Article 1: The Pupil
Marc A. Bouffard, MD. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1194–1214.
PURPOSE OF REVIEW
The goal of this article is to review the anatomy and physiology of pupillary function and then employ that information to develop a comprehensive framework for understanding and diagnosing pupillary disorders.
The contribution of rods and cones to the pupillary light reflex has long been known. A third photosensitive cell type, the intrinsically photosensitive retinal ganglion cell, has recently been discovered. This cell type employs melanopsin to mediate a portion of the pupillary light reflex independent of rods and cones (the postillumination pupillary response) and photic regulation of circadian rhythm.
The autonomic nervous systemregulates pupil size in response to stimuli. The parasympathetic nervous system causes miosis in response to light and near visual stimuli. These stimuli activate supranuclear pathways that project to the Edinger-Westphal nuclei. The sympathetic nervous system causes mydriasis in response to a variety of arousing factors, both physiologic (wakefulness) and pathologic (pain). Abnormalities of physiologic function cause disturbances of pupil size, shape, and response to stimuli. The clinical approach to pupillary abnormalities should focus on the clinical and pharmacologic assessment of the pupil’s expected response to diverse stimuli.
- The pupillary sphincter muscle is located concentrically near the inner margin of the iris and mediates pupillary constriction via cholinergic stimulation from parasympathetic neurons.
- The pupillary dilator is composed of muscles radially arranged around the pupil that are stimulated by the sympathetic nervous syndrome via adrenergic input.
- The pupil constricts to both light and viewing of a near target. These two reflexes share the same anatomic efferent limb, the first-order neuron of which is located in the parasympathetic Edinger-Westphal nucleus and the second-order neuron of which is located in the ciliary ganglion. However, the parasympathetic neurons that mediate the near reflex outnumber those involved in the pupillary light reflex by a ratio of 30:1.
- Rods, cones, and intrinsically photosensitive retinal ganglion cells all contribute to the pupillary light reflex.
- Retinal ganglion cells stimulate the ipsilateral olivary pretectal nucleus in response to light. Each olivary pretectal nucleus innervates the bilateral Edinger-Westphal nucleus, although the contralateral Edinger-Westphal nucleus is more highly innervated.
- The near triad encompasses pupillary miosis, convergence, and accommodation. Accommodation refers to relaxation of the ciliary body and a resulting increase in the concavity of the lens to allow for focus on an object at near; accommodation does not refer to the miosis that accompanies it as part of the near triad.
- Axons originating from the third-order sympathetic neurons in the superior cervical ganglion that innervate the superior and inferior Müller tarsal muscles and the pupillary dilator form a plexus around the internal carotid artery. Axons originating from third-order sympathetic neurons in the superior cervical ganglion that innervate the sweat glands of the face adhere to the external carotid artery on route to their target.
- Every examination of patients with anisocoria should include a detailed assessment of eye movements including cover-uncover testing) and of lid position and function.
- Anisocoria resulting from parasympathetic denervation is maximized in the light (when both pupils should constrict maximally).
- Chronic mydriasis in complete isolation is extraordinarily unlikely to result from a third nerve palsy.
- Tonic pupils are irregular, display sectoral hypokinesis (which may require the aid of a slit lamp to visualize), are slow to redilate after constriction (thus their name), and demonstrate light-near dissociation (reacting better to near stimuli than light). They may be idiopathic, occur frequently in young women, and are only rarely associated with other pathologic processes. Ninety percent of cases are monocular.
- Constriction of a mydriatic pupil by dilute pilocarpine (0.125%) was traditionally thought to be specific to tonic pupils. However, this is incorrect; preganglionic third nerve palsies resulting from compression and trauma may result in a mydriatic pupil responsive to 0.125% pilocarpine.
- Pilocarpine 2%will cause constriction of anymydriatic pupil other than one that is pharmacologically dilated.
- Anisocoria resulting from sympathetic denervation of the pupil is maximized in the dark (when both pupils should dilate maximally).
- The ptosis that results from sympathetic denervation is often subtle (1mmto 2 mm), and frequently both the upper and lower lids are affected (as both the superior and inferior tarsus receive sympathetic innervation), which sometimes results in the optical illusion of enophthalmos (pseudoenophthalmos).
- Apraclonidine, a weak α-2 agonist, has largely supplanted cocaine and hydroxyamphetamine in confirmation of sympathetic denervation of the pupil. Denervation supersensitivity may take up to 1 week to occur; apraclonidine testing will not detect acute sympathetic denervation of the pupil. Apraclonidine cannot be used in young children because of the possibility of respiratory depression.
- Tonic pupils, which are mydriatic at the outset, may eventually become miotic and irregular.
- Bilaterally small pupils may result from bilateral sympathetic denervation of the pupillary dilator, from factors causing predominance of parasympathetic tone over sympathetic tone, or fromchronic reinnervation as seen with bilateral tonic pupils.
- Bilaterally small irregular pupils should prompt consideration of chronic tonic pupils and Argyll Robertson pupils. Treponemal syphilis serologies should be ordered.
- When in doubt as to the etiology of an irregularly shaped pupil, enlist the aid of an ophthalmologist who can employ a slit lamp to look for important anatomic details and signs of inflammation that are difficult to observe with the naked eye.
- The most common congenital causes of irregular pupils include coloboma, aniridia, and pupillary decentration, referred to as corectopia.
- When evaluating irregular pupils, consider trauma, inflammation with synechiae formation, tonic pupils, and Argyll Robertson pupils.
- Light-near dissociation typically localizes to the ciliary ganglion, dorsal midbrain, or bilateral optic nerves.
Article 2: Ischemic Optic Neuropathy
Mark J. Morrow, MD, FAAN. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1215–1235.
PURPOSE OF REVIEW
Vision is often threatened or lost by acute ischemic damage to the optic nerves. Such pathology most often affects the anterior portion of the nerve and is visible on funduscopic examination. Ischemic optic neuropathy is associated with typical vascular risk factors and with one systemic disease in particular: giant cell arteritis (GCA). This article provides an overview of the three major classes of ischemic optic neuropathy, including information on risk factors, differential diagnosis, evaluation, and management.
Optical coherence tomography provides precise anatomic imaging in ischemic optic neuropathy, showing neural loss weeks before it is visible on examination. Refinements of optical coherence tomography reveal optic nerve microvasculature and may assist in understanding pathogenesis and verifying diagnosis. New diagnostic algorithms and cranial vascular imaging techniques help define the likelihood of GCA in patients with ischemic optic neuropathy. Finally, intraocular drug and biological agent delivery holds promise for nonarteritic ischemic optic neuropathy, whereas newer immunologic agents may provide effective steroid-sparing treatment for GCA.
It is essential to recognize ischemic optic neuropathy upon presentation, especially to determine the likelihood of GCA and the need for immediate steroid therapy. A broad differential diagnosis should be considered so as not to miss alternative treatable pathology, especially in cases with retrobulbar optic nerve involvement.
- Anterior ischemic optic neuropathy presents as acute, painlessmonocular visual loss that may progress over several days.
- Anterior ischemic optic neuropathy must be distinguished from optic neuritis, compressive masses, and retinal artery and vein occlusions. This distinction is usually clear-cut after a thorough history and examination, but imaging is occasionally needed in equivocal cases. Blood work for giant cell arteritis and vascular risk factors is indicated in most cases.
- Nonarteritic anterior ischemic optic neuropathy is the most common cause of acute optic neuropathy in people older than age 50, peaking in incidence around age 60 and somewhat more common in men than women. It is most strongly linked to congenitally crowded optic discs. Other putative risk factors include hypertension, diabetes mellitus, and obstructive sleep apnea.
- Examination in arteritic and nonarteritic anterior ischemic optic neuropathy shows visual field impairment, variable loss of acuity, a swollen optic disc, and a relative afferent pupillary defect in the affected eye. Visual loss and optic disc swelling tend to be worse in the arteritic form (arteritic anterior ischemic optic neuropathy).
