NEUROLOGICAL UPDATE

Neuro-ophthalmology and neuro-otology update

Daniel R. Gold1,2,3,4 David S. Zee1,2,4

Received: 11 June 2015 / Accepted: 11 June 2015

Springer-Verlag Berlin Heidelberg 2015

Abstract This review summarizes topical papers from

the fields of neuro-ophthalmology and neuro-otology

published from August 2013 to February 2015. The main

findings are: (1) diagnostic criteria for pseudotumor cerebri

have been updated, and the Idiopathic Intracranial Hyper-

tension Treatment Trial evaluated the efficacy of acetazo-

lamide in patients with mild vision loss, (2) categorization

of vestibular disorders through history and ocular motor

examination is particularly important in the acute

vestibular syndrome, where timely distinction between a

central or peripheral localization is essential, (3) the newly

described sagging eye syndrome provides a mechanical

explanation for an isolated esodeviation that increases at

distance in the aging population and (4) eye movement

recordings better define how cerebellar dysfunction and/or

sixth nerve palsy may play a role in other patients with

esodeviations that increase at distance.

Keywords Neuro-ophthalmology Neuro-otology Pseudotumor cerebri Vertigo Divergence insufficiency Sagging eye syndrome

Pseudotumor cerebri: update

Update on the diagnosis of pseudotumor cerebri

(PTC)

Optic disc swelling due to increased intracranial pressure

(ICP) is called papilledema, and can be caused by many

processes. ICP is considered elevated when greater than or

equal to 25 cm CSF in adults or 28 in children (25 if the

child is not sedated and not obese) [13]. Pseudotumor

cerebri (PTC) is diagnosed when papilledema is present,

the opening pressure (OP) on lumbar puncture is elevated,

and when there is no mass lesion, infection, malignancy, or

inflammatory process on neuroimaging or examination of

the cerebrospinal fluid (CSF). The term PTC syndrome

(PTCS) includes both primary (idiopathic) and secondary

etiologies, for example due to cerebral venous sinus

hypertension, changes in CSF composition, or increase in

villous resistance to absorption of the CSF. Neurologic

examination should be normal, although disturbances of

cranial nerve six are allowed. The criteria for a diagnosis of

PTC were recently updated [4], driven by advances in

neuroimaging and descriptions of signs of elevated ICP on

MRI. Not only were typical neuroimaging signs incorpo-

rated, but a controversial entity, PTC without papilledema,

was also more clearly defined. To diagnose PTC without

papilledema, OP must be elevated and there must be a sixth

nerve palsy, or the elevated OP must be accompanied by

three of the following neuroimaging signs: empty sella,

flattening of the posterior sclera, distention of the perioptic

& Daniel R. GoldDgold7@jhmi.edu

David S. Zee

dzee@jhu.edu

1 Department of Neurology, The Johns Hopkins School of

Medicine, 600 N Wolfe St, Pathology 2-210, Baltimore,

MD 21287, USA

2 Department of Ophthalmology, The Johns Hopkins School of

Medicine, 600 N Wolfe St, Pathology 2-210, Baltimore,

MD 21287, USA

3 Department of Neurosurgery, The Johns Hopkins School of

Medicine, 600 N Wolfe St, Pathology 2-210, Baltimore,

MD 21287, USA

4 Department of Otolaryngology-Head and Neck Surgery, The

Johns Hopkins School of Medicine, 600 N Wolfe St,

Pathology 2-10, Baltimore, MD 21287, USA

123

J Neurol

DOI 10.1007/s00415-015-7825-1

nerve sheath, and transverse venous sinus stenosis [46]. If

papilledema and other characteristic historical and exami-

nation features are present but the OP is normal, proba-

ble PTCS can be diagnosed since ICP can fluctuate [4].

