurol. 2005;62:1714-1717

Author Affiliations:
Department of Neurology,
University of Southern
California Medical School,
Los Angeles.
M
OST STUDIES OF MUL-
tiplecranialneuropathy
(MCN)addressspecific
causes in small groups
of cases, with emphasis
on benign recurrent cranial neuropathy. To
obtain an overview in a large inpatient popu-
lation, I reviewed my experience with MCN.
METHODS
Records of inpatients whom I personally ex-
amined over the past 34 years in the wards of
the Los Angeles County/University of South-
ern California Medical Center, Los Angeles,
and the Rancho Los Amigos National Rehabili-
tation Center, Downey, Calif, were studied.
Patients with MCN are routinely admitted for
evaluation at the Los Angeles County/Univer-
sity of Southern California Medical Center,
making the inpatient basis for this study rea-
sonably 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 simulta-
neous or serial involvement of 2 or more dif-
ferent cranial nerves. Previously described pa-
tients1-8 were included. Patients with botulism,
but not those with myasthenia, were included.
Neither postpapilledema optic atrophy nor chi-
asmal damage was tallied as second-nerve in-
volvement. The first and ninth cranial nerves
were not examined systematically and were not
tabulated. Diagnoses were based on extensive
inpatient evaluation using contemporary con-
trast studies and computed scans, spinal fluid
examination, electrophysiological studies, and
biopsies, as clinically indicated. Probable diag-
noses were favored over no diagnosis.
RESULTS
Multiple cranial neuropathy is uncom-
mon but not rare; these 979 cases com-
pose 7.3% of the patients in my files.
ETIOLOGY
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 metasta-
ses (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 plas-