- The optic disc in the unaffected eye almost always shows a small cup in nonarteritic anterior ischemic optic neuropathy. Over 1 to 3 months, optic disc swelling resolves to a flat, atrophic disc in all cases of anterior ischemic optic neuropathy. Optical coherence tomography shows evidence of retinal ganglion cell body loss after only a few weeks.
- Because no treatment has been established for nonarteritic cases, it is especially important to exclude giant cell arteritis as a cause of anterior ischemic optic neuropathy.
- Although most patients with nonarteritic anterior ischemic optic neuropathy will show some spontaneous improvement, many are left with significant deficits. No therapy has been proven to improve outcomes, although several clinical trials are ongoing.
- Nonarteritic anterior ischemic optic neuropathy strikes the second eye in 15% to 20% of patients over 5 years. Limited evidence has shown that aspirin may reduce risk over the first few years, but no clear long-term benefit of aspirin or any other preventive treatment has been proven. Vascular risk factors such as hypertension and diabetes mellitus should be addressed as a matter of general health maintenance.
- Arteritic anterior ischemic optic neuropathy, like giant cell arteritis itself, is more common with advancing age (mean 70 to 75 years) and in women by at least 2:1 over men. Although most patients presenting with arteritic anterior ischemic optic neuropathy have signs and symptoms of giant cell arteritis, about 20% present with visual problems alone and have no systemic features; this has been described as occult giant cell arteritis. Thus, a high level of suspicion is essential.
- Erythrocyte sedimentation rate and C-reactive protein are the most sensitive tests for giant cell arteritis, each being elevated in about 85% of cases. These test results are nonspecific, however, and both are negative in about 10% of patients. Thrombocytosis and anemia are also common in giant cell arteritis and should increase diagnostic suspicion if present.
- Temporal artery biopsy remains the gold standard for the diagnosis of giant cell arteritis and should be arranged within the first few days of a suspected presentation. Although pathologic findings are eventually altered by therapy, these changes take weeks and are not a consideration with regard to the immediate initiation of corticosteroid treatment.
- For patients at moderate to high risk of giant cell arteritis who present with anterior ischemic optic neuropathy or transient visual loss, most experts recommend immediate initiation of high-dose IV steroids (eg, 1000 mg/d methylprednisolone) followed by oral therapy, typically prednisone 1 mg/kg or 80 mg/d. Many advocate initial hospital admission to monitor for steroid side effects, arrange temporal artery biopsy, and provide patient education.
- Corticosteroids are the mainstay of acute and chronic therapy in giant cell arteritis. They have many side effects, especially in the elderly population at highest risk for the condition.
- In most patients, systemic manifestations of giant cell arteritis respond quickly to treatment. Despite this, steroids must be tapered very slowly over 1 year or more to avoid relapse, while monitoring symptoms, erythrocyte sedimentation rate, and C-reactive protein. Various immune suppressant drugs have been used to augment steroids and reduce their long-term risks.
- Tocilizumab recently became the first US Food and Drug Administration–approved option for giant cell arteritis.
- The diagnosis of posterior ischemic optic neuropathy requires contrast imaging of the brain and orbits to exclude inflammatory and compressive conditions. Outside of the postoperative setting, giant cell arteritis should be suspected and thoroughly excluded.
- Posterior ischemic optic neuropathy is a diagnosis of exclusion because no confirmatory funduscopic findings are seen and many other processes may affect the retrobulbar optic nerve. It is reasonable to anticipate an ischemic cause of acute, fundus-negative optic neuropathy after major surgery and in giant cell arteritis.
- No specific treatment for posterior ischemic optic neuropathy has been established, other than in those cases presumed to be of arteritic origin.
Article 3: Optic Neuritis
Jeffrey L. Bennett, MD, PhD, FAAN. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1236–1264.
PURPOSE OF REVIEW
This article discusses the clinical presentation, evaluation, and management of the patient with optic neuritis. Initial emphasis is placed on clinical history, examination, diagnostic testing, and medical decision making, while subsequent focus is placed on examining specific inflammatory optic neuropathies. Clinical clues, examination findings, neuroimaging, and laboratory testing that differentiate autoimmune, granulomatous, demyelinating, infectious, and paraneoplastic causes of optic neuritis are assessed, and current treatments are evaluated.
Advances in technology and immunology have enhanced our understanding of the pathologies driving inflammatory optic nerve injury. Clinicians are now able to interrogate optic nerve structure and function during inflammatory injury, rapidly identify disease-relevant autoimmune targets, and deliver timely therapeutics to improve visual outcomes.
Optic neuritis is a common clinical manifestation of central nervous system inflammation. Depending on the etiology, visual prognosis and the risk for recurrent injury may vary. Rapid and accurate diagnosis of optic neuritis may be critical for limiting vision loss, future neurologic disability, and organ damage. This article will aid neurologists in formulating a systematic approach to patients with optic neuritis.
- The classic presentation of optic neuritis associated with multiple sclerosis is unilateral, moderate, painful vision loss with an afferent pupillary defect and normal fundus examination. Bilateral vision loss, lack of pain, and severe loss of vision should raise concern for an alternative inflammatory optic neuropathy.
- Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)–IgG optic neuritis cause severe vision loss and are more frequently bilateral. MOG–IgG optic neuritis frequently causes significant optic disc edema.
- Ophthalmic testing is not generally helpful in differentiating acute optic neuropathies. Visual evoked potentials may help to detect subtle optic nerve injury when clinical examination findings are uncertain.
- Optical coherence tomography may be useful in detecting subtle retinal pathology or documenting the extent of prior injury in cases of recurrent optic neuritis.
- MRI of the orbits is the most sensitive diagnostic test (90%) for optic neuritis; however, a normal orbital MRI scan does not exclude optic neuritis.
- The pattern of inflammation of the optic nerve on MRI may provide diagnostic information. NMOSD optic neuritis more often affects the optic chiasm, intracranial optic nerve, and optic tracts; MOG-IgG optic neuritis frequently inflames the intraorbital optic nerve and optic nerve sheath. Both disorders may be bilateral with longitudinally extensive lesions.
- Antinuclear autoantibodies are observed in many patients with optic neuritis; however, they are much less frequent in multiple sclerosis–associated optic neuritis.
- CSF pleocytosis may be highest inMOG-IgG optic neuritis, whereas CSF eosinophils are suggestive of NMOSD.
- Oligoclonal bands should suggest multiple sclerosis–associated optic neuritis, especially if they persist.
- Aquaporin-4 IgG is rarely, if ever, isolated to the CSF.
- High-dose IVmethylprednisolone (1000 mg/d IV for 3 days) is effective at improving the speed of recovery of optic neuritis. Small studies have demonstrated that the type of steroid andmode of delivery (oral versus IV) are likely inconsequential. Lower dosages of oral prednisone (1 mg/kg) are contraindicated for acute optic neuritis treatment because of a higher risk of relapse.
- Plasma exchange may be useful in treating steroid-resistant optic neuritis, severe optic neuritis due to NMOSD, and recurrent optic neuritis at risk for poor recovery. Time to administration of plasma exchange may be critical to treatment success.
- Optic neuritis is the initial presentation ofmultiple sclerosis in 25% of individuals. The presence of enhancing and nonenhancing brain MRI lesions meeting dissemination in space criteria by the 2017 McDonald criteria is diagnostic of multiple sclerosis. If no enhancing lesions are present, oligoclonal bands may provide dissemination in time criteria according to the 2017 McDonald criteria.
- It is important to differentiate optic neuritis due toNMOSD fromthat due to multiple sclerosis. The prognosis for visual recovery is poorer for NMOSD optic neuritis, and the risk for recurrence is high.
- NMOSD optic neuritis should prompt consideration for early plasma exchange.
- Treatments for multiple sclerosis, such as interferon beta, fingolimod, and natalizumab, have been documented to exacerbate NMOSD disease activity.
