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ABSTRACT
E valuating the patient with multiple cranial stem, and thus brainstem syndromes are often organized
neuropathies presents a unique challenge for the diag- into eponymic syndromes. However, these classically
nostician. The differential diagnosis is broad and in- described eponymic brainstem syndromes were reported
cludes many life-threatening processes. Just as with any in an era where disorders such as tuberculomas, syphilitic
other neurologic presentation, the first step in the gummas, and tumors were seen more often than today.1
evaluation requires correct localization. Processes affect- Many of these classically described brainstem syndromes
ing multiple cranial nerves may involve intramedullary were not due to ischemia. In the current era, the vast
structures of the brainstem as well as their extramedul- majority of brainstem syndromes are a result of vascular
lary course. The focus of this review will be on the insults, mainly brainstem infarctions and hemorrhages,
extramedullary disorders affecting multiple cranial often involving the lateral pons and medulla.2 Consid-
nerves. ering the dominance of vascular etiologies of the brain-
stem syndromes, a more practical classification of these
syndromes is by the anatomical area or the major blood
BRAINSTEM SYNDROMES vessel involved (Table 1). Examples of nonvascular
Prior to discussion of the extramedullary processes disorders that commonly affect the brainstem include
causing dysfunction of multiple cranial nerves, a few demyelinating disease (multiple sclerosis [MS], acute
points must be made about the brainstem syndromes. disseminated encephalomyelitis [ADEM]), intramedul-
Many of the early neurologic pioneer clinicians described lary neoplasms (such as brainstem gliomas/ependymo-
the findings due to a focal process affecting the brain- mas), brainstem encephalitis (Bickerstaffs encephalitis),
1
Department of Neurology, Naval Medical Center, Portsmouth, Disorders of the Cranial Nerves; Guest Editor, William W. Campbell,
Virginia; 2Department of Neurology, Uniformed Services University M.D., M.S.H.A.
of Health Sciences, Bethesda, Maryland. Semin Neurol 2009;29:5365. Copyright # 2009 by Thieme
Address for correspondence and reprint requests: Craig G. Carroll, Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
D.O., Head, Department of Neurology, Naval Medical Center Ports- 10001, USA. Tel: +1(212) 584-4662.
mouth, 620 John Paul Jones Circle, Portsmouth, VA 23708 (e-mail: DOI 10.1055/s-0028-1124023. ISSN 0271-8235.
craig.carroll@med.navy.mil).
53
54 SEMINARS IN NEUROLOGY/VOLUME 29, NUMBER 1 2009
Table 1 Summary of the Brainstem Syndrome Organized by Anatomic Region and Blood Vessel Involved
Syndrome Structures Involved Clinical Findings Comments
Midbrain syndromes Corticospinal tract; corticobulbar Contralateral weakness of arm, Due to occlusion of the interpeduncular
tract; cranial nerve III fibers; leg and face; ipsilateral cranial penetrating branches of the basilar
red nucleus; superior cerebellar nerve III; contralateral tremor; or posterior cerebral artery or the
peduncle contralateral ataxia posterior choroidal artery
Medial inferior pontine Paramedian pontine reticular Ipsilateral CN VI or horizontal gaze Due to occlusion of paramedian
formation; CN VI nucleus or palsy; ataxia. Paresis and perforating vessel
fibers; middle cerebellar peduncle; impaired lemniscal sensation of
corticospinal tract; medial contralateral limbs
lemniscus
Lateral inferior pontine Cranial nerve VII nucleus or fibers; Ipsilateral cerebellar ataxia; loss of Due to occlusion of anterior inferior
(AICA syndrome) middle cerebellar peduncle; inferior pain and temperature sensation cerebellar artery
cerebellar peduncle; corticospinal and diminished light touch sensation
tract; principle and spinal nucleus of face; impaired taste sensation;
of CN V; lateral spinothalamic tract; central Horners syndrome;
solitary tract; flocculus and inferior deafness; peripheral type of facial
surface of cerebellar hemisphere palsy. Loss of pain and temperature
sensation of contralateral limbs
Medial midpontine Middle cerebellar peduncle; Ipsilateral ataxia. Contralateral weakness Due to occlusion of paramedian
central pontine myelinolysis, ArnoldChiari malforma- have telltale clues such as long tract signs, gaze palsies,
tions, and syringobulbia. Considering that the brainstem internuclear ophthalmoplegia, and complex spontaneous
is such a compact structure, with cranial nerve nuclei, eye movement abnormalities. Focal brainstem lesions are
