“Me? I don't read books!”

“What do you read, then?”

“Nothing. I've become so accustomed to not reading that I don't even read what appears before my eyes. It's not easy: they teach us to read as children, and for the rest of our lives we remain the slaves of all the written stuff they fling in front of us. I may have had to make some effort myself, at first, to learn not to read, but now it comes quite naturally to me. The secret is not refusing to look at the written words. On the contrary, you must look at them intensely, until they disappear.”

If on a Winter's Night a Traveler

Italo Calvino

TABLE 1. Causes of Cerebral Visual Loss

Trauma is another frequent cause of visual cortical lesions. Direct injury to visual areas occurs from open head injury with penetration of the skull from falls, falling objects, knives, bullets, or blows. Closed head injury may involve rapid acceleration and deceleration of the head, as in a fall or when the head strikes the dashboard in a car crash. The brain continues forward because of inertia, and then moves back in the opposite direction. A coup injury produces bruising on the side of the impact and a contrecoup injury on the opposite side. Thus trauma to visual areas may follow a blow to either the occiput or the forehead.

Both cerebrovascular and traumatic brain injury can indirectly injure visual areas through cerebral edema. Because the skull is a closed compartment, edema can result in herniation syndromes. Tentorial herniation of the uncus may compress the posterior cerebral arteries, infarcting one or both occipital lobes, with severe and permanent visual deficits in survivors.

There are many other causes of cerebral visual loss (see Table 1). Vision impairment is frequent in Alzheimer's disease, the most common cause of dementia in older adults, and can even be the presenting complaint in patients with the visual variant of this disorder. This may perplex the eye specialist unaware of this manifestation of Alzheimer's disease and who has few tools for measuring the relevant visuoperceptual and cognitive impairments. Creutzfeldt-Jakob disease, a rare, rapidly progressive, incurable disorder, may likewise present with visual complaints prior to dementia, myoclonus, and the development of triphasic waves on electroencephalogram (EEG). In these cases, there are concerns about transmitting the infectious agent to other patients through inadequate sterilization of instruments.

Finally, in addition to increased incidence of pathologic impairments of the eye and brain in elderly persons, visual performance is also reduced through normal aging. Reduction in the speed of neural processing in the central nervous system results in cognitive slowing, reduced attention capacity, and shrinkage of the useful field of view despite apparently normal visual fields on conventional perimetry. Such visual impairment can affect daily activities such as reading, route finding, face recognition, and driving, and may increase the risk of injury from car crashes and hip fractures.

OPTIC TRACTS

The optic tract is the continuation of the anterior visual system from the optic chiasm to the LGN. Only the contralateral hemifield is represented. The decussated nasal retinal fibers are not initially well aligned topographically with the other eye's temporal retinal fibers, but retinal correspondence improves towards the termination of the tract at the lateral geniculate nucleus (LGN). The retinotopic map is also tilted in the optic tracts, so that the macula is represented dorsally, inferior retina (superior visual field) laterally, and superior retina (inferior visual field) medially (see Chapter 4, Fig. 9).¹ The magnocellular and parvocellular axons also may be segregated, with magnocellular axons more ventral.² Both of these topographies are mirrored in the LGN. The main vascular supply of the optic tract is the anterior choroidal artery.

The functional anatomy of the optic tract is reflected in several important clinical findings. First, partial lesions cause contralateral homonymous defects that can be markedly incongruous (different patterns of visual loss in the two eyes) because of the poor topographic alignment of the two retinal maps (Figs. 1 and 2).^3,4 In contrast, lesions of the optic radiations cause only mild incongruity and striate lesions are highly congruous. Complete transection of the optic tract leads to congruous complete hemianopia, although this is less frequent than partial lesions. Reduced acuity with an optic tract lesion indicates bilateral tract damage or extension of the lesion to the optic chiasm or optic nerves.^4,5

Second, because the axons in the optic tract originate from retinal ganglion cells, damage to the tract causes optic atrophy over time. This is present in both eyes, but because only half or less of the axons of each eye are affected, the atrophy is less severe than with most optic neuropathies. Also, the pattern of optic atrophy differs between the eyes. In the eye with temporal field loss, the axons from the nasal retina are affected. The fibers from the nasal periphery enter the nasal side of the disc, whereas those from the nasal macula enter the temporal disc in the papillomacular bundle. Atrophy is seen in these nasal and temporal wedges of the disc but the superior and inferior sectors are spared, because these contain fibers from the temporal retina. The result is “bow-tie” optic atrophy (see Fig. 1). In contrast, atrophy in the eye with nasal field loss affects the superior and inferior wedges and papillomacular bundle, but not the nasal wedge. This appears as diffuse or temporal disc pallor. Another distinctive optic disc picture occurs in the eye with temporal field loss when a mass lesion causes papilledema and compresses the optic tract. Disc swelling occurs in the superior and temporal disc but not in the atrophic bow-tie regions, creating “twin-peaks” papilledema (see Fig. 2).^6,7

Third, because fibers for the pupillary reflex also travel in the optic tract, often there is a relative afferent pupillary defect (RAPD). With a significantly incongruous hemianopia, the RAPD may be in the eye with greater visual loss. With a complete tract lesion the RAPD is in the eye with temporal field loss,^4,8 because the temporal hemifield is larger and there are slightly more axons from the nasal than temporal retina (ratio 53:47). The RAPD is a useful sign in optic tract hemianopia because it may be present at a time when optic atrophy has not yet developed (see Chapter 15).⁹

Other reported pupillary abnormalities include Wernicke's hemianopic pupil, which is an intraocular afferent pupil defect, with less pupillary constriction from light on the hemianopic hemiretina compared to light on the intact hemiretina. Wernicke's hemianopic pupil is difficult to elicit at the bedside because of intraocular light scatter,³ although it may be seen with computerized pupillometry (Fig. 3).

The combination of optic atrophy, RAPD and field incongruity is important to recognize with homonymous hemifield defects, because it changes the differential diagnosis of hemianopia (Fig. 14). Most hemifield defects from lesions of striate cortex or the optic radiations result from vascular disease or other intracerebral pathology. Most optic tract lesions are compressive extrinsic masses, with a differential diagnosis similar to that for optic chiasmal lesions (see Chapter 6). In fact, patients with combined damage to the optic tracts, chiasm, and nerve are not rare.^4,10–13 Pituitary adenomas, giant aneurysms of the internal carotid artery, meningiomas, and craniopharyngiomas are the chief causes of optic tract dysfunction. The investigation of choice is imaging of the parasellar region, with coronal and axial sections and contrast administration.

Less common lesions include inflammatory conditions such as multiple sclerosis^3,11,14,15 and sarcoidosis (see Fig. 1).¹⁶ Intrinsic optic pathway gliomas may occur in the optic tracts. Vascular lesions are rare, but there are reports of cavernous angiomata^10,17 or arteriovenous malformations.¹⁸ Optic tract infarction can complicate anterior temporal lobectomy, possibly from vasospasm of the anterior choroidal artery.¹⁹ Trauma can affect the optic tract.³ Radiotherapy of pituitary tumors may be followed years later by optic tract necrosis.¹³ Optic tract dysfunction is a side effect of alpha-interferon.²⁰ On occasion there is congenital absence of the optic tract ²¹; such patients are often unaware of their hemianopia.

Associated abnormalities are unusual.³ These include endocrine disturbances from hypothalamic dysfunction and memory impairment from temporal lobe involvement,²² reflecting the proximity of the optic tracts to these structures (see Chapter 4).

LATERAL GENICULATE NUCLEUS

The LGN is a subnucleus in the ventro-postero-lateral corner of the thalamus. Neighboring thalamic subnuclei include the medial geniculate nucleus ventromedially, ventral posterior nucleus dorsomedially, and pulvinar superiorly and dorsally. The medial geniculate nucleus gives rise to the acoustic radiations, which pass by the dorsomedial aspect of the LGN on their way to the auditory cortex in the temporal lobe. The optic radiations arise from the dorsolateral surface of the LGN. Ventrally, the hippocampus and parahippocampal gyrus face the LGN across the ambient cistern and the inferior horn of the lateral ventricle. The LGN has a dual blood supply: the anterior choroidal artery, a branch of the internal carotid artery, and the lateral choroidal artery, a branch of the posterior cerebral artery. The anatomy of the vascular territories within the LGN has been debated. Initial studies suggested that the anterior choroidal artery supplied the medial LGN as well as the optic tract and the lateral choroidal artery the lateral LGN. However, experience with surgical arterial lesions concluded that the anterior choroidal artery supplied both the lateral and medial aspects and the lateral choroidal artery supplied the hilus and midzone of the LGN.

In addition to its function as a relay in the visual pathway, the LGN is also a site of modulation, by back-projections from visual cortex^23,24 and afferent projections from the brainstem reticular formation and superior colliculus.²⁵ Some of the corticofugal input influences the stimulus selectivity of LGN neurons.²⁴ Others postulate that these nonretinal inputs play a role in gating visual transmission through the LGN, and thus participate in selective attention.²³

The LGN is a triangular shaped structure with six roughly horizontal layers containing segregated inputs from the two eyes (see Chapter 4, Fig. 8). The ventral two layers are the magnocellular layers, whereas the other four layers are the parvocellular component; these differ in many structural and functional aspects (see Chapter 4). The LGN has a retinotopic pattern that is a continuation of that found in the optic tract. The macula is represented in a dorsal wedge, including the hilum and projecting posteriorly, whereas the most peripheral fibers are located ventrally. Superior retinal fibers (contralateral inferior visual quadrant) are in the medial horn and inferior retinal fibers (contralateral superior visual quadrant) are in the lateral horn.

Because the LGN is small and relatively secluded, lesions here are rare. Its intimate relation to the optic tract and optic radiation make it difficult to be certain that a visual defect results from LGN damage rather than damage to these structures. Indeed, visual field defects from purported LGN lesions resemble visual field defects from optic tract or optic radiation lesions.

Three main types of hemianopic defects have been described. The first is an incongruous hemianopia, much like that seen with optic tract lesions, reflecting the continued segregation of ocular inputs in the LGN. The other two patterns are sectorial hemianopias reflecting the unusual territorial division between the anterior and lateral choroidal arterial supplies. With lateral choroidal ischemia, the hilum and middle zone of the LGN are affected, causing a wedge-shaped visual defect straddling the horizontal meridian (Fig. 4).²⁶ With anterior choroidal ischemia, the lateral and medial tips of the LGN are infarcted, resulting in the reverse defect, loss of the superior and inferior aspects of the contralateral hemifield with sparing around the horizontal meridian.^27,28 Unusual cases of presumed bilateral LGN damage have presented with an “hourglass” shape to either the visual field defect^29,30 or the region of spared vision.³¹

Optic atrophy often accompanies LGN lesions. If there is damage to almost all of the LGN, the optic atrophy has a similar appearance to that seen with optic tract lesions. If there is partial damage causing sectorial hemianopias, then the optic atrophy may be more subtle and restricted to the relevant sectors of the disc.^26,27 However, because the afferent fibers subserving the pupillary light reflex already have departed for the pretectum, there is no RAPD with lesions of the LGN. With incongruous hemianopia and optic atrophy, this is the only feature that permits distinction between optic tract and LGN lesions.

A variety of pathologies have been reported with LGN lesions. Infarction is the most likely cause of sectoranopia, given the dependence of such defects on the vascular anatomy,^26,27 but astrocytomas and arteriovenous malformations are also reported. Furthermore, the LGN appears to be a target of central pontine myelinolysis, a syndrome associated with excessively rapid correction of hyponatremia.^29,30,32 LGN damage rarely is a parainfectious complication of traveler's diarrhea.³¹

OPTIC RADIATIONS

The optic radiation may be affected anywhere in its course (see Chapter 4); the type of visual field defect reflects the site of damage. Ischemic or hemorrhagic lesions of the internal capsule affect the optic radiation while it is still a relatively compact bundle, usually causing a complete homonymous hemianopia. A similar defect can arise from damage close to the termination in striate cortex (Fig. 5). Lesions of the ventral fibers in the anterior temporal lobe cause a contralateral superior visual quadrant defect (Fig. 6). Most often this defect aligns on the vertical meridian, with variable extension toward the horizontal meridian and central vision.³³ Lesions of the dorsal fibers in the parietal lobe cause an inferior visual quadrant defect (Fig. 7). Because there is no sharp demarcation of the dorsal fibers from the ventral fibers in this portion of the posterior pathway, the defect seldom aligns along the horizontal meridian.³³ Overall, quadrantanopia is more frequent with lesions of striate cortex.³³ Lesions of the temporal lobe more than 8 cm posterior to its anterior tip can affect both upper and lower radiations. Small lesions also may affect certain portions of the radiations and spare others; for example, damage to the midportion of the optic radiation can mimic the sectoranopias of LGN lesions (Fig. 8).³⁴ Although there can be some incongruity to the visual field defects of optic radiation lesions, this is less marked than the incongruity with optic tract lesions.

Unlike lesions of the retino-geniculate pathway or LGN, lesions of the geniculostriate axons do not lead to optic atrophy (with the exception of some congenital lesions, through trans-synaptic degeneration) or pupillary defects. However, frequently there are other signs of cerebral damage,³³ especially if the lesion is large. Thus, temporal lobe lesions cause superior quadrantic defects and sometimes also complex partial seizures, auditory or complex visual hallucinations (some of which may be seizures), memory problems, or a Wernicke's aphasia if the dominant hemisphere is involved. Parietal lesions with mainly inferior quadrantic defects may cause cortical sensory disturbances, such as impaired two-point discrimination and graphesthesia, and impaired smooth pursuit toward the side of the lesion. With dominant hemisphere lesions, Gerstmann's syndrome (acalculia, finger anomia, right-left disorientation, and agraphia) may occur, as may a variety of aphasic syndromes, including alexia with or without agraphia, Wernicke's aphasia, or global aphasia.

The differential diagnosis of optic radiation lesions reflects the variety of cerebral hemispheric pathologies. Unlike lesions of the optic tract, most are infarcts in the posterior cerebral or middle cerebral artery territories. Tumors, vascular malformations, infections, and leukodystrophies are also possibilities. The temporal profile of the illness often is the major clue to the etiology.

STRIATE CORTEX

The primary visual area in the medial occipital lobe goes by several names: Brodmann's area 17, “visual area 1” or V1, “calcarine cortex,” and “striate cortex” (see Chapter 4). The exact position of striate cortex varies among individuals. Although the parieto-occipital fissure forms a reasonably reliable anterior dorsal boundary, the posterior limit containing the macular representation is more variable, extending from the medial occipital surface over the first one or two centimeters of the posterior surface of the occipital lobe (see Chapter 4, Fig. 10).

The main vascular supply of striate cortex derives from the posterior cerebral artery (see Chapter 4, Fig. 15). A parieto-occipital branch supplies the superior calcarine bank, a posterior temporal branch supplies its inferior bank, and a calcarine branch supplies the central region posteriorly; however, individual variation exists.³⁵ Perhaps most importantly, the occipital pole is at the junction (watershed zone) of the vascular territories of the posterior and middle cerebral arteries, and again there is marked variation as to which artery supplies the foveal representation in striate cortex.³⁵

The retinotopic arrangement in striate cortex is well known (see Chapter 4), and confirmed with recent imaging studies of lesions.³⁶ The foveal representation is posterior, at the occipital pole, and the far peripheral field is anterior, on the medial occipital surface.^37,38 The superior bank of the calcarine fissure receives input from the inferior visual field, whereas the inferior bank contains the representation of the superior visual field. The most anterior part of striate cortex represents the monocular temporal crescent, the region of temporal field in the contralateral eye that lies beyond the limits of the nasal field (60°) of the ipsilateral eye. As in most of the visual system, there are fewer neurons devoted to peripheral vision than to central vision: Over half of striate cortex is devoted to the central 10° (cortical magnification).^36,39 Occipital cortex contains a mixture of monocular and binocular cells arranged in ocular dominance columns, but large separations between the inputs of the two eyes are not present.