- MOG-IgG disease frequently causes recurrent optic neuritis. Bilateral optic neuritis, longitudinal optic nerve lesions, optic nerve sheath enhancement, and steroid responsiveness are important clinical and radiologic clues.
- GFAP-IgG encephalomyelitis is commonly associated with optic nerve papillitis. As a result, disc edema is prominent, but vision loss is rare.
- Perivascular radial enhancement on MRI is highly suggestive of GFAP-IgG disease. GFAP-IgG may be isolated to the CSF in a large fraction of patients.
- Autoimmune optic neuropathy, relapsing isolated optic neuritis, and chronic relapsing inflammatory optic neuropathy are idiopathic seronegative optic neuropathies characterized by their responsiveness to or dependency on steroid immunosuppression. They are currently a diagnosis of exclusion for patients with recurrent optic neuritis seronegative for AQP4-IgG and MOG-IgG.
- Isolated optic neuritis associated with systemic lupus erythematosus or Sjögren syndrome is rare. Patients diagnosed with systemic lupus erythematosus or Sjögren syndrome and optic neuritis should be tested for AQP4-IgG.
- Patients with systemic lupus erythematosus or Sjögren syndrome with optic neuritis who are seropositive for AQP4-IgG are at higher risk for poor visual recovery than patients with systemic lupus erythematosus or Sjögren syndrome without AQP4-IgG.
- Paraneoplastic optic neuritis associated with collapsin response mediator protein-5 (CRMP-5) autoantibodies may mimic idiopathic optic neuritis. Bilateral, asynchronous optic neuritis with prominent vitreitis and retinal leakage in an older adult should raise clinical concern.
- CRMP-5 optic neuritis is frequently accompanied by central or peripheral neurologic injury. The presence of transverse myelitis may mimic NMOSD.
- Sarcoid optic neuropathy may be extremely difficult to diagnose in the absence of ocular inflammation or systemic disease.
- Angiotensin-converting enzyme levels in the serum and CSF are notoriously insensitive for neurosarcoidosis. When suspicious, CT chest, gallium scan, or fludeoxyglucose positron emission tomography are recommended for identifying involved tissue amenable to biopsy.
- While multiple infectious agents have been associated with neuroretinitis, many cases are idiopathic. Exposure to common infectious causes should be evaluated. When the infectious workup is negative, alternative noninflammatory causes of optic disc edema with a macular star should be considered.
- Optic neuritis with disc edema and cranial neuropathies should be investigated for Lyme disease in endemic areas.
- Syphilitic optic neuritis is often associated with ocular inflammation. Optic disc edema, when present, is usually prominent. A detailed social history identifying high-risk behavior for HIV should be performed in suspicious cases.
- Optic neuritis due to direct viral infection is rare.Clinical and examination clues include recent zoster ophthalmicus, encephalitis, immunosuppression, risk for mosquito-borne illness, or associated retinitis or chorioretinitis.
- Optic neuritis from tuberculosis is often associated with uveitis and orbital apex syndrome. MRI brain findings include leptomeningeal enhancement, ependymitis, abscess, infarct, encephalitis, and tubercles.
Article 4: Toxic-Metabolic and Hereditary Optic Neuropathies
Cristiano Oliveira, MD. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1265–1288.
PURPOSE OF REVIEW
The diagnosis of visual loss from toxic-metabolic and hereditary optic neuropathies may be delayed in some cases because of a failure to elicit important information in the clinical history or to recognize typical examination findings. An understanding of the features specific to each type of toxic-metabolic and hereditary optic neuropathy, and of the underlying mechanism of insult to the optic nerve, could lead to earlier recognition, diagnosis, and treatment (when available).
Understanding of the role of mitochondria in toxic-metabolic and hereditary optic neuropathies is growing, particularly regarding the mechanism of insult of certain agents (medications and toxins) and of vitamin B12 deficiency. New developments in the quest for treatment for hereditary optic neuropathy, specifically Leber hereditary optic neuropathy, are being seen.
Toxic-metabolic and hereditary optic neuropathies present in a similar fashion, with painless, progressive, bilateral visual loss with dyschromatopsia and cecocentral visual field defects. The associated retinal ganglion cell and axonal loss is typically due to mitochondrial dysfunction caused by an exogenous agent (toxic), by insufficient or deficient substrate (metabolic or nutritional), or by abnormal proteins or mitochondrial structure determined by a genetic mutation (hereditary).
- Optic neuropathies present with visual acuity loss, dyschromatopsia (color vision dysfunction), and visual field defect. Toxic-metabolic and hereditary neuropathies should be considered when vision loss is bilateral, particularly when central or cecocentral (central defect extending to the physiologic blind spot) visual field loss is present.
- The underlying mechanism of retinal ganglion cell and axonal loss in toxic-metabolic and hereditary neuropathies is mitochondrial dysfunction caused by an exogenous agent (toxic), insufficient or deficient substrate (metabolic or nutritional), or abnormal proteins or structure of the mitochondria determined by a genetic mutation (hereditary).
- The mitochondria are responsible for adenosine triphosphate production via oxidative phosphorylation that occurs in the respiratory chain polypeptide complexes. They are also the major site of production of free radicals, which are highly reactive molecular fragments that can cause oxidative cellular damage.
- Mitochondrial dysfunction leads to damage of retinal ganglion cells and their axons through a double-hit mechanism. The first hit results from impaired axon organelle transportation and impulse conduction due to adenosine triphosphate deficit, and the second hit results from superoxide-induced oxidative damage and signaling of apoptosis.
- The papillomacular bundle is formed by the retinal ganglion cell axons located between the perineural macula and the optic disc, and its injury results in cecocentral visual field loss. The small diameter of the papillomacular bundle axons is thought to be the basis of their greater vulnerability when facing adenosine triphosphate deficit and increased superoxide production in the setting of mitochondrial dysfunction.
- Obtaining information regarding ongoing or previous toxic exposure (medications or other substances), prior surgery (bariatric or gastrointestinal resections and bypass), and dietary habits/restrictions is an essential step in the investigation of patients presenting with bilateral progressive visual loss.
- Ethambutol affects mitochondrial function by interfering with complexes I and IV and cytochrome coxidase. The ocular toxicity is dose related and more likely to occur in patients treated with 25 mg/kg/d or higher (dose must be adjusted for renal insufficiency). In addition to the bilateral cecocentral field defect, patients may present with bitemporal field defects, some with evidence of chiasmal abnormal signal. Early diagnosis and drug cessation are essential and may result in visual recovery.
- Antibiotics such as linezolid, chloramphenicol, and ciprofloxacin have been implicated in toxic optic neuropathies through inhibition of mitochondrial protein synthesis.
- Amiodarone has been associated with an optic neuropathy with optic disc swelling and visual acuity and field loss, similar to nonarteritic anterior ischemic optic neuropathy. However, it is more often bilateral, with an insidious course and protracted resolution of the disc edema.
- Toxic optic neuropathies due to tumor necrosis factor-α inhibitors and tacrolimus can be unilateral, bilateral, or sequential. As patients receiving these agents may be immunosuppressed, a thorough investigation to exclude infectious and neoplastic etiologies is particularly important.
- Vigabatrin causes retinal toxicity and a peculiar pattern of secondary optic nerve atrophy with nasal disc pallor sparing the temporal region (spared papillomacular bundle). Patients present with progressive concentric constriction sparing central vision.
- Nutritional optic neuropathies have a clinical presentation indistinct from most cases of toxic optic neuropathy and should be considered in patients who have had gastrointestinal bypass surgery, have stringent dietary restrictions, or have a history of substance abuse and secondary malnourishment.
- Vitamin B12 (cobalamin) is an intracellular superoxide scavenger, which is particularly important for unmyelinated axons in the papillomacular bundle. Cobalamin deficiency may cause superoxide accumulation, which is a signal for retinal ganglion cell apoptosis, therefore causing retinal ganglion cell and axon loss.
