REVIEW

Neuroradiological and clinical features in ophthalmoplegia

Stefan Weidauer1 & Christian Hofmann2 & Marlies Wagner3 & Elke Hattingen3

Received: 27 November 2018 /Accepted: 4 February 2019 /Published online: 12 February 2019# Springer-Verlag GmbH Germany, part of Springer Nature 2019

AbstractPurpose Especially in acute onset of ophthalmoplegia, efficient neuroradiological evaluation is necessary to assist differentialdiagnosis, clinical course, and treatment options.Methods Different manifestations of ophthalmoplegia are explained and illustrated by characteristic neuroradiological andclinical findings.Results To present those ophthalmoplegic disorders in a clear manner, this review refers to different neuroanatomical structuresand compartments. From neuroophthalmological point of view, diseases going ahead with ophthalmoplegia can be divided into(1) efferent infranuclear/peripheral disturbances involving oculomotor cranial nerves, (2) conjugate gaze abnormalities due tointernuclear or supranuclear lesions, and (3) diseases of the extraocular eye muscles or their impairment due to intraorbitalpathologies.Conclusion The knowledge of the relationship between neurological findings in ophthalmoplegia and involved neuroanatomicalstructures is crucial, and neuroradiology can be focused on circumscribed anatomical regions, using optimized investigationprotocols.

Keywords Ophthalmoplegia .MRI . Cranial nerve palsy . Conjugate gaze abnormality . Horner syndrome

Introduction

One of the cardinal clinical symptoms in ophthalmology isdiplopia. Since the perception of double vision (DV) is asubject ive sensat ion, i t is the main task for theneuroophthalmologist to objectify the symptoms [1]. Themore precise the clinical description and findings, the bet-ter the diagnostic clarification can be, which is a conse-quent step-by-step procedure. The first step is to differen-tiate between monocular and binocular DV, the former of-ten due to an optical problem or macular diseases.Binocular DV, however, is caused by an imbalance of

position or motility of both eyes. Almost any case of bin-ocular DV is accompanied by strabismus. As a second step,the neuroophthalmologist should examine the motility ofthe eyes in order to differentiate between non-paretic(concomitant) and paretic (incomitant) strabismus whichcan roughly be summarized as ophthalmoplegia (OP). OPcan be provoked by harmless and self-limiting causes, butit can also be the overture to a severe neurological disease.

Neuroimaging plays a central role in the diagnostic clarifi-cation of OP and planning of treatment options, particularly inthe case of acute onset [1–6]. For optimized imaging, it isessential to provide the neuroradiologist with precise informa-tion on the neuroophthalmologically involved structures [4,6]. Consecutive, neuroimaging can be focused oncircumscribed anatomical regions, using specialized investi-gation protocols, e.g., additional thin slice sequences to obtainmost appropriate neuroanatomical information [1, 2]. At thispoint, however, it must be mentioned that some causes of OP,such as neuromuscular junction disorders, cannot be identifiedby imaging [1].

From neuroophthalmological point of view, diseases beingaccompanied by OP can be divided into (1) efferentinfranuclear/peripheral neuroophthalmic disorders involvingoculomotor cranial nerves (CN), i.e., oculomotor nerve (CN

* Stefan Weidauerstefan.weidauer@sankt-katharinen-ffm.de

1 Department of Neurology, Sankt Katharinen Hospital, TeachingHospital of the Goethe University, Seckbacher Landstraße 65,60389 Frankfurt am Main, Germany

2 Department of Ophthalmology, Neuroophthalmology, GoetheUniversity, Frankfurt am Main, Germany

3 Institute of Neuroradiology, Goethe University, Frankfurt amMain, Germany

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III), trochlear nerve (CN IV), and abducens nerve (CN VI)(see Table 1, Fig. 1) [1, 7, 8]; (2) conjugate gaze abnormalitiesdue to internuclear or supranuclear disorders (see Table 2)

[1–4]; and (3) diseases of the extraocular eye muscles(EOM) and orbital diseases affecting the EOM (see Table 3)[1, 9–13]. In this review, characteristic neurological and

Table 1 Efferent infranuclear/peripheral neuroophthalmic disorders, additional neurological symptoms depending upon lesion site

Syndrome Clinical characteristics Lesion site Etiology

CN III palsy OphthalmologicalExotropia, hypotropia, reduction of adduction/

upgaze/downgaze, ptosis, anisocoria withinsufficient pupillary constriction(parasympathic fibers; mydriasis)

Peripheral/subarachnoid space Vasculopathic, inflammation, uncal herniation,tumor, aneurysm (PcomA, BA, SCA),intracranial hypotension (ICH), other(e.g., ophthalmoplegic migraine, congenital)

Additionalneurologicalsymptoms

Contralateral ptosis Nuclear (midbrain) Ischemia (microangiopathy), otherBCrossed brainstem syndromes^Contralateral: hemiparesis, hypokinesia,

rigor (Weber syndrome)Fascicular (midbrain and cerebral

peduncle)Ischemia, tumor, inflammation, other

Contralateral: sensation deficits, tremor,hyperkinesia, pyramidal tract signs(Benedikt syndrome)

Fascicular (midbrain, red nucleus) Ischemia, tumor, inflammation, other

Contralateral: ataxia (Claude-/Nothnagelsyndrome)

Fascicular (midbrain, tegmentum/tectum), superior cerebellar peduncle

Ischemia, tumor (pinealis), other

CN IV palsy OphthalmologicalRestricted downgaze in adduction,

excyclotropia, head tilt to thenon-affected side (Bielschowsky’s sign)

Peripheral/subarachnoid space Inflammation, tumor (e.g., schwannoma),intracranial hypotension, other

Additionalneurologicalsymptoms

Contralateral: dysmetria, ataxia Nuclear/fascicular (dorsal midbrain,superior cerebellar peduncle)

Ischemia, hemorrhage, tumor, inflammation,other

Contralateral: relative afferent pupillarydefect and/or Horner syndrome

Nuclear/fascicular (dorsalpontomesencephal junction,brachium of the superior colliculus)

Ischemia, hemorrhage, tumor,inflammation, other

CN VI palsy OphthalmologicalEsotropia, restricted abduction Peripheral/subarachnoid space Inflammation, ICH, ischemia, other

Skull base (Dorello’s canal) Trauma, tumor, inflammationAdditional

neurologicalsymptoms

Ipsilateral facial pain, facial numbness CNV/supraorbital nerve (Gradenigo syndrome)

Skull base / Petrous apex

Horner syndrome (possible) Cavernous sinus ICA aneurysmContralateral: hemiparesis, sensation deficits Caudal pontine bulb Ischemia, inflammation, otherIpsilateral: nuclear CN VII paresis (caudal

pontine bulb syndrome; Millard-Gublersyndrome/Foville syndrome)

Contralateral: sensation deficits, ipsilateral:CN VII paresis, ataxia, (caudal pontinetegmentum syndrome)

