Disconnection (Versus Direct Damage)

While some of the higher cortical disorders result from direct damage to vital cortical areas, such as the color center in the inferior occipitotemporal lobe, others, for example, result from disconnecting the occipital lobe from visual association areas. This disconnection concept was popularized by Geschwind. Examples would include a lesion involving white matter pathways connecting striate cortex and facial recognition centers or another connecting to language areas. Table 9.1 indicates which higher cortical visual disorders are thought to be disconnection syndromes versus those that are due to direct damage to cortical structures.

Simultaneous Occurrence

The higher cortical visual disorders are not mutually exclusive. Rather, because of the proximity of many of the important cortical areas and white matter tracts in the parietal, occipital, and temporal lobes, many syndromes occur simultaneously. For instance, a combination of visual field defects, visual recognition problems, and reading disorders often result from concomitant involvement of the occipital and occipitotemporal lobes (see Table 9.1 ).

Neuro-Ophthalmic Symptoms

Most subjective complaints due to involvement of visual association areas are vague, such as “I have blurry vision” or “I’m having trouble seeing.” Rarely, patients will complain of difficulty seeing colors or recognizing images. Many such patients have seen numerous eye specialists with reportedly normal examinations. Some individuals with inattention or dementia are unaware of their visual deficits, and the family members are the ones who bring them to medical attention. Another group of patients is seen after a stroke or neurosurgical intervention. Visual field loss may cause the dominant symptoms, but careful examination reveals that complaints of “trouble reading and seeing” may be the result of higher cortical dysfunction.

Neurologic Symptoms

Higher cortical visual disturbances should be suspected when patients complain of loss of memory, confusion, disorientation, or behavioral changes suggestive of a dementing illness or hemispheric lesion. Their families may report that patients seem no longer able to take care of themselves or get lost frequently.

Signs on Examination

Visual acuity is usually normal or near normal. Visual fields in each quadrant and with double simultaneous stimulation should be tested to exclude visual inattention. Color vision, reading, and writing should also be examined. In addition, magazine pictures with familiar faces and pictures with complex scenery can be used to screen for higher cortical dysfunction. Sometimes figure and clock drawings are also helpful. Table 9.2 highlights the various examination techniques helpful in patients with suspected higher cortical visual disorders, and these methods are reviewed in detail in Chapter 2 .

Alexia Without Agraphia

Often aphasic patients who have difficulty reading also have difficulty writing. However, patients with a left occipital lesion and ipsilateral simultaneous involvement of the splenium of the corpus callosum or adjacent periventricular white matter may develop alexia without agraphia (or pure alexia or “ word-blindness ”). First characterized by Dejerine, this has been considered a disconnection syndrome characterized by a right homonymous field deficit, with sparing of key language areas, but an inability to access lexical visual information processed in the right occipital lobe ( Fig. 9.2 ). Geschwind emphasized that reading is impossible if the left angular gyrus, which is responsible for converting written to spoken language, is deprived of visual information. Affected patients are therefore unable to read words, but they are able to write, speak, comprehend, and repeat normally. Ironically, they are unable to read what they write. Patients commonly read letter-by-letter, during which they sequentially name each letter of a word. Letter-by-letter reading is argued to be due to lack of access to the visual word form area (discussed later) within the left fusiform gyrus and not simply a compensatory technique, but this is uncertain.

Classic localization of the left occipital lesion ( dotted area ) in patients with alexia without agraphia and right homonymous hemianopia. Because of the left lateral and mesial occipital lobe involvement, visual information ( open arrow ) can come only from the right occipital lobe. However, owing to disruption of the paraventricular white matter and the outflow of the corpus callosum ( C.C. ), this visual information ( small arrow ) cannot access the angular gyrus in the language areas.

Many variations on the classic description of alexia without agraphia have been described:

• 1.
  

  Other lesions. Alexia without agraphia due to infarction of the left lateral geniculate body and splenium of the corpus callosum has been reported.

  
  
• 2.
  