- Toxins and malnutrition can have a synergistic effect, causing optic neuropathy and visual loss. Carriers of genetic mutations determining mitochondrial dysfunction may be more vulnerable to both toxic and metabolic optic neuropathies.
- More than 90% of all Leber hereditary optic neuropathy cases have been associated with one of the three primary mitochondrial DNA mutations of genes coding for protein subunits of complex I (m.11778G>A, m.14484T>C, m.3460G>A), with the first being the most prevalent mutation.
- Leber hereditary optic neuropathy presents with sudden unilateral painless central visual loss with fellow eye involvement within weeks to months (sequential optic neuropathy). More than 90% of the carriers become symptomatic before 50 years of age, with peak onset in the second and third decades of life.
- In Leber hereditary optic neuropathy, dilated funduscopy may be completely normal or may show a hyperemic optic nerve with swelling of the retinal nerve fiber layer and tortuosity of the central retinal vessels. Optic disc temporal pallor is typically seen within 6 weeks of onset of visual loss, and cupping may also be observed.
- Because of the level of visual loss at presentation and the infrequent visual recovery, the visual prognosis in Leber hereditary optic neuropathy is typically poor. Patients with the 14484 mutation are the most likely to recover, followed by those with the 3460 mutation.
- No treatment has been proven effective for Leber hereditary optic neuropathy. The early use of idebenone, an antioxidant that can transport electrons directly to complex III bypassing a dysfunctional complex I, may be beneficial. Gene therapy trials are currently under way.
- Most patients with and carriers of autosomal dominant optic atrophy harbor mutations in the OPA1 gene, a nuclear gene on chromosome 3 that codes for an inner mitochondrial membrane protein essential for maintenance of the mitochondrial cristae network. The mutation results in a decrease in adenosine triphosphate production and increased formation of reactive oxygen species.
- Typical patients with autosomal dominant optic atrophy present with a history of insidious, bilateral, painless loss of visual acuity and color vision beginning in the first or second decades of life, with cecocentral field loss and the finding of optic disc temporal pallor. Of patients with autosomal dominant optic atrophy, 50% to 75% will experience further visual decline later in life, and no spontaneous recovery has been reported.
- The assessment of patients with a history of progressive bilateral visual loss and bilateral optic disc pallor should include a thorough medical history and examination, followed by laboratory testing for vitamins B12, B1, and B6; folate; methylmalonic acid; copper; and zinc and contrast-enhanced MRI of the brain and orbits. Genetic testing is typically done as a subsequent step in the workup.
- No proven treatment is available for autosomal dominant optic atrophy. Routine follow-up examinations to assess visual acuity and color vision as well as Humphrey visual field testing and optical coherence tomography to assess structural changes help ensure that patients are following the natural history of the disease and can identify concurrent pathology when deviation from the expected clinical evolution is seen.
- Although a 50% risk of transmission to offspring exists in autosomal dominant optic atrophy, because of variable penetrance, the risk of developing visual loss is 60% to 88%. Even among those who develop the disease, great variability may exist in the level of visual dysfunction.
Article 5: Idiopathic Intracranial Hypertension
Matthew J. Thurtell, MBBS, MSc, FRACP. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1289–1309.
PURPOSE OF REVIEW
Idiopathic intracranial hypertension is a syndrome of increased intracranial pressure of unclear etiology that most often occurs in obese women of childbearing age but can also occur in men, children, and older adults. This article reviews the diagnostic criteria, clinical features, neuroimaging findings, differential diagnosis, and management options for this condition.
Recent population studies have found that the annual incidence of idiopathic intracranial hypertension is increasing in association with obesity rates, whereas recent scientific studies indicate a possible role for androgen sex hormones and adipose tissue in the pathogenesis of the disease. Prospective clinical trials have demonstrated a role for weight loss, acetazolamide, and topiramate in the management of mild disease. A recently begun randomized multicenter trial of surgical interventions will provide insight into the indications for surgical intervention, optimal timing and choice of intervention, and long-term outcomes.
Idiopathic intracranial hypertension is a disorder producing symptoms and signs of increased intracranial pressure in the absence of an alternative cause. The main goals of treatment are to preserve visual function and alleviate symptoms, which can usually be achieved with a combination of weight loss, medical therapies, and surgical interventions depending on the severity of symptoms and vision loss, response to treatment, and subsequent clinical course.
- Idiopathic intracranial hypertension is a syndrome of increased intracranial pressure that usually occurs in obese women of childbearing age.
- Idiopathic intracranial hypertension is a diagnosis of exclusion. Therefore, other etiologies of increased intracranial pressure must be ruled out based on clinical history, neuroimaging, and CSF examination.
- The incidence of idiopathic intracranial hypertension appears to be increasing and is strongly correlated with obesity rates.
- Greater levels of weight gain are associated with increased risk of idiopathic intracranial hypertension, although the condition can also develop in the setting of moderate weight gain in patients who are not obese.
- Headache is the most common symptom of idiopathic intracranial hypertension. However, many patients have headaches that have features of other primary headache disorders, such as migraine and tension headache.
- Headache in idiopathic intracranial hypertension is often disabling and associated with poorer quality of life but is not correlated with intracranial pressure and, thus, may not improve with lowering of intracranial pressure.
- Transient visual obscurations are the second most common symptom of idiopathic intracranial hypertension. They are thought to result from transient ischemia of the optic nerve head and are associated with higher grades of papilledema.
- Progressive visual field loss may not be appreciated by patients, underscoring the importance of formal perimetry (visual field testing) in the evaluation and monitoring of idiopathic intracranial hypertension.
- Pulse-synchronous (pulsatile) tinnitus occurs in about half of patients with idiopathic intracranial hypertension and is thought to arise because of turbulent blood flow across transverse venous sinus stenoses.
- Papilledema is the most common and important sign in idiopathic intracranial hypertension. It is usually bilateral and symmetric. The threat of vision loss is correlated with its severity.
- If untreated, papilledema can result in progressive and irreversible vision loss with optic atrophy.
- Visual field loss is difficult to exclude with confrontation visual field testing. Consequently, formal perimetry is mandatory in the evaluation and monitoring of idiopathic intracranial hypertension.
- An enlarged physiologic blind spot is the first visual field defect to develop in idiopathic intracranial hypertension, followed by arcuate visual field defects (initially in the inferonasal visual field) and, subsequently, progressive constriction with sparing of central vision until late.
- Sixth and seventh nerve palsies can occur as false localizing signs in patients with idiopathic intracranial hypertension.
- Ophthalmic investigations are necessary to determine the severity of vision loss and papilledema. In patients with equivocal papilledema or possible pseudopapilledema, consultation with an ophthalmologist or, ideally, a neuro-ophthalmologist is suggested.
- In patients with an atypical or fulminant presentation of idiopathic intracranial hypertension, magnetic resonance venography of the head with contrast should be obtained to exclude cerebral venous sinus thrombosis.
- Common imaging findings in idiopathic intracranial hypertension include an empty sella turcica, increased optic nerve sheath dilation and tortuosity, posterior globe flattening, optic disc elevation and enhancement, inferior cerebellar tonsillar descent, and transverse venous sinus stenosis.
- In adults, a CSF opening pressure of greater than 25 cm H2O is high, while an opening pressure of 20 cm H2O to 25 cm H2O is probably abnormal if symptoms, signs, and imaging findings are consistent with increased intracranial pressure. In children, recent studies suggest that a CSF opening pressure of greater than 28 cm H2O is high.
- Retinal nerve fiber layer thickness from optical coherence tomography correlates with papilledema severity. However, retinal nerve fiber layer thickness measurements must be interpreted with caution in patients who could have combined optic disc edema and atrophy.
- Raster scans obtained through the optic nerve head with optical coherence tomography may show biomechanical changes that correlate with increased intracranial pressure and might be useful for monitoring response to treatment.