Caudal pontine tegmentum Ischemia, inflammation, other

Duane syndrome (I–III) Peripheral/nuclear Congenital, otherMöbus syndromeIpsilateral CN VII palsy, ipsiversive

conjugate gaze palsy(facial colliculus syndrome)

Nuclear Ischemia, inflammation, other

Combined CN III, IV, VI palsies Peripheral/subarachnoid Inflammation, e.g., anti-GQ1b-antibodysyndrome (Miller Fisher syndrome,Guillain-Barré syndrome)

Intracranial hypotension, otherCavernous sinus/skullbase Thrombosis

Carotid-cavernous sinus fistulaTolosa Hunt syndromeInflammation, neoplasmICA aneurysm, fungal infectionCongenital fibrosis syndromes

Nuclear/fascicular Inflammation, e.g,. multiple sclerosisBickerstaff’s brainstem encephalitis

(anti-GQ1b-antibody syndrome)Metabolic (e.g., Wernicke encephalopathy,

Leigh syndrome), other

BA basilar artery, CN cranial nerve, ICA internal carotid artery, PcomA posterior communicating artery, SCA superior cerebellar artery

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neuroimaging findings and also differential diagnostic aspectsare presented for the individual groups. Taking clinical rele-vance into account, additionally the oculosympathetic paresis(Horner syndrome) is discussed (see Table 4) [1, 7, 8].However, description and analysis of the different forms ofpathological nystagmus forms, impairment of saccades, aswell as pathologies of the optic nerve go beyond the scopeof this review and will not be discussed.

Neuroimaging protocol

Neuroimaging of small structures requires high-resolutionMR sequences with thin slices, e.g., slice thickness of 0.75up to 3 mm [14–17]. For example, the trochlear nerve (CN IV)has a diameter of 0.75 to 1.00 mm [18] and sequences with aslice thickness of 1.00 mm in maximum without gap are nec-essary for clear anatomical detection [14, 15]. Therefore,strongly T2-weighted 3D sequences as well as isovolumetrichigh-resolution high contrast T1-weighted 3D sequences afteradministration of gadolinium contrast agent are recommended[14–17]. These sequences allow the reconstruction of the CNcourses in the subarachnoid space, the skull base, the cavern-ous sinus, and the orbit. Due to the often small size of mesen-cephalic and other brainstem lesions with a diameter between2 and 4 mm, neuroimaging of the posterior fossa structuresalso requires thin slice sequences [18–20]. Because fluid-attenuated inversion recovery (FLAIR) sequences are proneto artifacts in this region, one should prefer spin-echo T2-weighted images (WI) with thin slices. Depending on the neu-rologically suspected etiology of the lesion, e.g., ischemicbrainstem disorders, additional diffusion-weighted imaging

(DWI) [21] in axial and coronal acquisition may be necessary.MR studies focusing on suspected lesions in the orbits and thecavernous sinus should include axial and coronal spin-echoT1 WI with a slice thickness of 3 mm at most and fat satura-tion (FS) after intravenous administration of gadolinium (pcT1 WI FS) [12, 22].

Efferent infranuclear/peripheralneuroophthalmic disorders

Isolated CN paresis

Isolated paresis of the CN III, IV, and VI are often caused byischemia, and typical vascular risk factors are diabetes andhypertension [1, 7]. From neurological point of view, clinicalexamination cannot reliably differentiate between peripheral(infranuclear) and nuclear CN palsy [5, 7, 20]. In contrast,while neuroimaging in peripheral CN palsies is oftennegative—apart from inflammatory etiologies, pathologies in-volving CN nuclei often have a neuroradiological correlate[20].

Painless diabetic-induced CN III palsy often spares theparasympathetic fibers (i.e., external OP) and may be causedby impaired microcirculation within the CN as well as bycircumscribed paramedian mesencephalic infarcts (Fig. 2)[21–24]. However, ischemic involvement of the Edinger-Westphal nucleus in the neighborhood causes additional para-sympathetic neurological features with mydriasis and ptosis(Fig. 2).

An important differential diagnosis is the acute painfulparesis of CN III due to a so called ophthalmoplegic

Fig. 1 Schema of the oculomotor cranial nerve (CN) courses and relatednuclear regions. a: Ncl. Edinger Westphal (nuclei accessorii autonomici);b: oculomotoric nerve nucleus (CN III; extraocular muscles); c: trochlearnerve nucleus (CN IV); d: medial longitudinal fascicle (MLF); e:paramedian pontine reticular formation (PPFR); f: abducens nerve

nucleus (CN VI); g: Dorello’s canal at the clivus; h: cavernous sinus; i:lateral rectus muscle; j: ciliar ganglion; k: optic nerve (CN II); l: superioroblique muscle; m: superior rectus muscle; n: ophthalmic artery; o: inter-nal carotid artery (ICA); p: posterior communicating artery (PcomA)

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aneurysm with consecutive CN compression (Fig. 3) [25].Aneurysm-related CN III palsy typically leads to mydriasiswith unequal size of pupils (anisocoria; Fig. 3b) due tocompromised parasympathetic fibers in the external layersof the nerve (internal OP) besides variable palsies of theEOM innervated by the CN III (external OP). This repre-sents an emergency situation and acute neuroimaging

followed by prompt aneurysm treatment is necessary[26–29]. Most often, aneurysm arises from the terminalsegment of the internal carotid artery (ICA) at the originof the posterior communicating artery (PcomA; Fig. 3e).Rarer aneurysms of the superior cerebellar artery (SCA) orthe tip of the basilar artery might also cause affection of thethird CN [1, 2, 7, 30].

Table 2 Conjugate gaze abnormalities (internuclear and supranuclear disorders), additional neurological symptoms depending upon lesion site

Conjugategazeabnormality Ophthalmological and clinical characteristics Lesion site Etiology

Horizontal gaze deficits Pons/mesencephalonInternuclear ophthalmoplegia (INO):

ipsilateral limitation of adduction,preserved convergence, contralateral abductingnystagmus

MLF (upper) pontine tegmentum Inflammation, e.g., multiplesclerosis

Ischemiaother

One-and-a-half syndrome: bilateral limitation ofadduction and monocular abduction paresis

MLF (lower) pontine tegmentumand CN VI nucleus (PPRF)

InflammationIschemiaotherEight-and-a-half syndrome: additional CN VII palsy Additional CN VII fascicle

Foville syndrome: ipsilateral horizontal gaze palsy,CN VII palsy; contralateral hemiparesis

Caudal tegmental pons InflammationIschemiaother

Locked-in syndrome: horizontal gaze palsy,partially sparing of upward gaze andblinking; quadriplegia, anarthria

Ventral and central pons IschemiaHemorrhage

Bilateral abduction deficit (CN VI palsy),nystagmus; additional: disturbance ofconsciousness (Bglobal state of confusion^),ataxia