Visual Field Defects from Striate Lesions

Focal destruction of striate cortex produces a homonymous contralateral visual hemifield defect. Unlike the scotomata from lesions of the optic radiations and especially the optic tracts, the hemianopic defects from striate lesions are highly congruent, with virtually identical defects in the two eyes.

Complete destruction of striate cortex causes complete visual loss in the contralateral visual hemifield. Because this involves not only peripheral vision but also the contralateral half of the foveal region it is called a macula-splitting homonymous hemianopia. This may occur with posterior cerebral artery ischemia in a patient whose entire striate cortex is supplied by that artery. Macula-splitting hemianopias can occur with complete lesions anywhere along the retrochiasmal visual pathways, and thus lack localizing value (see Fig. 5). Other signs may help in localization. Reading is particularly impaired by involvement of the central 5°.⁴⁰

Partial lesions of the striate cortex are frequent. With posterior cerebral infarcts, a macula-sparing hemianopia occurs in patients with adequate collateral circulation of the macula region (occipital pole) from the middle cerebral artery (Fig. 9).³⁵ Previously, macula-sparing was thought to result from bilateral representation of a small stripe flanking the vertical meridian, which expanded to as much as 3° at the fovea.⁴¹ However, studies of monkey V1 do not find bilateral representation of the hemimaculae,⁴² and computed tomography (CT) and magnetic resonance imaging (MRI) studies in humans with hemianopia document the correlation of macular sparing with sparing of the occipital pole.^43,44 Also, careful perimetry of hemianopes with the scanning laser ophthalmoscope shows that, although there is a slight overlap from the seeing field into the blind field along the meridian, macular sparing of 2° to 5° is only present in some patients.^45,46 Therefore sparing more likely reflects the extent of occipital pathology than retinal anatomy. Macula-sparing has some localizing value, because it is seen mainly with lesions of striate cortex.

The upper and lower banks can also be involved separately. Ischemia can do this because the banks have separate blood supplies. Upper bank infarcts cause homonymous contralateral inferior quadrantanopia (Fig. 10) and lower bank infarcts cause superior quadrantanopia. Although altitudinal defects have been reported occasionally,^47,48 most quadrantic defects do not align at the horizontal meridian, because the upper field merges without interruption into the lower field in the depths of the calcarine fissure. Thus it has been argued that quadrantic defects that respect the horizontal meridian are caused by involvement of area V2, surrounding striate cortex,⁴⁹ which remains controversial. Quadrantanopias are three times more common with striate lesions than with optic radiation lesions.³³ Striate quadrantanopias are more frequently isolated signs but can be associated with other signs of higher cortical visual dysfunction, such as pure alexia or hemiachromatopsia, whereas optic radiation quadrantanopias usually are accompanied by hemiparesis, dysphasia, or amnestic problems.³³

Selective lesions can also occur along the anterior-posterior extent of striate cortex. A lesion of the occipital pole alone causes homonymous central hemiscotomata (Fig. 11).^44,50 This can occur with watershed infarcts during systemic hypoperfusion. Slightly more anterior lesions in the middle zone of striate cortex cause homonymous peripheral scotomata (Fig. 12). The highly congruent, homonymous nature of these defects and their restriction to one hemifield differentiate these from ocular causes of central or paracentral visual loss. Lesions with such small field defects can be missed on CT.⁴³ MRI with coronal sections through the occipital lobes should be performed, although even this may miss small lesions, particularly at the occipital pole.

A near-complete lesion that spares only the most anterior portion of V1 causes a nearly pathognomonic field defect, hemianopia with sparing of the monocular temporal crescent (Fig. 13). The hemianopia involves the whole nasal hemifield of the ipsilateral eye but the temporal hemianopia of the contralateral eye spares a crescent-shaped island of vision in the far periphery.⁵¹ This is the monocular temporal crescent, the region of the visual field that is represented in the temporal field of one eye but not the nasal field of the other. The initial sense of incongruity may raise suspicions of an optic tract lesion; however, the absence of optic atrophy and RAPD, the high congruity of the homonymous defect inside 60°, and the location of the crescent outside 60° eccentricity, indicate that the lesion must be in striate cortex. The converse defect, a monocular temporal crescentic scotoma, can occur with a retrosplenial lesion, along the parieto-occipital sulcus.⁵²

Most striate lesions are infarction, mainly from posterior cerebral artery occlusion (Fig. 14), with sudden onset visual loss and sometimes headache.⁵³ In about half, the visual field defect is the only deficit,⁵³ but in others damage to medial occipito-temporal regions causes amnesia, prosopagnosia, and color perception defects. A syndrome of agitated delirium and hemianopia occurs with lesions of the medial occipital lobe, parahippocampus, and hippocampus.^54–56 Brainstem signs include impaired level of consciousness, III nerve palsy, dysarthria and hemiplegia.⁵³ Causes of ischemia are most frequently cardiac emboli and vertebrobasilar occlusive disease; migraine is a rare cause of permanent defects.⁵³ Hemorrhage, vascular malformations, primary and secondary malignancies are much less common.³³

Bilateral lesions of striate cortex are not rare. Focal midline lesions such as tumors or traumatic injury may affect both striate cortices concurrently, because the right and left striate cortices face each other on the medial occipital surface. The most common cause, however, is posterior circulation ischemia.⁵⁷ This can affect both striate cortices either simultaneously or sequentially,⁵⁷ because the right and left posterior cerebral arteries have a common origin from the basilar artery. Twenty-two percent of patients with a unilateral occipital infarction develop bilateral infarction over 3 years.⁵⁸ Bilateral incomplete hemianopia is distinguished from bilateral optic nerve or ocular disease by the high congruity of the visual fields and step defects along the vertical meridian which indicate the hemifield nature of the visual loss (Fig. 15).⁵⁷ Such steps are important to seek with a skilled perimetrist, but even so they can be difficult to demonstrate with bilateral hemiscotomata from occipital pole lesions.⁵⁹ Bilateral quadrantanopias can occur,^47,48 often in patients with prosopagnosia and achromatopsia for example, and may mimic the altitudinal defects of optic neuropathy.

Cerebral Blindness

Cortical blindness is a loosely used term, at times referring to visual loss from occipital lobe damage, even if the loss is incomplete. Hence hemianopia or bilateral quadrantanopia has been called cortical blindness. It is best reserved for bilateral complete or severe hemianopia, with acuity at light perception only or worse, and no detectable peripheral vision. Because lesions may involve both gray and white matter, cerebral blindness is a better term.

Cerebral blindness can be persistent or transient. The most frequent cause of persistent cerebral blindness is cerebrovascular infarction.⁶⁰ In addition to the common causes of emboli or atherosclerosis, it has been reported with vertebrobasilar arteritis,⁶¹ subclavian steal,^62,63 and hypotension from antihypertensive medication.^64,65 Cerebral blindness can complicate cardiac surgery, through hypotension or emboli.⁶⁰ A rare vascular cause is rupture of occipital mycotic aneurysms with endocarditis.⁶⁶

Cerebral blindness is distinguished from ocular disease by both normal pupillary light responses and normal fundoscopic examination. These may lead to an erroneous diagnosis of factitious visual loss. Associated signs of damage to parietal or temporal structures help to confirm cerebral blindness but may not always be present. Visual evoked potentials are of limited diagnostic value. They can be altered voluntarily by subjects without visual loss⁶⁷ and can be normal in patients with striate lesions.^68,69 They cannot differentiate between blind and seeing children with neurologic disease,⁷⁰ and normal or abnormal results do not predict visual outcome.^60,71 Absent evoked responses are rare and may only occur early in the course.⁷⁰ Absent alpha rhythm on electroencephalography^72,73 is reportedly a more sensitive diagnostic sign than abnormal visual evoked potentials.⁶⁰ CT scans can be normal, but modern MR imaging with coronal images through the occipital lobe should reveal most striate or optic radiation lesions with complete and persistent visual loss (Fig. 16). Single photon emission computed tomography (SPECT) scans may reveal bilateral functional defects in cases with unilateral MRI lesions.⁷⁴

Among adults with infarction, blindness is permanent in 25%⁵⁷ and residual visual field defects are common in the rest. Bioccipital CT lucencies carry a poor prognosis for recovery, but abnormal visual evoked potentials do not correlate with severity or outcome.⁶⁰ Although the abnormalities on visual evoked potentials are not diagnostic, they tend to improve as vision returns.^75–77

Transient cerebral blindness can last hours to days, often with full recovery (Table 2). Both ictal and post-ictal cerebral blindness are reported in children and adults.^78–80 Transient cerebral blindness can occur with metabolic insults,^81–83 hypertensive encephalopathy,⁸⁴ hydrocephalus,⁸⁵ trauma,^72,86 and cortical venous thrombosis.⁸⁷ Toxins are an important cause, especially chemotherapeutic agents.^88–92 Cerebral blindness is associated with the iodinated contrast agents used in angiography:^60,93,94 CT scans with contrast show disruption of the blood–brain barrier in the occipital lobes^93,94 as early as 1 hour after angiography.⁹⁵

TABLE 2. Causes of Transient Cerebral Blindness

The pathogenesis of transient cerebral blindness varies with the cause. Vasospasm is blamed in head trauma,⁹⁶ eclampsia,^97,98 methamphetamine abuse,⁹⁹ and meningitis, which also may induce vasculitis.^77,100 Circumstantial evidence for vasospasm includes a correlation of traumatic cerebral blindness with prior migraine.⁸⁶ Angiographic contrast agents may cause breakdown of the blood–brain barrier under osmolar stress and subsequent neurotoxic effects,⁹⁵ providing a rationale for dexamethasone and mannitol as specific therapy in this context.

Pediatric cerebral blindness is not uncommon. Children may not complain of visual loss but present with agitation, disorientation, and unsteadiness.^73,96,101 During tests of vision they may not respond or may confabulate answers.^101,102 Further observation shows that they do not fix, follow, or make saccades to objects, blink to threat, or show optokinetic responses.^70,73,102 There can be an associated strabismus. Major causes include head trauma, bacterial meningitis,^{76,77,100,102} and hypoxia from cardiac or respiratory arrest.¹⁰² Other causes include encephalitis, as well as metabolic^83,102,103 and toxic⁹⁹ conditions (Table 3). Seizures are common, and mental retardation is a frequent complication in children with cerebral blindness after meningitis.

TABLE 3. Causes of Pediatric Cerebral Blindness

Posttraumatic transient cerebral blindness is a syndrome that affects children and young adults.^73,104,105 It occurs in about 1% of closed head injuries.^72,86,106 The impact is often in the parieto-occipital region.^{72,73,105,107}Headache, confusion, anxiety, nausea, and vomiting are frequent,¹⁰⁵ as is loss of consciousness at the time of injury in young children and adults.⁸⁶ Blindness may occur immediately or after a few minutes,^{73,86,105,107} and in adolescents sometimes after a few hours.⁸⁶ Vision recovers within 24 hours,^105,107 although the course in adults is more variable, with occasional residual deficits.⁸⁶ CT of the head often is normal,^101,105,107 but EEG shows bilateral occipital slowing.⁷³ Protracted recovery, especially in children, may indicate cerebral contusions¹⁰⁷ or occipital lobe infarction from tentorial herniation.¹⁰⁸ There can be a personal or family history of seizures and migraine.⁸⁶

The course of cerebral blindness is variable. Blindness can last hours, days, or weeks; or evolve into a hemianopia or other field defect. The patient may recover fully, or the deficit may become permanent.^71,76,102 If there is recovery, it usually occurs within 5 months.⁷¹ Recovery of useful vision is more likely in children than adults.¹⁰² The prognosis is better with hypotension during cardiac surgery than with other causes.⁷¹ The prognosis with hypoxia is worst for preterm infants, who tend to have periventricular leukomalacia rather than parasagittal watershed infarctions. Optic radiation damage on their CT or MRI is a poor sign.¹⁰⁹ Normal MRI in most other settings is a good prognostic sign^71,109 and significant recovery can occur if hypoxic damage is limited to the visual cortex.¹⁰⁹ Spike-and-wave discharges on EEG are associated with multiple handicaps and poor visual recovery.⁷¹

Transient cerebral blindness occurs in about 1% to 15% of patients with pre-eclampsia or eclampsia.^97,98,110 Fluctuations in blood pressure with peripartum blood loss may contribute.¹¹¹ The pathogenesis is analogous to that of hypertensive encephalopathy, with development of petechial hemorrhages and focal edema from impaired cerebral vascular autoregulation, and ischemia from vasospasm.^98,112 CT scans may be normal or show bi-occipital lucencies.^98,113 MRI is more sensitive, showing T2 hyperintensities and T1 hypointensities similar to those in hypertensive encephalopathy.^112,114 Management is that of eclampsia, with magnesium sulfate, fluid restriction, and blood pressure control. The prognosis is good, with virtually all women regaining vision within a few hours to a week, rarely as long as 3 weeks.⁹⁸

The differential diagnosis of eclamptic visual loss includes cerebral venous thrombosis¹¹⁵ and systemic hypoperfusion resulting from pulmonary emboli.¹¹⁶ Antiphospholipid antibodies may be associated with infarction or venous thrombosis.¹¹⁷ Eclampsia also can affect the eye, causing retinopathy with retinal detachment, edema, and vascular thrombosis¹¹⁸ or, more rarely, anterior ischemic optic neuropathy.¹¹⁹ Pituitary apoplexy can present with severe headache and visual loss and is a medical emergency.