- Several medications (eg, tetracycline antibiotics, retinoids, and lithium) and cerebral venous outflow obstruction (eg, due to cerebral venous sinus thrombosis) can cause a clinical syndrome that mimics idiopathic intracranial hypertension.
- Weight loss of 6% to 10% of initial body weight can be effective in inducing a remission of idiopathic intracranial hypertension. Bariatric surgery can be effective in patients who are morbidly obese and struggle to lose weight.
- Treatment of idiopathic intracranial hypertension with acetazolamide produces improvement in visual field loss, papilledema, symptoms, and quality of life. Common side effects of acetazolamide therapy include paresthesia, dysgeusia, nausea, vomiting, and diarrhea.
- Topiramate is effective in treatment of mild to moderate idiopathic intracranial hypertension and can be considered in patients who are unable to tolerate acetazolamide or when headache is prominent. Common side effects of topiramate therapy include mental slowing, lethargy, paresthesia, and loss of appetite.
- Surgical therapies are usually reserved for patients with idiopathic intracranial hypertension who have a fulminant presentation and for patients who fail to improve or worsen despite maximally tolerated medical therapy.
- CSF shunting is effective for rapidly reducing intracranial pressure. Complications can include infection, obstruction, and migration of shunt tubing; shunt revision is often needed.
- Optic nerve sheath fenestration is effective in relieving pressure on the optic nerve, thereby reducing papilledema and improving visual function. Complications can include vision loss, tonic pupil, and diplopia.
- Transverse venous sinus stenting has been reported to improve symptoms, signs, visual function, and intracranial pressure. Complications can include in-stent thrombosis, subdural hemorrhage, and development of new stenoses proximal to the stent.
- The indications for surgical intervention in idiopathic intracranial hypertension, the timing and choice of surgical intervention, and long-term outcomes remain unclear.
- The main goals of treatment of idiopathic intracranial hypertension are to preserve vision and alleviate symptoms. Thus, the management is tailored depending on the severity of vision loss, papilledema, and symptoms as well as the patient’s response to medical therapy and ability to tolerate medical therapy.
- Patients with idiopathic intracranial hypertension with minimal to mild vision loss can usually be managed with weight loss and medical therapy, whereas patients with moderate to severe vision loss often need a combination of weight loss, aggressive medical therapy, and, occasionally, surgical intervention.
- Patients with idiopathic intracranial hypertension should be managed in coordination with an ophthalmologist or neuro-ophthalmologist, since formal perimetry and monitoring of papilledema severity is needed to guide management.
Article 6: Chiasmal and Postchiasmal Disease
Heather E. Moss, MD, PhD, FAAN. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1310–1328.
PURPOSE OF REVIEW
This article reviews the anatomy, symptoms, examination findings, and causes of diseases affecting the optic chiasm, optic tracts, optic radiations, and occipital lobes.
Modern ophthalmic imaging can be used to monitor the effects of diseases of the optic chiasm and tract on the retinal ganglion cells. It can also be used to visualize transsynaptic degeneration of the anterior visual pathway in the setting of acquired retrogeniculate lesions. Visual prostheses that directly stimulate the occipital lobe are a potential strategy for rehabilitation that is in active clinical trials.
Detecting and characterizing visual deficits due to optic chiasm and retrochiasmal disease are important for the diagnosis, localization, and monitoring of neurologic disease; identifying patient disability; and guiding rehabilitation.
- Central vision can be affected in chiasmal lesions but is spared in unilateral retrochiasmal lesions.
- If a homonymous field defect is complete, localization beyond a retrochiasmal location is not possible based on peripheral vision testing alone.
- Confrontation visual field deficits are specific but not sensitive for peripheral vision loss.
- Optic nerve head pallor in both eyes is diagnostic of chronic injury to the retinal ganglion cells in both optic nerves, the chiasm, or one optic tract.
- Lack of optic nerve head pallor does not exclude injury to the ganglion cells in the optic nerves, chiasm, or optic tracts.
- Relative afferent pupillary defects can occur in asymmetric chiasm and unilateral optic tract lesions.
- Lesions affecting the anterior chiasm affect the peripheral temporal fields, whereas those affecting the posterior chiasm affect the central temporal fields with sparing of the periphery.
- The optic chiasm is best viewed on coronal or sagittal MRI or CT sequences obtained with narrow slice spacing.
- Homonymous peripheral vision loss affects navigation, and homonymous visual field loss that reaches central vision affects reading.
- Homonymous visual field loss with an afferent pupillary defect on the same side of the visual field loss suggests a contralateral optic tract lesion.
- Visual symptoms due to optic radiation disease are usually accompanied by other neurologic symptoms localizing to the affected territory.
- Congruous homonymous visual field loss is a hallmark of occipital lobe disease.
- Posterior cerebral artery infarcts often spare central vision and far peripheral vision in the affected field, which can limit disability from vision loss.
- Posterior cortical atrophy and Creutzfeldt-Jakob disease can cause homonymous visual field loss with only subtle neuroimaging findings.
Article 7: Higher Cortical Visual Disorders
Sashank Prasad, MD; Marc Dinkin, MD. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1329–1361.
PURPOSE OF REVIEW
This article reviews the disorders that result from disruption of extrastriate regions of the cerebral cortex responsible for higher visual processing. For each disorder, a historical perspective is offered and relevant neuroscientific studies are reviewed.
Careful analysis of the consequences of lesions that disrupt visual functions such as facial recognition and written language processing has improved understanding of the role of key regions in these networks. In addition, modern imaging techniques have built upon prior lesion studies to further elucidate the functions of these cortical areas. For example, functional MRI (fMRI) has identified and characterized the response properties of ventral regions that contribute to object recognition and dorsal regions that subserve motion perception and visuospatial attention. Newer network-based functional imaging studies have shed light on the mechanisms behind various causes of spontaneous visual hallucinations.
Understanding the regions and neural networks responsible for higher-order visual function helps the practicing neurologist to diagnose and manage associated disorders of visual processing and to identify and treat responsible underlying disease.
- After initial processing in the primary visual cortex, numerous adjacent cortical areas continue the work of analyzing specific aspects of visual information. These areas, which are situated in the occipital, temporal, and parietal lobes, are given names such as V2, V3, V4, V5, lateral occipital area, or fusiform face area.
- Anton syndrome refers to cortical blindness with lack of awareness (ie, anosognosia) of the deficit.
- Visual agnosia refers to a specific impairment of the ability to recognize or interpret visually presented information although elementary aspects of vision remain intact.
- In apperceptive visual agnosia, although spatial acuity is preserved, the remaining steps of visual processing are disrupted at a very early stage, rendering patients unable to perceive even the most basic geometric relationships that create the contours of a visual object.
- Associative visual agnosia describes a disorder in which basic visual perception is preserved, including grouping of visual forms, but visual percepts cannot be associated with relevant stored semantic knowledge.
- Central hemiachromatopsia describes loss of color recognition in the hemifield contralateral to a lesion of V4, a region in which neurons are selectively responsive to specific wavelengths of light. In clinical practice, lesions often encompass this area as well as the adjacent inferior striate cortex (V1), causing an overlapping superior quadrantanopia, so that the achromatopsia is only evident in the seeing inferior visual field.
- Processing in V4 adjusts for the spectral balance of incident light so that the apparent color of an object is perceived as being fairly constant despite considerable differences in lighting environments. This phenomenon is known as color constancy.
- Alexia without agraphia, also referred to as pure alexia or pure word blindness, describes the loss of the ability to read, although the ability to write remains spared. It is often the result of a lesion affecting both the left occipital cortex and the splenium of the corpus callosum. A right homonymous hemianopia ensues, while visual information in the right occipital cortex cannot reach the left-sided language areas to allow linguistic analysis of the visualized symbols.
- Alexia without agraphia may also result from a single lesion in the visual word form area within the fusiform gyrus.
