OCULAR MOTILITY DISORDERS DUE TO BRAINSTEM DISEASE

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1 OCULAR MOTILITY DISORDERS DUE TO BRAINSTEM DISEASE Eric R. Eggenberger, DO, MSEpi Michigan State University Lansing, MI LEARNING OBJECTIVE 1. Review brainstem anatomy and its relevance to clinical presentations CME QUESTIONS 1. The interstitial nucleus of Cajal serves as the: a. Neural integrator for vertical gaze b. Torsional burst cell locale c. Center of vestibular function d. Conduit from the abducens to the oculomotor nuclei e. Region most related to auditory function 2. The rostral interstitial nucleus of the MLF (rimlf): a. Lies within the pons b. Contains excitatory burst neurons generating vertical and torsional saccades c. Is a subnuclei of the oculomotor nucleus d. Innervates vergence motor neurons e. Serves as the neural integrator 3. Parinaud dorsal midbrain syndrome may produce all the following EXCEPT: a. Lid retraction (Collier sign) b. Limitation of vertical gaze c. Convergence retraction nystagmus d. Contralateral hemiparesis e. Light-near pupil dissociation KEYWORDS 1. Brainstem 2. Eye Movements 3. Saccades INTRODUCTION The brainstem is a complex series of nuclei and interconnections divided into 3 primary component, midbrain, pons and medulla. The conceptual framework of a house serves as a model to teach the brainstem anatomy. The attic is the Mickey Mouse shaped midbrain, overlying the 1 st floor bridge of the pons, and the butterfly basement of the medulla. These 3 structures share rich connections with the cerebellum (the garage of the posterior fossa house). MIDBRAIN ANATOMY The midbrain is the attic of the house. Axial imaging reveals the familiar Mickey Mouse configuration with cerebral peduncle (pyramidal tract) ears and cerebral aqueduct mouth. Within the midbrain, key neuroophthalmic structures include the nuclei of CN3 & 4, rimlf, INC, posterior commissure, superior colliculus and the red nucleus. KEY FEATURES/STRUCTURES CN3 CN3 (oculomotor nerve) is responsible for the majority of extraocular muscle control, including superior, inferior, and medial rectus, levator palpebrae, and pupil sphincter muscles. The nucleus of CN3 is a complex conjoined structure within the dorsal midbrain. From the nucleus, CN3 fascicles emerge ventrally and diverge, running through the red nucleus and substantia nigra prior to converging and exiting via the medial aspect of the cerebral peduncle into the interpeduncular fossa, then piercing dura to enter the cavernous sinus, where they reside in the superior lateral region. The nerve enters the orbit via the superior orbital fissure to innervate its target muscles. Central Caudal Nucleus This single CN3 subnuclei innervates the levator palpebrae muscles. Edinger Westfall (EW) Nuclei The EW subnucleus of CN3 is a V-shaped structure providing parasympathetic innervation to the ciliary ganglia, controlling pupil constriction and accommodation Annual Meeting Syllabus 433

2 Superior Rectus CN3 Subnuclei This CN3 subnuclei CROSSES to innervate the contralateral superior rectus; note the evolutionary parallel with its fellow superior globe muscle (superior oblique) and CN4 crossing. These unique features provide a set of constraints for nuclear CN3 palsies, including: Bilateral levator sparing or affliction (which may be asymmetric) Ipsilateral CN3 paresis with contralateral superior rectus involvement Bilateral pupil affliction or sparing Fascicular Organization The fascicle of CN3 is organized into a recognizable pattern even within the midbrain. Within the cerebral peduncle, the fibers running from medial to lateral appear: pupil inferior rectus lid medial rectus superior rectus inferior oblique. Rare lesions of the peduncle may selectively involve one aspect of the fascicle. CN4 The trochlear nuclei reside in the dorsal midbrain and give rise to CN4 fascicles which emerge DORSALLY and cross before turning ventrally, wrapping around the cerebral peduncles and entering the cavernous sinus in the lateral wall region. The nerve enters the superior orbital fissure to innervate the superior oblique muscle. A trochlear nuclear lesion is identical to a CN4 fascicle lesion (NB, crossing fibers within the superior medullary velum). Rarely, an intrinsic dorsal midbrain lesion produces the combination of CN4 palsy and an RAPD. Interstitial Nucleus of Cajal (INC) The INC is the neural integrator for vertical gaze. The INC projects to the ocular motor nuclei via the posterior commissure, and selective dysfunction of this nucleus results in vertical gaze