nerve fascicles, and long ascending and descending tracts often characterized by crossed syndromes, consisting of
all closely juxtaposed, a plethora of clinical findings are ipsilateral cranial nerve dysfunction and contralateral
usually present to help in localization. Most brainstem long motor or sensory tract dysfunction. Due to the
cases with involvement of multiple cranial nerves will rich vestibular and cerebellar connections, patients with
MULTIPLE CRANIAL NEUROPATHIES/CARROLL, CAMPBELL 55
brainstem disease will often complain of vertigo, skull base. Next, a brief discussion of extramedullary
gait unsteadiness, ataxia, discoordination, nausea, and vascular etiologies, bone disorders, and traumatic con-
vomiting. Thus, a history aimed at eliciting these symp- siderations as well as peripheral nerve considerations will
toms as well as a careful complete neurologic exam ensue. Finally, disorders of specific cranial nerve groups/
looking for these associated signs is necessary to aid in syndromes will be discussed.
localizing a process to the brainstem.
CHRONIC MENINGITIS
MULTIPLE CRANIAL NEUROPATHIES:
OVERVIEW Infectious Meningitis
There are 12 pairs of cranial nerves that innervate most Chronic meningitis is always in the differential diagnosis
of the structures of the head and neck. The afferent and of multiple cranial neuropathies. Chronic meningitis
efferent connections of these 12 cranial nerves traverse usually presents in a subacute or insidious manner.
the meninges, subarachnoid space, bony structures of the Common presenting symptoms include insidious head-
skull, and superficial soft tissues. Dysfunction of these ache, fever, and neck stiffness; however, cranial nerve
nerves may occur at any of these sites along their course. abnormalities are not an uncommon presentation. The
Therefore, it is not surprising that a large number of neurologic signs and symptoms of chronic meningitis are
pathologic processes initially are manifested by cranial often nonspecific, and the pursuit of this diagnosis often
nerve dysfunction.3 These disease processes may involve requires an intensive investigation of potential exposures
homologous nerves on the two sides (i.e., bilateral facial and associated systemic symptoms. Furthermore, the
the United States, tuberculosis remains, from a global gitis most often presents with headache, fever, vomiting,
standpoint, one of the more common infectious agents photophobia,8 and encephalopathy9; however, cranial
associated with chronic meningitis. It is estimated that nerve palsies are reported in up to 19%.10 The sixth
about one third of the worlds population has been nerve is usually involved first and is most frequently
infected with tuberculosis.4 In one series of patients affected.3 Although neurosyphilis is rare today, it still
with chronic meningitis without a known predisposing must be considered as a cause of multiple cranial neuro-
cause, 40% were found to have tuberculous meningitis.7 pathies. Cranial neuropathies are seen in about one
As is common with any meningitis, tuberculous menin- third.5 Less commonly reported bacterial infections
MULTIPLE CRANIAL NEUROPATHIES/CARROLL, CAMPBELL 57
associated with multiple cranial neuropathies include nerves may be involved as a result of meningeal involve-
Mycoplasma and Pseudomonas aeruginosa.11,12 ment as well as from brainstem involvement. CNs II and
CNS fungal infections, although rare, have in- VIII are most commonly affected.24
creased due to the increased prevalence of immunosup- Systemic vasculitides have varied neurologic com-
pression from acquired immunodeficiency syndrome plications. Several forms of vasculitis deserve special
(AIDS), organ transplantation, corticosteroid use, and mention due to their association with multiple cranial
chemotherapy. The most common fungal pathogen is neuropathies. Wegeners granulomatosis is the one with
Cryptococcus neoformans, which accounts for more than the greatest tendency to affect multiple cranial nerves. In
half of all CNS fungal meningitis cases.4 Other fre- a review of 324 consecutive patients seen at the Mayo
quent fungal infections include Coccidiodes immitis, Clinic, 33.6% had documented neurologic involvement
histoplasmosis, and blastomycosis. In those at risk for with mononeuritis multiplex; cranial neuropathies were
opportunistic infections, Aspergillus sp., mucormycosis the most common neurologic findings.25 In another
(Zygomycetes species), and Candida species must also review, the CNS was affected in only 8% of patients.26
be considered, often from extension to the orbit from CNs II, VI, VII, and VIII were most often affected.