- Prosopagnosia is a specific form of visual agnosia in which face perception is impaired while elementary aspects of vision, such as acuity and visual field, remain intact.
- Facial recognition in the visual system is particularly sensitive to the orientation of an image, much more so than other types of object processing.
- Riddoch syndrome describes the preserved ability to detect motion in an otherwise blind visual field.
- Balint syndrome describes a profound disruption of visuospatial attention mechanisms resulting from bilateral parietal lesions. Its key features are simultanagnosia, optic ataxia, and ocular apraxia.
- Simultanagnosia refers to an ability to perceive the local elements of a scene but not the global elements in their totality.
- Optic ataxia refers to impaired reaching under visual guidance, in which reaching under proprioceptive guidance (ie, back to one's own nose) is preserved. Ocular apraxia refers to inaccurate saccades stemming from a disorder of visuospatial attention.
- Unilateral parietal lobe lesions, especially of the right parietal cortex, often cause hemispatial neglect to the contralateral side.
- Charles Bonnet syndrome refers to “release” hallucinations that occur in the context of visual loss, often due to anterior lesions such as cataracts or macular degeneration.
- Lhermitte peduncular hallucinosis describes vivid, dreamlike hallucinations that occur during normal wakefulness and may result from lesions to areas of the midbrain and thalamus that regulate the sleep-wake state and normally prevent dreams from encroaching on wakefulness.
Article 8: Approach to Diplopia
Christopher C. Glisson, DO, MS, FAAN. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1362–1375.
PURPOSE OF REVIEW
“Double vision” is a commonly encountered concern in neurologic practice; the experience of diplopia is always sudden and is frequently a cause of great apprehension and potential disability for patients. Moreover, while some causes of diplopia are benign, others require immediate recognition, a focused diagnostic evaluation, and appropriate treatment to prevent vision- and life-threatening outcomes. A logical, easy-to-followapproach to the clinical evaluation of patients with diplopia is helpful in ensuring accurate localization, a comprehensive differential diagnosis, and optimal patient care. This article provides a foundation for formulating an approach to the patient with diplopia and includes practical examples of developing the differential diagnosis, effectively using confirmatory examination techniques, determining an appropriate diagnostic strategy, and (where applicable) providing effective treatment.
Recent population-based analyses have determined that diplopia is a common presentation in both ambulatory and emergency department settings, with 850,000 such visits occurring annually. For patients presenting to an outpatient facility, diagnoses are rarely serious. However, potentially life-threatening causes (predominantly stroke or transient ischemic attack) can be encountered. In patients presenting with diplopia related to isolated cranial nerve palsy, immediate neuroimaging can often be avoided if an appropriate history and examination are used to exclude worrisome etiologies.
Binocular diplopia is most often due to a neurologic cause. The onset of true “double vision” is debilitating for most patients and commonly prompts immediate access to health care services as a consequence of functional impairment and concern for worrisome underlying causes. Although patients may seek initial evaluation through the emergency department or from their primary care/ophthalmic provider, elimination of an ocular cause will not infrequently result in the patient being referred for neurologic consultation. A logical, localization-driven, and evidence-based approach is the most effective way to arrive at the correct diagnosis and provide the best outcome for the patient.
- A detailed history and systematic examination can often accurately localize the cause of diplopia.
- Monocular diplopia is rarely due to neurologic pathology.
- Eliciting the orientation of the double image (horizontal, vertical, or oblique), whether diplopia is present at distance or near, and whether the diplopia worsens in any direction of gaze are fundamental to accurate localization.
- Diplopia that occurs with fatigue does not necessarily imply myasthenia gravis; long-standing and decompensated ocular misalignment can also become symptomatic when patients are tired or under stress or in the setting of concomitant illness.
- Diplopia/ocular misalignment that does not change with the direction of gaze is classified as comitant; diplopia that varies depending on the direction of gaze is termed incomitant and most often indicates extraocular muscle dysfunction.
- Assessment of fixation is commonly overlooked during the ocular motility examination but is essential in identifying potential pathologic features that may be associated with diplopia.
- Neuroimaging has a low diagnostic yield in isolated fourth, pupil-sparing third, and sixth nerve palsies in older patients with vascular risk factors. However, a small number of patients older than 50 years of age may have other causes including neoplasm, infarction, and giant cell arteritis.
- While the localization of isolated diplopia can be relatively straightforward, the complex nature of ocular motility and coordination makes them susceptible to disruption by more diffuse cerebral dysfunction.
- Internuclear ophthalmoplegia is best identified by testing saccades.
- Patients presenting with cranial nerve VI palsy should be evaluated for signs and symptoms of increased intracranial pressure, which includes fundus examination.
- Myasthenia gravis can mimic any pupil-sparing ocular motility deficit.
- Antibody and electrophysiologic testing for myasthenia gravis may be supportive, but this remains a primarily clinical diagnosis.
- Patients with known or suspected thyroid ophthalmopathy should have periodic monitoring with formal visual fields because of the possibility of peripheral vision constriction by compression of the optic nerves as a consequence of enlarging extraocular muscles.
- For patients with new-onset (eg, microvascular) or transient (eg, myasthenia gravis–related) diplopia, monocular occlusion for mitigation of symptoms is immediately effective and can be employed as needed when symptoms are present.
- Prism correction is useful for patients with stable or comitant ocular misalignment; eye alignment surgery is useful for patients with incomitant diplopia.
Article 9: Nystagmus and Saccadic Intrusions
Janet C. Rucker, MD. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1376–1400.
PURPOSE OF REVIEW
This article provides an overview of nystagmus and saccadic intrusions with the goal of facilitating recognition and differentiation of abnormal eye movements to assist with accurate diagnosis of neurologic disease and evidence-based specific treatment of oscillopsia. Myriad advances have been made in the understanding of several types of nystagmus and saccadic intrusions, even in the past 5 to 10 years, especially regarding underlying pathophysiology, leading to pharmacologic advances rooted in physiologic principles.
Specific recent advances in the study of nystagmus and saccadic intrusions include (1) improved understanding of the underlying etiologies and mechanisms of nystagmus enhanced or unmasked by provocative maneuvers such as supine position or head shaking; (2) recognition of the differences in behavior and treatment responsivity of acquired pendular nystagmus in demyelinating disease versus oculopalatal myoclonus; (3) recognition that oculopalatal myoclonus results froma dual mechanism of abnormal inferior olivary gap junction connection formation and maladaptive cerebellar learning; and (4) well-controlled clinical trials to evaluate the efficacy of pharmacologic interventions, such as memantine for acquired pendular nystagmus and 4-aminopyridine for downbeat nystagmus.
Accurate recognition of nystagmus and saccadic intrusions, including familiarity with the subtleties of examination techniques that allow such eye movements to be unmasked, is critical to proper diagnosis and ultimate alleviation of the visual impairment these patients experience.
- Nystagmus can be congenital or acquired; it tends to be rhythmic and regular and, if present in central gaze, continuous and sustained. Saccadic intrusions are more often nonrhythmic, intermittent, and unsustained.
- The initial abnormal eye movement with nystagmus is always a slow drift of the eyes that is also called a slow phase; in contrast, saccadic intrusions are initiated by a fast saccadic eye movement.
- The two main types, or waveforms, of nystagmus are jerk and pendular, both of which may have horizontal, vertical, and/or torsional trajectories, which may be different in the two eyes, especially for pendular nystagmus.
- Even if no nystagmus is seen on standard examination with the patient in the upright position, provocative maneuvers often unmask nystagmus and assist with diagnosis. Thus, they should be incorporated into the examination of any patient with symptoms of oscillopsia, imbalance, or vertigo.
- Saccadic intrusions are divided into two broad categories: those with an intersaccadic interval between subsequent saccades and those lacking such an interval.
- Saccadic intrusions with an intersaccadic interval include square-wave jerks, macro–square-wave jerks, and macrosaccadic oscillations. Saccadic intrusions without an intersaccadic interval include ocular flutter and opsoclonus.