  No hemianopia. Less commonly patients have been described with alexia without agraphia but with normal visual fields. It is possible that periventricular white matter lesions in the left occipital lobe alone may spare striate cortex but interfere with the transfer of visual information from both ipsilateral and contralateral striate cortex to the language areas by undercutting the angular gyrus. In addition, pure alexia due to left fusiform lesions alone has been described.

  
  
• 
  

  Recent evidence suggests the existence of a “visual word form area” (VWFA) in the posterior part of the left midfusiform gyrus in the occipitotemporal region. Focal lesions in the VWFA have resulted in pure alexia, and anatomical connections of this region to peri-Sylvian language areas provide evidence that this area is a key visual processing region necessary for reading.

  
  
• 3.
  

  Left hemiparalexia. Individuals with isolated lesions of the splenium of the corpus callosum may have intact visual fields but may be unable to transfer visual information from the right occipital lobe to the left angular gyrus. This may cause an inability to read the left side of words despite the absence of a hemianopia.

  
  
• 4.
  

  Other associated higher cortical visual disturbances. Several cases have been reported where alexia without agraphia occurs together with various combinations of apperceptive visual agnosia, prosopagnosia, visuospatial disorientation, optic ataxia, optic aphasia, hemiachromatopsia, and color naming deficits (these are all discussed later).

While the most common cause of alexia without agraphia is a posterior cerebral artery distribution stroke, it has also been reported in association with intracerebral hemorrhages, arteriovenous malformations, tumors ( Fig. 9.3 ), abscesses, migraine, herpes encephalitis, demyelination, and Creutzfeldt–Jakob disease.

Alexia without agraphia and right homonymous hemianopia following biopsy of a left thalamic tumor. Postoperative T2-weighted MRI scan of the brain shows an exophytic mass and hemorrhage in the surgical bed. The white arrow and cross refer to the inability of visual information from the right occipital lobe to reach the angular gyrus and language areas in the left hemisphere, owing to the disruption of the forceps major and splenium of the corpus callosum.

(Reprinted from Tamhankar M, Coslett HB, Fisher MJ, et al. Alexia without agraphia following biopsy of a left thalamic tumor. Pediatr Neurol 2004;30:140–142, with permission from Elsevier).

Other related reading disorders . In contrast, alexia with agraphia is a syndrome characterized by the inability to read or write without other obvious language deficits. Caused by an isolated lesion of the angular gyrus or the posterior left inferior temporal lobe, there is often an accompanying right homonymous hemianopia because of involvement of the adjacent optic radiations.

Alexia without agraphia should not be confused with hemianopic alexia, in which patients have difficulty reading because their right homonymous hemianopia, particularly if macular splitting, interferes with their ability to see the right side of a word.

Cerebral Hemiachromatopsia

More than a century ago, Verrey described hemiachromatopsia, the loss of color vision in one hemifield, and claimed that a functionally separate cortex existed for color processing. However, only in the past few decades has the notion of a neuroanatomically distinct region for color vision been accepted. Initially, lesion studies in primates and humans have designated a region of the visual association cortex known as V4 to be critical for color processing. In humans the V4 homologue resides in the lingual and fusiform gyri, located in the ventromedial occipitotemporal cortex ( Fig. 9.4 ). There is a similar area on both sides of the brain, and each mediates color vision in the opposite hemifield.

Medial view of the brain demonstrating the location of area V4 complex, the human color center, which lies primarily in the posterior fusiform gyrus, with a lesser contribution from the lingual gyrus.

Functional neuroimaging and electrophysiologic techniques have helped to confirm the specialization of V4 and have elucidated other adjacent areas responsible for mediating color vision in humans. A region in the fusiform gyrus anterior to V4, area V8, was found to mediate conscious perception of color and color afterimages and color synesthesia. In addition, other adjacent color-sensitive cortical regions termed VO and V4-α have been identified. Herein, for the purposes of this chapter, these neighboring regions (V4, V8, VO-1, and V4-α) will be collectively termed area V4 complex .