Pontine tegmentum, tectum,periaqueductal gray,mammillary bodies,thalamus, other

Wernicke encephalopathy(Vit. B1 deficiency)

Other, e.g., Leigh syndrome,multiple system atrophy(corticobasal syndrome)

Abnormal horizontalconjugate gazedeviations

SupratentorialThe patient looks at the lesion; Bright way eyes^

sign (contralateral hemiparesis)Prefrontal cortical eye fields

(Brodman’s area 8)Ischemia(Focal) epileptic activity

(e.g., tumor,inflammation)

the patients looks away from the lesion „wrongway eyes Bsign

InfratentorialIpsilateral gaze paresis and contralateral gaze preference CN VI nucleus or PPRF Ischemia, hemorrhage, other

Vertical gaze deficits Infra-/supratentorialParinaud syndrome (pretectal syndrome): upgaze

palsy, convergence-retraction nystagmus,light-near pupillary dissociation, lid lag

(riMLF), posterior commissure:Dorsal midbrain, tectum

Pinealis region: tumor, cyst,glioma, hydrocephalus,ischemia, infection, other

Top-of-the-basilar-artery syndrome(variable paramedian mesencephalic andthalamic symptoms)

Bilateral paramedianrostromesencephalicand infero-medial thalamiclesions (PTPA; Percheron’s ar-tery)

Ischemia, hemorrhage

Progressive supranuclear palsy (PSP), typicallydownward > upward; Batypical parkinsonism^

Midbrain (hummingbirdsign),thalamus, brainstem

Neurodegenerative disorder(tau protein)

Additional variable neurological symptoms Metabolic diseasesM. WhippleOther, e.g., paraneoplastic

brainstem encephalitisOcular tilt reaction: skew deviation (vertical

squinting), head tilt, binocular concordantcyclorotation, tilt of subjective vertical

Dorsolateral medulla oblongata Ischemia, other

Ipsilateral: Horner syndrome, ataxia, facial sensorydeficits (CN V); contralateral: hypalgesia;dysphagia, dysarthria (Wallenberg syndrome)

Downward deviation of both eyes with/withoutconvergence, miosis

Thalamus Ischemia, hemorrhage,infection, tumor, other

CN cranial nerve, MLF medial longitudinal fascicle, PPRF paramedian pontine reticular formation, PSP progressive supranuclear palsy (SteeleRichardson Olszewski- or Richardson syndrome), PTPA posterior thalamoperforating arteries, riMLF rostral interstitial nuclei of the medial longitudinalfasciculus

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In up to 35%, painful oculomotor nerve palsy precedessubarachnoid hemorrhage (SAH) as a Bwarning leak^ or sen-tinel leak [26, 29]. However, most often, clinical presentationof ruptured distal ICA aneurysms is the apoplectic type withSAH.

Another emergency situation represents CN III paresiswith initial mydriasis in case of supratentorial space occu-pying lesions leading to transtentorial herniation with ipsi-lateral nerve compression at the level of the plicapetroclinoidea. If possible, acute neurosurgical interven-tion is required [5, 6].

In contrast to CN IV paresis but similar to CN III affection,lesions of the abducens nerve (CN VI) are also common(Fig. 4) [1, 7]. Besides disturbance of microcirculation in pa-tients suffering from diabetes, possible etiologies include in-flammation (Fig. 4), pathological processes of the scull basewith involvement of the clivus and Dorello’s canal (Fig. 1) [1,2, 7, 17], and in rare cases also infraclinoidal intracavernousICA aneurysms [7, 31].

Differential diagnosis of CN VI palsy include Duane’sretraction syndrome caused by hypo- or aplasia of the

abducens nerve and/or the CN nucleus [32]. Due to para-doxical coinnervation of the lateral and medial rectusmuscles, clinical examination exhibits retraction of theglobe and narrowed palpebral fissure in attempted adduc-tion [1, 32]. Based on ocular muscle electromyography,three subtypes could be differentiated [33]. Type 1 is themost common pattern characterized by impaired abduc-tion, normal adduction, and retraction of the adductedglobe [34]. MRI typically shows absence of the CN VI(see Fig. 5) [35–37]. Type 2 is rare going ahead withnormal abduction and impaired adduction, and in type 3both abduction and adduction are impaired [1, 33]. High-resolution MRI using heavily T2 WI may provide addi-tional information of innervation abnormalities of theextraocular muscles (EOM) [35]. However, also orbitalblow-out fractures with entrapment of the medial rectusmuscle may mimic Duane’s syndrome, i.e., pseudo-Duane’s retraction syndrome [1].

OP due to CN paresis occurs in nearly one-third of pa-tients suffering from intracranial hypotension (ICH), whencerebrospinal fluid volume is reduced via spinal meningescaused by spontaneous leakage or iatrogenic procedures,e.g., lumbar puncture (see Fig. 6) [38–42]. Uni- or bilateralabducens nerve paresis (> 80%) is the most common insymptomatic spontaneous ICH [39]. Although the preciseetiology of CN palsy is unclear, one reason therefore maybe traction of the CN due to downward displacement of thebrainstem [39]. From pathophysiological point of view, theabducens nerve is favored to traction-related injury due tothe long prepontine subarachnoid course, the subsequenttravel through Dorello’s canal, and attachment to theGruber ligament [43, 44]. CN III and CN IV palsies areless common and in advanced cases with progressive her-niation, CN compression as well as brainstem injury maybe likely consequences [38, 39, 42].

Table 3 Disorders of the extraocular eye muscles (EOM) andintraorbital pathologies

Thyroid-associated orbitopathy (Graves or endocrine ophthalmopathy)

Primary ocular myopathies (e.g., Kearns Sayre syndrome, chronicprogressive external ophthalmoplegia)

Neuromuscular junction/myasthenia gravis

Orbital inflammatory pseudotumor, i.e., IgG 4-related ophthalmicdisease (IgG-4ROD; idiopathic orbital inflammation)

Vascular

Neoplasia

Inflammation

Trauma/blow-out fractures (Bpseudo-Duane syndrome^)

Table 4 Different Horner syndromes (HS)

Form Localization Etiology Symptoms

Central (first-order neuron)sympathetic tract

Uncrossed: hypothalamus–pons–dorsolateralmedulla oblongata–lower cervical spinalcord at the level of ciliospinal center ofBudge and Waller (C8–Th2)

Hemorrhage, infarct, tumor Wallenberg syndrome: ipsilateral:CN V, IX, X with Horner syndrome,ataxia, hypo-/anhidrosis; contralateral:hypalgesia

Preganglionic(second-order neuron)

Spinal nerve roots C8–Th2, aortic arch (le.)and subclavian artery (ri.)—superiorcervical ganglion at the level of theICA origin

Traumatic spinal nerve rootlesion, pancoast-tumor,aortic arch dissection

Horner syndrome; Ggl. stellatum:hypo-/anhidrosis arm and face;superior cervical ggl.: facialhypo-/anhidrosis