evoked nystagmus; in practice, many lesions that restrict vertical gaze involve the INC in part, highlighting the nuclei s role in additional vertical gaze function. Unilateral INC lesions produce the ocular tilt reaction with ipsilesional torsional fast phases. Rostral Interstitial Nucleus of the MLF (rimlf) The rimlf lies dorsomedial to the red nucleus and rostral to the INC, and contains excitatory burst neurons generating vertical and torsional saccades. These neurons send fibers to innervate yoked muscle pairs, bilaterally to elevator muscles, but unilaterally to depressor muscles; additionally, there are neurochemical differences distinguishing upward from downward saccadic eye movements. The right rimlf drives clockwise torsional fast phases, while the left rimlf performs counterclockwise fast phases. The paired rimlf receive blood from the thalamo-subthalamic paramedian artery, which often involves a single artery of Percheron providing the basis for infarction as the most 434 North American Neuro-Ophthalmology Society common rimlf lesion. The rimlf may also be involved in degenerative tauopathies such as progressive supranuclear palsy (PSP). Unilateral lesions of the rimlf should produce ipsitorsional fast phase defects; however, such restricted lesions are rare. Infarction within this territory often involves the INC or bilateral rimlf. The latter produce loss of downward or all vertical saccades. Posterior Commissure The posterior commissure involves not just projections from the INC, but also axons from the nuclei of the posterior commissure, which appear to function in vertical gaze and eyelid function. Lesions within this clinically produce the dorsal midbrain syndrome. Superior Colliculus While superior colliculus function in nonhuman primates has been well established to participate in saccades, such lesions in isolation in humans are exceedingly rare. CLINICAL SYNDROMES: Weber Ipsilateral CN3 + contralateral hemiparesis = midbrain peduncle pyramidal tract region Nothnagel Ipsilateral CN3 + Ipsilateral ataxia = superior cerebellar peduncle region Benedikt Ipsilateral CN3 = contralateral tremor/chorea = red nucleus/ substantia nigra region Claude Ipsilateral CN3 + contralateral ataxia = dentatorubralthalamic cerebellar crossing fiber region These eponyms have often been used in the descriptions of varying combinations of midbrain CN3 deficits, and accordingly lack specific value. While the clinical features and related anatomic localization is important, the specific eponym often is not. Parinaud Dorsal Midbrain Syndrome Lesions of the dorsal midbrain often produce Parinaud syndrome, with various components typically in combination. The syndrome consists of 7 primary features: 1. Lid retraction (Collier sign) 2. Limitation of vertical gaze 3. Convergence retraction nystagmus 4. Vergence dysfunction 5. Square wave jerks 6. Light-near pupil dissociation 7. Skew deviation Most patients present with a few of these features (not all); convergence retraction nystagmus is essentially pathognomonic of the syndrome, while other features may be observed in various locations. The most common pathophysiologies producing Parinaud syndrome include

3 neoplasms of the pineal gland, hydrocephalus, infarct, demyelination, and trauma. Vertical 1.5 Syndrome (one-and-one-half) Loss of all vertical eye movements in one eye, and either an upward or downward defect in the fellow eye have been termed vertical one-and-one-half syndrome; such lesions likely result from combination of INC, posterior commissure or oculomotor nuclei fascicles. SPECIFIC DISEASES Progressive supranuclear palsy (PSP) PSP is a rare degenerative tauopathy with classic ocular motor implications including functions residing within the midbrain. Core features of PSP criteria include (mandatory inclusion criteria) 1. gradually progressive disorder 2. onset age >40 years 3. either vertical supranuclear palsy, or both slowing of vertical saccades and prominent postural instability with falls in the first year of onset 4. no evidence of other disease explanation SUPPORTIVE FEATURES 1. symmetric akinesia or rigidity, proximal > distal 2. abnormal neck posture, especially retrocollis 3. poor or absent response to levodopa 4. early dysphagia and dysarthria 5. early cognitive impairment with at least 2 of: a. apathy b. impaired abstract thought c. decreased fluency d. frontal release signs EXCLUSION CRITERIA 1. recent history of encephalitis 2. alien limb syndrome, cortical sensory deficits, focal frontal or T-P atrophy 3. hallucinations or delusions