Symptoms. Many patients with hemiachromatopsia are unaware of their color deficit, perhaps because the other hemifield has intact color vision, or because they ignore their deficit (anosognosia). Hemiachromatopsia can occur in the left or right hemifield. When bilateral V4 complex lesions occur, patients may develop central achromatopsia, or defective color vision in both hemifields. Compared with those with hemiachromatopsia, bilaterally affected patients may be more likely to describe their color deficit, which may differ from a loss of brightness to a complete inability to perceive colors. The described effect is a “graying” or “washing-out” of vision. Some liken the impact to a switch from a color television to a black-and-white one.

Signs. Since acquired cerebral color deficits tend to occur in quadrants or hemifields, they are best detected during confrontation field testing using colored swatches, sticks, or threads. Color plate testing may also reveal a defect if the patient consistently misses the left-sided digits, for instance. However, color plate identification and formal color testing, such as D-15 or Farnsworth–Munsell 100-Hue tests (see Chapter 2 ), can be normal if color vision is normal within central fixation.

Associated signs. Cerebral hemiachromatopsia is rarely an isolated finding. More commonly a combination of a contralateral homonymous upper quadrantanopia and defective color vision in the inferior quadrant is observed clinically ( Fig. 9.5 ). This pattern of deficits is likely the result of the proximity between the lingual and fusiform gyri and the inferior optic radiations, inferior striate cortex, and inferior extrastriate cortex (V2/V3). Visual acuity is normal when the lesions are unilateral. Hemiachromatopsia may also be associated with alexia without agraphia (see previous discussion) when the lesion is left sided, or prosopagnosia (see later discussion) because the areas responsible for color and face processing are in close proximity in the occipitotemporal cortices.

Visual field and neuroimaging in a patient with cerebral hemiachromatopsia of the left hemifield. A . Goldmann perimetry demonstrates a left homonymous superior quadrantanopia with an intact inferior quadrant. Axial ( B ) and sagittal ( C ) magnetic resonance imaging reveals an infarction involving the right occipitotemporal gyri ( arrows ).

(Reprinted from Paulson HL, Galetta SL, Grossman M, et al. Hemiachromatopsia of unilateral occipitotemporal infarcts. Am J Ophthalmol 1994;118:518–523, with permission from Elsevier Science).

When isolated cerebral full-field hemiachromatopsia occurs, it is often in the setting of a developing or receding hemianopia. Albert et al. described a monocular man who suffered cortical blindness only to recover with a partial right superior quadrantanopia yet complete left-sided color vision loss. In Kölmel’s two cases, a homonymous hemianopsia resolved eventually to an upper quadrant hemiachromatopsia, in one instance following a transient full-field hemiachromatopsia.

Etiology . Infarction in the distribution of the posterior temporal or common temporal arteries, branches of the posterior cerebral artery, is the most common cause of hemiachromatopsia. Other less common etiologies include removal of an arteriovenous malformation, trauma, neoplasm, hemorrhage, multiple sclerosis, abscess, subarachnoid hemorrhage, and carbon monoxide poisoning. Transient full-field achromatopsia has been attributed to migraine, occipital epilepsy (after the recovery of form vision), and vertebrobasilar insufficiency.

Other cortical color processing deficits. Patients with color anomia, or color name aphasia, have an inability to name colors and difficulty pointing to named colors, despite normal performance on color matching and pseudoisochromatic color plate testing. This disorder can be associated with alexia without agraphia (see previous discussion), and patients commonly have a right homonymous hemianopia. The usual etiology is a left posterior cerebral artery stroke involving the mesial occipitotemporal region. Those with color agnosia, or color amnesia, have trouble naming the specific color of common objects, such as blood or a stop sign, despite normal color perception and language function. In one published case, color agnosia was acquired due to bilateral medial temporal and left inferotemporooccipital infarctions, but in another the deficit was life-long without any obvious cortical lesions on magnetic resonance imaging (MRI). Both color anomia and color agnosia are rare.