Postganglionic(third-order neuron)

Superior cervical ganglion: as internal carotidplexus in the arterial wall of the ICA—asexternal carotid plexus (sudomotoric fiberstowards the facial sweat glands on thesurface of the ICAwall)

ICA dissection, cervical tumor,lesions of the skull base orcavernous sinus

Painful Horner syndrome, oftenwithout facial anhidrosis

CN cranial nerve, ICA internal carotid artery, Ggl ganglion

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Combined CN III, IV, and VI palsies

Whereas the CN III, IV, and the first and second branch of thetrigeminal nerve (CN V; ophthalmic nerve and maxillarynerve) run in the lateral wall of the cavernous sinus [22], theabducens nerve (CN VI) partially accompanied by additionalsympathetic ocular fibers and the ICA are located in the ve-nous compartment of the cavernous sinus itself [22, 45, 46].Therefore, pathological processes in the cavernous sinus mayresult in different combinations of CN paresis, often accom-panied by retro- or periorbital pain (Figs. 7 and 8; see Table 1)[1, 2, 5, 7].

Tolosa-Hunt syndrome

The Tolosa-Hunt syndrome (THS) represents a painful OPcharacterized by paresis of the CN III, IV, and VI andsevere unilateral retro- or periorbital pain, quicklyresponding to steroids [47–49]. In addition, the first andsecond branch of the trigeminal nerve may be involved,and in rare cases, also the optic nerve (CN II). THS iscaused by a nonspecific granulomatous lymphocytic in-flammation with the soft-tissue mass involving the cavern-ous sinus with possible extension towards the superior or-bital fissure and the orbital apex (Fig. 9) [47–49]. Per

Fig. 2 A 73-year-old womansuffering from nuclear right-sidedincomplete oculomotor nervepalsy with abduction of the rightbulb, ptosis and mydriasis (a).Axial fluid-attenuated inversionrecovery (FLAIR) images (b) anddiffusion weighted images (DWI;c: ax.; d: cor; b = 1000 s/mm2)showing a rostromesencephalicparamedian infarct (arrow) withrestricted diffusion (c, d) and in-volvement of the NucleusEdinger-Westphal

Fig. 3 Painful complete leftcranial nerve (CN) III palsy (a, b)in a 70-year-old man. Time offlight (ToF) source image (c) andaxial T2 WI (d) disclosing distalleft internal carotid artery (ICA)aneurysm (white arrow) andshifted ipsilateral oculomotornerve (d, black arrow). e 3D ro-tational digital subtraction angi-ography (DSA) demonstratingophthalmoplegic ICA aneurysm(arrow) at the origin of the poste-rior communicating artery(PcomA; arrowhead) and sche-matized course of the CN III(yellow line) in another patient

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definition, the inflammation may also involve the ICAwall, i.e., periarteritic granuloma [47]. Diagnostic criteriafor the THS given by the International Headache Society(IHS) are the following: (1) one or more episodes of uni-lateral orbital pain persisting for weeks if untreated; (2)singular or combined paresis of the CN III, IV, and VIand/or detection of granuloma by MR imaging or biopsy;(3) paresis within a 2-week period after pain onset; (4)remission of pain and paresis within 72 h when treatedadequate with steroids; and (5) exclusion of other causesby accurate investigation [49, 50].

MRI features could be classified into primary and sec-ondary criteria [22, 51]. Primary criteria include (1) pres-ence of a lesion within the anterior cavernous sinus(Fig. 9), (2) local increasing size of the cavernous sinus,and (3) bulging of the dural contour of the cavernous sinus.Secondary criteria include (1) involvement of the orbitalapex and the optic nerve, (2) extension toward the superiororbital fissure, (3) involvement of the ICA, and (4) blurreddural boarder on T2 WI. If solely intraorbital masses arepresent, differential diagnosis should include idiopathic in-flammatory orbitopathy (orbital pseudotumor; Fig. 10).However, with regard to histopathological findings, it issupposed that THS [11, 52–54], orbital pseudotumor [10,55–57], and hypertrophic pachymeningitis [58, 59] arethree different manifestations of a common underlying pa-thology, i.e., IgG 4-related diseases [54].

Carotid-cavernous fistula

According to the Barrow classification, carotid-cavernous fistula(CCF) can be differentiated into direct (Barrow type A) and

Fig. 4 Abducens nerve palsyright (a) with collocate doublevision when looking to the rightside. Axial T2 WI (b) and T1 WIpc (c) showing the abducensnerve (arrow) just before enteringDorello’s canal with slight en-hancement (c) due tooligoradiculitis cranialis

Fig. 5 Duane syndrome type I. a Primary position with mild esotropia inthe left eye. b Left gaze with almost complete restriction of abduction inthe left eye. c Right gaze with mild restriction of adduction in the left eyeand obvious retractionwith reduction of the palpebral fissure. d ax. T2WI(another patient) demonstrating aplasia of the left abducens nerve(arrowhead) and normal right CN VI (arrow)

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Fig. 6 Spontaneous intracranial hypotension (ICH) due to CSF leakage in a 45-year-old man suffering from postural headache and bilateral CNVI palsy.Axial T2 WI (a, b) showing bilateral SDH (a), narrowing of the basal cisterns (b, arrow); c (sag. T1WI pc): downward displacement of cranial contents

Fig. 7 Combined cranial nerveparesis right sided with externaloculomotor nerve (CN III) paresis(a: adduction deficit right),abducens nerve (CN VI) paresis(b: lateral rectus muscle palsyright), and trochlear nerve (CNIV) paresis (c: superior obliquemuscle palsy) due to a spaceoccupying lesion (metastasis) inthe anterior lateral cavernous si-nus (d: ax. T2WI; e, f: ax. T1WI;arrow) and the superior orbitalfissure (f, arrowhead) with accen-tuated peripheral enhancement (f,g: arrow; g: cor. pc T1 WI)

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Fig. 8 Right-sided acute incomplete cavernous sinus syndrome in an 84-year-old woman with abducens nerve palsy (a) and oculomotor nervepalsy (b) including ptosis and mydriasis. Axial T2 WI (c) and ax. T1WI pc (d) 5 years before showing enlarged cavernous sinus (c, d: arrow)with inhomogeneous flow void (c, arrowhead). Actual pc CT (e, f)

disclosing impressive extension of the intracavernous internal carotidartery (ICA) aneurysm (white arrow) with partial thrombosis (e, whitearrowhead) and partial enhancement (e, f: black arrow). Note also ectasiaof the basilar artery and the left ICA (e, f: black arrowhead)

Fig. 9 Tolosa-Hunt syndrome.Axial (a, b) and coronal (c, d) T1WI disclosing slight enlargementof the anterior lateral cavernoussinus left (arrow) with inhomo-geneous enhancement (b–d, ar-row). Complete remission afterfour weeks of high dosage steroidtherapy (not shown)

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indirect fistula (Barrow type B–D) [60]. Direct CCF are definedby a direct vascular connection between the ICA and the cav-ernous sinus and are often caused by traumata involving theskull base [60, 61]. However, also intracavernous ICA aneurysmrupture or iatrogenic lesions caused by surgical orneurointerventional procedures may lead to direct CCF [31, 62].