Anton's Syndrome

About 10% of patients with cerebral blindness are not aware of their deficit and insist that they can see.^57,60 This syndrome may be considered a form of anosognosia (denial of acquired impairment) that has been attributed to right hemispheric dysfunction or disconnections between the thalamus and right parietal lobe.¹²⁰ Denial of blindness can also occur in patients with ocular or optic nerve disease when there is concurrent dementia or a confusional state. In contrast, altered mental status is not a necessary accompaniment of denial of blindness with lesions of the visual cortex. Thus, Anton's syndrome might be more specifically defined as denial of blindness in the absence of dementia or delirium. However, even this presentation is not specific to lesions of visual cortex, as it can result from unusual combinations of bilateral optic neuropathy and bilateral frontal lobe disease.¹²¹

Abnormalities in the Remaining Visual Field

Some patients with hemifield visual defects complain of difficulties with their remaining vision, such as visual fatigue or blurring, especially in tasks with high attentional demands such as reading, finding a face in a crowd, or driving a motor vehicle. There is evidence that unilateral lesions produce not only contralateral scotomata but also deficits in both the remaining ipsilateral and contralateral visual fields. There are spatial and temporal contrast sensitivity deficits in the supposedly normal ipsilateral hemifields of patients with homonymous hemianopia.¹²² There is reduced sensitivity and increased response times to signals in both hemifields and reduction in the “useful field of view.”¹²³ Saccadic response times to visual targets in the ipsilateral hemifield are also reduced.¹²⁴

The origins of these subtle bilateral effects of unilateral lesions are unclear. One hypothesis is that the inevitably associated white matter damage disrupts visual connections, including projections from V1 to other visual areas, callosal connections between the same or different visual areas in the two hemispheres, and feedback projections from a higher visual area to a lower one. A lesion in one area thus can affect the functioning of another, more distant area (diaschisis). Disrupted connections can impair the synthesis of information from other vision areas and both hemispheres, producing “long-range” disturbances in both hemifields, outside the limited contralateral scotoma. Damage to extrastriate regions may have similar bilateral long-range effects, as shown in monkeys with lesions of area V4, for example. Thus associated extrastriate damage may contribute to impaired processing efficiency in the ipsilateral field of patients with hemianopia.¹²³

Standard kinetic and automated static perimetry are not designed to detect such deficits. These tests ignore response speed and minimize the role of attention to get maximal estimates of sensory function, an effective approach for gauging the classic field defects resulting from dysfunction of the retino-geniculo-striate pathway. However, the working visual capacity in elderly or brain-damaged individuals is better approximated by tests of vision under conditions of increased attentional load.^123,125 Measures of this useful field of view (UFOV) have been designed, using central or peripheral distractors during perimetric tests of localization ability to gauge the effects of attention. UFOV evaluation may reveal defects associated not only with hemianopia but also with aging and Alzheimer's dementia, where they may have practical import, in that UFOV reduction predicts crashes in driving simulations.¹²⁶

Rehabilitation of Homonymous Defects

Partial recovery within 2 to 3 months occurs in 15% of patients with hemifield defects.¹²⁷ A scotoma that persists beyond several months is permanent. The larger and closer to fixation the scotoma is, the worse are the effects on daily activities such as reading and driving.^128,129 Efforts aimed at restoring the visual fields have met with considerable difficulty and produced limited success, and the validity of some of the results can be questioned as to whether true recovery was achieved versus shifts in bias.^130–133 However, it is possible to train individuals to scan the hemianopic field with eye movements,¹³⁴ a strategic adaptation that also occurs without training as long as subjects do not have additional hemineglect.^135,136 Adaptive changes to improve reading can also be trained.¹³⁷ There are even some claims that these reading and scanning adaptations improve visual fields slightly,^131,137 which need verification. Another potential adaptive treatment for the navigational behaviour of hemianopes is the use of prisms to shift elements of the blind side of space into the seeing hemifield.¹³⁸ Although this distorts the field of vision to some degree, the ability to detect stimuli rapidly on the blind side can offer some advantages while walking.

Blindsight and Residual Vision

Patients with visual loss due to lesions of the striate cortex or optic radiations may have some remnant visual function in their blind field. Some of these patients retain some awareness of visual stimuli, and hence have “residual vision,”^139–141 implying a severe relative field defect. Others deny awareness of stimuli, even though they perform better than chance when asked to indicate or guess at some property of the stimulus: These are said to possess “blindsight.”^142–144 Whether the pathophysiology of residual vision differs from blindsight is unclear. Perceptual awareness varies along a spectrum: Patients may retain a vague awareness of the presence of a stimulus but not of its particular features, which they can nonetheless discriminate or act on.¹⁴⁵ Stimulus parameters can be manipulated so that a patient shows residual vision under some conditions and blindsight under others.^146,147

VARIETIES OF BLINDSIGHT PHENOMENA.

Some studies find that saccades to locations within hemianopic fields are weakly correlated with target position, mainly for a limited range of paracentral locations.^{142,148–150} Other studies have failed to find saccadic localization.^151–153 Reaching and pointing also is usually weak and variable, sometimes only in patients with residual vision,^141,154,155 but there are other reports of nearly normal manual localization.^145,150

Target localization was easier with moving rather than stationary targets in some reports^156,157 but not another.¹⁵⁸ This is reminiscent of Riddoch's phenomenon,¹⁵⁹ in which movement is appreciated before static targets in recovering hemianopic defects.¹⁵⁹ Studies of blindsight motion perception show some residual perception of the speed and direction of rapid bright spots.^139,141,160 With larger stimuli such as optokinetic gratings, some patients can discriminate motion direction¹⁶¹ and a few may experience an illusion of self-motion.¹⁶² Some of these motion abilities may actually be derived from spatial position or flicker rather than true motion velocity: Studies with random dot stimuli that minimize these confounds found no residual motion perception in 13 patients.^163,164

Motion information might also guide eye movements. Recovery of optokinetic responses was reported in one patient with cortical blindness¹⁶⁵ but not in two others,^155,166 nor in three hemianopic patients.¹⁶¹ Pursuit and saccadic responses to motion were not found in patients with medial occipital lesions sparing the lateral human motion area.¹⁵²

An early report claimed that one patient could discriminate large X and O forms, perhaps through orientation perception.^144,150 However, form discrimination was not found in seven other patients,^141,149,167 nor orientation discrimination in two others.^168,169 Despite this, three patients could arrange the orientation of their grasp correctly when they reached for objects in their blind field.^145,168,170 This may be consistent with evidence for a dissociation between pathways for object recognition and action.¹⁷¹

Although early blindsight studies found no evidence of chromatic perception,^141,150 later studies showed detection of colored targets,¹⁷² and evidence of color-opponent interactions in the spectral sensitivity curves.¹⁷³ One patient can perceive the motion of equiluminant colored spots¹⁷⁴ and is aware of hue, although these responses seem to represent an average from the entire blind hemifield.¹⁷⁵

Studies of temporal and spatial contrast sensitivity have yielded mixed results, even when done on the same patient “GY”.^176–178

The standard pupillary light reflex that is clinically measured is a response to changes in luminance. However, there are also pupillary responses to gratings and isoluminant colors. Pupillary responses to such stimuli in the blind hemifield were shown in one patient.^179,180 In another study, color stimuli caused afterimages that evoked pupillary responses in normal subjects; in the blind hemifield of two patients, there were “after” pupillary responses without any conscious afterimage.¹⁸¹

A direct pathway between the pulvinar and the amygdala may mediate reactions to frightening stimuli.¹⁸² One patient could process fearful and angry faces in his blind hemifield,¹⁸³ and this appeared to correlate with activity in his amygdala.¹⁸⁴ Another study of a cortically blind patient showed that associating a visual stimulus with a painful shock caused the development of startle reflexes to that stimulus, despite the lack of conscious perception.¹⁸⁵

INTERACTIONS BETWEEN BLIND AND NORMAL HEMIFIELDS.

Traditional blindsight methods are awkward in that they ask a patient to respond to something they cannot see. However, a number of innovative studies have circumvented this by examining how responses to visible stimuli might be modified by stimuli in the blind field.

Spatial summation occurs when two simultaneous stimuli generate faster responses than a single stimulus. Temporal summation is the decrease in reaction time when a stimulus is preceded by another that provides a temporal prompt. Evidence for summation between seeing and blind fields has been inconsistent and found only in a minority of subjects.^{154,186–188} The opposite, a distraction effect, in which targets in the blind field slow down response times to stimuli in the seeing field, has been shown for saccades but not manual reaction times.¹⁸⁹ This finding could not be replicated in another study.¹⁹⁰ “Inhibition of return” is a normal phenomenon in which a stimulus delays the detection of a target appearing in the same location a short time later. This phenomenon was generated in the blind hemifield of one patient.¹⁹¹

Word perception can be influenced in blindsight. The choice of meaning of an ambiguous word (i.e., LIGHT) in the seeing field can be influenced by a word in the blind field (i.e., DARK versus HEAVY).¹⁴⁵ Completion effects have been reported for form perception. Two patients had completion effects for afterimages or with illusory contours such as the Kanisza triangle.¹⁴⁵ The width of one patient's grasp as he reached for an object varied with the size of objects in his blind field, but only when the leftmost part of the object fell in his seeing hemifield.¹⁷⁰ Another study used an interference task with a stimulus flanked by distractors either different or identical to the stimulus. Reaction times to seen letters and colors were prolonged by differing flankers placed in the blind field in a patient with an occipital lesion.¹⁹² Last, one study tested whether perception of optic flow within the intact hemifield could be enhanced by optic flow in the blind hemifield: this could be shown in two patients with very limited damage to striate cortex (Fig. 17).¹⁸⁷

BLINDSIGHT AND HEMIDECORTICATION.

Patients lacking a cerebral hemisphere are of interest in the debate over whether blindsight requires extrastriate cortex. Some have found that hemidecorticate infants look toward their blind field when a target is presented there,¹⁹³ and adults with such lesions have some residual manual localization of blind field targets.^156,158 Also reported are motion and form perception^156,158,194 and a “spatial summation” effect, in which patients responded faster to a seen flash when there was another simultaneous flash in the blind hemifield.¹⁹⁵ However, the validity of these findings is in question. Some have failed to find blindsight outside of a narrow strip along the vertical meridian, which could be explained by receptive field overlap or light scatter.^196,197Other studies have also shown that the residual vision in hemispherectomized patients can be attributed to light scatter.^198–201

ARTIFACT AND BLINDSIGHT.

Valid blindsight results require careful elimination of artifacts as alternative explanations of better than expected performance. Four issues need special consideration. First, poor fixation may allow the subject to place the target in the seeing hemifield. Eye position monitors can help, as long as both head and eye position are controlled or detected, because gaze direction is a function of both.²⁰² Second, light scatter may diffuse from blindfield stimuli into the seeing field and mimic blindsight.^{152,198–200,203} Controls for scatter include testing the physiologic blind spot,¹⁴⁴ control patients with pregeniculate lesions^{148,149,156,192} or hemispherectomies.^161,200 Flooding of the seeing field with light has also been used to minimize scatter. Third, careful perimetry may reveal that the blind field has surviving islands of vision that account for the residual perception.^204–207Fourth, blindsight may simply represent a “criterion shift.” Subjects may reply more liberally when asked to choose between alternatives than when asked if they see something: this has been shown for normal subjects.^203,208,209 Signal detection analysis has been used to answer this criticism,^172,210,211 although it has also suggested that changes in criterion bias may indeed explain some blindsight motion perception results.²¹²

EXPLANATIONS OF BLINDSIGHT.

Several different anatomic pathways are invoked to explain blindsight. Spatial localization may be accounted for purely by a subcortical pathway from retina to superior colliculus.^148,196 It is claimed that better blindsight in the temporal than nasal hemifield of patients is a signature of collicular mediation.^189,213 Pattern or motion detection may require extrastriate cortex, through a relay involving the superior colliculus and pulvinar. Because the colliculus lacks color opponency, chromatic blindsight^{172,173,175,192,214,215} may indicate yet another relay, perhaps direct projections from surviving LGN neurons to extrastriate cortex.²¹⁶

The monkey evidence most strongly supports the retino-tecto-pulvinar relay to extrastriate regions, particularly those regions involved in motion perception. Lesions of V1 do not abolish responses in V5^217–219 or V3A²²⁰ unless accompanied by lesions of the superior colliculus.^217,22 Stabilization of an early direct projection from LGN to V5, which normally regresses with development, may occur in infant cats with striate lesions,²²² but evidence of this has not been found in infant monkeys.²²³

Physiologic techniques in humans have also provided some support. In normal subjects, evoked potentials²²⁴ and some transcranial magnetic stimulation studies²²⁵ (but not others²²⁶) suggest that visual motion signals may arrive in V5 before and independent of V1. Positron emission tomography (PET) scans,¹⁴⁰ magnetoencephalography²²⁷ and evoked responses²²⁸ have shown residual activation of V5 by rapid but not slow-moving stimuli in the blind hemifields of one patient, GY. An intriguing fMRI study of GY that varied stimuli to obtain responses with and without awareness showed that residual vision was associated with activation of extrastriate visual areas and dorsolateral prefrontal cortex, and blindsight with activation in superior colliculus and medial prefrontal cortex.¹⁴⁶

Theories of blindsight must also account for its variability. Recent series, representing 46 patients in total, suggest that blindsight is rare.^163,205,206 One important variable may be the extent of additional damage to the optic radiations and extrastriate cortex. However, correlations between blindsight abilities and lesion anatomy have proved elusive.^{151,152,163,186,229} A requirement for very focal striate damage is also difficult to distinguish from a need for partial striate damage,¹⁸⁷ pointing back to a potential artifactual explanation. Another important variable may be the timing of the lesion. Blindsight may require neural plasticity. If so, age at onset, time since lesion, and possibly training may be important.¹⁴³ In both humans and nonhuman primates, infants or children may be more likely to develop blindsight or residual vision,^{141,156,222,230} although not all studies find that age matters.¹⁹⁴ The efficacy of training in eliciting blindsight is controversial, with both negative^141,20 and positive^{157,229,231–233} opinions.

DISORDERS OF COLOR PROCESSING

Cerebral Dyschromatopsia

Cerebral (central) achromatopsia refers to complete loss of color perception, whereas cerebral dyschromatopsia indicates some residual color perception, as is most often the case. Both are rare. Hemiachromatopsia refers to color loss restricted to the contralateral hemifield,^234,235 and may be more common but under-recognized.

Achromatopsic patients generally are symptomatic, complaining that the world appears in shades of gray.^236–239 Some also report that the world appears less bright²⁴⁰ or has a “dirty gray” tinge.²⁴¹ Less frequently, patients report a tinge to the world, as if peering through a colored filter.²⁴² Daily activities that use color discrimination are impaired, such as distinguishing coins, stamps, or traffic lights: A good account exists of the experience of an achromatopsic artist.²⁴³

Effects on “color constancy” are an important issue. The wavelengths reaching the eye from an object depend on both its reflectant properties and the light illuminating the scene. Yet, the color of objects remains stable under a wide range of environmental and lighting conditions.^244,245 For instance, an apple continues to look red in sunlight, incandescent light, and fluorescent light, in an orchard or a grocery display. This ability to “discount the illuminant” depends on neural computations in retina and cortex.²⁴⁴ These computations likely average the spectral luminance over large regions of the surrounding background to deduce the nature of the illuminant, and this information is then taken into account to derive the true color of any object in the scene.^244,246

A defect in color constancy should result in color percepts that vary with changes in illumination. Patients with achromatopsia have a more severe deficit, in that they lack any color percept at all. Testing such patients for constancy of something they do not perceive is paradoxical, but this can be done on dyschromatopsic patients, who have some residual hue sensitivity. Some studies have shown that color constancy is impaired in these patients.^247–250 These patients all had bilateral lingual and fusiform gyral lesions, except for one unilateral case.²⁴⁸

Not all color perception is lost in achromatopsia. Some color input from the cones and retinal ganglion cells of the parvocellular pathway still can be processed. Thus, both trichromacy and color opponency have been shown in photopic spectral sensitivity curves^247,251,252 and evoked potential or psychophysical measures of chromatic contrast sensitivity.^252,253 Likewise, performance with anomaloscope testing can resemble an anomalous trichromat rather than a monochromat, despite the experience of the world as monochromatic “shades of gray.”²⁵⁴ Achromatopsics can use color-opponent signals to locate chromatic boundaries, even though they cannot perceive the colors that determine those boundaries. Thus achromatopsics can detect the movement of chromatic stimuli,^255,256 even performing at normal levels with suprathreshold chromatic contrast.²⁵⁷ This indicates that wavelength variation is still perceived, even if color is not.

Achromatopsia is seldom an isolated finding. Most commonly it forms one component of a tetrad that includes superior quadrantanopia, prosopagnosia, and topographagnosia. Superior field loss is almost always present, because the ventral occipito-temporal lesion that causes achromatopsia frequently extends into the inferior calcarine cortex or optic radiation. Similarly, only a few cases without prosopagnosia have been reported.²⁵⁸ Experimental testing has revealed in some patients a problem with detecting stimuli with low salience,²⁵⁹ which has also been described in monkeys with V4 lesions, and thought to indicate inefficient attentional allocation in form processing. Other occasionally associated defects include visual object agnosia,^251,260 alexia in achromatopsic patients with right hemianopia,^238,258 and amnesia with additional ventral temporal lobe damage.^238,260

Achromatopsia is caused by lesions of the lingual and fusiform gyri,^245,261 as confirmed by modern imaging.^{240,241,251,254,258,262} Lesions of the middle third of the lingual gyrus or white matter behind the posterior tip of the lateral ventricle may be critical.^240,263 Bilateral lesions are necessary for complete achromatopsia.