Visual Agnosias

A visual object agnosia is an inability to recognize visualized objects despite relatively normal vision, memory, language, and intellectual function. In this condition, naming function is intact; patients are able to identify objects by touching and feeling them or by listening to a verbal description. Functional neuroimaging and case studies suggest shapes and textures are processed separately in the lateral occipital (LO) and collateral sulcus (CS) regions, respectively, to recognize objects ( Fig. 9.6 ). Classically, a distinction between associative and apperceptive agnosias is made.

A . Underside view of the brain, highlighting the cortical areas active specifically during tasks of facial (FFA, STS, and OFA) and object recognition (CS and LO). The V4 complex (not shown) lies more posteriorly in the fusiform gyrus (see Fig. 9.4 ). For simplicity, the highlighted areas, which are all bilateral, are labeled on only one side of the brain. B . T2-weighted axial magnetic resonance imaging of a patient with prosopagnosia following a hemorrhage in the right occipitotemporal region ( arrow ). In one event, she picked up the wrong grandchild from the floor, and in another, she entered a car with a person she thought was her husband, but the person was someone else.

Associative visual object agnosia . Patients with this type of agnosia have relatively normal vision within intact visual fields. They are able to draw or copy what they see, indicating their perception is relatively normal. Upon request, they can also produce accurate drawings of objects they are unable to recognize visually, indicating intact visual memory and imagery.

Associative visual object agnosia suggests bilateral medial inferior occipitotemporal lesions disrupting the inferior longitudinal fasciculus, a white matter pathway connecting striate cortex with visual association areas in the temporal lobe. This is usually due to bilateral posterior cerebral artery occlusion and produces a “visual–verbal disconnection syndrome.” Many cases of associative visual object agnosia also exhibit alexia without agraphia, likely reflecting concomitant involvement of the corpus callosum in such instances. Many are also associated with prosopagnosia (see later discussion). Less commonly, isolated unilateral left or right hemispheric lesions can produce associative visual object agnosia.

Apperceptive visual object agnosia . In this type, also termed visual form agnosia, patients have confounding deficits in shape and form perception, although elemental acuity and fields are still relatively normal. For instance, patients with apperceptive visual agnosia have difficulty copying geometric figures. In one study, patients also had difficulty recognizing and naming line drawings, recognizing complex shapes, and mentally manipulating objects by rotation, for instance. The exact anatomic substrate is unclear, but some neuroimaging and PET studies have demonstrated lesions or hypoperfusion in bilateral temporooccipital cortices. One patient with a closed head injury developed an apperceptive agnosia and prosopagnosia from selective damage to the right lateral fusiform gyrus. A number of cases of apperceptive visual agnosia have been reported following carbon monoxide toxicity, which has a predilection for causing occipital lobe damage. In another case, anoxic injury to bilateral occipital lobes resulted in apperceptive visual agnosia, which was thought to be due to severe deficits in processing line orientation, an important function of the occipital cortex.

Prosopagnosia

This section reviews facial recognition and the related disorder, prosopagnosia, which is a dramatic visual agnosia for faces. The observation that there are individuals with prosopagnosia but without visual agnosia for other objects suggests facial recognition is a modular-specific task of the human brain.

Facial recognition . The ability to recognize a familiar face is an extremely important behavior, used in almost every live interpersonal interaction. Even young infants have this ability, emphasizing its social and evolutionary importance. Facial recognition requires first perceiving the face, then analyzing its features; matching it to stored faces; and, in many instances, retrieving its name.