Update on pseudotumor cerebri associations

and pathophysiology

Typically, PTC occurs in young, obese women, and loss of

vision is the most feared complication [7]. The term be-

nign intracranial hypertension may apply to some

patients, but should be avoided as permanent loss of vision

is not uncommon [8]. Although the pathophysiologic

mechanism(s) remains elusive, several theories have been

recently advanced which are based on abnormalities within

the cerebral venous system. Elevated venous sinus pressure

and altered cerebral venous flow play a role, as evidenced

by the many PTC patients with transverse sinus stenosis

(TSS) [9, 10]. Therefore, MR or CT venograms not only

rule out cerebral venous thrombosis, but also assess the

patency of the venous system. However, the distinction

between TSS caused by elevated ICP and TSS causing

elevated ICP is not always clear [11]. This distinction is

important because those patients whose PTC is caused by

TSS may benefit from a TS stenting procedure [12]. It is

also possible that both mechanisms play a role. TSS caused

by elevated ICP leads to elevated venous pressure which

then perhaps impedes CSF drainage in the arachnoid

granulations, thus generating a vicious cycle of escalating

ICP [13]. Although obesity and being female have long

been associated with PTC, the pathophysiologic and/or

neuroendocrine mechanisms are not known. Endocrino-

pathies such as Addisons disease and medications such as

tetracycline and its derivatives, however, have been asso-

ciated with secondary PTCS, perhaps related to alteration

of specific metabolites and hormones that regulate choroid

plexus water and ion transport, and/or influence CSF

absorption via the arachnoid granulations [14]. In the pri-

mary PTC population, it is not clear to what degree

mechanical (e.g., TSS) and/or neuroendocrine abnormali-

ties are to blame.

Update on the medical treatment of pseudotumor

cerebri

Acetazolamide is a carbonic anhydrase inhibitor that

reduces sodium transport across the choroid plexus.

Although acetazolamide has long been thought to decrease

ICP, a randomized controlled trial of its efficacy was only

recently performed. The Idiopathic Intracranial Hyperten-

sion Treatment Trial (IIHTT) enrolled patients with rela-

tively mild vision loss as judged by Humphrey 24 visualfield testing and the perimetric mean deviation. The latter

variable corresponds to the average decrease in retinal

sensitivity across the entire field tested compared with age-

matched controls (measured in decibels, typically ranging

from ?2 dB, which is better than an age-matched normal,

to -30 dB, which is severe vision loss) [15]. Patients

included in the trial had mean deviations ranging from -2

to -7 dB. All patients followed a diet low in sodium and

calories and at 6 months, vision in the acetazolamide group

(average dose of 2.5 g/day) was compared with the placebo

group. Although vision improved more in the acetazo-

lamide group, the actual difference in visual function

between the groups was small (\1 dB). Notably, onlypatients with mild loss of vision were enrolled and those

with moderate or severe loss were excluded, mainly related

to ethical issues in withholding potentially vision-saving

surgery or having such patients randomized to the placebo

group. Given the mild loss of vision to begin with, it was

surprising that any effect of medication was demonstrated

at all [16]. Another important finding was that patients with

advanced papilledema (grades 35) seemed to have more

recovery (2.27 dB) compared with patients with milder

papilledema (grades 12; -0.67 dB), and it was clear that

acetazolamide improved the papilledema itself, although

this does not necessarily translate into better visual func-

tion. Finally, the acetazolamide group lost more weight

(7.50 kg) compared with the placebo group (3.45 kg),

possibly due to the loss of appetite induced by the drug. A

relatively modest decrease (6 %) in a patients weight can

make a significant difference in papilledema, so diet and

exercise is clearly an important part of the management of

PTC [17]. In summary, this trial showed that acetazolamide

is a useful treatment for mild loss of vision in PTC in

conjunction with a low calorie, low sodium diet, and the

effects of the medication were greater in patients with

higher grade papilledema. Surgical options for PTC include

gastric surgery (for weight loss), optic nerve sheath fen-

estration, lumbo- or ventriculoperitoneal shunting, and

venous sinus stenting. Randomized controlled trials are

needed to determine efficacy, although patients being

evaluated for these procedures have typically failed con-

servative measures and have significant vision loss.

Therefore, placement of a patient with moderate to severe

vision loss into the placebo or medical management arm of

a trial would pose an ethical dilemma. No such clinical

trials are underway.

Vertigo: update

Categorizing vertigo/dizzy syndromes

Evaluation of the dizzy or vertiginous patient is often an

anxiety-provoking experience for both the patient and the

J Neurol

123

physician. Traditional concepts about the classification of

diagnoses of vertigo based on the symptoms are changing,

and new techniques of the bedside examination are being

emphasized. Therefore, a thoughtful, stepwise contempo-

rary approach from a historical and examination standpoint

is essential. A simplified classification scheme was pro-

posed by Brandt et al. [18] in which most vestibular dis-

orders fall into one of five distinct categories defined by

symptom onset, symptom quality (although this can occa-

sionally be misleading [19]), triggers, associated symptoms,

and duration: (1) paroxysmal positional vertigo [benign

paroxysmal positional vertigo (BPPV)], (2) spontaneous

recurrent vertigo attacks (Menieres, vestibular migraine),

(3) acute prolonged vertigo (stroke/TIA, vestibular neuri-

tis), (4) frequent spells of dizziness or imbalance [superior

canal dehiscence syndrome (SCDS), vestibular paroxys-

mia], and (5) postural imbalance without other neurological

symptoms (bilateral vestibular loss, phobic postural vertigo/

chronic subjective dizziness). This classification of patients

leads to focused examination techniques with provocative

maneuvers (e.g., DixHallpike when BPPV is suspected;

valsalva maneuvers or observation of Henneberts sign

when SCDS is suspected; hyperventilation when acoustic

neuroma or vestibular paroxysmia is suspected), neu-

roimaging and/or audiovestibular testing when appropriate.