In monkeys, color-selective responses are found in area V4.²⁴⁵ However, lesions of V4 do not impair hue perception significantly.^264–269 Rather, defects in chromatic perception require extensive bilateral lesions, including areas TE and TEO.^270,271 In humans, functional imaging reveals several areas involved in color processing, notably a V4 homologue and a second area named V4 alpha or V8 in the fusiform gyrus,^272,273 as well as other more distant regions.^274–276 Thus color processing involves a network of regions, and it is probable that a severe achromatopsic defect may require damage to or disconnection of several components of the network, rather than just a lesion of a single region like the human V4 homologue.^267,277,278

Achromatopsia is most often caused by strokes. Bilateral sequential or simultaneous infarctions in the territories of both posterior cerebral arteries can occur, or multiple infarcts may result from a coagulopathy.²⁷⁹ Achromatopsia may be the first symptom of a stroke or the outcome of an initial cortical blindness. Other bilateral lesions causing achromatopsia include herpes simplex encephalitis,²⁵¹ cerebral metastases,²⁵⁸ repeated focal seizures,²⁸⁰ focal dementia,²⁸¹ and even migraine aura, causing a transient achromatopsia.²⁸² Temporo-occipital white matter damage has caused a reversible dyschromatopsia in one patient with carbon monoxide poisoning,²⁸³ a condition that usually causes an apperceptive agnosia with spared color perception.²⁴⁵

HEMIACHROMATOPSIA.

Achromatopsia in the contralateral hemifield alone can follow unilateral right or left occipital lesions (Fig. 18). Patients are typically asymptomatic until the defect is demonstrated on examination.^234,235 Hemiachromatopsia is usually associated with a superior quadrantanopia;^234,235,241 therefore, the color defect is only demonstrable in the remaining inferior quadrant. The preserved color vision in the ipsilateral hemifield allows normal or near-normal performance on centrally viewed tests of color vision such as pseudoisochromatic plates. The incidence of hemiachromatopsia is probably underestimated, given its asymptomatic nature and the failure of routine clinical color tests to detect its presence.

Two rare cases with quadrantic field defects for color have also been described.²⁸⁴ It is not clear if these were true chromatic defects or subtle relative scotomata, but the quadrantic representation of the human V4 area on functional imaging²⁷⁸ suggests that a very discrete lesion could theoretically create such a defect.

TESTING ACHROMATOPSIC PATIENTS.

Color naming is not an adequate test for cerebral dyschromatopsia, because residual color perception may allow an approximate categorization of colors.

The deficits in color perception in the full syndrome of cerebral achromatopsia can be tested with the same standardized tests used to assess patients with retinal and optic nerve disorders.^285–287 Pseudoisochromatic plates such as the American Optical Hardy-Rand Rittler²⁸⁸ and Standard Pseudoisochromatic Plates, Part 2²⁸⁹ are useful, even in patients with alexia or aphasia, who can do this test by tracing perceived patterns with their fingers. However, some patients with achromatopsia still may pass this test, particularly if the plates are presented so distant that the individual color dots cannot be resolved.^{238,251,262,289}

Color arrangement tests consist of color chips mounted in caps that can be arranged in a unique sequence. They vary in the number of chips, the difficulty of the discriminations required, and the dimension of color space they probe, namely hue, saturation, or brightness. The Farnsworth-Munsell 100 Hue evaluates hue discrimination of tokens that do not vary in luminance. The D-15 test is a shorter version that screens for severe hue discrimination loss along protan, deutan, or tritan axes. The Lanthony New Color Test similarly tests hue discrimination, but at different saturation levels, and it also asks which colors are confused with grays. The Sahlgren Saturation Test²⁹⁰ evaluates saturation discrimination by testing the ability to separate five greenish-blue and five bluish-purple caps of varying saturation. The Lightness Discrimination Test consists of caps of different grays, to be ranked from dark to light.^291,292 Achromatopsic patients often have abnormal discrimination of hues and saturation^251,262,293 but normal perception of brightness.^239,262,293

Anomaloscopic techniques have also been applied to study cerebral achromatopsia.^240,254 With the Nagel anomaloscope, the observer tries to match a yellow monochromatic light in one test field with a mixture of yellow-green and yellow-red lights in another, by varying the proportion in the mix. Normal observers rapidly find the unique proportion needed, whereas individuals with congenital color defects or acquired cerebral achromatopsia lack a unique solution, but have abnormal matches over a wide range.

The achromatopsic abnormality affects all hue perceptions diffusely, unlike that of congenital color blindness, although the magnitude of the defect along red-green and blue-yellow axes may vary relatively.²⁴⁰ The degree of achromatopsia can vary among patients, from complete to partial defects. Functional imaging studies suggest that this may depend on the extent of damage to not just one but a number of color processing regions in occipitotemporal cortex.²⁹⁴

Hemiachromatopsia is more difficult to test. Hemifield color loss can be detected by having patients report on the appearance of large color tokens moved from the ipsilateral to the contralateral hemifield. For example, a red pen may appear to turn grayish to the patient as it is moved into the aberrant field. Yet it is difficult to quantify the color loss because the aforementioned standard color tests are designed for viewing within the central few degrees of vision, where color vision is best. Hemiachromatopsic patients can achieve normal color scores on these tests because of spared color vision near fixation.²⁴⁰ This, coupled with the asymptomatic nature of hemiachromatopsia, suggests that color loss is often unrecognized in patients with unilateral inferior occipitotemporal lesions

Color Anomia and Agnosia

Some patients cannot recognize or name colors, even though they can perceive them. Thus, although patients with achromatopsia cannot discriminate hue and saturation but can name some colors, those with color anomia and color agnosia can discriminate colors accurately but not name them. Such patients may not be aware of their deficits.

Color anomia may occur as part of a more general anomia in aphasic patients, or as an isolated entity. Several types of specific color anomia have been described, all with left occipital lesions and often an associated right homonymous hemianopia, rather than the upper quadrant defects of achromatopsia. When it accompanies pure alexia and right homonomous hemianopia, color anomia may be part of an interhemispheric visual–verbal disconnection.^295–298 Disruption of callosal connections in the splenium between the intact right striate cortex and left angular gyrus prevents accurately perceived colors in the remaining left hemifield from gaining access to language processors. Thus these subjects cannot read words or name colors that they see accurately in the left hemifield. On the other hand, some but not all of these subjects can name visual objects. Preservation of object naming has suggested that, unlike colors, objects can activate not only visual but also somasthetic representations of object shape, and that these representations could be transferred to the left hemisphere through more anterior corpus callosum.²⁹⁶ This remains to be proved.

In color dysphasia, another type of color anomia, patients not only cannot name visible colors, but cannot name the colors of familiar objects they see or imagine, tasks that patients with the disconnection anomia can do well.²⁹⁷ This defect is attributed to the loss of an internal lexicon of colors. Most of these patients display left angular gyrus lesions, with associated alexia and agraphia, right hemifield defects, and Gerstmann's syndrome.

Color agnosia is also unusual.^299–301 These patients can sort and match colors, and some can even name colors they see. However, they cannot name the colors for either visually presented or verbally named objects, cannot color line drawings of objects correctly, and cannot learn paired associations between seen objects and seen colors (a visual–visual task). Associated defects include pure alexia, object anomia, and poor performance on imagery tests for other object properties. Most of these subjects had left occipitotemporal lesions, some with a right hemianopia

VISUAL AGNOSIA

Patients with visual agnosia no longer recognize previously familiar objects nor learn to identify new objects by sight alone.^302,303 A long-standing debate centers on the necessary and sufficient impairments that generate agnosia and the extent to which these impairments involve memory rather than perception. Teuber³⁰⁴ defined agnosia as an associative disorder in which percepts are stripped of their meanings. This associative agnosia can be considered a selective disturbance of visual memory. In contrast, perceptual dysfunction is the main cause of disordered visual recognition in apperceptive agnosia.³⁰⁵ However, this apperceptive/associative distinction is rarely encountered in a pure form: most patients with agnosia have a combination of impairments of visual perception and memory.

Complete assessment of patients with higher visual disorders such as agnosia begins with an examination of basic visual sensory functions like visual acuity, visual fields, and spatial contrast sensitivity. Dysfunction of basic visual processes must be excluded before a patient's complaints can be attributed to a more complex problem. Higher visual functions require more specialized neuropsychological visual tests that include tests of visual recognition, memory, reading, mental imagery, visual perception, visuoconstruction, and visual attention.^306,307 Although detailed assessment of cognitive and intellectual function^308,309 requires referral to a neuropsychologist, some tests can be administered easily and quickly in a neuro-ophthalmology clinic.

The Benton Visual Retention Test (Fig. 19) requires a patient to reproduce ten-line drawings of geometric designs after a brief viewing.³¹⁰ It detects impairments of visual memory, perception, and visuoconstruction. The Judgment of Line Orientation Test probes orientation discrimination for line segments (Fig. 20). Visuoconstruction is assessed by drawing and writing to dictation, copy, and spontaneous writing and by the Block Design subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R). The Rey-Osterreith Complex Figure Test requires subjects to copy a complex geometric figure and provides another reliable index of visuoconstructional ability (Fig. 21).

On the Boston Naming Test a subject is asked to name line drawings of objects (Fig. 22). The Visual Naming subtest of Multilingual Aphasia Exam requires the naming of photographs of objects. The Facial Recognition Test³¹¹ asks patients to select which of several pictures of faces, photographed at different angles and in different lighting conditions, match a target face (Fig. 23). Because these faces are unfamiliar, this tests face perception rather than face recognition. Face recognition can be tested by presenting pictures of presidents, movie stars, and famous athletes.

Reading can be tested using the reading subtest of the Wide Range Achievement Test or the Chapman-Cook Speed of Reading Test (Fig. 24). Visual attention can be tested using a line bisection test, line cancellation test, or by having patients comment on the goings on in picture scene, such as the Cookie Theft Picture from the Boston Diagnostic Aphasia Examination.³¹² Patients with hemineglect or simultanagnosia can fail these tests. General intellect is often measured by a neuropsychologist, using the WAIS-R and taking age and level of education into account.

The Hooper Visual Organization Test³¹³ probes mental imagery by requiring a patient to identify 30 different items (e.g., shoe, fish) from cut-up, rearranged line drawings of the items (Fig. 25). Mooney's Closure Faces Test^314,315 provides information similar to the Hooper test by asking patients to judge age and sex in 44 incomplete cartoons of faces. Performance on this test is also dependent on memory.

Prosopagnosia

Prosopagnosia is the impaired ability to recognize familiar faces or learn facial identity.³¹⁶ Although impaired face recognition can be part of more generalized problems of perception, cognition, and memory, as in macular degeneration,³¹⁷ Alzheimer's disease,^318–320 Huntington's disease,³²¹ and Parkinson's disease,^322,323 the term prosopagnosia should be reserved for cases with selective deficits in face recognition; that is, where the problem of recognizing faces is disproportionately severe compared with other visual or cognitive dysfunction.

Prosopagnosic patients cannot recognize most faces as familiar. To identify people they rely mainly on voices or nonfacial visual cues, such as gait or mannerisms. On occasion they may use distinct face-related cues such as an unusual pair of glasses, hairstyle, or scars, cues that bypass the need to recognize the actual face. At other times the context of an encounter prompts their recognition, so that they recognize a physician in the hospital but not on the street.^324–326 Some patients have an anterograde prosopagnosia: they cannot learn new faces met after the onset of their lesion, but they recognize old acquaintances easily.^327,328 Most prosopagnosic patients are aware of their problem and its social difficulties, except for some cases with childhood onset.^324,325,329 Some patients find their disability quite distressing and are severely dysphoric.

Some prosopagnosics have a more extensive defect that affects other facial information such as gaze direction, emotional expression, age, and sex.^{324,325,329,330} In others the face processing defect is fairly specific for identity alone.^331–335 Evidence from functional imaging and monkey studies suggest that areas that encode facial identity and facial social signals may be separate,^336–338 supporting proposals that these functions may be dissociable in prosopagnosia.

Despite their failure to recognize faces, some prosopagnosics appear to have unconscious or “covert” face recognition.^339,340 Covert face familiarity or knowledge has been shown with physiologic measures such as electrodermal skin conductance^327,341,342 and visual evoked potentials.³⁴³ Behavioral methods have also been used to demonstrate covert knowledge of faces, such as forced-choice guessing of which face belongs to a name,^344–346 the speed to learn to pair names with famous versus anonymous faces,^{331,344,345,347} scanning eye movements when viewing famous faces,³⁴⁸ and priming and interference effects from faces on tasks that involve classifying names.^349,350 Current hypotheses about covert recognition suggest that it represents the residual functioning within a damaged face processing network.^351–354

Is the prosopagnosic defect truly specific for faces only? This point is relevant to debates about modular organization of high-level visual processes.^355,356 Most prosopagnosics can identify objects at some basic level or category, unlike patients with generalized visual agnosia. However, some cannot identify subtypes (subordinate categories) such as types of cars, food, or coins, or specific individuals (exemplars) such as buildings, handwriting, or personal clothing.^{329,357–359} On the other hand, other patients reportedly can identify personal belongings,³⁶⁰ individual animals,^331,361 specific places,^331,334 cars,^3,31,362 flowers,³³⁴ vegetables,³⁶² and different eyeglasses.³⁶³ Thus, in some patients the defect appears to be highly specific for faces, which supports a module dedicated to faces.

However, detailed measures of reaction time and signal detection parameters in two prosopagnosic patients show that deficits in nonface processing are present even when accuracy rates are normal.³⁶⁴ Judging the status of a prosopagnosic's ability to recognize subtle differences in other object categories also requires careful consideration of premorbid expertise: better car recognition should be expected of car buffs, for instance. Few objects have as universal interest to humans as faces: a recent review of vegetable and fruit recognition in a series of prosopagnosics found impairments in all subjects.³⁶⁵ This suggests that face recognition may be merely the most dramatic example of a type of high-level discriminative processing that is impaired in prosopagnosia, in contrast to the modular account.

TESTING IN PROSOPAGNOSIA.

Objective demonstration of impaired face recognition usually involves a battery of photographs of public persons, as in the Famous Faces test.³⁶⁶ Ideally such a test should include unfamiliar faces as distractors,³⁴⁶ and the patient should be asked to provide names or biographic data for faces. Ideally, failure should be contrasted with intact recognition of famous voices. Interpretation of results must take into account the cultural and social background of the patient, to determine which faces should be familiar to them. If this is a problem, photographs of friends or relatives can be used.

The faces subtest of the Warrington Recognition Memory Test³⁶⁷ assesses short-term learning and retention of facial identity. This test shows subjects 50 faces and then asks them to identify the same faces later when mixed with 50 other anonymous faces.

The Benton Face Recognition Test (BFRT) (see Fig. 23)³⁶⁸does not tap into the issue of familiarity and does not establish a diagnosis of prosopagnosia. Indeed, some patients are impaired on the BFRT but not prosopagnosic.³⁶⁹ However, failure to match faces suggests a degree of impaired face perception.

THE FUNCTIONAL DEFICIT IN PROSOPAGNOSIA.

In cognitive models, a complex task such as face recognition can be depicted as a series of stages, as in the Bruce and Young model.³⁷⁰ Visual processing generates a face percept. The percept is matched to “face recognition units,” a memory store of previously encountered faces. A successful match activates person–identity nodes that contain names and biographic data. These nodes can also be accessed through other perceptual routes, such as voice or gait analysis. Defective performance theoretically can arise at several levels. In patients with large lesions, damage may not be restricted to a single level, although a certain type of dysfunction may predominate.