unrelated to dopamine therapy 4. cortical dementia of Alzheimer type 5. prominent early cerebellar symptoms or unexplained dysautonomia 6. severe asymmetric parkinsonian signs 7. neuroradiologic evidence of relevant structural abnormalities 8. Whipple s disease confirmed by PCR EYE MOVEMENTS Although eye movement abnormalities are perhaps the most distinct feature of PSP, the primary clinical aspect emphasized by the disease title, and often present early, it is important to realize that ocular motility abnormalities are occasionally late or absent. Slow vertical saccades are often the initial ocular motor abnormality. The quick phases of OKN are often slow or absent, so that a single slow phase is noted without resetting fast phases. Vertical saccades early in the disease may take an oblique course ( round the house sign). Horizontal saccades tend to be hypometric, but slowing in the horizontal plane often does not appear until later in the course. Frequent or continuous square wave jerks are a characteristic PSP finding. This in combination with the parkinsonism feature of impaired blink constitutes a useful clinical sign. WHIPPLE DISEASE Tropheryma whippelii produces combinations of GI symptoms, arthralgia lymphadenopathy and CNS symptoms. The latter may simulate PSP with vertical gaze dysfunction leading to global ophthalmoplegia. Oculomasticatory or oculofacioskeletal myorhythmia are pathognomonic for Whipples disease; however, this occurs in the minority of patients. The diagnosis is often quite challenging, but may be made with PCR of spinal fluid or small bowel biopsy. The disease is treatable with prolonged course of antibiotics. PONS ANATOMY The pons is the first floor great room of the brainstem house. The name pons is derived from the Latin literally meaning bridge, and on axial imaging, imagine sitting in the river of the 4 th ventricle, one can imagine a bridge over this river. KEY FEATURES/STRUCTURES CN6 The abducens nuclei contains neurons destined to innervate the lateral rectus in addition to internuclear neurons innervating the medial longitudinal fasciculus (MLF); accordingly, a lesion of the CN6 nucleus produces a ipsilateral horizontal gaze palsy (not CN6 palsy), sparing vertical gaze and vergence (vergence fibers synapse directly with the medial rectus subnuclei of CN3). The CN6 fascicle exits the pons ventrally, ascends along the clivus, then enters the cavernous sinus under Gruber s ligament in Dorello s canal. The nerve courses anteriorly in the middle of the cavernous sinus adjacent to the carotid artery. Like CN3 and 4, it enters the orbit via the superior orbital fissure, and then innervates the lateral rectus muscle. Paramedian Pontine Reticular Formation (PPRF) The PPRF houses several neuronal populations related to ocular motor control including excitatory burst neurons for horizontal saccades (nucleus pontis centralis caudalis), omnipause neurons (nucleus raphe interpositus) inhibiting burst neurons, inhibitory burst neurons (dorsal paragigantocellular nucleus), and the adjacent paramedian tracts (PMT) projecting to the flocculus, plus fibers conveying vestibular, pursuit and gaze holding signals to the CN6 nucleus. In general, unilateral lesions of the PPRF produce ipsilateral horizontal gaze palsies that may involve saccades or all classes of eye movement Annual Meeting Syllabus 435

4 Bilateral pontine lesions may impair vertical saccades via loss of coordinated omnipause cell interaction with burst cells. Medial Longitudinal Fasciculus (MLF) & Internuclear Ophthalmoplegia (INO) MLF lesions produce internuclear ophthalmoplegia (INO), a critical neuro-ophthalmic syndrome with the fundamental finding of slowed/weak adduction; additional features include contralesional abducting nystagmus, skew deviation (often with ipsilesional hypertropia), upbeat with torsional (slow phase moves upper eye pole contralesional) or dissociated vertical nystagmus, vertical gaze evoked nystagmus (especially bilateral INOs). Numerous pathophysiologies have been reported to produce INO, most commonly including ischemic (paramedian pontine perforator endartery territory) and demyelination (~50% of MS patients), but also neoplasms, infectious, trauma, nutritional/metabolic and toxic etiologies. Wall-eyed bilateral INO (WEBINO) is a subset of bilateral INOs that present with primary positon exotropia. Vergence capabilities in the presence of INOs are variable and not consistently reliable for localization purposes. CN7 The facial nuclei resides in the dorsal pons, and sends fibers in a