- Square-wave jerks are pairs of small saccades, typically in the horizontal plane, that remove the eyes from and then return them to the midline without crossing it and have an intersaccadic interval.
- Square-wave jerks occur excessively, sometimes nearly continuously, in patients with Friedreich ataxia, multisystem atrophy, or progressive supranuclear palsy, although they may also occur in idiopathic Parkinson disease at any stage of the illness.
- Macrosaccadic oscillations are runs of horizontal saccades that are larger than square-wave jerks, have an intersaccadic interval, cross the midline, and build and decay around the central fixation point in a crescendo-decrescendo pattern.
- Ocular flutter and opsoclonus consist of erratic bursts of very-high-frequency, high-velocity, back-to-back saccades that oscillate about the midline and have no intersaccadic interval between subsequent saccades. This is termed ocular flutter when the saccades occur only in the horizontal plane. Opsoclonus, in contrast, contains saccades in all trajectories: horizontal, vertical, and torsional.
- Flutter and opsoclonus occur in two main clinical settings: paraneoplastic conditions and parainfectious brainstem encephalitis.
- Acquired pendular nystagmus occurs most often in the setting of demyelinating disease or within the context of oculopalatal myoclonus following a brainstem ischemic or hemorrhagic stroke.
- Acquired pendular nystagmus is typically very visually disabling because of the constant slow to-and-fro foveal drifting it creates.
- Nystagmus induced by the vestibular system, via peripheral or central disruption, is jerk nystagmus with linear-velocity slow phases that tends to follow the Alexander law, with worsening of the amplitude and frequency of fast phases in the direction of gaze of the nystagmus fast phases (ie, right-beat jerk nystagmus worsens in right gaze).
- Posterior canal benign paroxysmal positional vertigo represents over 80% of benign paroxysmal positional vertigo cases and is confirmed by the presence of a vertical-torsional nystagmus induced by the Dix-Hallpike maneuver.
- Observation of the patient over several minutes is required when pure horizontal jerk nystagmus is present, as this type of nystagmus may also occur with periodic alternating nystagmus. However, with periodic alternating nystagmus, the nystagmus will reverse horizontal direction approximately every 90 to 120 seconds, often with a few beats of vertical nystagmus during the transition zone.
- In nearly all cases, vertical and torsional nystagmus should be present in central gaze fixation with the patient upright, although the oscillations may be of very tiny amplitude in this patient position and only visible with magnified views of the eye, such aswith high-resolution infrared video or during ophthalmoscopy.
- Upbeat nystagmus is most commonly seen with Wernicke encephalopathy secondary to thiamine deficiency (in combination with horizontal gaze deficits and often with accompanying gaze-evoked nystagmus), demyelinating disease, or stroke of the medulla or midbrain.
- Downbeat nystagmus, one of the most common forms of acquired central nystagmus seen clinically, is jerk nystagmus induced by slow upward drifts of the eyes followed by resetting downward fast phases. It may or may not follow the Alexander law by increasing in downward gaze (and often does not), but it nearly always increases in amplitude and frequency in downward lateral gaze.
- Downbeat nystagmus, in most cases, represents cerebellar dysfunction, typically with lesions involving the vestibulocerebellum (flocculus, paraflocculus, nodulus, and uvula), although cases are also reported due to primary brainstem lesions, usually involving a group of brainstem neurons called the paramedian tracts.
- One of the prevalent forms of physiologic nystagmus commonly seen on clinical examination is gaze-evoked nystagmus, which is also variably called end-gaze nystagmus or direction-changing nystagmus.
Article 10: Paraneoplastic Syndromes in Neuro-ophthalmology
Lynn Gordon, MD, PhD; Marc Dinkin, MD. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1401–1421.
PURPOSE OF REVIEW
This article discusses the varied types of paraneoplastic syndromes that commonly have neuro-ophthalmologic manifestations. Diagnostic considerations and therapeutic options for individual diseases are also discussed.
Paraneoplastic syndromes can affect the afferent and efferent visual systems. Paraneoplastic syndromes may result in reduced visual acuity from retinal degeneration, alterations in melanocyte proliferation and uveal thickening, or acquired nystagmus. Ocular motor abnormalities related to paraneoplastic syndromes may present with symptoms from opsoclonus or from neuromuscular junction disease. Diagnosis remains challenging, but serologic identification of some specific antibodies may be helpful or confirmatory. Treatment, in addition to directed therapies against the underlying cancer, often requires systemic corticosteroids, plasma exchange, or immunosuppression, but some specific syndromes improve with use of targeted pharmacologic therapy.
Diagnosis and therapy of paraneoplastic syndromes presenting with neuro-ophthalmic symptoms remain a challenge, but strategies are evolving and new approaches are on the horizon.
- Neuro-ophthalmologic paraneoplastic syndromes arise from remote tumor effects largely through autoimmune responses against normal tissue that arise or are triggered by tumor expression of neuronal proteins that elicit immune responses.
- Detection of specific antibodies against neuronal antigenic targets can be helpful in identifying paraneoplastic disease. However, the practitioner should be aware of false-negative and false-positive errors, the possibility of novel antibodies not yet described or available for testing, and the spectrum of varied clinical presentations for any one antibody.
- Paraneoplastic syndromes may precede a cancer diagnosis by months or even years.
- The characteristic afferent visual paraneoplastic syndromes involve the retina in conditions such as cancer-associated retinopathy, melanoma-associated retinopathy, and bilateral diffuse uveal melanocytic proliferation, but a paraneoplastic optic neuropathy may also occur, although rarely.
- Workup for possible paraneoplastic syndromes affecting the afferent visual system should include visual acuity, color vision, pupillary testing, formal visual field testing, funduscopy, optical coherence tomography of the retina, and electroretinogram.
- The symptoms of cancer-associated retinopathy reflect its target cell: the photoreceptor. Loss of acuity, color vision, and central visual field as well as sensitivity to light and glare, photopsia, and flickering lights all result from cone dysfunction, while paracentral (ring) scotomas, impaired dark adaptation, and nyctalopia (difficulty seeing at night) result from damage to the rods.
- Testing for paraneoplastic antibodies should not be used as a screening tool for paraneoplastic disease in the absence of a suspicious clinical presentation.
- Antibodies against recoverin, a photoreceptor protein involved in phototransduction, were the first to be described in cancer-associated retinopathy. Cancer-associated retinopathy associated with antibodies against α-enolase is more likely to involve pure cone dysfunction and to present months or years after the cancer diagnosis.
- Some of the identified antibodies in cancer-associated retinopathy initiate retinal degeneration by entering retinal photoreceptors and inducing cell death, while others appear to be induced by release of immunologic proteins from the dying photoreceptors and may either further propagate retinal cell death or, in some cases, serve only as markers of the disease.
- Some evidence exists for reversal of some of the retinal findings in cancer-associated retinopathy with treatment.
- Rarely, melanoma-associated retinopathy can precede the diagnosis of melanoma.
- Melanoma-associated retinopathy is typically associated with a response on the electroretinogram that reflects bipolar cell dysfunction.
- Management of melanoma-associated retinopathy includes immunosuppression and treatment of the underlying cancer. However, checkpoint inhibitors used to treat melanoma have been associated with the occurrence or exacerbation of melanoma-associated retinopathy in rare cases.
- POEMS is a paraneoplastic syndrome whose name describes the protean clinical manifestations of cytokine production, driven in part by vascular endothelial growth factor, all resulting from a monoclonal plasma cell disorder. Papilledema may accompany the disorder, in which case CSF evaluation may reflect an increase in protein and intracranial pressure.
- Management of paraneoplastic optic neuropathy includes treatment of the underlying cancer with or without the use of adjunctive therapy, including systemic corticosteroids, mycophenolate mofetil, or plasma exchange.