Classical accounts divide prosopagnosia into two broad classes: (a) failure to form a sufficiently accurate facial percept (apperceptive prosopagnosia), and (b) inability to match an accurate percept to facial memories (associative prosopagnosia).^371,372

In apperceptive prosopagnosia, the patient cannot form an accurate percept of faces. In the past, this diagnosis has been indirectly deduced from performance on other visual tests, such as overlapping figures, silhouettes, Gestalt completion tests and global texture patterns.^{326,334,373,374} However, it is not clear that these tests probe skills specific to face recognition. Failure to match faces in the BFRT is more relevant but problematic because the BFRT is a test of visuoperceptual discrimination for unfamiliar faces that can also be failed by nonprosopagnosic patients.^369,375,376 Recent studies show that prosopagnosic patients with lesions that involve the fusiform face area are markedly impaired in perceiving the precise spatial arrangement of the features within a face,^377,378 a geometric property that is important in normal face recognition.^379,380

In associative prosopagnosia, there is failure of perceptual data to access to face memory stores.^327,371,372 In some cases this may be because of a disconnection between facial percepts and the memory stores.³²⁶ In others the facial memories may be lost. The diagnosis of associative prosopagnosia traditionally has been indirect, based on demonstration of intact face perception, as from normal performance on the BFRT. A more direct probe of the status of facial memories is imagery.³²⁶ Batteries of questions test whether subjects can recall details about the appearance of well-known faces. Although more posterior occipitotemporal lesions are associated with only mildly impaired face imagery, anterior temporal lesions are associated with severe loss, suggesting that facial memory stores are lost in these patients.³⁵⁴

The last element in the cognitive model of face processing is the person–identity node, containing biographic information about individuals. Because these biographic data can be accessed from several routes, this leads not to prosopagnosia, in which patients can still recognize people from other sensory cues, but to a people-specific amnesia, in which no cues can prompt recollection of other people, although other types of memories remain intact. This has been described with right temporal pole lesions.^334,381,382 This localization is consistent with functional imaging studies showing that name and face recognition both activate the anterior middle temporal gyrus and temporal pole.^383,384

ASSOCIATED CLINICAL FINDINGS.

Prosopagnosia is frequently associated with other clinical findings: a field defect, achromatopsia or hemiachromatopsia in those with fusiform lesions, and topographagnosia. The field defect is commonly a left or bilateral upper quadrantanopia but sometimes a left homonymous hemianopia.^{326,348,365,385} These associated findings depend on the extent of damage among neighboring structures in the medial occipital lobe and are not invariably associated with prosopagnosia.

Some prosopagnosic patients also have evidence of a mild visual object agnosia.^324,329 Those with more anterior temporal damage can have visual or verbal memory disturbances.^342,386 Other occasional deficits include simultanagnosia,^331,387 palinopsia, visual hallucinations, constructional difficulties, and left hemineglect.^326,386

ANATOMY AND PATHOPHYSIOLOGY OF PROSOPAGNOSIA.

There are three main categories of prosopagnosic lesions. The classic lesion is bilateral damage to the lingual and fusiform gyri of the medial occipito-temporal cortex (Fig. 26).^359,388 Functional MRI studies show that faces activate a region in the fusiform gyri, more on the right than the left, which has been called the fusiform face area (FFA).^389–391 Analysis of lesions in prosopagnosia show that many that are relatively posterior involve the FFA.³⁷⁷ A second lesion category is a unilateral right occipitotemporal lesion.^{326,332,347,360,386,392} Such lesions may also affect the FFA.³⁷⁷ A third type is anterior temporal lesions (Fig. 27).^334,354,393 It is hypothesized that anterior temporal lesions are more likely to cause the associative form of prosopagnosia, whereas occipitotemporal lesions cause an apperceptive form.^354,371,377The pattern of face processing deficits caused by unilateral versus bilateral occipitotemporal lesions is a target of active research.

The most common causes of prosopagnosia are posterior cerebral artery infarctions, head trauma, and viral encephalitis,^326,359,377 partly because of the potential of these lesions to cause bilateral damage. Tumors, hematomas, abscesses, and surgical resections are less frequent, but common among cases with unilateral lesions.^372,386,394 Progressive forms occur with focal temporal atrophy.^334,378,395 Prosopagnosia can be a transient manifestation of migraine.³⁹⁶ There is increasing interest in a developmental form of prosopagnosia also,^{324,325,329,397–399} which may be associated with social developmental disorders such as Asperger's.³²⁵

There is no known treatment for prosopagnosia. One patient reportedly learned new faces when asked to rate faces for a personality trait or remember semantic data about them, but this benefit did not translate to recognition of other views of the same faces.⁴⁰⁰ Otherwise, patients may benefit socially from learning to use nonfacial and nonvisual cues more effectively in identifying people

Other Disorders of Face Perception

Older reports showed that right hemispheric lesions can impair some aspects of face processing in patients who are not overtly prosopagnosic. There are reports of defective perceptual matching of unfamiliar faces,^375,376 although a more recent study that examined both accuracy and reaction times for famous and nonfamous faces in patients found that the perception of these two classes of faces were not truly independent processes.⁴⁰¹ A less-studied aspect of the face processing is the analysis of dynamic facial information, such as gaze, expression, and age. The monkey and functional imaging data suggest that these are more likely to be associated with damage to the lateral occipitotemporal region, which may be a homologue of the superior temporal sulcus in monkeys.^330,391 One older study found that judgment of facial age could be impaired by right hemispheric lesions.⁴⁰² Another study showed that a selective defect for facial expression occurred with left hemispheric lesions.⁴⁰¹ More data are needed.

Some patients have false recognition of unfamiliar faces. They mistake strangers for people they know.^403–405 This phenomenon has been described mainly with large right middle cerebral artery strokes, affecting lateral frontal, temporal, and parietal cortex.^403,404 Some of these patients appear to have prosopagnosia on testing, yet deny problems in recognizing people.⁴⁰⁴ Others have intact face recognition.^403,406 Most have right prefrontal damage, which may impair self monitoring and decision making, leading to hasty mistaken judgments of facial similarity based on partial or fragmentary data, and failure to reject incorrect matches.⁴⁰⁶

ACQUIRED ALEXIA

Acquired alexia is loss of reading ability in previously literate persons. Reading requires intact “low-level” visual processes such as adequate spatial resolution at the fovea, complex visual functions such as pattern and form perception, accurate deployment of visuospatial and ocular motor skills in line scanning to generate shifts of attention and a series of alternating fixations and saccades, and finally, competent linguistic analysis. Not surprisingly, a wide variety of anatomic lesions and functional disturbances can impair reading.

Pure Alexia

Patients with pure alexia (alexia without agraphia) can write but cannot read well, despite good visual acuity and intact oral and auditory language skills. At the severe end of the spectrum, patients with global alexia⁴⁰⁷ cannot read numbers, letters, and other abstract symbols, such as musical notation for pitch, road signs, and map symbols,^408,409 let alone words. At the mild end, patients have slow reading with occasional errors, diagnosable only by comparison with controls of similar educational level.⁴¹⁰ These patients decipher words one letter at a time (letter-by-letter reading). The characteristic sign is the word-length effect, in that the time needed to read a word increases with the number of letters in the word.^411,412

There is evidence of covert processing in pure alexia. Some patients can rapidly indicate whether a string of letters form a word or not,^412–414 point to words that they cannot read aloud,⁴¹⁵ or identify letters more quickly when they are part of real words rather than random letter strings.⁴¹¹ Some can categorize words semantically,⁴¹² or match words to objects.^413,416

Pure alexia frequently is associated with a right hemianopia or superior quadrantanopia, sometimes with hemiachromatopsia.^417,418 Patients often have anomia for colors^296,417 and sometimes other visual objects. Anomia can involve items heard or felt as well as seen, indicating a linguistic rather than visual disturbance.⁴¹⁹ There may be impaired verbal memory, other visual agnosias, or a pattern of optic ataxia, in which the right hand has difficulty reaching for objects in the left visual field.^417,419

Almost all lesions causing pure alexia are in the left hemisphere. Most are located in the medial and inferior occipito-temporal region.^407,417The most frequent cause is left posterior cerebral artery stroke, but other causes include primary and metastatic tumors,^420–422 arteriovenous malformations,^423,424 hemorrhage,⁴²⁵ herpes simplex encephalitis,⁴²⁶ multiple sclerosis,⁴²⁷ and posterior cortical atrophy.^409,428

Two major explanations exist for pure alexia. Some cases may represent a (white matter) disconnection of visual input from both hemifields from language areas in the left hemisphere.^296,429 Most commonly, a left occipital lesion produces a complete right hemianopia and extends anteriorly to the splenium, forceps major, or periventricular white matter surrounding the occipital horn,^417,430 interrupting callosal fibers from the intact right occipital lobe. Visuolinguistic disconnection may result from the combined effects of bilateral occipital lesions in patients with bilateral field defects, without spenial damage.⁴¹⁸ Less commonly, lesions of the white matter underlying the left angular gyrus may disconnect visual input to this language region, even without right hemianopia.^420,421,426 Support for disconnection derives from unusual cases in which pure alexia results from the combination of a splenial lesion and a right hemianopia from nonoccipital lesions, such as left geniculate infarction.^431,432

Other cases of pure alexia may represent a visual agnosia from dysfunction of the left ventral extrastriate cortex. Apperceptive defects,^374,433 simultanagnosic-like defects,^434–437 and associative defects^438,439 have been proposed. The word-length effect, the letter-by-letter strategy, and greater difficulties with handwritten script and briefly shown words⁴³⁴ suggest an inability to grasp words as a whole. Pure alexia can be associated with impaired processing of local textural features³⁷⁴ and four of five letter-by-letter readers were shown recently to have impaired identification of complex objects in line drawings.⁴³³ Studies of face recognition in a patient with object agnosia, alexia, but not prosopagnosia, implicated dysfunction of a component-based perceptual system.⁴⁴⁰ Some indirect support for the agnosia argument comes from pathologic reports inconsistent with disconnection. One patient had a lesion of the left fusiform and lingual gyrus but no splenial degeneration, which should have occurred if callosal fibers had been affected.⁴⁴¹ Another without hemianopia had a lesion in the left lateral occipito-temporal cortex, too ventral to interrupt fibers to the angular gyrus.⁴⁴² Alexia in the setting of neurodegenerative disease is presumably more likely to be agnosic than disconnective in nature.⁴³⁷

The prognosis for alexia is variable and depends on the underyling pathology. Global alexia can resolve into spelling dyslexia.⁴³⁰ Interest in rehabilitation of reading in alexic patients is high, with many imaginative strategies currently evolving. These include altering text to highlight the spacing between words or phrases,^443,444 enhancing oral articulation during reading,⁴⁴⁵ repetitive oral reading of text,⁴⁴³ attempts to enhance implicit or covert processing of whole words,⁴⁴⁴ and finger tracing of letters in patients presumed to have a disconnection syndrome.^444,446 The success of these approaches in improving both speed and accuracy requires further evaluation and will likely require tailoring to the specific reading defect in a given patient.

Hemialexias

The disconnection hypothesis for pure alexia^429,447 actually requires two disconnections of the left angular gyrus, one for each hemifield. Each has also been described in isolation. In left hemialexia, reading is impaired in the left hemifield only, because of isolated damage to the splenium or the callosal fibers elsewhere.^448,449 This disconnection has been visualized recently in one patient with a combination of fMRI and diffusion tensor imaging.⁴⁴⁹ Right hemialexia has been reported with a lesion of the left medial and ventral occipital lobe.⁴⁵⁰ Left hemiparalexia is a rare syndrome reported with splenial damage after surgery for arteriovenous malformations.⁴⁵¹ Patients make substitution and omission errors for the first letter of words, much like neglect dyslexia (discussed later), but they do not have hemineglect, and have left-sided lesions with right hemianopia rather than the converse.

Alexia with Agraphia

In some patients both reading and writing are impaired but oral and auditory language is preserved. Alexia with agraphia is associated with lesions of the left angular gyrus^429,452 or sometimes the adjacent temporo-parietal junction.⁴⁵³ Little is known about this rare disorder. It may be accompanied by acalculia, right-left disorientation, and finger agnosia, the other elements of Gerstmann's syndrome. It has been described in unusual conditions such as posterior cortical atrophy⁴⁵⁴ and Marchiafava-Bignami's disease, a demyelinating disorder in chronic alcoholics.⁴⁵⁵

Patients with Broca's aphasia from left frontal lesions have trouble with all expressive language output, and therefore also with reading aloud and writing. However, some also have marked difficulty understanding written material, in contrast to relatively preserved comprehension of spoken language.^456,457These patients are better at occasionally grasping a whole word, although unable to name its constituent letters, hence the name “literal alexia” or “letter blindness.” These patients also have impaired comprehension of syntax in written or spoken language, similar to the agrammatism of their verbal output.

Secondary Alexia

VISUAL LOSS AND READING.

Bilateral loss of visual acuity of any etiology impairs reading ability and is not likely to be missed on eye examination. Visual field defects that do not affect central acuity can impair reading too. Bitemporal hemianopia can cause hemifield slide, in which the absence of overlapping regions of binocular visual field leads to unstable binocular alignment with transient duplication or disappearance of words during reading.⁴⁵⁸

Homonymous field defects cause hemianopic dyslexia, when the central 5° are affected.^40,45 Overall reading speed is more prolonged for patients with right hemianopia than for those with left hemianopia.^40,459 With languages written from left to right, patients with left hemianopia have trouble finding the beginning of lines, because the left margin disappears into the field defect as they scan rightward.^40,460 Marking their place with an L-shaped ruler helps. Right hemianopia prolongs reading times, with increased fixations and reduced amplitude of reading saccades to the right.^40,459,460 Smaller type and learning to read obliquely with the page turned nearly 90° may help. Reading performance can improve with time as both types of patients learn adaptive strategies.⁴⁰

ATTENTION AND READING.

Patients with left hemineglect from right parietal or frontal lesions make left-sided reading errors, known as neglect dyslexia.⁴⁶¹ They omit reading the left side of lines or pages. With individual words, they make left-sided omissions (bright read as right), additions (right read as bright) or substitutions (right read as light). Vertically printed text is not affected.⁴⁶¹ The impairment represents a combination of both a space-centered deficit, in which text on the left side of space is ignored, and an object-centered deficit, in which the left side of words is ignored, even if the words are on the right side of space. Rarely, it may occur without other signs of hemineglect.⁴⁶²

An “attentional dyslexia” has been described in which the perception of single items is adequate, but perception of several objects simultaneously is impaired.^435,436 These patients identify single words normally but not several words together, and identify single letters but cannot name the letters in a written word. When reading they make literal migration errors, in which a letter from one word is substituted into another word (poor baby read as boor baby). Letters are mistaken for others that look similar (o and c).⁴³⁶ This dyslexia has been reported with lesions in the left parietal lobe⁴³⁵ or temporo-occipital junction.⁴³⁶

EYE MOVEMENTS AND READING.