posterior arc (forming the facial colliculus) wrapping around the abducens nuclei to exit the pons laterally as the CN7/8 complex. CLINICAL SYNDROMES Gaze palsy As mentioned previously, a lesion of the abducens nucleus produces an Ipsilateral gaze palsy; similarly, lesions of the CN6 nerve and contralateral MLF produce a gaze palsy. Internuclear Ophthalmoplegia (INO) The medial longitudinal fasciculus connects the CN6 nucleus within the pons to the contralateral CN3 nucleus (medial rectus subnucleus) in the midbrain, and lesions of the MLF produce an internuclear ophthalmoplegia. In contrast to classical teaching, most INOs do not have overt limitation of adduction, but rather slowed adduction speed. The best method to detect these saccadic INO is to elicit horizontal saccades while the examiner views the nasal bridge, attentive for adduction slowing. 1.5 The one-and-one half syndrome was originally described by Freeman et al and coined by C Miller Fisher. This lesion subtends the abducens nuclei and the adjacent MLF, producing a combination of an Ipsilateral gaze palsy and INO; the only remaining horizontal eye movement is abduction of the contralateral eye. The syndrome may be due to any one of various pathophysiologies including multiple sclerosis (MS), infarct, neoplasm or arteriovenous malformations. 8.5 The eight-and-one half syndrome simply adds CN7 to the 1.5 syndrome. These brainstem syndrome names are not relevant, but their importance lies in understanding the pontine anatomy. Recognition of an INO, CN6 palsy, gaze palsy, 1.5 and 8.5 syndromes mandates a working understanding of clinical pontine anatomy syndrome and cochlear (CN8) involvement with deafness. (Cummins et al) Bilateral CN syndrome (Man et al). Oculopalatal tremor (OPT) OPT is related to disruption of the Guillain-Mollaret triangle, often within the pontine central tegmental tract (see inferior olive and OPT under medulla). SPECIFIC DISEASES MSA Slowed saccades Pontine diseases may be associated with slowed horizontal saccades; possibilities include genetic (SCA, Huntington, CADASIL), degenerative (PSP, DLB, Alzheimer (late), Parkinson disease (late), FTD, Neiman Pick type C, Gaucher, ALS (late), CJD), infectious (Whipple, tetanus), toxic (AED, benzodiazepine overdose), inflammatory (paraneoplastic Ma2), mitochondrial (CPEO, MELAS). Selective saccadic palsy following cardiac surgery Presumably impairment of bilateral PPRF function is involved in this syndrome, although no clear and consistent pathologic correlate has been found in the few cases examined. MEDULLA ANATOMY The medulla is identifiable in axial imaging as the small caudal butterfly, and represents the basement of the model brainstem house. KEY FEATURES/STRUCTURES Vestibular Nuclei The vestibular nucleus partially resides within the medulla; however, lesions of this structure may produce varied nystagmus including horizontal, vertical, torsional or mimic those of peripheral vestibular lesions. NPH/MVN The medial vestibular nucleus and nucleus prepositus hypoglossi are key structures involved in gaze holding, comprising part of the neural integrator responsible for pulse step calculations. Lesions within this region produce gaze evoked nystagmus. 436 North American Neuro-Ophthalmology Society

5 Inferior Olive The inferior olive emits climbing fibers destined for the contralateral cerebellum, and is involved in the syndrome of oculopalalatal tremor. Lateral Medulla The lateral medulla is the site of Wallenberg syndrome, most often caused by infarct, but also possible as the result of demyelination, neoplasm, trauma, etc. The critical structures within this region correlating with symptoms include the vestibular nuclei and otolith fibers, descending tract of CN5, CN9/10, climbing fibers destined for the Purkinje cells of the cerebellum via the inferior cerebellar peduncle. SPECIFIC DISEASES/CLINICAL SYNDROMES Wallenberg Lateral Medullary Syndrome Wallenberg is the most common brainstem stroke syndrome, and usually results from vertebral artery disease (more than PICA disease). Wallenberg causes a constellation of features including ipsilateral Horner, facial numbness, CN9/10 dysfunction (dysarthria and dysphagia), and contralateral body hypesthesia. Ocular features include lateropulsion with eye closure and with ipsilesional saccades (loss of climbing fiber input from the contralateral inferior olive to the Purkinje cells produce increased fastigial nucleus inhibition), impaired contralesional smooth pursuit, mixed horizontal-torsional nystagmus, and the ocular tilt