When evaluating a patient with acute vertigo, common

pitfalls include: [Kerber KA, Newman-Toker DE. Misdi-

agnosis of dizzy patients: Common pitfalls in clinical

practice. Neurol Clin 2015 (in press)] (1) overemphasis on

the type of symptome.g., assuming that non-specific,

non-rotational dizziness must not be stroke-related; [19];

(2) underuse or misuse of timing and triggers to categorize

patients (see above classification scheme by Brandt et al.

[18]); (3) underuse or misuse of the DixHallpike (DH)

maneuvere.g., not doing the DH maneuver in an appro-

priate patient, or overemphasizing the exacerbation of

symptoms with a DH in a patient with acute constant vertigo

and spontaneous nystagmus in which any head move-

ment/positioning maneuver will cause symptoms to worsen;

(4) overemphasis on age, vascular risk factors, general

neurological examination and a negative head CT scan; (5)

underemphasizing the ocular motor examination [20].

Acute prolonged vertigo

The ability to differentiate central from peripheral etiolo-

gies in patients presenting with the acute vestibular syn-

drome (i.e., rapid onset of vertigo, nausea/vomiting,

unsteadiness, sustained spontaneous nystagmusdue to a

central process about 20 % of the time) was dramatically

improved by the description of HINTS (head impulse,

nystagmus, test of skew) [20]. With HINTS, a peripheral

process such as vestibular neuritis is supported by

unidirectional nystagmus, positive head impulse test (HIT),

and lack of skew deviation, while a central process such as

stroke is supported by gaze-evoked nystagmus (GEN),

negative HIT, and/or skew deviation. HINTS had better

sensitivity than a brain MRI in the first 48 h following the

onset of symptoms as diffusion weighted imaging is neg-

ative initially in about 1218 % of the time in the acute

vestibular syndrome due to stroke [20, 21].

Isolated central vertigo syndromes

Isolated central vertigo syndromes are uncommon, but may

be easily confused with a peripheral vestibulopathy [2123].

The anterior inferior cerebellar artery (AICA) supplies

central and peripheral structures including the labyrinth,

making acute hearing loss a red flag for ischemia [24]. In

addition to HINTS, horizontal head-shaking nystagmus

(HSN) helps distinguish peripheral and central syndromes.

Perverted nystagmus (vertical nystagmus with horizontal

shaking), HSN that is directed oppositely to the spontaneous

nystagmus (or when HSN in the opposite direction of what

would be expected based on the side of vestibular hypo-

functioni.e., ipsilesional beating HSN) can be seen with

central lesions and strongHSN seenwith weak head-shaking

or a strongly biphasic HSN (first in one direction and then in

the other) also suggests a central localization [25, 26].

Description of the ocular motor and vestibular signs that

constitute the nucleus prepositus hypoglossi syndrome is

currently in flux and will not be discussed [23, 27].

Vestibular nucleus (VN) syndrome

An article in this Journal by Kim et al. [28] highlighted the

complex clinical presentation of an isolated lesion of the

VN, specifically the overlap between peripheral and central

vestibular features. The interface between peripheral and

central is ambiguous in this region as vestibulocochlear

nerve fibers have just entered the medullary parenchyma on

their way to the medial and inferior VN. Like a peripheral

vestibulopathy, contralesional horizontal-torsional nystag-

mus (slow phase of nystagmus towards the pathological

side and fast phase in the opposite direction) is often seen

as well as an ipsilesional positive HIT. Peripherally, the

superior division of the vestibular nerve innervates the

lateral canal, anterior canal, and utricle, and these struc-

tures are commonly affected in vestibular neuritis. There-

fore, positive HIT in the planes of the lateral and anterior

canals may be seen acutely with a peripheral vestibulopa-

thy [29]. Centrally, fibers from the lateral and posterior

canals go to the MVN while fibers from the anterior canals

go to the MVN and SVN, so that an isolated medullary VN

lesion may cause positive HIT in the planes of the lateral

and posterior canals [28]. Gaze-evoked nystagmus (GEN)

J Neurol

123

is often seen owing to the horizontal neural integrator

properties of the MVN [28].