Neurological examination discloses (in-)complete com-bined paresis of the CN III, IV, and VI resulting in (in-)com-plete internal and external OP on the affected side (Fig. 11a,b). In addition, patients typically suffer from orbital pain, pro-gressive proptosis, conjunctival injection, chemosis, and sec-ondary glaucoma [5, 7, 63].

Fig. 11 Painful complete ophthalmoplegia left accompanied byexophthalmos, chemosis, and conjunctival bleeding (a) due to traumaticdirect carotid cavernous sinus fistula (CCF). b After CCF occlusiondeclined exophthalmos and conjunctival bleeding, but persistingcomplete ophthalmoplegia with mydriasis. c ax. CT pc showingenlarged cavernous sinus (arrow) and dilated superior orbital vein

(arrowhead). d, eDigital subtraction angiography (DSA) disclosing directCCF (d, arrow) and early retrograde filling of the dilated superior orbitalvein (d, arrowhead). e Coil embolization (white arrow) and normal fillingof the ophthalmic artery (black arrow). Note also regular filling of middlecerebral artery (MCA) and anterior cerebral artery (ACA) branches afterendovascular CCF occlusion

Fig. 10 Orbital pseudotumor.Coronal T2 WI (a) and T1 WI pc(b) showing a space occupyinglesion (a, b: arrow) withinhomogeneous contrastenhancement (b, arrow) andinvolvement of the optic nerve (a,b: arrowhead)

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Characteristic MRI features include asymmetric dilation ofthe cavernous sinus with increased flow void, dilatation of thesuperior orbital vein, and sometimes protrusion of the eyeball(Fig. 11) [63]. Time-resolved CT and MR contrast-enhancedangiography could demonstrate early enhancement of the cav-ernous sinus, and MR time of flight (TOF) angiography mayshow arterialized flow signal in the cavernous sinus [60, 61,64–66]. In contrast, indirect vascular connection between theICA and cavernous sinus (CCF Barrow types B–D) caused bydural arterial branches are often low-flow fistula [60]. In manycases, these CCF are only detectable on digital subtractionangiography (DSA), which is the gold standard [62]. CCFBarrow type B show arteriovenous fistula by meningealbranches of the ICA, Barrow type C meningeal branches ofthe external carotid artery (ECA), and type D of both ICA andECA [60, 67].

Anti-GQ1b antibody syndrome

OP is also a core clinical feature in (Miller) Fisher syndrome(MFS) [68] and Bickerstaff’s encephalitis (BE) [69], bothrepresenting different conditions of the anti-GQ1b antibodysyndrome [70, 71]. While in MFS the peripheral nervous sys-tem (PNS) involvement is more prominent, in Bickerstaff’sencephalitis as the so-called central nervous system (CNS)variant of the anti-GQ1b antibody syndrome, the alterationof the reticular formation with impaired consciousness is atypical clinical feature (see Fig. 12) [70–73]. However, neu-rological presentation may be incomplete and a continuousspectrum with variable PNS and CNS involvement exists[70]. Moreover, there is also an overlap between MFS andan axonal subtype of the Guillain-Barré-Syndrome, i.e., acutemotor axonal neuropathy (AMAN) [74, 75].

Erdheim-Chester disease

In case of unclear intracranial lesions and additional bonychanges of the facial skull, in particular sinus walls andorbit, the differential diagnosis should include ECD, a raresystemic non-Langerhans cell histiocytosis of unknownetiology [76–78]. Erdheim-Chester disease (ECD) is char-acterized by bilateral symmetric long-bone involvement;however, in a recent study, up to 47% of patients had ad-ditional neurological symptoms [78, 79]. The widespreadspectrum of neurological disorders encompasses cerebellarand pyramidal signs (41 resp. 45%), sensory disturbances,CN palsies, and ocular symptoms including DV and visualfield defects [77–79]. Neuroimaging most often exhibitsextraaxial mass lesions by foamy histiocytes with involve-ment of the meninges, the hypothalamic-pituitary axis, theorbit, and facial and/or skull base bone thickening [76,80–82]. Intraaxial lesions are less common (17–23%) andMRI often shows infratentorial hyperintense signal abnor-malities on T2 WI especially in the brainstem, the dentatenucleus, and the middle cerebellar peduncle [76–78,81–84].

Conjugate gaze abnormalities (internuclearand supranuclear disorders)

Horizontal gaze deficits

Internuclear opthalmoplegia

The medial longitudinal fascicle (MLF) is an internuclearpathway between the nuclei of CN III and VI, providing

Fig. 12 Autoimmune (Bickerstaff) encephalitis. A 36-year-old male suf-fering from progressive double vision, cranial nerve palsies III, IV, andVI, and gait ataxia. Ax. T2 WI (a, b) showing nearly symmetrical

hyperintense signal changes of the mesencephalon and tegmentum(arrow) with inhomogeneous enhancement on pc T1 WI (c, arrow)

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conjugated sideways gaze [1, 3–5]. MLF travels from therostral midbrain along the pontine tegmentum to the cervi-cal spinal cord (Fig. 1). Circumscribed lesion in the courseof the MLF causes internuclear opthalmoplegia (INO) andneurological examination shows impaired bulb adductionipsilateral and dissociated nystagmus of the abducted bulbcontralateral, resulting in collocate DV during lateral gaze(Fig. 13) [1, 3–5]. Both MLF are located close together,therefore INO is often bilaterally. In younger patients, eti-ology is most often multiple sclerosis (MS; Fig. 13)[85–89], whereas in the elderly, vascular lesions accordingto ischemia are more common (Fig. 14) [90–92]. Besideatherosclerosis of the basilar artery leading to occlusion ofthe orifices of the median and paramedian pontine perfo-rators, microangiopathy may also cause lacunar infarcts inthe dorsal brainstem (Fig. 14) [21, 90–92]. Lesions at thelevel of the paramedian pontine reticular formation (PPFR)(Fig. 1) additionally involve the nucleus of the abducensnerve (CN VI), and the clinical feature is Bone and a halfsyndrome^ [1, 3, 5, 93, 94]. In neurological examination,ipsilateral bulb adduction and abduction as well as contra-lateral bulb adduction is nullified, and only abduction ofthe contralateral eyeball with dissociated nystagmus is pre-served (see Fig. 15) [1, 93, 94]. Moreover, additional facialnerve involvement during his course around the CN VInucleus (inner CN VII knee) will cause the so-called eightand a half syndrome with additive ipsilateral peripheral CNVII palsy [95–97].