the sinuses. Renal involvement is frequently present in patients
Viruses are a rare cause of chronic meningitis, who have neurologic manifestations.27 Granulomatous
with the exception of human immunodeficiency virus masses may also extend from the nasal and paranasal
(HIV), which often causes a persistent meningitis.13 sinuses causing a restrictive ophthalmoplegia simulating
HIV-1 has had a known association with cranial neuro- cranial nerve palsies. Another systemic granulomatous
pathies; however, more recently HIV-2 has also been vasculitis with a predilection for the CNS is lymphoma-
neuropathies,36 primary amyloidosis less commonly CNs II and V is also common whereas facial nerve
presents in this fashion.37 palsies are uncommon. CN XII may be affected in
advanced cases with extensive involvement of the skull
base. Additionally, radiotherapy for this tumor may itself
Neoplastic Meningitis cause cranial neuropathies, especially of CN XII. At
Neoplastic processes are an important cause of multiple times, nasopharyngeal carcinomas may also even erode
cranial neuropathies, especially when the patient presents through the clivus. A combination of CN VI and XII
subacutely (days to weeks) in the absence of pain. Patients palsies is particularly suggestive of a neoplastic process
with neoplastic meningitis usually have accompanying involving the clivus.1 Another tumor that commonly
headache, meningeal signs, and evidence of increased involves the clivus and often presents with multiple
ICP. Important causes of neoplastic meningitis include cranial neuropathies is a chordoma, a rare primary
carcinomatous and lymphomatous meningitis. Neoplastic bone tumor derived from the remnants of the primitive
meningitis is diagnosed in up to 15% of patients with notochord that usually presents in men in the sixth
systemic carcinomas or hematologic malignancies, and decade. Although histologically benign, with posterior
may be the first presentation in 5 to 10% of patients.5 extension it may become locally invasive causing cranial
Small cell lung cancers, melanomas, and myeloblastic nerve dysfunction and even brainstem compression.
leukemias are the most likely tumors to spread to the Other skull-based neoplasms that may present in a
meninges.38,39 Although breast cancer has a low predi- similar fashion include metastasis, meningioma, lym-
lection for spread to the meninges, it is one of the most phoma, myeloma, histiocytosis, neurinoma, giant cell
common tumors to cause neoplastic meningitis because tumor, hemangioblastoma, and various primary bone
is invariably involved and in some patients, other cranial causes must also be considered in this context. For
nerves may also be affected. The etiology of lower cranial example, cranial neuropathies, sometimes multiple, are
neuropathy in carotid dissection is unclear, but may be a well-established complication of carotid endarterecto-
related to compression, to stretching by the aneurysmal mies, posterior triangle lymph node biopsies, and other
dilatation, or to ischemia of the segmental arteries surgical procedures on the head and neck, especially
supplying the nerves, particularly the ascending phar- radical procedures.