HINTS exam: ?(ipsilesional) HIT suggests peripheral,but if also associated with ?GEN suggests central and

overrides the peripheral implication of a ?HIT (Table 1).

Flocculus syndrome

Supplied by the AICA, unilateral strokes of the flocculus

are rare, although a case report described ipsilesional

spontaneous nystagmus, contraversive ocular tilt reaction

(OTRskew deviation, ocular counterroll, head tilt), and

small but positive contralesional more than ipsilesional

?HIT with normal bithermal calorics, suggesting an

important role of the flocculus in modulating the VOR [30].

HINTS exam: small, ?(contralesional[ ipsilesional)HIT suggests peripheral, ?GEN and OTR suggest

central and overrides the usual peripheral implication of

?HIT (Table 1).

Tonsil syndrome

Supplied by the posterior inferior cerebellar artery (PICA),

a patient with a unilateral tonsilar (paraflocculus) infarction

was reported, in whom spontaneous ipsilesional beating

nystagmus was noted with fixation removed. With visual

fixation, mild GEN with rebound nystagmus was noted as

well as a contraversive OTR, and nearly absent ipsilesional

and impaired contralesional directed smooth pursuit [31].

VOR and saccades were normal.

HINTS exam: -HIT suggests central (Table 1).

Nodulus syndrome

Patients with an isolated stroke of the nodulus can present

with isolated vertigo, severe imbalance, and may have

ipsilesional beating nystagmus, central patterns of HSN

(possibly related to the role of the nodulus in controlling

the brainstem velocity storage mechanism), periodic

alternating nystagmus, or positional nystagmus [3237].

Nystagmus is with a quick phase directed ipsilesionally,

and usually increased by head-shaking (see above) given

the role of the nodulus in velocity storage. Perverted HSN,

periodic alternating nystagmus, positional nystagmus

(downbeat or apogeotropic horizontal [38]) and impaired

tilt suppression of postrotatory nystagmus have also been

described.

HINTS exam: -HIT and ?OTR suggest central(Table 1).

Inferior cerebellar peduncle (ICP) syndrome

The ICP contains fibers connecting the vestibulocerebel-

lum to VN, and a unilateral ICP lesion can cause vertigo,

imbalance, ipsilesional nystagmus, impairment of ipsile-

sional smooth pursuit, and contraversive OTR. HIT and

saccades are normal [23].

HINTS exam: -HIT and ?OTR suggest central(Table 1).

Esotropia greater at distance: update

Children

The acute onset of an esotropia that is comitant (the degree

of to which the eyes turn in is the same in all directions of

gaze) in a child may be benign such as with accommoda-

tive esotropia (easily treated by correcting the hyperopia

with spectacles), or potentially lethal such as with a pos-

terior fossa tumor [39]. When esotropia increases at dis-

tance without limited abduction, the terms divergence

paresis/paralysis or divergence insufficiency (DI) are often

Table 1 HINTS evaluation of isolated central vertigo syndromes

Central vertigo

syndrome

Head impulse test Spontaneous

nystagmus

Gaze-evoked

nystagmus

Ocular tilt reaction

(including skew)

Characteristic feature(s)

Vestibular Nucleus ?Ipsilesional Contralesional ? Ipsiversive Overlapping central and peripheral

Flocculus ?Small contra

[ ipsilesional possibleIpsilesional ? ?Contraversive Bithermal calorics may be normal

Tonsil - Ipsilesional ? ?Contraversive Poor pursuit

Nodulus - Ipsilesional - ?Contraversive Central patterns of HSN; PAN;

positional nystagmus

Inferior cerebellar

peduncle

- Ipsilesional - ?Contraversive Impaired ipsilesional pursuit

HSN head-shaking nystagmus, PAN periodic alternating nystagmus

J Neurol

123

used. When DI is accompanied by papilledema, nystagmus

or other posterior fossa neurologic symptoms or signs,

neuroimaging is indicated. However, isolated DI without

abduction deficits can also be caused by cerebellar tumors

(astrocytoma, medulloblastoma) or ArnoldChiari type 1

malformation [4043]. No criteria exist to determine which

children with isolated comitant esotropia, worse at dis-

tance, require imaging.

Many of these isolated cases were not thought to be due

to unilateral or bilateral sixth nerve palsies in the absence

of appreciable abduction deficits. However, multiple

papers support the theory that the DI in children who have

elevated ICP is related to paresis of the sixth nerve(s),

given slowed abducting saccades and subtle abduction

paresis with eye movement recordings [39, 44].