Abnormal fixation and saccades may impair reading. Most unilateral cortical lesions cause only minor eye movement problems, but the acquired ocular motor apraxia from bilateral frontal or parietal lesions can impair reading severely.^463–466 In bi-parietal cases this may reflect simultanagnosia as much as the saccadic dysfunction. Brainstem or subcortical lesions may cause more severe saccadic and fixation abnormalities: reading difficulty with progressive supranuclear palsy has been attributed to square wave jerks disrupting fixation and hypometric and slow saccades impairing scanning,⁴⁶⁷ but paresis of downward gaze also makes reading material inaccessible

Central Dyslexia

More subtle acquired dyslexic deficits have been described that reflect impaired central reading processes rather than attention or vision. Central dyslexias are formulated in terms of parallel processing channels in reading models from cognitive neuropsychology.⁴¹⁰ After letters are identified visually, there are at least two distinct means of processing. One is a “direct” phonologic route, in which generic pronunciation rules convert a string of letters into sound. The other is an “indirect” lexical route, in which the whole word is perceived and identified in an internal dictionary of written words, which then generates the pronunciation of the word. Patients with phonologic dyslexia have lost the direct route, and so are not able to reasonably guess at the pronunciation of pseudowords or words they have not seen before.^468–471 Patients with surface dyslexia have lost the indirect route, and so are not able to pronounce correctly irregular words like yacht and colonel.^472–475 Deep dyslexia resembles phonologic dyslexia, but patients characteristically substitute words with a similar meaning for the correct one (boat read as ship).⁴⁷⁶

Assessment of Reading

First, spatial resolution must be assessed. Tests of basic visual function must minimize the use of number or letters to avoid confusion. One can use simplified test forms such as the directional “E's” of the Snellen chart, for example, or gratings at high contrast. Second, one must also assess for other elements of dysphasia, particularly in oral and auditory language, to ensure that the reading dysfunction is not just one manifestation of aphasia, rather than true alexia. Standard testing can help exclude aphasia (e.g., Boston Diagnostic Aphasia Examination or Multilingual Aphasia Examination). Third, writing must be tested, by writing a sentence to dictation and spontaneously. Overlearned segments such as signatures are not an adequate test. Difficulty in writing that can not explained by associated weakness or incoordination implies a more pervasive language disturbance, such as alexia with agraphia.

Reading aloud and reading for comprehension can be assessed informally with any available material. Premorbid intellect and reading skills always must be considered. Standardized assessments of reading, including the Wide Range Achievement, require the reading aloud of words of increasing difficulty until the subject makes a string of errors. In addition to reading aloud, comprehension of written material should be tested. The Chapman-Cook Speed of Reading Test has subjects read brief paragraphs and cross out the word that spoils the meaning of the paragraph. Comprehension tests that do not require a verbal response include the BDAE Reading Sentences and Paragraphs. These avoid confusing impaired verbal output with defective reading comprehension.

Analysis of the pattern of reading-aloud errors can be useful. The word-length effect points to a letter-by-letter reading strategy in spelling dyslexia. Errors restricted to the left side of text or words point to neglect dyslexia. More specific semantic substitutions or phonologic mistakes are characteristic of the central dyslexias.⁴¹⁰

TOPOGRAPHAGNOSIA

One symptom of patients with extrastriate lesions may be that they get lost in familiar surroundings. With a complex task such as route-finding, this symptom may have a number of different causes.⁴⁷⁷

One form is frequently associated with prosopagnosia and achromatopsia.^{324,329,332,334,341,386,394} In these patients, the problem is an inability to identify familiar landmarks and buildings, “landmark agnosia.”⁴⁷⁸ This form occurs with right ventral temporo-occipital lesions.^479,480 The origins of landmark agnosia are debated. Some propose that it reflects a selective multimodal memory disturbance rather than a strictly visual problem.⁴⁸⁰ However, functional imaging also suggests that buildings and places activate a specific region in occipito-temporal cortex, the “hippocampal place area,” which is adjacent to the fusiform face area.⁴⁸¹ Lesions of this region could create an agnosia specific for landmarks, and the frequent association with prosopagnosia may reflect the proximity of face and place processing in cortex.

In a second form, the spatial processing needed to describe, follow, or memorize routes is disrupted, usually by right parietotemporal lesions.^479,482 It has been suggested that the key deficit with such lesions is an “egocentric disorientation,” in which subjects cannot represent the location of objects and buildings with respect to themselves.⁴⁷⁷

A third, related form is a “heading disorientation,” in which there is a failure in representing direction with respect to cues in the external environment, rather than in reference to the subject. This has been associated with posterior cingulate lesions.⁴⁸³ This may have been the case with a rare patient with a left parahippocampal and retrosplenial lesion who had defective route-finding associated with alexia and other severe visual amnestic deficits.⁴⁸⁴

Parahippocampal lesions have also been implicated in an “anterograde topographagnosia,” in which new routes cannot be learned, although old routes are still known.⁴⁸⁵

BALINT'S SYNDROME

Balint's syndrome^486,487 is a loosely associated triad of visuospatial dysfunctions: simultanagnosia, optic ataxia, and ocular motor apraxia.

Patients have a deficit in distributing spatial attention, in which they cannot pay attention to more than a few objects at a time. Thus these patients have trouble with visual search tasks⁴⁸⁸ and in maintaining attention over large regions of space.⁴⁸⁹ This defect may be equated to simultanagnosia, the inability to interpret a complex scene with multiple interrelated elements, despite intact perception of the individual elements.⁴⁹⁰ What constitutes an element or object is a complex matter, depending not only on visual properties, but also cognitive factors. For example, such patients can identify single letters but have difficulty identifying multiple letters in a random string. However, if that string is a word or even a pronounceable nonword, performance is better, indicating that the letters have been grouped into a single linguistic element.⁴⁶⁶ Similarly, improvement in detecting multiple objects improves if they are semantically related.⁴⁸⁸

An additional spatial problem is visual disorientation.⁴⁶⁴ This is a defect in judging the spatial position and distance of objects. This problem may contribute to optic ataxia, which is difficulty in guiding reaching movements to visual targets despite normal limb strength⁴⁹¹ and position sense. Misreaching may represent more than just visuospatial misperception, because it can affect one arm more than the other⁴⁸⁶ and affect reaching to somatosensory targets, such as the patient's own body parts.⁴⁹² Thus, a multimodal spatial targeting system for hand guidance may be dysfunctional. Laboratory measures of reaching, pointing and grasping have shown increased latency, abnormal hand trajectories, increased variability of the end of the reach, tendency to reach to one side, as well as dissociations of distance and direction control (Fig. 28).^493–495

The ocular motor abnormalities of Balint's syndrome are not well characterized. There are probably several components. Psychic paralysis of gaze or acquired ocular motor apraxia indicates a difficulty in initiating voluntary saccades to visual targets.^487,496 Although reflexive saccades to suddenly appearing visual objects or noises are normal, these patients may have great difficulty making a saccade on command. A related problem is spasm of fixation.⁴⁹⁷ Today this is more narrowly defined as a problem in initiating saccades away from a fixation point that remains visible.⁴⁹⁸ Once saccades are generated, there may be gross inaccuracies in saccadic targeting, causes the eyes to make a series of wandering saccades in search of the target, which is nevertheless visible.^464,491 Once on the target, patients can also have trouble maintaining fixation.

To diagnose Balint's syndrome one must exclude more general cognitive dysfunction, hemineglect, and extensive visual field defects. Perimetry can be difficult because of inattention, fatigue, and difficult fixation.^499–501 Many reports of Balint's syndrome are marred by inadequate documentation of visual fields. Extensive peripheral scotomata leaving only “keyhole vision”⁵⁰² can create signs that mimic all components of the Balint triad. Simultanagnosia usually is tested by asking the patient to report all items and describe the events depicted in a complex visual display with a balance of information in all quadrants, such as the Cookie Theft Picture from the Boston Diagnostic Aphasia Examination.³¹² Patients omit elements and fail to realize the story being shown. At the bedside, patients can be asked to pick up a number of coins scattered on a table.⁴⁶⁴ To test for optic ataxia, easily seen items are placed at different locations within arm's reach of the patient, who is asked to touch or grasp them, with each hand tested separately for each side of hemispace.⁵⁰³ With unilateral lesions, the problem tends to be worse for reaches with the contralateral hand or hemispace. Misreaching for visual targets is contrasted with reaching to parts of their own bodies, although more diffuse disturbances in parietal spatial representation may impair both.⁴⁹² Such generalized misreaching can be confused with cerebellar dysmetria, but the latter usually is accompanied by intention tremor and dysdiadocokinesia. Ocular motor apraxia is confirmed by comparing the patient's difficulty in making saccades to command with the ease in making reflexive saccades to sudden targets in the natural environment, such as an unexpected noise.

Although simultanagnosia has been held responsible for optic ataxia and ocular motor apraxia,⁴⁹¹ each of the elements of Balint's syndrome is dissociable.^{464,474,491,504} Therefore the ocular, reaching, and attentional disturbances may each have a different pathophysiologic origin, even if they contribute to each others' manifestations. The incapacity to combine elements into a whole seen in simultanagnosia was thought to reflect an inhibitory action of a focus of attention on surrounding regions.⁵⁰² Failure of long-range spatiotemporal processes to sustain and distribute attention are likely.^488,489 Reaching under visual guidance may be mediated by recursive processes involving intercommunication among a cerebral sensorimotor network,⁵⁰⁵ which can be disrupted at a number of key points, including parietal and frontal cortex.^506,507Inaccurate saccades and difficulty initiating saccades reflects damage to specific structures involved in saccadic control, likely homologues of the lateral intraparietal area⁵⁰⁸ and/or the frontal eye field.

There are often other disturbances. These include a variety of bilateral hemifield defects, usually affecting the lower quadrants more severely, and other visuospatial defects such as left hemineglect, akinetopsia, and astereopsis.^487,509,510 Smooth pursuit often is impaired. Patients may complain of distorted perception, with metamorphopsia, micropsia, and macropsia, or visual perseverations such as palinopsia and monocular polyopia. Visual agnosias may be present with more extensive lesions.⁵¹¹ Visual evoked potentials may be normal⁵¹² or abnormal,^511,513 probably depending on the extent of associated damage.

Balint's syndrome results from bilateral occipito-parietal damage (Fig. 29). The early reports emphasized the role of the angular gyri, although the lesions clearly were more extensive, involving the splenium, white matter, and pulvinar.^464,486 Modern imaging associates simultanagnosia with lesions of the dorsal occipital lobes in Brodmann's areas 18 and 19.⁴⁸⁹ The lesions of optic ataxia are more variably localized, including premotor cortex, occipitoparietal regions, cortex inferomedial to the angular gyri,⁴⁹⁵ and occipital-frontal white matter connections,^507,514 and can be unilateral.^493,507,515 Acquired ocular motor apraxia in its dramatic form requires bilateral lesions of the frontal eye fields, inferior parietal lobes, or both,^464,465,491 although it has been described in one patient after unilateral pulvinar resection.⁵¹⁶

The most common causes of Balint's syndrome are ischemia, particularly watershed infarctions,^517,518 and degenerative disorders such as Alzheimer's disease^519,520 and posterior cortical atrophy.^{409,513,521,522} Other causes include tumors, abscesses, trauma,⁵¹¹ leukoencephalopathies, Marchiafava-Bignami's disease,^523,524 prion disorders, and, in patients with AIDS, progressive multifocal leukoencephalopathy⁵²⁵ and HIV encephalitis.⁵²⁶ Recurrent transient episodes can occur rarely with migraine.⁵²⁷

The prognosis varies with etiology. Patients with acute infarction can recover significantly with time, whereas those with posterior cortical atrophy deteriorate. Little is known about treatment. Cognitive and perceptual rehabilitative approaches involving verbal cues and organizational search strategies have been reported to improve visual function and reaching in three patients.⁵²²

CEREBRAL AKINETOPSIA

Cerebral akinetopsia is a selective impairment in motion perception. Two cases of akinetopsia from bilateral lesions have been particularly well described, LM and AF. LM has been the subject of many reports.^528–536 Symptomatically, LM had no impression of motion in depth or of rapid motion,⁵²⁸ with fast targets appearing to jump rather than move.⁵²⁹ Patients with motion deficits from unilateral lesions are either asymptomatic or have more subtle complaints, such as “feeling disturbed by visually cluttered moving scenes” and trouble judging the speed and direction of cars.^537,538

Tests for motion perception require computer animated displays, and are not available in most clinics (Fig. 30). It is not possible to infer perceptual deficits solely from impaired motor responses to moving stimuli, such as smooth pursuit eye movements. Although LM and AF had impaired smooth pursuit,⁵²⁸ patients with unilateral lesions impairing motion perception may have normal smooth pursuit, and conversely patients with abnormal pursuit may have normal motion perception.⁵³⁹

Experimentally, many different aspects of motion perception can be tested. Even with extensive bilateral lesions, not all motion perception is lost. Distinguishing moving from stationary stimuli is still possible,⁵²⁸ and the contrast sensitivity for moving striped patterns is almost normal.⁵³⁰ LM could discriminate the direction of small spots⁵²⁹ and random dot patterns in which all dots were moving in the same direction.^531,532 However, LM and AF had trouble perceiving differences in speed, and their perception of direction was severely affected when even small amounts of random motion or stationary noise was added to displays.^531,532,540

These deficits are reflected in a number of perceptual tasks involving motion cues. When searching among multiple objects for a target, LM could not restrict her attention to moving objects.⁵³⁵ LM and AF could not identify two-dimensional shapes defined by differences in motion between the object and its background. LM was also impaired for three-dimensional shapes defined by motion.^532,540 When lipreading, LM had trouble with polysyllables uttered rapidly, and her judgment of sound was biased by auditory rather than visual cues.⁵³⁴ On the other hand, LM could easily see “biological motion” (e.g., identifying the movements of a human body).

LM suffered sagittal sinus thrombosis with bilateral cerebral infarction of lateral occipitotemporal cortex.⁵²⁹ AF had acute hypertensive hemorrhage with similar bilateral lateral occipito-temporal lesions.⁵⁴⁰ In monkeys, motion-specific responses are found in areas V5 (middle temporal area, or MT) and V5a (medial superior temporal area, or MST), in the superior temporal sulcal region.⁵⁴¹ The lateral occipitotemporal area has been identified from histologic markers and functional imaging as homologous to monkey area V5 (Fig. 31).^542–545 The correspondence of this lateral occipitotemporal region to monkey V5 is strengthened by a study showing similar patterns of deficits and spared abilities in LM and monkeys with V5 ablations.⁵³³

Unilateral lesions of the human V5 area cause more subtle abnormalities of motion perception. Some small series report contralateral hemifield defects for speed discrimination,^546,547 detecting boundaries between regions with different motion, and discriminating direction amidst motion noise.⁵⁴⁸ As in LM and AF, motion detection and contrast thresholds for motion direction were normal.^546,547At present, there are little data on hemispheric differences. Although an earlier study found a predominance of right-sided lesions,⁵⁴⁹ similar defects have been identified subsequently with damage to either side.^548,550

Are different types of motion perception affected by different lesions? First-order motion refers to stimuli from which motion can be computed by correlating the spatial distribution of luminance in the visual scene over time. However, we can also discern the motion of other types of stimulus attributes besides luminance, such as contrast, texture, stereopsis, and flicker. These are known as second-order motion. Initial case studies suggested that first- and second-order motion may have separate loci, with second-order motion affected by a lesion near the V5 region^537,551 and first-order motion affected by a medial occipital lesion, near areas V2 and V3.⁵³⁸ However, recent studies have found that deficits of first- and second-order motion perception in the contralateral hemifield colocalize to the V5 region.^552,553 However, some segregated processing of these is still possible, because dissociations between impaired first-order and preserved second-order motion perception are occasionally encountered in patients with smaller peri-V5 lesions.⁵⁵³ An fMRI study⁵⁵⁴ suggested that signals from second-order motion first emerge in areas V3 and VP, and may be later integrated with first-order motion signals in area V5. In addition to first- and second-order motion, more long-range integration of position data can also give rise to apparent or “high-level” motion perception. Defects in high-level motion perception arise from parietal rather than occipitotemporal lesions, and may be related more to defects in transient visual attention than the processing of motion signals.^555,556

The relation of pursuit eye movements to motion perception is of interest. During pursuit, the fMRI signal related to motion perception is enhanced in V5 and in a more dorsal parieto-occipital location.^545,557Some of the neural activity in the middle superior temporal area (area V5a) during pursuit may be information about the eye movement itself (efference copy). Because movement of images on the retina can be generated either by moving objects while the eye remains still, or by eye movement while the world remains still, efference copy may serve to disambiguate the two. A patient with vertigo induced by moving objects could not take his own eye movements into account when estimating object motion.⁵⁵⁸ He had bilateral occipito-parietal lesions, possibly of a homologue of area V5a.