Functional studies have established that occipitotemporal structures bilaterally are specialized, arguably specifically, for human facial perception and recognition ( Fig. 9.6a ). These areas include the fusiform and lingual gyri, in a region labeled as the fusiform face area (FFA), one more posteriorly in the inferior occipital cortex in an area called the occipital face area (OFA), and another in the superior temporal sulcus (STS). These areas activate more strongly during viewing of faces compared with seeing scrambled faces, common objects, houses, and human hands. The FFA and OFA are likely more important for identification of faces, while the STS likely subserves processing of facial expression and gaze. Less specifically, limbic structures such as the amygdala and hippocampus, in addition to anterior temporal cortex and right parahippocampal gyrus, and the frontal lobe also participate in facial recognition, highlighting the core structural networks necessary for this task.

Signs and symptoms in prosopagnosia . Often very aware of their condition, patients with prosopagnosia commonly report the inability to recognize the faces of friends and family. A typical complaint is that the patient finds his or her own face in the mirror unfamiliar, but knows that the image must be theirs. Likewise, prosopagnosics usually report knowing that they are looking at faces, and often they can identify the gender, race, and approximate age of the person. Often patients use contextual clues such as posture, body movement, and especially voices to identify familiar faces. Most patients exhibit both a retrograde and anterograde defect, as they often cannot recognize old faces or learn new ones. Sometimes the disorder is so striking and odd that affected patients may be mistakenly diagnosed with a psychiatric disease.

Associated signs . Prosopagnosia may be isolated but more commonly is associated with elemental visual or other higher cortical deficits. Unilateral homonymous hemianopias are typically present, but because the responsible lesions are typically occipitotemporal (see later discussion), superior altitudinal or upper quadrantanopias are also seen. Occasionally bilateral visual field deficits and related visual acuity loss are observed. Associated higher cortical abnormalities include achromatopsia, alexia without agraphia, left hemispatial neglect, visual memory deficits, visual object agnosia, visuospatial disorientation, impaired visual imagery, color agnosia, and anosognosia.

Neuropsychological aspects . Because prosopagnosia is a type of visual agnosia, the condition is probably characterized by varying degrees of associative and apperceptive components (see Visual Agnosias ). Evidence for an associative component can be seen in patients with prosopagnosia who can still correctly draw generic faces, scan faces, estimate a person’s age and gender, and interpret and imitate facial expressions. Patients with a more apperceptive type would be expected to have more difficulty with a face-matching task, using a series of faces in the Benton–Van Allen facial recognition test, than those with an associative type. Further evidence of an apperceptive component can be seen in patients with prosopagnosia who have difficulty discerning curved stimuli and face-related features such as eye gaze, gender, spatial relation of facial features, and facial configuration.

Similar to patients with blindsight (see Chapter 8 ), some patients with prosopagnosia report an inability to remember or distinguish faces, but careful testing may reveal some unconscious or covert ability to do so.

Prosopagnosia may not be specific for human faces, as affected individuals may also have difficulty recognizing familiar animals. One former bird watcher lost the ability to identify birds with the onset of her prosopagnosia. Likewise, a farmer reported the inability to recognize his cattle, although he was able to do so before the onset of prosopagnosia. However, another patient began acquiring sheep after developing prosopagnosia. He was more successful on identification tasks involving his sheep than on identical tasks with human faces.

Etiology and associations . The most common cause of prosopagnosia is a posterior cerebral artery stroke, although any process that can damage the occipitotemporal lobes may be responsible. Other etiologies include carbon monoxide poisoning, temporal lobectomy, encephalitis, neoplasms, right temporal lobe atrophy, trauma, Alzheimer’s disease, frontotemporal lobar degeneration, and primary progressive aphasia. More diffuse processes include alcohol intoxication, autism, and psychosis due to schizophrenia and mescaline. One epidemiological study found that prosopagnosia occurred significantly more frequently in men than in women, which might be a reflection of a higher incidence of stroke or a different lateralization of facial recognition in men.

Congenital prosopagnosia due to meningitis or stroke in infancy has also been described. In addition, a rare developmental variety of prosopagnosia exists in which individuals never acquire a normal ability to recognize faces. In pure developmental cases there are no obvious visual abnormalities or lesions on neuroimaging, and familial cases of developmental prosopagnosia have been reported. Developmental prosopagnosia has been associated with reduced gray matter volume in the temporal cortex and reduced connectivity in the ventral occipitotemporal cortex, but normal social cognition.