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 macytoma appeared to originate in the nasopharynx. Of 33
intramedullary brainstem tumors, 28 were gliomas, 3 were Table 1. Causes of Multiple Cranial Neuropathies
metastases, 1 was ependymoma, and 1 was primary lym-
phoma. (The tuberculoma and histiocytoma also were lo- Overall Cases, Recurrent
Cause No. (%) Cases, No.
cated within the brainstem.) An apoplectic onset charac-
terized 7 of the 16 pituitary adenomas. Less common tu- Tumor 305 (30) 2
Vascular disease 128 (12) 0
mors included chordoma (14 cases), leukemia (8 cases),
Trauma 128 (12) 1
epidermoid (7 cases), and glomus tumors (6 cases). Of 22 Infection 102 (10) 1
miscellaneous tumors, 4 were plasmacytomas, 4 were primi- Guillain-Barré syndrome 62 (6) 0
tive neuroectodermal tumors, 3 were fibrosarcomas, 2 were Fisher syndrome 29 (3) 0
rhabdomyosarcomas, 2 were cholesteatomas, and there was Idiopathic cavernous sinusitis 56 (5) 10
1 case each of chondroma, myeloma, ependymoma, cranio- Surgical complication 54 (5) 0
pharyngioma, hemangioblastoma, Ewing tumor, and en- Multiple sclerosis and ADEM 54 (5) 0
Functional disease 26 (3) 0
dolymphaticsactumor.The40leptomeningealtumorscom- Diabetes mellitus 25 (2) 14
prised 20 cases of solid tumor metastases (6 cases of lung Benign 23 (2) 14
cancer, 6 cases of breast cancer, 2 cases of gastric cancer, Miscellaneous 22 (2) 0
and 6 cases of unknown primary origin), 10 cases of lym- Unknown 14 (1) 0
phoma, 7 cases of leukemia, and 1 case each of sarcoma, Total 1028* 43
myeloma, and inflammation associated with an epidermoid.
The majority of the vascular cases (85 of 128 cases) Abbreviation: ADEM, acute demyelinating encephalomyelitis.
*Some cases had more than 1 cause.
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 con-
nective tissue disease, and syphilis. Of 28 hemorrhages, Table 2. Tumors Causing Multiple Cranial Neuropathies
24 were pontine, 2 were pontomesencephalic, 1 was cer-
Tumor Type No. (%)
ebellar with brainstem compression, and 1 was cerebral
with transtentorial herniation; 21 hemorrhages were at- Schwannoma 53 (17)
tributed to hypertension (1 to eclampsia), 3 to arterio- Metastases 49 (16)
Meningioma 41 (13)
venous malformations, 3 to cavernous and complex an- Lymphoma 29 (10)
giomas, and 1 to trauma. Aneurysms (8 carotid cavernous Pontine glioma 28 (9)
aneurysms, including 1 traumatic aneurysm,5 and 1 mid- Nasopharyngeal carcinoma 26 (9)
basilar aneurysm) were responsible for 9 cases, and ca- Pituitary adenoma 16 (5)
rotid-cavernous fistulae were responsible for 6 cases. Chordoma 14 (5)
Of 92 cases with blunt trauma, there were 46 cases of Leukemia 8 (3)
Epidermoid 7 (2)
automobile accidents, 22 cases of falls and beatings, 13 cases
Glomus jugulare 6 (2)
of motorcycle accidents,6 7 cases of pedestrians hit by ve- Miscellaneous 22 (7)
hicles, 2 cases of automobiles falling from jacks (twice in Unknown 6 (2)
1 case!), and 1 case each of bicycle and horse accidents. Total 305
Penetrating injury (36 cases) was less than half as com-
mon 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 au- Cases of Fisher syndrome (29 cases) blended seam-
tomobile accident victim sustained a cervical fracture with lessly with those of Guillain-Barré syndrome (62 cases)
vertebral artery injury and delayed pontine infarction.7 and, when combined, formed the fifth most common cause
Infection composed 102 (10%) of the 979 cases, with 48 of MCN, with 91 cases. Idiopathic cavernous sinusitis (To-
cases of meningitis (22 acute bacterial, 9 tuberculous losa-Hunt syndrome) was the next most common (56
[Figure], 9 cryptococcal, 3 unknown, and 2 herpes zos- cases), and it was a common cause (10 cases [23%]) among
ter cases, and 1 case each of coccidioides, histoplasmosis, the 43 cases of recurrent MCN. Surgical complications in
and viral cause, with 3 cases acting through brainstem in- 54 patients involved procedures for 16 cases of menin-
farcts), 10 cases of botulism (6 of which were wound-re- giomas, 9 of schwannomas, 9 of aneurysms, 5 of epider-
lated), 8 cases of mucormycosis, 6 of cysticercosis, 8 of vi- moids, 4 of pituitary adenomas, 2 of chordomas, and 1 each
ral encephalitis, 4 of syphilis, 3 of osteomyelitis, 3 of bac- of glomus tumor, pineoblastoma, hemangioblastoma, tu-
terial sphenoid sinusitis, 3 that were hepatitis-related, 2 of mor of unknown type, arteriovenous malformation, fi-
otitis,2ofcavernoussinusaspergillus,2ofbacterialabscesses, brous dysplasia, carotid-cavernous fistula (balloon re-
1 of tuberculoma, 1 of geniculate zoster, and 1 infectious pair), carotid endarterectomy, and tonsillectomy.
mononucleosis-related case. Of 22 patients with AIDS (tal- Demyelinating disease (54 cases) included cases of proven
lied under specific causes), 10 had lymphoma and 12 had and probable multiple sclerosis as well as acute demyelin-
infections that included 5 cryptococcal infections, 1 each ating encephalomyelitis. The 26 cases with functional cra-
of histoplasmosis, zoster meningitis, and cytomegalovirus nial nerve signs represented various combinations of hys-
encephalitis infections, and 4 probable viral brainstem en- terical loss of smell, sight, facial sensation, and hearing,
cephalitis infections. (One patient had human immunode- and, less frequently, face and tongue paralysis, ipsilateral
ficiency virus–related Bell palsy with functional overlay.) to functional hemiplegia or, in 6 instances, to Bell palsy.2

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 A Table 3. Location of Cranial Nerve Damage

Location No. (%)

Cavernous sinus 252 (25)
Brainstem 217 (21)
Nerve 182 (18)
Clivus and skull base 128 (13)
Subarachnoid space 101 (10)
Cerebellopontine angle 86 (8)
Will (functional) 26 (3)
Neck 21 (2)
Unknown 1 (0)
Total 1014*

B *Some cases had more than 1 location.