Wernicke encephalopathy

Wernicke encephalopathy (WE) is characterized a global stateof confusion, ataxia, OP, and nystagmus [98]. However, clin-ical presentation is often incomplete and isolated oculomotordisorders or disturbance of consciousness may be present[98–100]. The underlying etiopathology of this serious dis-ease is thiamine (vitamin B1) deficiency often caused by mal-nutrition, e.g., chronic alcoholism, and if untreated, WE maybe followed by an irreversible amnestic syndrome, i.e.,Korsakow psychosis [98]. Oculomotor disturbances most of-ten consist of an incomplete horizontal gaze palsy with accen-tuated abduction deficits and horizontal nystagmus (Fig. 16a–c) [4, 98]. The accountable lesions are located in theperiaqueductal gray matter and the tectal plate (Fig. 16d–f)[84, 98–101]. In addition, MRI may show often symmetricallesions in the periventricular regions of the hypothalamus andthalamus with a high rate of thiamine-related glucose andoxidative metabolism, the pulvinar, the mammillary bodies,the bottom of the forth ventricle, and midline structures of thecerebellum [99–101]. Due to the severe irreversible cause ofthe disease without sufficient thiamine (vitamin B1) substitu-tion, the knowledge of typical MRI features of WE is of crit-ical importance [99, 100]. Moreover, MRI may be the key forcorrect diagnosis especially in patients showing only psycho-pathological abnormalities or incomplete symptoms on neu-rological examination [100, 102]. Whereas in the acute stageof the disease within the first 6 days, contrast enhancement of

Fig. 13 Bilateral internuclear ophthalmoplegia (INO) in a 32-year-oldman suffering from primary progressive multiple sclerosis (MS). a INOleft with adduction deficit left; see also divergent eyeballs on ax. T2WI; c

black arrow. b INO right presenting with adduction deficit right. c bilat-eral hyperintense lesions (white arrows) along the course of the mediallongitudinal fascicles (MLF) in the pontine tegmentum

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the above-mentioned structures may be detectable, in the sub-acute and chronic phase hyperintense signal changes on T2WI and FLAIR accompanied with different degrees ofcircumscribed atrophy are detectable (Fig. 16) [99]. In addi-tion, DWI may exhibit slight lowering of ADC values inthe acute phase [103, 104]. When treated sufficiently indue time, clinical syndromes as well as MRI abnormalities

may resolve completely. However, residual slight hyperin-tense signal changes on T2 WI and FLAIR may persistover time [99, 103].

Also affecting respective mesencephalic and otherbrainstem regions, other inflammatory diseases, e.g.,Bickerstaff encephalitis [69–73, 105], Beh et’s disease,and paraneoplastic brainstem encephalitis, metabolic

Fig. 15 One-and-a-half’ syndrome in a 41-year-old woman. Axial (a)and sag. (d) T2 WI demonstrating lacunar infarct (arrow; b, c: ax. andcor. DWI; b = 1000 s/mm2; arrow) in the lower pontine tegmentum

paramedian right at the level of the abducens nucleus (see alsoFig. 14d). Right (e) and left (f) gaze exhibiting complete horizontal pare-sis of the right eye and adduction deficit of the left eye

Fig. 14 Axial (a) and sag. (d) T2WI showing a small hyperintense lesion of theMLF in the pontine tegmentum paramedian right (a, arrow) due to acuteinfarction (b, c: ax. and cor. diffusion-weighted images, DWI; b = 1000 s/mm2; arrow) in a 66-year-old man suffering from INO right

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disorders including mitochondriopathies, e.g., KearnsSayre Syndrome [19, 106], Wilson disease, and neoplasticlesions, e.g., brainstem glioma, may cause gaze palsy and/or combined CN palsies [19]. However, detailed descrip-tion goes beyond the scope of this review, and it is referredto further specific literature.

Abnormal horizontal conjugate gaze deviations

The frontal eye fields located in the prefrontal cortex, i.e.,cortical Brodman’s area 8, initiate and regulate the contralat-eral gaze movements [1, 5]. Therefore, lesions affecting thecortical frontal eye fields result in a gaze preference toward the

Fig. 16 A 56-year-old woman suffering fromWernicke’s encephalopathywith impairment of consciousness, gait ataxia, and oculomotor distur-bances. a Gaze straight on with slight convergence especially left. bGaze to the left with abduction deficit left and adduction impairmentright. c Gaze to the right with abduction deficit right and adduction

impairment left. d–f ax. Fluid-attenuated inversion recovery (FLAIR)images showing symmetrical hyperintense lesions of the upper pontinetegmentum (d, arrow), the tectal plate (e, arrow), and the periaqueductalregion (f, arrow)

Fig. 17 Axial T2 WI (a–c) showing nearly symmetrical hyperintense lesions due to bilateral paramedian rostromesencephalic (a, arrow) andinferomedial thalamic (b, c: arrow) infarcts; d: cor. diffusion-weighted images, DWI; b = 1000 s/mm2)

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side of lesion due to preponderance of the contralateral corti-cal eye fields [1, 2, 5]. This Bdeviation conjugée^ is also calledBright way eyes^ sign, and depending on to the extent of thelesion, additional contralateral neurological symptoms such ashemiparesis and sensation deficits may be present. Most often,large infarcts in the middle cerebral artery (MCA) territorywith involvement of the prefrontal branches (anterior M2 seg-ment) cause a Bdeviation conjugée^ toward the side of lesion[1, 2, 5]. However, exceeding stimulation of the frontal eyefields may provoke preponderance for the contralateral gaze,so-called Bwrong way eyes^ sign [1, 2, 5]. Etiology for themore rarely contralateral Bdeviation conjugée^ includes sei-zures especially with focal epileptic activity and atypical lo-cated intracerebral hemorrhages [1, 2]. Regarding acute strokemanagement, it is of interest if the horizontal conjugate gazedeviation is conquerable or not and therefore represents animportant item in the National Institute Health Stroke Scale(NIHSS).

Vertical gaze deficits

Paramedian rostromesencephalic and inferomedial thalamicinfarcts

Vertical gaze palsy may be due to bilateral paramedianrostromesencephalic and inferomedial thalamic infarcts(Fig. 17) leading to dysfunction of the rostral interstitial nu-cleus of the MLF (Bender’s theory) [22–24, 107–112]. Theinfarcts are located in the territory of the posteriorthalamoperforating arteries (PTPA) originating from the P1-segment (precommunicating segment) of the posterior cere-bral artery (PCA) [23, 24, 111–117]. Bilateral inferiorparamedian infarcts are a likely consequence, when the originof the PTPA is a common trunk according to type II ofPercheron (Percheron’s artery) [113, 114]. Due to the highlyvariable vascular supply of the rostromesencephalic andparamedian thalamic nuclei [90, 115, 116], additional neuro-logical symptoms such as impairment of consciousness, som-nolence up to coma, cognitive deficits, hemisyndromes, andoculomotor nerve palsies may occur (Btop of the basilar arterysyndrome^) [110]. Besides Bender’s theory with bilateral in-nervation of vertical eye movement, also unilateralparamedian thalamic infarcts may cause vertical gaze palsy[8, 118–120]. One reason therefore might be thatfrontocortical neuronal pathways decussate in the medial thal-amus and unilateral infarcts may cause interruption ofsupranuclear input [118].