Other defects are associated with motion perception deficits. The proximity of the optic radiations means that hemianopic defects are frequent, and may obscure motion perception defects in the contralateral hemifield. The two akinetopsic patients had large lesions and, not surprisingly, defects on other nonmotion perceptual tasks. AF was poor at recognizing objects seen from unusual angles and in incomplete line drawings, and on spatial tests such as hyperacuity, line orientation, line bisection, spatial location, and stereopsis. LM also had poor perception of forms constructed from cues of texture, stereopsis, or density.⁵³²

The prognosis of motion perceptual deficits is still unclear. Two cases studied sequentially showed significant improvement over 6 to 12 months.^552,559 In monkeys the pace and degree of recovery is correlated with the size of the lesion and the extent of damage to both V5 and V5a.⁵⁶⁰ Recovery with larger lesions presumably reflects adaptation within other surviving motion-responsive regions of cortex.

ASTEREOPSIS

One of the important clues to distance from the observer is the disparity between the retinal images of the object in the two eyes. Astereopsis occurs in patients with bilateral occipito-parietal lesions.^509,561 Milder deficits occur with unilateral lesions, and there may be other associated visuospatial defects. Patients may complain that the world looks flat and that they cannot tell the depth of objects, and they may misreach for objects in depth but not direction. Whether astereopsis can explain all these symptoms can be debated, because there are many other clues to distance besides stereopsis, which do not require two eyes. These include relative differences in object size and intensity (which artists exploit), and differences in object motion as the observer's head moves (motion parallax). Whether these other depth perceptual functions are also impaired in these patients needs further investigation. Stereotests, which are cards viewed with different polarized or colored glasses worn by the two eyes, can diagnose deficient stereopsis.⁵⁶²

VISUAL PERSEVERATION

The persistence, recurrence, or duplication of a visual image is a rare complaint. Several varieties exist, including palinopsia, polyopia, and illusory visual spread. Palinopsia (or paliopsia) is the perseveration of a visual image in time.⁵⁶³ Thus the palinopsic illusion contains elements of a recently viewed scene. Cerebral diplopia or polyopia is the perseveration of a visual image in space, when two or more copies of a seen object are perceived simultaneously.^564–567 In “illusory visual spread,” the contents or surface appearance of an object spread beyond the spatial boundaries of the object.⁵⁶³ Thus wallpaper patterns spread beyond the surface of the wall, and cloth patterns spread from a shirt to the wearer's face.⁵⁶³

Palinopsia

There are at least two forms of palinopsia, an immediate and a delayed type. With the immediate type, an image persists after the disappearance of the actual scene, fading after several minutes. This has some similarity to the normal after-image of a bright object. Some have concluded that the differences between normal after-images and palinopsic images are primarily quantitative,⁵⁶⁸ although others disagree.⁵⁶⁹ With the delayed type of palinopsia, an image of a previously seen object reappears after an interval of minutes to hours, sometimes repeatedly for days or even weeks.⁵⁶⁸

The perseverated image can occur anywhere in the visual field. It may persist in the same retinal location as the original image, usually at the fovea, and thus move as the eyes move, much like a normal after-image.⁵⁷⁰ Sometimes the image is translocated into a visual field defect.⁵⁶³ Sometimes the image is multiplied across otherwise intact visual fields.⁵⁶⁵ On rare occasions, the location of palinopsic images is contextually specific: after viewing a face on television, everyone else in the room has the same face as the person on television.^563,565,571

There are four main pathophysiologic hypotheses for palinopsia.⁵⁶⁹ First, in some cases it may represent a pathologic exaggeration of normal after-images, with colors complementary to those of the real object.⁵⁶⁸ However, this is not true of all cases.^569,572 Second, it may be a seizure disorder, an assertion based on circumstantial evidence. Some patients have other ictal features such as episodic loss of consciousness, tongue biting, and confusion,^563,569 and there can be epileptiform abnormalities on EEG and a good response to anticonvulsants.^573–576 Third, it may be a hallucinatory state. Some patients have both palinopsia and nonpalinopsic hallucinations, and the confinement of some perseverative images within visual field defects suggests release hallucinations. Also, drugs that induce hallucinations can cause palinopsia.⁵⁶⁸ Last, a psychogenic explanation holds that palinopsia may be a confabulatory response to other visual dysfunction.⁵⁶³ Palinopsia without visual dysfunction can occur in a psychiatric context, in association with other perseverative and misidentification delusions like Capgras' syndrome.⁵⁷⁷

Intoxication, metabolic and psychiatric conditions must first be considered in the differential diagnosis. Intoxication with hallucinogens such as mescaline, LSD and “Ecstasy” can cause palinopsia, sometimes permanently.^578,579 There are reports of palinopsia with prescribed medication, such as clomiphene,⁵⁸⁰ interleukin 2,⁵⁸¹ trazodone,⁵⁸² nefazodone,⁵⁸³ mirtazapine,⁵⁸⁴ or withdrawal from paroxetine.⁵⁸⁵ Second, it can occur with metabolic states such as nonketotic hyperglycemia.⁵⁸⁶ Third, palinopsia can occur in psychiatric conditions such as schizophrenia^577,587 and psychotic depression,⁵⁸⁸ but this is always accompanied by other signs of mental illness.

Once these are excluded, visual perseveration suggests a cerebral lesion. A variety of lesions are possible, including brain abscess,⁵⁸⁹ tuberculoma,⁵⁹⁰ hemorrhage,⁵⁹¹ and Creutzfeld-Jakob's disease.⁵⁹² The localizing value of palinopsia is not clear. Occipito-parietal lesions are most described, right, left, or bilateral.^{563,569,591,593} There are also reports of medial occipital and occipito-temporal lesions.^{565,571,590,594}

There are even cases of perseverative phenomena with noncerebral visual damage. Palinopsia has been reported in two patients with optic neuritis, one with Leber's hereditary optic neuropathy, and one after photocoagulation for diabetic maculopathy.^595,596 A survey of 50 patients with severe visual loss from ocular lesions found that, in addition to release hallucinations, one or two had palinopsia, polyopia, or illusory visual spread.⁵⁹⁷ Also, there are rare patients with palinopsia who have apparently normal neurologic and ophthalmologic function and no history of drug use.⁵⁹⁶

Various symptoms can accompany palinopsia. A hemifield defect is virtually always present, with reports of both upper⁵⁷¹ and lower⁵⁶⁸ quadrantanopias. There may be other spatial illusions, such as metamorphopsia, macropsia, and micropsia.^{563,568,569,574} Less frequently, ventral stream deficits have been reported, such as topographagnosia, prosopagnosia, and achromatopsia.^386,569 Some patients have auditory or somatosensory perseverative symptoms too.^570,598

The prognosis for visual perseveration is not clear. It can be a transient phase in either the resolution or progression of a visual field defect, lasting days to months.⁵⁶⁹ However, palinopsia can persist for months to years.^{568,570,572,573} Anticonvulsant medication such as carbamazepine may help some patients^573,599 but not others.⁵⁷⁰

Cerebral Polyopia

Cerebral polyopia or diplopia is much less frequently described than palinopsia. It occurs with monocular viewing, distinguishing it from diplopia caused by ocular misalignment. Unlike the monocular diplopia from refractive aberrations, as with cataracts, it does not resolve with viewing through a pinhole, and it is present with either eye viewing alone. In some patients cerebral polyopia occurs only in certain gaze positions, but unlike ocular misalignment, the deficit can persist with one eye closed.⁵⁶⁴ The number of polyopic images exceeded a hundred in a unique case of “entomopia.”⁵⁶ Associated signs include frequent visual field defects,⁶⁰⁰ optic ataxia, achromatopsia, object agnosia, and abnormal visual after-images.

Cerebral polyopia can be a transient phase in the recovery from cortical blindness resulting from occipital missile wounds.⁵⁶⁴ In two cases recovery followed a progression from cortical blindness to cerebral polyopia, then cerebral diplopia. Other causes in the older literature include encephalitis, multiple sclerosis, and tumors.⁵⁶⁴ A more recent patient had an infarct in peristriate cortex.⁶⁰⁰

The origins of this rare symptom are obscure. Polyopia might be a variant of palinopsia, with perseverated and real images coexisting in time.⁶⁰⁰ Some suggest an analogy with the monocular diplopia that sometimes develops in strabismic patients who have both a true and a false macula, along with a disorder of unstable fixation that would cause the retinal image to shift over these falsely localizing regions.^564,601 However, the necessity of abnormal fixation has been contested.^566,567

VISUAL HALLUCINATIONS

Hallucinations are perceptions without external stimulation of the relevant sensory organ. Individuals vary in the degree to which they recognize that these experiences are not real. Hallucinations sometimes are divided into simple and complex forms. Simple hallucinations consist of brief flashes of points of light, colored lines, shapes, or patterns.^602–604 Complex hallucinations contain recognizable objects and figures,⁶⁰⁵ such as scenes of humans and animals,^606–609 with a potential for bizarre, dreamlike imagery of considerable detail and clarity.^610,611 There is debate over the value of the simple/complex dichotomy in terms of its diagnostic and localizing value.

In the differential diagnosis of hallucinations, one of the chief considerations is whether there is any associated mental or cognitive dysfunction.

Hallucinations with Altered Mental States

Drugs and toxic-metabolic confusional states are important causes of hallucinations. These include bupropion,⁶¹² baclofen withdrawal,⁶¹³ dopaminergic agonists,^614,615 ganciclovir,⁶¹⁶ vincristine,⁶¹⁷ and serotonin reuptake inhibitors such as fluoxetine and sertraline.⁶¹⁸ Visual hallucinations predominate in alcohol withdrawal.⁶¹⁹ With illicit drugs, hallucinations can occur for several months after use, sometimes recurring years later in relation to use of alcohol or medication.⁶²⁰ A transcranial magnetic stimulation study has shown that subjects with hallucinations related to Ecstasy use have hyperexcitable occipital cortex, probably related to alterations in serotonin levels.⁶²¹

Hallucinations also occur in psychiatric disorders, although visual hallucinations usually are accompanied by hallucinations in other sensory modalities (especially auditory) and by other signs of mental illness.

Hallucinations with Cognitive Dysfunction

Visual hallucinations are a well known symptom in patients with dementia.⁶²² Among patients with Alzheimer's disease, hallucinations may be more common in patients with poor refraction or cataracts.⁶²³ They are also correlated with atrophy of the occipital lobe,⁶²⁴ greater cognitive deficits, accelerated rate of decline, and parkinsonism.⁶²⁵

Hallucinations are one of the defining criteria for diffuse Lewy body dementia, along with parkinsonism, dementia, and fluctuating levels of arousal. They occur in 90% of patients with this condition, compared to 25% of patients with Alzheimer's disease.⁶²⁶ In diffuse Lewy body disease their incidence correlates with the density of Lewy bodies in inferior temporal cortex.⁶²⁷

Hallucinations also occur in 25% of patients with Parkinson's disease.⁶²⁸ They are almost exclusively visual and complex.⁶²⁹ Although in some cases these can be caused by medications, it appears increasingly likely that in other they are a manifestation of the underlying disease.^629,630 Risk factors for hallucinations are longer duration and greater severity of parkinsonism, depression and sleep disturbances, and cognitive impairment.^628–631 Many factors may contribute to the pathogenesis of hallucinations in Parkinson's disease. REM-sleep anomalies have been described, raising analogies with the hallucinatory experience in narcolepsy^632,633 and implicating cholinergic and serotonergic brainstem pathways.⁶⁰⁵ Impaired visual function may play a role, as hallucinations are correlated with worse visual acuity,⁶³⁰ defective visual memory,⁶²⁸ and poor performance on object recognition tasks.⁶³⁴ Cognitive problems are more common and may contribute through a general degradation in information processing or a disruption in the ability to monitor reality and the origins of internal experience.^628,634

Treatment of hallucinations in neurodegenerative disorders involves identifying drugs that might exacerbate the problem. A visual examination should determine if there are correctible causes of visual impairment, such as cataracts.⁶³⁵ Better refraction can improve hallucinations.⁶²³ Last, medications could be used. In Parkinsons's disease, there has been some success with cholinesterase inhibitors such as rivastigmine,⁶³⁶ and agents that treat REM-sleep disorders such as clonazepam.⁶³³

Release Hallucinations, or Charles Bonnet's Syndrome

Visual loss of any origin can result in visual hallucinations.⁶³⁷ These are called release hallucinations because it is thought that they represent spontaneous activity in visual cortex that is released through the absence of incoming sensory impulses. Release hallucinations are associated with central or peripheral visual field defects, which are usually binocular. Estimates of their prevalence vary from 15% among patients with retinal disease⁶³⁸ to 57% of patients with a variety of visual loss.⁶⁰⁹ The true incidence is underestimated because of the reluctance of patients to mention hallucinations for fear of being labeled crazy: 73% of patients in one series had never mentioned the hallucinations to a physician.⁶¹¹ In fact, patients with release hallucinations are mentally lucid. The majority are aware that the visions are not real, and most are not distressed by them.⁶¹¹

Release hallucinations can be simple or complex. Simple stimuli include flashes or highly intense colors, termed hyperchromatopsia.⁵⁹⁷ In 10% to 30% the hallucinations are complex.^{609,610,639,640} Sometimes the vision is a recognizable image from the patient's past.^{606,608,611,641} Overall, simple hallucinations are probably twice as common as complex ones.⁶⁰⁹ Some patients have simple hallucinations that evolve into complex ones.^606,608,642 Because the type of release hallucination does not correlate with the site of visual loss,⁶⁰⁶ the distinction between complex and simple release hallucinations is not important.

Some of these visual hallucinations have perseverative features. A recent survey coined several terms for these.⁵⁹⁷ Among patients with ocular causes of severe visual loss, 37% had tessellopsia, in which the hallucinations had a fine repetitive geometric pattern, and 14% had dendropsia, in which a repetitive branching motif is seen.