Table 4. Number of Nerves Involved

Overall Cases Recurrent Cases

of Cranial Nerve of Cranial Nerve
Cranial Nerve Involved, No. Involved, No.
II 155 1
III 339 36
IV 143 2
V 353 10
VI 565 26
VII 466 48
VIII 180 3
X 220 2
XI 48 0
XII 163 2
Total 2632 130
Mean No. of cranial nerves 2.7 3.0
involved per patient

cases) and trauma (66 cases). Brainstem involvement (217

Figure. A, Patient with tuberculous meningitis attempting to open his eyes,
showing bilateral third- and left seventh-nerve palsies. B, Computed
tomographic scan shows associated hydrocephalus.
Diabetes mellitus (25 cases) and benign self-limited
cases (23 cases) were uncommon. The 21 miscella-
neous cases comprised 3 cases of benign intracranial hy-
pertension 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 malforma-
tion, syringes, and platybasia, 2 cases each of Wernicke
encephalopathy, sarcoidosis, chronic demyelinating in-
flammatory polyneuropathy, and undefined degenera-
tive diseases, and 1 case each of brainstem histiocytosis,
systemic lupus erythematosis with generalized neuropa-
thy, an adult with previously undiagnosed Moebius syn-
drome, radiation necrosis, basilar ectasia, neurofibro-
matosis with unexplained hydrocephalus, and an
undiagnosed case with aqueductal stenosis.
LOCALIZATION
The cavernous sinus was the most frequent site of involve-
ment (252 cases) (Table 3), particularly by tumors (81
cases) was dominated by vascular causes (113 cases); non-
localized 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 men-
ingeal infection and tumor (97 cases).
CRANIAL NERVES
Reflecting frequent involvement in cavernous sinus le-
sions and meningeal processes, the sixth cranial nerve
(565 cases) was most commonly involved by a wide mar-
gin (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. Cra-
nial nerves III (466 cases) and V (353 cases) were most
commonly damaged within the cavernous sinus. Recur-
rent 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 num-
ber 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.

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Table 5. Common Combinations of Involved Cranial Nerves
Cranial Nerve Overall Bilateral
Combination Cases, No. Cases, No.
III and VI 285 64
V and VI 214 11
V and VII 209 14
VII and VIII 135 2
III, IV, and VI 126 30
V, VI, and VII 125 7 netic resonance imaging and spinal fluid analysis.
II, III, and VI 98 7
X and XII 89 17
V, VII, and VIII 86 1
VI and XII 71 14
X, XI, and XII 21 5
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 cra-
nial 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.
COMMENT
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 idio-
pathic 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 idio-
pathic, 1 had trauma, 1 had brainstem infarct, 1 had Chi-
ari malformation, 1 had paraneoplastic syndrome, 1 had
cluster headache, and 1 had probable herpes zoster.
Most descriptions of MCN focus on the fascinating en-
tity of benign recurrent cranial neuropathy, first character-
ized by Symonds.12 It is relatively common in several coun-
tries 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 cra-
nial neuropathies in idiopathic cavernous sinusitis16and id-
iopathic cranial pachymeningitis17 has been posited.
Otherwise, most descriptions of MCN concern 1 or a few
cases of unusual entities. Of particular interest are presen-
tations that may elude the unfocused magnetic resonance
image or its interpreter, such as osseous infection18 and me-
tastasis,19 or intraneural spread of cutaneous malignancies.20
In the present study, only 22% of MCN cases origi-
nated 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. Be-
cause an origin of cranial nerve signs in the neck is rare
(3% in this study) and may be overlooked on radiologic
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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 tu-
mor 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 localiza-
tion prior to a workup—usually centered on focused mag-
Accepted for Publication: December 30, 2004.
Correspondence: James R Keane, MD, Los Angeles
County/University of Southern California Medical Cen-
ter, Room 5641, 1200 N State St, Los Angeles, CA 90033.
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 con-
tent: Keane. Study supervision: Keane.
Acknowledgment: Frances C. Keane, RN, MPH, helped
to organize and retrieve patient files.
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