Localization and unilaterality versus bilaterality of the lesions . Most cases of prosopagnosia have bilateral lesions in the occipitotemporal region demonstrated at autopsy, computed tomography (CT), or MRI. However, multiple cases have been reported of prosopagnosics with only right-sided lesions as uncovered by autopsy, CT, or MRI ( Fig. 9.6b ). Prosopagnosia was also observed in a patient who had undergone a right hemispherectomy and right temporal lobectomy for intractable epilepsy. These instances reveal that unilateral right-sided lesions are sufficient to cause the deficit. One study compared the performance of right-lesioned to left-lesioned patients (both groups classified using CT data) on a facial identification task. Patients with right-sided lesions performed significantly worse than left-lesioned patients and controls. In one case of progressive prosopagnosia due to anterior temporal lobe atrophy, diffusor tensor imaging revealed loss of the integrity of the right inferior longitudinal fasciculus (ILF), indicating a potential important role of the right ILF in prosopagnosia. Cases of prosopagnosia due to isolated left-sided lesions are extraordinary and in one instance occurred in a left-handed individual, suggesting anomalous lateralization.

Critical lesion . Most of the reported disturbances are localized within the right occipitotemporal region. However, the critical structure involved in this area can vary between the inferior occipitotemporal cortex, the fusiform gyrus, and the hippocampal region. A larger study correlated two separate extrastriate lesion positions to two cognitive deficits. Damage to the fusiform gyri, when accompanied with right-sided infarcts in the occipitotemporal or ventromedial regions, leads to problems in perceiving facial detail. Patients with damage to the right parahippocampal gyrus and the accompanying occipitotemporal ventromedial damage in the right hemisphere exhibited a deficit in connecting faces to memory stores. One metaanalysis of published cases of prosopagnosia and detailed studies of a single patient suggested damage to the OFA was more critical than damage to the FFA in causing this syndrome.

Outcome . Although it may be an enduring condition, patients may eventually recover from prosopagnosia, especially if damage is confined to the right hemisphere. A prosopagnosic with a right-sided lesion, as observed with MRI, regained the ability to recognize famous faces as well as friends and family 2 months after the onset of his symptoms. However, he remained unable to identify the faces of people whom he met after the onset of symptoms. Patients with developmental and acquired prosopagnosia may improve their facial recognition abilities using compensatory techniques such as increasing attention to specific facial features such as the eyes or treatment with oxytocin in cases of developmental prosopagnosia.

Capgras and Frégoli syndromes . These syndromes, which are delusional misidentification disorders, can be similar to prosopagnosia. A patient with Capgras syndrome believes that a friend or relative has been replaced by an impostor. There are some authors who feel that some patients with Capgras syndrome have prosopagnosia. Etiologies include neurodegenerative and psychiatric illnesses and bilateral occipitotemporal lesions. In Frégoli syndrome, the affected individual believes that a stranger is a familiar person.

Other Types of Visual Agnosias

Landmark agnosia and topographagnosia . In this unusual syndrome, affected individuals are unable to recognize previously familiar landmarks to orient themselves. In fact, specialized occipitotemporal regions have been identified that are specific for building recognition. In a related disorder, topographagnosia, patients cannot recognize familiar scenes. One reported patient had a right medial occipitotemporal stroke. A 43-year-old woman with congenital prosopagnosia was investigated using functional MRI, and a lack of activation of the hippocampal formation and retrosplenial cortex during attempts at making a cognitive map of the environment was noted.

Optic Aphasia

Patients with optic aphasia, which is a condition closely related to visual object agnosia, are unable to name visually presented material or point to named objects although they recognize them. They are able to name and recognize what they hear or feel. The responsible lesion is usually unilateral and involves the left posterior cerebral hemisphere, as noted in a 79-year-old patient after a left posterior cerebral artery stroke. This disorder likely is another visual–verbal disconnection syndrome. However, patients with optic aphasia may have better recognizing capabilities than those with object agnosia because of relatively preserved access to right hemispheric perceptual–semantic systems.