- Opsoclonus is a form of saccadic intrusion characterized by omnidirectional, chaotic, high-frequency saccadic movements that may be of large amplitude and lack an intersaccadic interval.
- Reflective of brainstem or cerebellar damage, opsoclonus may result from paraneoplastic disease, with or without myoclonus, typically from neuroblastoma in children and small cell lung carcinoma or ovarian cancer in adults. Responsible antibodies include antineuronal nuclear antibodies type 1 (anti-Hu) and type 2 (anti-Ri).
- Lambert-Eaton myasthenic syndrome is a disease in which antibodies against the P/Q voltage-gated calcium channel located on the presynaptic terminal of the neuromuscular junction result in their dysfunction and secondary weakness that improves with exercise. Neuro-ophthalmic manifestations may include diplopia and ptosis, the latter of which may improve with upgaze. The underlying cause may be paraneoplastic or primary immune.
- Myasthenia gravis is an autoimmune disease in which an antibody-mediated attack on the acetylcholine receptors on the postsynaptic junction of the neuromuscular junction result in fatigable generalized weakness, often accompanied by ptosis and ophthalmoparesis. A minority of cases are associated with thymoma, which, despite its typically indolent nature, can be invasive and, rarely, malignant.
- Involvement of bilateral medial rectus muscles in myasthenia gravis may mimic a bilateral internuclear ophthalmoplegia.
- The Cogan lid twitch is an overshoot of the eyelid when the patient looks upward following a period of fixation on a target in downgaze. Although not pathognomonic for myasthenia gravis, it may provide supporting clinical evidence for the disease.
Article 11: Infectious Optic Neuropathies
Eric R. Eggenberger, DO, FAAN. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1422–1437.
PURPOSE OF REVIEW
This article reviews common infectious optic neuropathies, focusing on the more common and globally important entities.
Novel infections continue to emerge and drift geographically over time; not infrequently, these have important neurologic or ocular features. Malarial retinal findings comprise a relatively specific set of findings and serve as an invaluable aid in the diagnosis of cerebral malaria. Therapy continues to evolve and is best formulated in concert with an infectious disease expert.
Infectious optic neuropathies are less common than inflammatory or ischemic optic neuropathies; may present with varied, overlapping, and nonspecific clinical appearances; and comprise an important differential consideration demanding specific therapy.
- Infectious optic neuropathy often presents with a nonspecific clinical picture including adjacent structures, most commonly the retina and vitreous. Travel and increasingly global exposures influence the differential diagnosis. New pathogens continue to emerge and frequently involve ocular structures.
- Tuberculosis is a common worldwide infection and shares a synergistic interconnection with HIV. Diagnosis can be challenging; however, interferon-based laboratory tests represent a useful advance.
- Tuberculosis can affect any part of the visual system from the globe, optic nerve, chiasm, and tracts to the occipital lobe. Optic nerve and ocular involvement are accompanied by uveitis in the vast majority of cases.
- Neuroretinitis is a nonspecific clinical syndrome that may be related to any of several different infectious agents in addition to inflammatory or neoplastic pathophysiologies.
- Although Borrelia is an important neuropathogen, retrobulbar optic neuropathy related to Lyme disease is extremely rare.
- Syphilis rates are increasing, and diagnostic testing can be challenging; diverse clinical presentations and a well-earned reputation as “the great mimic” make syphilis an important treatment-altering point in the differential of many clinical neuro-ophthalmologic presentations.
- Syphilis may involve the brain and ocular structures at any stage. When syphilis affects the eye, uveitis is the most common form; however, the disease is notoriously variable and may affect the bulbar or retrobulbar segment of the optic nerve with granulomatous, nongranulomatous, or ischemic pathophysiologies.
- Acute retinal necrosis is an important ocular condition producing rapidly progressive retinal vasculitis with retinal necrosis, often with coincident or subsequent papillitis.
- Zika virus is the latest in novel infectious epidemics, with a relatively distinct congenital syndrome of microcephaly and retinal/optic nerve changes.
- Cerebral malaria is often associated with relatively distinct retinal changes, including retina whitening, retinal vascular changes, retinal hemorrhage, and occasional papilledema.
- Toxoplasmosis is widespread geographically and the most common infectious cause of uveitis in many clinics. Treatment is effective at preventing visual loss in most patients.
- Fungal infections are rapidly progressive in the immunocompromised host, with frequent lethal outcomes in the absence of early diagnosis and aggressive therapy.
Article 12: Imaging in Neuro-ophthalmology
Fiona Costello, MD, FRCPC; James N. Scott, MD, MSc. Continuum (Minneap Minn). October 2019; 25 (5 Neuro-Ophthalmology):1438–1490.
PURPOSE OF REVIEW
This article discusses an approach to imaging in patients with neuro-ophthalmologic disorders, with emphasis on the clinical-anatomic localization of lesions affecting afferent and efferent visual function.
Advances in MRI, CT, ultrasound, and optical coherence tomography have changed how neuro-ophthalmic disorders are diagnosed and followed in the modern clinical era.
The advantages, disadvantages, and indications for various imaging techniques for neuro-ophthalmologic disorders are discussed, with a view to optimizing how these tools can be used to enhance patient care.
- The diagnostic pursuit of “what” the problem is in neuro-ophthalmology is often spearheaded by knowledge of “where” the problem is because of the elegant topographic organization of the afferent and efferent visual systems.
- The diagnosis of optic neuritis associated with neuromyelitis optica spectrum disorder can be aided by adding orbital MRI sequences to cranial imaging; orbital views typically reveal longitudinal lesion(s) that extend back to the optic chiasm.
- MRI of the brain, orbits, and spinal cord can help identify patterns of central nervous system inflammation that are pathognomonic for neuromyelitis optica spectrum disorder.
- Anti–myelin oligodendrocyte glycoprotein IgG–associated optic neuritis commonly presents with optic disc edema and MRI evidence of perineural enhancement of the optic nerve extending into surrounding tissues in the orbit.
- Autoimmune glial fibrillary acidic protein–IgG astrocytopathy presents with a highly characteristic radial pattern of periventricular enhancement best seen with cranial MRI.
- Optic perineuritis with MRI evidence of a tram-track sign is a nonspecific radiologic finding and may be seen in a variety of inflammatory and neoplastic disorders affecting the optic nerve. Complementary CT images can reveal calcification in suspected cases of optic nerve sheath meningioma, but in other cases a systemic evaluation of the patient may be needed to render the diagnosis.
- Enhanced-depth optical coherence tomography can be used to detect buried optic disc drusen, which appear as signal-poor structures surrounded by a hyperreflective rim.
- Tortuosity of the optic nerve sheaths, flattening of the posterior globes, an empty sella turcica, and transverse venous sinus stenosis are radiologic signs of raised intracranial pressure in patients with idiopathic intracranial hypertension.
- Optical coherence tomography–derived ganglion cell–inner plexiform layer analysis can detect the presence of a compressive lesion in the region of the optic chiasm, sometimes in advance of visual field loss. Moreover, the extent of optical coherence tomography– measured retinal nerve fiber layer thinning and ganglion cell–inner plexiform layer loss in the preoperative phase can help predict the extent of postoperative visual recovery after surgical or medical decompression of compressive lesions.
- In cases of tumefactive multiple sclerosis, lesions can appear masslike and may be confused with neoplasms. In this setting, the so-called open pattern of ring enhancement is a useful radiologic sign to help distinguish demyelinating lesions.
- Recently, a punctate pattern depicted with MRI (referring to T2-weighted hyperintense or enhancing punctate lesions) has been shown to be a highly specific feature of progressive multifocal leukoencephalopathy and may be the first detectable imaging feature.
- Specific MRI patterns of brainstem involvement are highly suggestive of neuromyelitis optica spectrum disorder, including lesions of the dorsal medulla and area postrema structures.
- In addition to vascular insults, the brainstem is also vulnerable to demyelinating, neoplastic, neurodegenerative, inflammatory, infectious, and metabolic disorders.