Progressive supranuclear palsy

In the first clinical description by Steele, Richardson, andOlszewski [121], this neurodegenerative disease was charac-terized with the neurological triad of (1) supranuclear vertical

gaze palsy, (2) slowing of vertical saccades, and (3) posturalinstability (Fig. 18). However, for clinical diagnosis of pro-gressive supranuclear palsy (PSP), new criteria have beenestablished, because two-third of all patients suffering fromPSP lack to show characteristic oculomotor disorders[122–124]. The Richardson syndrome (PSP–RS) is consistentwith the initial description mentioned above [123]. In addi-tion, different clinical phenotypes of PSP were defined includ-ing corticobasal syndrome, PSP with Parkinsonism (PSP–P),semantic variant of primary progressive aphasia (PPA), andthe non-fluent agrammatic variant of PPA [122, 123]. Thesenew diagnostic PSP criteria defined by the MovementDisorder Society differentiate three levels of diagnostic cer-tainty, i.e., probable, possible, and suggestive PSP [123].However, definite diagnosis of PSP requires neuropathologi-cal conformation of protein tau aggregates. The different clin-ical features of PSP may be a likely consequence of differentanatomic seeding and spreading properties of intracellular ag-gregates of protein tau.

Structural MRI in PSP presenting with the classicalRichardson syndrome (PSP–RS) disclose midbrain atrophywith reduction of the midbrain anterior-posterior (ap.) diame-ter and concavity of the dorsolateral midbrain margins(Mickey Mouse or Morning Glory sign; Fig. 18) [125–127].The reduction of the ap. diameter below 15 mm at the level ofthe interpeduncular fossa was described to be specific for PSP[125–128]. However, reduction of the midsagittal midbrainarea in manual performed measurement seems to be a sensi-tive tool for PSP identification and differentiation from othermultisystem atrophies (MSA), e.g., cerebellar type of MSA(MSA-C; formerly: olivo-ponto-cerebellar atrophy; OPCA)[124, 128]. Moreover, the MR Parkinsonism index (MRPI),which includes also evaluation of the superior and middlescerebellar peduncles, is a very reliable MR biomarker for thediagnosis of PSP–RS [123, 124, 128, 129]. Additionally, T2WI may show also symmetrical planar hyperintense signalchanges in the dorsolateral mesencephalon caused by the neu-rodegenerative process [126].

Parinaud syndrome

Characteristic neurological presentation in Parinaud syn-drome includes vertical gaze palsy, disturbance of the pu-pillary motoric going along with mydriasis, light–near–dis-sociation, and convergence–retraction nystagmus [1, 5,130, 131]. The syndrome is often caused by compressionof the dorsal midbrain and pretectal area, e.g., space-occupying lesions of the pineal gland and the tectal plate.Most often, tectal tumors are gliomas, but also focal dys-plasias as well as ganglioneural tumors may occur [130,131]. However, also hydrocephalus and periaqueductal le-sions may generate Parinaud syndrome [5, 9].

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Disorders of the extraocular eye musclesand intraorbital pathologies

Widespread different pathological processes in the orbit cancause OP, such as inflammatory diseases including IgG4-

related orbital diseases (IgG4-ROD) and other systemic auto-immune associated pathologies, tumors, e.g., lymphoma, me-ningioma, and hemangioma, and also traumatic orbital lesions(see Table 1) [132, 133]. Besides isolated orbital myositis orsystemic myositis (Fig. 19) [134–137], the extraocular

Fig. 19 T1 WI (a: cor; b, c: pc cor. and ax.) showing impressivehypertrophic extraocular muscles (a–c: arrowhead) with compression ofthe optic nerve (a–c: arrow) in endocrine orbitopathy. d, e: cor. T1 WI (e:

pc fat sat.) disclosing especially enlarged superior rectus muscle (arrow)in ocular myositis (arrowhead: optic nerve)

Fig. 18 Vertical gaze palsy (a) ina 75-year-old man suffering fromprogressive supranuclear gazepalsy (PSP). Axial (b) and sag. (c)T2 WI showing mesencephalicatrophy dorsolateral accentuated(b, white arrow; BMickey Mousesign^; c: black arrow: BHummingbird sign^) with widened ambienscistern (b, arrowheads)

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muscles (EOM) may be affected by myasthenia gravis or met-abolic disorders [132, 133, 136]. Typical metabolic etiologiesinclude endocrine orbitopathy (Fig. 19) [138–142] and mito-chondrial related disorders, the latter often manifesting aschronic progressive external OP [143]. In Kearns-SayreSyndrome, MR imaging may show hyperintense brainstemlesions on T2 WI especially in the pontine tegmentum [19].

An important differential diagnosis of orbital inflammatoryprocesses is the IgG4-ROD (Fig. 9) [9–11, 53–57, 144, 145].Histopathology of this multifocal inflammatory disease ex-hibits dense lymphocytic infiltrates especially containingIgG-4 plasma cells and fibrosis causing tumefactive lesions[53, 144]. Usually, the disease responds promptly to systemicsteroid therapy, but relapses may occur and escalation of im-munosuppressive therapy using monoclonal antibodies, e.g.,Rituximab, is a likely consequence. IgG4-ROD may involvethe lacrimal glands, the EOM, and the orbital soft tissue [9–11,53–57]. Most often, the so called orbital inflammatorypseudotumor is an IgG4-ROD [53, 132, 144]. In orbital trau-ma and OP, differential diagnosis should include fracture ofthe orbital bottom with herniation and entrapment of the infe-rior rectus muscle and also pseudo-Duane syndrome [1, 2].

Oculosympathic paresis (Horner syndrome)

The Horner syndrome (HS) is defined by ptosis andmiosis butnormally reactive pupil, and facultative anhidrosis due to

ipsilateral disturbance of oculosympathetic fibers [5, 45].Failed sympathetic innervation of the iris dilator muscle onthe affected side caused miosis with consecutive anisocoria,and paresis of the Müller’s muscles of the eyelids results inptosis, also called Bupside down ptosis^ or Breverse ptosis^(Fig. 20a) [45]. The combination of the upper eyelid ptosisand the lower eyelid elevation visually is suggestive ofenophthalmus [5, 45]. However, this is not a trueenophthalmus. Due to synaptic interconnections, three topo-graphic locations of the disturbed oculosympathetic pathwaycan be differentiated: (1) central or first-order neuron HS, (2)preganglionic or second-order neuron HS, and (3) postgangli-onic or third-order neuron HS (see Table 4) [5, 45, 146–148].