yngeal artery.43 Although diabetes often causes isolated
cranial neuropathies, only rarely does it affect more than
one cranial nerve at a time.44 Finally, sickle cell disease DISORDERS OF CRANIAL NERVE GROUPS
has rarely been reported as a cause of multiple cranial In some locations, two or more cranial nerves are
neuropathies, mainly CNs V and VII.45 bundled in a common anatomic space, and when a focal
disease process occurs, the entire cluster of nerves may be
involved. Most often, disorders of cranial nerve groups
BONE DISORDERS are due to mass effect and are commonly secondary to
Although less common in comparison to many of the neoplasms. As with the vascular brainstem syndromes,
above considerations, disorders of bone can also result many of these carry eponyms. Many of these syndromes
in compressive cranial neuropathies. Osteopetrosis are rare, however, in neurologic practice. Familiarity
(AlbersSchonberg or marble bone disease) is a rare with the more common of these syndromes may aid
congenital bone disorder characterized by defective os- in localization when the relevant cranial nerves are
teoclastic bone resorption. Subsequently, a generalized involved. Relatively common anatomical syndromes
cavernous-carotid fistula.49 A carotid cavernous fistula is The initial symptoms are usually progressive sensorineu-
a communication between the carotid artery and the ral hearing loss and tinnitus. Because of the slow-
cavernous sinus. These may be further classified into growing nature and the ability of the vestibular system
direct or indirect fistulas. In direct fistulas, the cavernous to compensate, frank vertigo is unusual; however, gait
carotid artery and cavernous sinus are in direct continu- dysequilibrium is not uncommon. As the mass expands,
ity. These often develop spontaneously from a ruptured cranial nerve dysfunction ensues accompanied by dys-
cavernous aneurysm as above, or may be secondary to function of CN VII causing a lower motor neuron facial
trauma, such as a closed head injury. They are charac- paresis without hyperacusis. CN V dysfunction causing
terized by the classic triad of chemosis, pulsatile exoph- facial sensory loss is also common. CNs VI, IX and X
thalmos, and an audible bruit over the eye on are less commonly involved, usually later in the
auscultation. These often require complex interventional course. If the lesion continues to grow, pressure on
management.49 In indirect fistulas, shunts are estab- the cerebellum or its peduncles result in ipsilateral
lished through meningeal branches from the carotid ataxia and incoordination. Nystagmus and gaze palsies
system. These tend to be more insidious with arteriali- may result from pontine compression.
zation of the conjunctival vessels without an audible
bruit and often resolve spontaneously. Cavernous sinus
thrombosis usually results from paranasal sinus infec- Lower Cranial Nerve Syndromes
tions, orbital cellulitis, or a facial infection (such as a The lower cranial nerve syndromes involve CNs IXXII
furuncle). Staphylococcus is the most common causative unilaterally in various combinations. These nerves exit
organism; however, pneumococcal and fungal infections the skull just above the foramen magnum. CNs IXXI
involvement (Horners syndrome). This is also referred specific peripheral nerve entity, which has been well
to as the retropharyngeal space syndrome. If the inciting characterized. This syndrome often presents with con-
process extends into the retroparotid space, there may be stant, usually retroorbital, facial pain followed suddenly
additional CN VII involvement. The same etiologic by cranial nerve palsies. The cranial nerves most com-
considerations apply for all these syndromes; therefore, monly involved are the oculomotor, trochlear, and abdu-
from a practical standpoint, considering all collectively as cens, followed by the trigeminal and facial nerves. The
jugular foramen syndromes stands to reason. Finally, lower cranial nerves may also be involved.11 The etiology
although not technically a lower cranial nerve syndrome, remains unknown, and some have speculated an overlap
the petrous apex syndrome can progress to include the with TolosaHunt syndrome, especially considering the
lower cranial nerves. Otherwise known as Gradenigos mutual response to steroids. Although they can occasion-
syndrome, this syndrome is typically associated with ally present with bulbar dysfunction, neuromuscular
suppurative otitis media affecting the petrous apex of junction disorders and myopathies can usually be distin-
the temporal bone. It typically presents with pain in a guished by clinical history.
trigeminal nerve distribution combined with abducens
palsy. If the infection spreads to the skull base, then
features of jugular foramen syndrome may coexist. DIAGNOSIS
The diagnostic possibilities for multiple cranial nerve
palsies are legion, and the diagnosis remains a formidable
PERIPHERAL NERVOUS SYSTEM challenge despite the advances of modern medicine.