reaction (contralesional hypertropia, ipsilesional head tilt and cyclodeviation of upper eye poles). Despite its commonality, lateral medullary infarcts often go unrecognized as such in the ED due to the absence of weakness. Paramedian Medulla NPH and MVN connect with cerebellum and control gaze holding; accordingly, gaze evoked nystagmus is typical for lesions within this area (infarct, demyelination). In addition, lesions within this area, potentially involving the paramedian tracts, may produce varied types of jerk nystagmus including downbeat, upbeat, torsional and hemiseesaw. Medullary causes of both upbeat and downbeat may violate Alexander s law, producing nystagmus that dampens with gaze in the direction of the fast phase. There are several medullary structures which when lesioned result in upbeat nystagmus. Medial medullary infarcts produce contralateral hemiparesis and position sense loss, tongue paralysis (either side depending upon lesion location), nystagmus (often horizontal with slow phase away from lesion side, but also upbeat and rarely downbeat occur), skew, ocular tilt reaction and possible contrapulsion of saccades (inferior olive climbing fibers destined for the cerebellum). Oculopalatal Tremor (OPT) Oculopalatal tremor is the delayed result of a lesion with the Guillain-Mollaret triangle (inferior olive contralateral deep cerebellar nuclei/dentate nucleus red nucleus/ central tegmental tract). The inciting lesion is usually infarction within the central tegmental tract, but can result from various pathophysiologies including cavernoma, hemorrhage, trauma, or neoplasm within various locations including the cerebellum or superior cerebellar peduncle. This syndrome has its onset following a delay ranging from weeks to years following the acute insult. The nystagmus is most often 2 Hz vertical pendular, but may have elliptical, torsional or seesaw components. The palatal tremor mirrors the ocular movements, and may also involve the diaphragm, larynx and rarely other motor areas. OPT is characterized by MRI-demonstrable inferior olive hyperintensity ( pimento sign ; S Johnstone, personal communication), which appears histologically as degenerative hypertrophy. The disruption of this feedback circuit may allow the inferior olive to develop an abnormal synchronous pacer-like signal creating a cerebellar derived maladaptive response. Treatment options such as gabapentin, clonazepam, memantine and anticholinergics produce modest improvement in some patients in our experience. Progressive Ataxia with Palatal Tremor (PAPT) A small subgroup of patients with OPT later develop progressive ataxia in addition to the oculopalatal findings. This tends to be primarily gait disabling, and in several of our patients has resulted in wheelchair bound status after progressive courses ranging from months to years in duration. We have been unsuccessful in providing any pharmacologic symptomatic treatment for this syndrome. Wernicke Hypovitaminosis B1 produces the classic triad of ophthalmoplegia, ataxia and confusion. In practice, eye movement dysfunction may include CN6 palsy, but also gaze evoked and upbeat nystagmus; the latter may disobey Alexander s law, implying a lesion in the NPH-MVN region. CONCLUSIONS The brainstem is an understandable collection of wires and nuclei, and obligatory working battle field knowledge for every neuro-ophthalmologist. The concept of brainstem as a house, with midbrain attic, first floor pons, and basement medulla helps when teaching brainstem anatomy. CME ANSWERS 1. a 2. c 3. d 2016 Annual Meeting Syllabus 437

6 REFERENCES 1. Liu GT, Crenner CW, Logigian EL, Charness ME, Samuels MA. Midbrain syndromes of Benedikt, Claude, and Nothnagel: Setting the record straight. Neurology 42;1992: Leigh RJ, Zee DS. The Neurology of Eye Movements, 5 th edition. Oxford University Press, New York, NY Wray S. Eye Movement Disorders in Clinical Practice. Oxford University Press, New York, NY Wall M, Wray SH. The one-and-a-half syndrome: a unilateral disorder of the pontine tegmentum a study of 20 cases and review of the literature. Neurology 1983;33: Freeman W, Ammerman HH, Stanley H. Syndrome of the pontile tegmentum: Foville s syndrome: report of three cases. Arch Neurol Psychiatry 1943; 50: North American Neuro-Ophthalmology Society

BRAINSTEM SYNDROMES OF NEURO-OPHTHALMOLOGICAL INTEREST

BRAINSTEM SYNDROMES OF NEURO-OPHTHALMOLOGICAL INTEREST Steven L. Galetta, MD NYU Langone Medical Center New York, NY I. Anatomical Considerations The brain stem is about the size of a fat forefinger and