Adults

Adults may also develop DI, and when primary (idio-

pathic), a loss of fusional divergence amplitude has been

proposed as the mechanism [45]. Secondary DI due to

neurodegenerative processes such as parkinsonian syn-

dromes or cerebellar ataxias may relate to defects in the

midbrain or cerebellar vergence systems [46, 47]. Other

causes of secondary DI include myasthenia gravis, pseu-

dotumor cerebri, and giant cell arteritis [48]. The neuro-

logical history and examination helps distinguish primary

from secondary DI, and when found in isolation, a benign

process is likely. Subtle abduction pareses may be easier to

appreciate in adults, particularly with thorough testing

using alternate cover, coveruncover, and/or Maddox rod.

Abducting saccades are normal in adults with uncompli-

cated DI [49].

Primary DI in adults

Recently, Chaudhuri and Demer proposed a mechanical

explanation for primary DI in adults [50]. With aging, there

is involution of orbital connective tissues including the

supportive band connecting the superior rectus (SR) to the

lateral rectus (LR), thereby altering the normal paths of

rectus muscles and their tendons [50]. As this SR-LR band

becomes distended or ruptures completely, one or both

eyes may sag down into the orbit. If this process is

mainly unilateral and asymmetric, the ipsilateral eye

becomes hypotropic and relatively extorted. If the disten-

tion/rupture of the SR-LR band is bilateral and symmetric,

the consequence is slight mechanical weakening of the LR

leading to DI. This so-called sagging eye syndrome

probably explains many cases of primary DI, and has also

been referred to as age-related distance esotropia [51, 52].

Common associated features include high lid creases sug-

gesting dehiscence or disinsertion of the levator, and a

prominent superior sulcus produced by the sagging

eye(s). Prior blepharoplasty for bilateral ptosis is not

uncommon. Again, the history and examination is most

important to distinguish primary and secondary causes.

Secondary DI in adults

In a recent article, patients presenting to the German Center

for Vertigo and Balance Disorders were assessed for DI

[53]. In this population, DI was found in patients with

cerebellar dysfunction who also showed saccadic dysme-

tria, impaired smooth pursuit, spontaneous downbeat nys-

tagmus (DBN), and alternating hypertropia with changes in

horizontal gaze or skew. Patients who were diagnosed with

a cerebellar disorder were at 13.3 times higher risk of

having DI compared with the control group (which included

bilateral vestibular loss, vestibular migraine, Menieres,

etc.). Subtle abduction defects appreciated with eye move-

ment recordings were also noted with DI, particularly when

horizontal GEN was present. Because DI was strongly

associated with DBN, a finding mainly associated with

bilateral floccular lesions, it was proposed that DI in this

population could also be from abnormal function of the

flocculus. This study provides further support for a cere-

bellar role in binocular control and processing of signals for

vergence [46, 47]. Dysfunction of the flocculus may also

play a role in some children with isolated DI in whom

posterior fossa lesions were identified, as subtle cerebellar

eye signs or abduction pareses may have been difficult to

appreciate without the aid of eye movement recordings.

Further aspects of disorders of eye alignment with

cerebellar disease were recently discussed by Patel and Zee

[54] and they focus on the close relationship of eye

misalignment to abnormal processing of otolith informa-

tion normally used for translational vestibuloocular

reflexes. They also emphasize that in patients with a

spontaneous nystagmus, the way in which the nystagmus

changes as the patient moves their direction of gaze (e.g.,

DBN developing a torsional component on looking later-

ally) or the change in the intensity of the nystagmus as they

change their direction of gaze (e.g., the intensity of DBN as

they look up or down or right or left) are often clues to

which particular ocular motor subsystem is at fault (e.g.,

the rotational VOR, the translational VOR or the neural

integrators for gaze-holding).

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Neuro-ophthalmology and neuro-otology updateAbstractPseudotumor cerebri: updateUpdate on the diagnosis of pseudotumor cerebri (PTC)Update on pseudotumor cerebri associations and pathophysiologyUpdate on the medical treatment of pseudotumor cerebri

Vertigo: updateCategorizing vertigo/dizzy syndromesAcute prolonged vertigoIsolated central vertigo syndromesVestibular nucleus (VN) syndromeFlocculus syndromeTonsil syndromeNodulus syndromeInferior cerebellar peduncle (ICP) syndrome

Esotropia greater at distance: updateChildrenAdultsPrimary DI in adultsSecondary DI in adults

References