CONSIDERATIONS Although the list of possibilities is exhaustive, many
Table 4 Possible Evaluation of Patients with Multiple are available. If the diagnosis remains obscure, repeated
Cranial Neuropathies CSF sampling should be considered in this fashion. At
Blood least 10 to 20 cc should be sent for cytologic evaluation.
Complete blood count and Angiotensin converting Flow cytometry should be performed when leukemic or
differential enzyme lymphomatous meningitis is suspected as it may be more
Chemistry panel Lyme antibody sensitive than conventional cytology.4 Analysis of cell
Erythrocyte sedimentation rate FTA lines may be very illuminating. If the cells are mono-
C reactive protein HIV clonal, the process is likely neoplastic; if polyclonal, then
Antinuclear antibody Cryptococcal antigen infectious. C12 taps may be considered in lieu of high-
Extractable nuclear antibody volume lumbar taps. The point is to study the CSF at the
Antineutrophilic cytoplasmic base of the brain because that is where the pathology is.
antibodies It is not in the CSF in the lumbar sac.
Rheumatoid factor As already mentioned, routine imaging studies are
Cerebrospinal fluid often unremarkable. In cases where bony detail needs to
Cell count and differential PCR studies: be delineated, such as in craniomaxillofacial trauma or in
Glucose and protein Lyme cases of neoplasms with erosion or tumor extension into
Bacterial and fungal culture CMV cranial foramina, computed tomography (CT) scans may
Cytology (high volume) EBV be necessary. This is particularly true in skull base
Flow cytometry Mycobacterium lesions. Furthermore, skull base lesions often also involve
the extracranial and intracranial soft tissues; as such,
biopsy was diagnostic in only five patients: Mycobacterium a fungal meningitis, treatment with fluconazole should
tuberculosis was found in one, neoplasia in three, and be considered. Often a decision must be made whether
granulomatous angiitis in one patient.59 The diagnostic or not to start empiric steroids. From an evidence-based
yield of meningeal biopsy can be increased by targeting view, this answer remains elusive. Considering that
regions that enhance with contrast on MRI.58 In another neuroimaging will exclude many neoplastic processes
study of patients with chronic meningitis, a definite (particularly skull-based tumors), vascular disorders
diagnosis by meningeal biopsy was possible in only and bone diseases, the clinician is often left with con-
39%. The yield increased to 80% if the biopsy was siderations of an infectious versus an inflammatory
obtained from an enhancing area noted on the MRI.58 process. When the CSF reveals a pleocytosis indicative
The yield without MRI enhancement was only 10%. A of meningeal inflammation and every attempt to exclude
repeat biopsy was obtained in four patients and revealed infectious causes has been made, then inflammatory
adenocarcinoma, sarcoidosis, demyelinating disease, and etiologies, which often respond to corticosteroids, be-
chronic inflammation in one patient each.58 The yield of come high on the differential. Therefore, despite the lack
the biopsy is slightly higher when obtained from the of evidence-based answers, empiric corticosteroids seem
posterior fossa than from the cerebral cortex, and if a logical management option. In one series of 49 patients
possible, should include both the meninges and under- with chronic idiopathic meningitis in whom no etiology
lying brain. Common diagnoses made from biopsies was found, 52% responded symptomatically to empiric
include neurosarcoidosis, hypertrophic pachymeningitis, corticosteroids. Despite symptomatic improvement, no
leptomeningeal metastasis, vasculitis, and infections.4 effect on ultimate outcome was demonstrated, as 85% of
Depending on the clinical suspicion, a portion of the those without a clear diagnosis had a benign long-term
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