Hallucinations often begin close to the time of visual loss. Most often they follow its onset by several days or weeks, but this delay can be even longer.^607,608 When the disease causing visual loss is ocular, it is often not until the second eye loses vision that hallucinations develop.^607,642 Among patients undergoing photocoagulation for macular degeneration, hallucinations occur in about 60%, usually a few days after the procedure.⁶⁴³ Hallucinations may also occur simultaneous to the onset of visual loss, so that in some cases it is the complaint of visual hallucinations that leads to the discovery of a visual field defect. Rarely, it has been possible to show that hallucinations actually preceded hemianopia by a few days.⁶⁰² Among four patients with visual loss from giant cell arteritis, hallucinations were reported to begin 1 to 10 days before visual loss, and to disappear within a few weeks.⁶⁴⁴

The hallucinations can be brief, with each episode lasting a few seconds or minutes, or can be virtually continuous.⁶¹⁰ Frequency varies from several per day to twice a year.⁶¹¹ They tend to occur in the evening and night, under poor lighting, and during periods of inactivity or solitude.⁶¹¹ The duration of the problem may be limited in some cases, lasting from a few days to a few months,⁶³⁹ but hallucinations can persist or recur for long periods, sometimes years or decades.^607,608,611

Any type of binocular visual loss can lead to release hallucinations.⁶⁰⁷ The most common damage is cerebral infarction.⁶⁰⁹ Cataracts, macular degeneration, and diabetic retinopathy are frequent among ocular causes.⁶¹¹ Although most series report that all patients have some visual loss in both eyes,^606,607 others question the need for binocular pathology.⁶⁰⁹ Also, there are occasional patients who have no or minimal demonstrable visual loss, and yet have similar visual hallucinations.^607,609,645 Release hallucinations can occur in normal subjects in sensory deprivation experiments,⁶⁴⁶ and it may be that some subjects with hallucinations but not binocular visual loss suffer a similar deprivation in conditions of social isolation, especially because their hallucinations can resolve with a change in surroundings.⁶⁴⁵

No other pathology besides the disorder causing visual loss is required for release visual hallucinations; that is, they are not a direct manifestation of an underlying cerebral lesion, but a physiologic reaction to loss of vision. However, if so it remains to be determined why all subjects with binocular visual loss do not have hallucinations.⁶¹¹ Some suggest that a mild degree of cognitive impairment may contribute,⁶⁴⁵ although another study found no such evidence.⁶⁴⁷ One report found increased incidence of posterior periventricular white matter lesions on MRI in patients with hallucinations from ocular disease.⁶⁴⁸

Other factors may also contribute. Age is one possible factor. In one review 80% of patients with hallucinations were over 60 years old,⁶¹⁰ and the mean age at onset in another study was 72 years.⁶¹¹ This may simply represent the demographics of bilateral visual loss, however, and even subjects as young as 6 years can have release hallucinations.^610,649,650 Social isolation is another potential factor, thought to act by accentuating the sensory deprivation of visual loss.⁶⁴⁵ One prospective study found a trend toward hallucinatory patients living alone or being widowed.⁶⁴⁰ Hallucinations in some cases have been potentiated by medication.⁶⁵¹

The various theories about the mechanism of visual release hallucinations have been summarized.⁶¹⁰ Hallucinations have been attributed to visual seizures in patients with cerebral visual loss,⁶⁰⁸ but they differ from seizures in their longer duration and variable, non-stereotyped content.⁶⁰⁷ With visual loss due to media opacities such as cataracts, another hypothesis was that hallucinations were entoptic phenomena, being the subject's interpretation of the image of retinal blood vessels and other ocular structures cast on the retina. The entoptic theory is untenable in patients with enucleations. Most today believe that all release hallucinations have a similar cerebral origin. In the brain, visual experience is represented by patterns of coordinated impulses within the vast neural network within visual cortex. These patterns usually are generated by sensory stimuli, but the brain also has the capacity to generate these neural patterns spontaneously, and does so in the absence of sensory stimulation, from either imposed isolation⁶⁴⁶ or pathologic denervation.⁶¹⁰ This may also account for the fact that these hallucinations tend to occur when patients are alone or inactive, in the evening or night, when the lighting is poor.⁶¹¹ The association of release hallucinations with spontaneous cerebral activity in extrastriate cortex and the thalami has been demonstrated recently with SPECT and functional imaging.^652–655

Release hallucinations do not bother most patients.^610,611 Most have insight that the hallucinations are not real, although insight can fluctuate and may only be achieved after an early attempt to interact with the hallucinations.⁶³⁷ For these, treatment consists of reassurance that the hallucinations are benign. Only 10% of patients find the hallucinations sufficiently annoying to consider medication.⁶¹¹ Unfortunately, there is no consensus on treatment. Carbamazepine is probably the treatment of choice,⁶⁵⁶ but anticonvulsants have improved the hallucinations in some cases^{608,657–659} but not others.^607,608 Mixed results have occurred with haloperidol^642,645 and there are isolated reports of benefit with neuroleptics such as risperidone and melperone.^656,660 Moving socially isolated patients into a more stimulating environment may lessen the hallucinations.⁶⁴⁵

Visual Seizures

Only about 5% of epileptic patients have visual seizures.⁶⁶¹ These occur exclusively in patients with occipital or temporal lesions (Fig. 32).⁶⁶² As with release hallucinations, content can be simple or complex. Whether the content has localizing value for seizures, in contrast to the situation with release hallucinations, is debatable.⁶⁰⁷ Older human stimulation experiments⁶⁶³ found that simple unformed flashes of light and colors resulted from electrical activity in striate cortex, whereas stimulation of visual association cortex in areas 19 and temporal regions resulted in complex formed images. A similar distinction may hold for epileptic visual hallucinations, although there are discrepancies in the literature. Patients with occipital lesions are more likely to have simple hallucinations,^662,664,665 although there are some exceptional cases with complex hallucinations.^665,666 In these, spread of ictal activity into extrastriate cortex is likely responsible for the complex character of the hallucinations.^665,667 Seizures originating in occipitotemporal or anterior temporal structures are more likely to be associated with complex hallucinations,⁶⁶⁸ but these can also have simple hallucinations.⁶⁶² Overall, a study of 20 patients concluded that elementary hallucinations could occur with either temporal or occipital foci, but that complex hallucinations were far more likely to indicate a temporal origin of seizures.⁶⁶²

The distinction between visual seizures and release hallucinations can be difficult in patients with cerebral lesions. Some suggest that release hallucinations are continuous and non-stereotyped in content, whereas visual seizures are brief and stereotyped.⁶⁰⁷ However, release hallucinations can be episodic rather than continuous and their content can be repetitive.⁶¹⁰ Association with other ictal phenomena or a visual field defect is more helpful, although not always present. Accompanying head or eye deviation and rapid blinking are common accompaniments of occipital seizures.⁶⁶⁵ More distant spread of seizure activity may cause confusion, dysphasia, tonic-clonic limb movements, and automatisms. Homonymous field defects indicate the possibility of release hallucinations but do not exclude seizures, because lesions that cause epilepsy may also cause visual field defects. Seizure monitoring may help, although scalp electroencephalographic leads often do not localize the occipital focus accurately, and intracranial electrodes may be required eventually.^665,667 Visual seizures are treated with the anticonvulsants used for focal seizures, such as carbamazepine.⁶⁶¹

Although a variety of pathologies in visual cortex may be associated with visual seizures, one syndrome requiring emphasis is “benign childhood epilepsy with occipital spike-waves.”⁶⁶⁹ This is an idiopathic epilepsy syndrome that begins between ages 5 and 9 and ceases spontaneously in the teenage years. Seizures are characterized by blindness and/or hallucinations of both simple and formed types, and may progress to motor or partial complex seizures. Some children develop nausea and headache following the visual seizure, leading to an erroneous diagnosis of migraine. The diagnosis is established by occipital spike-waves occurring during eye closure on EEG.

Migrainous Hallucinations

A variety of visual phenomena can occur in migraine.⁶⁷⁰ Photopsic images are most common, described as spots, wavy lines, or a shimmering like heat waves over a road on a hot day.⁶⁷¹ The “scintillating scotoma” is a blind region surrounded by a margin of sparkling lights, which often slowly enlarges over the time of its presence. In some individuals the sparkling margin can be discerned as a zigzag pattern of lines,⁶⁷² usually in one hemifield, and on the leading edge of a C-shaped scotoma. There may be several sets of zigzag lines in parallel, often shimmering or oscillating in brightness.⁶⁷³ They may be black and white⁶⁶⁴ or vividly colored.^672,673 These zigzag lines begin near central vision (Fig. 33) and expand toward the periphery with increasing speed over about 20 minutes, with both the speed and size of the lines increasing with retinal eccentricity. The relation of speed and size to eccentricity is predicted by the cortical magnification factor, which is a measure of the area of visual field represented in a given amount of striate cortex as a function of retinal eccentricity.^672,674 This suggests that these migrainous hallucinations are generated by a wave of neuronal excitation spreading from posterior to anterior striate cortex at a constant speed, leaving a transient neuronal depression that causes the temporary scotoma in its wake.⁶⁷³ The zigzag nature of the lines may reflect the sensitivity to line orientation of striate cortex and the pattern of inhibitory interconnections within and between striate columns.^673,674

Distinguishing migraine from epilepsy is an important problem for hallucinations, especially as visual seizures rarely progress to other clearly ictal symptoms.⁶⁶¹ Both migraine and visual seizures can feature abnormal hallucinations followed by headache and vomiting.^661,675 It has been suggested that the two disorders can be distinguished by their visual content, with black and white zigzag lines in migrainous hallucinations and colored circular patterns in ictal hallucinations.^664,676 However, migraine-like hallucinations have been described with occipital seizures from cysticercosis.⁶⁷⁷ Other important distinguishing features are that seizures are shorter, usually lasting a few seconds or minutes, spread more rapidly than migrainous hallucinations, and always occur in the same hemifield.⁶⁶¹ Episodes are also more frequent for visual seizures than for migraine. Accompanying eyelid fluttering or eye deviation would suggest seizure rather than migraine.

Other Hallucinatory States

PEDUNCULAR HALLUCINATIONS.

Hallucinations with midbrain lesions are rare.^678,679 Their characteristics resemble complex release hallucinations. They can be continuous^680,681 or episodic.^682,683 They often contain very detailed form imagery^681,682,684 and are not stereotyped, varying from one episode to the next. In some cases with thalamic lesions the hallucinations are from events in the patient's past.⁶⁸⁵ Patients often have insight that they are not real,^680,682,686 but others do not⁶⁸⁵ and may even interact with the hallucinations.⁶⁸⁷ Similar hallucinations have been described for sounds⁶⁸⁸ and some patients have multimodality hallucinations, involving vision, touch, sound, and even the sense of body posture.^681,682

Unlike release hallucinations, peduncular hallucinations are invariably associated with inversion of the sleep–wake cycle, with diurnal somnolence and nocturnal insomnia.^{678,680,681,684,685} Other associated signs from damage to adjacent structures in the midbrain include unilateral or bilateral third nerve palsy,^678,680,684 hemiparkinsonism,⁶⁸³ hemiparesis,⁶⁸⁰ and gait ataxia.^678,687 Many patients have had pre-existing visual loss,^680,687 prompting some to speculate that this is a contributing factor. However, other cases have relatively intact vision.^682,686

Since the original pathologic description,⁶⁷⁹ there have been reports demonstrating unilateral or bilateral infarction of the peduncles.^680,683 A detailed pathologic study showed bilateral infarction of the substantia nigra pars reticulata.⁶⁸² The correlation of neuronal activity in this structure with REM sleep stages and its connections with the pedunculopontine nucleus suggest an anatomic correlate to the disturbed sleep–wake cycle thought to underlie both the hallucinations and the associated inversion of the sleep–wake pattern in these patients. Others have postulated damage to the reticular formation and the ascending reticular activating system with similar consequences.⁶⁸⁷ There are also a few cases with similar hallucinations from lesions restricted to the paramedian thalamus, which may affect the thalamic reticular nucleus.^685,687,689

The most frequently described etiology is infarction.^{680,682,683,687,690} It has also been described as a vascular complication of angiography⁶⁸⁶ and transiently after microvascular decompressive surgery for trigeminal neuralgia.⁶⁸¹ There are two cases with extrinsic midbrain compression by tumours, a craniopharyngioma⁶⁹¹ and a medulloblastoma.⁶⁸⁴ In cases with infarction, the hallucinations can persist indefinitely,⁶⁸² although the episodes may become shorter⁶⁸⁵ or disappear in some cases.⁶⁸⁷ Hallucinations have resolved after relief of extrinsic tumor compression.^684,691

HALLUCINATIONS DURING EYE CLOSURE.

Miller Fisher has described a number of cases with hallucinations only with eye closure.^692,693 In two cases the visual hallucinations were attributed to drug toxicity resulting from atropine and probably lidocaine given for local anesthesia; in the other the hallucinations occurred during a respiratory infection with high fever. Parallels were drawn with hypnogogic hallucinations, with a hypothesis of disturbed sleep–wake cycle mechanisms.

DYSMETROPSIA

Illusions about the spatial aspect of visual stimuli include three main categories: micropsia, the illusion that objects are smaller than in reality; macropsia, the illusion that objects are larger than in reality; and metamorphopsia, the illusion that objects are distorted. Of these, micropsia is probably the more common and has the largest variety of causes.

Micropsia

Convergence-accommodative micropsia is a normal phenomenon, in which an object at a set distance appears smaller when the observer focuses at near rather than far. Investigations of this induced micropsia at near conclude that vergence is responsible.^694–696 Convergence micropsia may play a role in preserving size constancy at small distances.⁶⁹⁵ Accommodative micropsia is not a source of complaints.

Retinal micropsia occurs in conditions where the distance between photoreceptors is increased, as with macular edema. Visual acuity is also reduced because of photoreceptor separation, and grating acuity correlates with psychophysical measures of micropsia.⁶⁹⁷ Causes of macular edema and micropsia include central serous retinopathy, severe papilledema, and retinal detachment.^697,698 The condition may resolve or persist for years.⁶⁹⁸ Retinal micropsia is often monocular, but can be binocular, depending on the ocular pathology. Psychophysical measures of micropsia relative to the normal eye can serve as a useful monitor of disease progression.^697,698

Cerebral micropsia is rare. In contrast to retinal micropsia, it is binocular. Unusual variants include hemimicropsia in the contralateral hemifield.^699,700 One unusual case had hemimicropsia only for faces.⁷⁰¹ The localization value of cerebral micropsia is uncertain. Occipito-temporal lesions have been reported, either medial^701,702 or lateral.⁷⁰⁰

Complaints of episodic micropsia or macropsia may occur in normal individuals during fever or the hypnogogic state, and correlate with a history of migraine.⁷⁰³ This migrainous micropsia may be related to prior reports of micropsia during migraine.⁷⁰⁴

Macropsia and Metamorphopsia

Macropsia is rare. Retinal macropsia can occur in the late scarring stage of macular edema. It has been reported as a side effect of zolpidem.⁷⁰⁵ Cerebral macropsia has occurred with seizures,⁷⁰⁴ and cerebral hemimacropsia with a left occipital tumor⁷⁰⁶ and a right occipital infarct.⁷⁰⁷

Ocular causes of metamorphopsia are more common than cerebral metamorphopsia, and usually related to macular edema or vitreoretinal traction as with an epiretinal membrane or possible scleral buckling.^698,708,709 Cerebral metamorphopsia has been described with seizures from tumors or arteriovenous malformations.^574,710,711 It has also occurred with posterior cerebral infarction,⁷¹² sometimes as a transient stage in the development of cortical blindness.⁷¹³ The lesions with infarcts have been medial. One lesion involved only the left cingulate gyrus and retrosplenial area.⁷¹² There is one report of metamorphopsia with a brainstem lesion.⁷¹⁴

Regarding higher cortical deficits, attempts at retraining visual recognition in patients with visual agnosia have been ineffective.⁷²⁰ Theoretically, agnosic patients could be trained to use tactile and auditory cues, and prosopagnosic patients could learn to focus on unique nonfacial visual features such as gait, and local facial cues like hair style and glasses. Many develop these abilities on their own with time. Cerebral achromatopsia is annoying but rarely disabling, because patients can still perceive object shapes and boundaries, navigate the environment, and have good spatial resolution. Certain color tasks in the environment pose special difficulties. Traffic lights are an example; however, patients can learn to use other visual cues, such as the conventional order of red being the top light and green the bottom. Patients with acquired pure alexia have a more profound disability, given the importance of literacy in society. Rehabilitation of this problem remains in its infancy.

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