Central or first-order neuron HS

In central HS, the lesion of the uncrossed sympathetic fibers islocated in their course beginning at the posterolateral hypo-thalamus, passing through the lateral brainstem and the me-dulla oblongata downwards to the ciliospinal center of Budgeand Waller in the intermediolateral gray matter of the spinalcord at the level C8–T2 [5, 45, 147]. The heterogeneous eti-ology includes hypothalamic bleedings, tumors, brainstem in-farcts, and inflammatory or infectious myelitis of the lowercervical and upper thoracic spinal cord. Typical clinical pre-sentation of dorsolateral medulla oblongata infarcts (Fig. 20)is the Wallenberg Syndrome, defined by ipsilateral HS, ataxia,dysfunction of the CN V, IX, X, and contralateral hypalgesia

Fig. 20 Central Horner syndrome (HS) right with ptosis and miosis (a)due to dorsolateral infarction of the medulla oblongata with hyperintensesignal changes on ax. T2 WI (b, arrow) and restricted diffusion (c, d: ax.

and cor. diffusion-weighted images; b = 1000s/mm2) causing Wallenbergsyndrome in a 76-year-old man

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[148, 149]. Most often, Wallenberg’s syndrome is caused byipsilateral distal vertebral artery occlusion at the level of theintradural V4 segment, but also diseases of the proximal pos-terior inferior cerebellar artery (PICA) compromising the cir-cumferential branches supplying the lateral and especially thedorsolateral medulla oblongata are possible pathologies [149].

Preganglionic or second-order neuron HS

The lesion of the sympathetic fibers is located between the exitfrom the ciliospinal center and the synapses in the superiorcervical ganglion at the level of the proximal ICA [5, 45, 148].Beside traumatic spinal root and/or brachial plexus lesions,also apical lung diseases, e.g., Pancoast tumor or otherspace-occupying processes (e.g., metastasis or lymphoma) inthe neighborhood of the fiber course toward the superior cer-vical ganglion as well as inflammatory etiologies may causeHS (see Table 4). Neuroimaging should encompass completecourse of preganglionic fibers including the aortic arch [45,146, 150].

Postganglionic or third-order neuron HS

The postganglionic oculosympathetic fibers run in the ICAwall, i.e., the internal carotid plexus, whereas the sudomotoricfibers, which innervate the facial sweat glands, travel along theexternal carotid plexus on the surface of the arterial wall [45].Therefore, HS caused by ICA dissection is often referred to asan incomplete HS, because facial anhidrosis does not occur dueto spared sympathetic sudomotoric fibers in the external carotid

plexus (Fig. 21) [45, 151–154]. Within the cavernous sinus, theoculosympathetic pathway travel a short distance along withthe CN VI and then switch over to the first portion of thetrigeminal nerve (CN V), i.e., the ophthalmic nerve.Therefore, the combination of CN VI palsy and HS is highlysuggestive for a lesion in the dorsolateral portion of the cavern-ous sinus [45, 155]. More peripherally located pathologies ofthe ophthalmic nerve, e.g., Herpes zoster ophthalmicus, maycause HS. In addition, besides ICA dissection, also neck tu-mors, skull base lesions, and diseases of the cavernous sinusmay induce postganglionic HS [45, 146, 148].

In a large case series of 450 patients, Maloney WF et al.[147] reported 65% (270 pat.) to have a demonstrable causefor the HS. These 270 patients showed preganglionic HS in44%, postganglionic HS in 43%, and the remaining 13% suf-fered from central HS. In isolated HS, neuroimaging detectsunderlying pathology in 20%, most often ICA dissection(Fig. 21) [153]. Therefore, especially painful isolated HS con-stitutes a red flag, implicating diagnostic clarification in anemergency setting [146, 153]. However, when planning theMRI scan, it should be kept in mind that in the acute stage ofICA dissection within day 1–4, especially proton density-weighted images (PD WI) are sensitive for intramural hema-toma with hyperintense signal changes [151, 153]. In contrast,unenhanced T1 WI with fat suppression (FS) discloseisointense signal of the hematoma due to absent intracellularmethemoglobin within the first days after dissection onset.Hyperintense signal of the intramural hematoma will appearafter day 4 caused by metabolism of desoxyhemoglobin intomethemoglobin [151, 153].

Fig. 21 Young woman sufferingfrom acute onset of painfulHorner syndrome (HS) right (a)due to ipsilateral internal carotidartery (ICA) dissection. b, c: ax.T2 WI (b) and T1 WI with fatsaturation (FS, c) showing hyper-intense intramural hematoma (b,c: white arrow) without relevantvascular narrowing (b, blackarrow)

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Key learning points

1. OP and HS can be the overture to a life-threatening neu-rological disorder, especially when pain is present at thesame time. In this respect, imaging plays a central role inthe clarification of OP or HS at acute onset.

2. A precise neurological diagnosis with topical assign-ment of the anatomical structures involved is essentialfor a targeted neuroimaging using specialized investiga-tion protocols.

3. Diseases going ahead with OP can be divided into (a)efferent peripheral neuroophthalmic disorders involvingoculomotor CN, (b) conjugate gaze abnormalities due tointernuclear or supranuclear disorders, and (c) diseasesof the orbit and the EOM.

4. Isolated or combined oculomotor CN palsies may occurparticularly in the subarachnoid, cavernous, and orbitalcompartments, and have heterogeneous etiologies.

5. Painless induced CN III palsy may be caused by im-paired microcirculation within the CN as well as bycircumscribed paramedian mesencephalic infarcts.

6. Due to its long cisternal course and subsequent entry intothe Dorello canal with ligamentary fixation, theabducens nerve is particularly vulnerable to intracranialhypotension.

7. Horizontal gaze deficits are often caused by lesions ofthe MLF.

8. Differential diagnosis of acute vertical gaze deficitsshould include paramedian rostromesencephalic andinferomedial thalamic infarcts, most often bilaterally.

9. Widespread different pathological processes in the orbitcan cause OP, such as inflammatory diseases includingIgG4-ROD and other systemic autoimmune associatedpathologies, tumors, and also traumatic orbital lesions.

10. The knowledge of pathophysiological aspects of OP iscrucial, especially since some entities of OP cannot beidentified by imaging, e.g., in neuromuscular junctiondisorders.

Acknowledgments We thank Dr. Michael Nichtweiß for generously of-fering his advice and expertise during the process of this review.

Funding No funding was received for this study.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict ofinterest.

Ethical approval All procedures performed in the studies involving hu-man participants were in accordance with the ethical standards of theinstitutional and/or national research committee and with the 1964Helsinki Declaration and its later amendments or comparable ethicalstandards.

Informed consent Informed consent was obtained from all individualparticipants included in the study.

Publisher’s note Springer Nature remains neutral with regard to jurisdic-tional claims in published maps and institutional affiliations.

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