Visual Memory Disturbances

The ability to remember visual information requires storing then retrieving it. Functional MRI studies suggest that extrastriate cortical regions used for visual perception are also initially utilized in visual memory tasks. Subsequently, a network involving temporal lobe, hippocampal, and ventrolateral prefrontal cortex mediates human visual working memory, which is the process of retaining visual information for a brief period so that it is available for immediate use. Then visual information is stored using long-term memory systems.

Clinical observations in brain-damaged individuals support these notions. Ross reported two patients with bilateral posterior temporal lobe infarctions and loss of visual recent memory. Tactile, verbal, and nonverbal auditory memory functions were normal, but they could not recognize faces. Attributing the visual memory deficit to a disconnection syndrome, he hypothesized the bilateral lesions disrupted tracts between primary visual cortex and structures important for memory, such as the medial temporal lobe. Other patients with similar bilateral temporal lobe lesions and prosopagnosia have been described, suggesting recognition of faces and visual memory share similar mechanisms.

Evidence for lateralization and the role of the right temporal lobe in visual memory is provided by studies in right temporal lobectomy patients, who exhibit defective recognition of visual material; a patient with damage to the right frontotemporal region following middle cerebral artery aneurysm rupture who had defective memory of new visual objects and faces; and posterior cerebral artery amobarbital tests, which suggest the right temporal lobe is important for remembering visual aspects of an object, while the left temporal lobe is more critical for recalling the object’s verbal representation.

Other similar patients with impaired visual memory have been described following damage to the right dorsomedial thalamic nucleus, the anterior commissure and right fornix, and splenium, structures also important in the formation and retrieval of visual information.

Akinetopsia

Lateral occipitotemporal lesions affecting area V5 ( Fig. 9.7 ), which lies in the posterior bank of the superior temporal sulcus, can result in defective motion perception, or akinetopsia. Animal experiments suggest that the comparable location in monkeys, area MT (middle temporal), contains cells that receive direct connections from striate cortex and are highly motion selective. Lesions to area MT impair motion perception in the contralateral hemifield.

Functional magnetic resonance imaging (fMRI) demonstrating motion-sensitive areas of the brain. A . Stimulus consisting of concentric rings, one cycle per degree of visual angle, which expanded and contracted at a speed of 1 degree of visual angle per second. The gray and light-gray ring contrast is 22%. The stimulus paradigm alternated eight cycles of 30 seconds of moving rings, then 30 seconds of stationary rings. B . Areas (V5 and V3a) activated by the moving rings but not the stationary ones are superimposed on the subject’s corresponding T1-weighted image. The height threshold of the activation map was set at p <0.001 (“uncorrected”).

(Courtesy of G. R. Bonhomme, A. Miki, and G.T. Liu.)

Experimental evidence in normal humans and animals confirms the existence of occipito-temporo-parieto regions, separate from the striate cortex, that mediate visual motion perception. These include PET functional MRI (see Fig. 9.7 ), electrical cortical stimulation, magnetoencephalography (MEG), and transmagnetic stimulation (TMS) studies.

Zihl et al. described a seminal patient with defective motion perception due to bilateral cortical venous infarctions involving the temporoparietal and occipital periventricular and subcortical white matter, posterior portion of the middle temporal gyrus, and lateral occipital gyri. Striate cortex was spared. When the patient poured tea or coffee into a cup, the fluid “appeared to be frozen, like a glacier.” She was unable to judge the speed of a moving car, but could identify the car without difficulty. Follow-up studies reported the patient’s MRI, which confirmed the bilateral lesions involving the upper part of the occipital gyri and the adjacent portion of the middle temporal gyri, with the main focus of damage in the upper banks of the anterior occipital sulcus. Subsequently, other patients with deficits in motion perception have been described in association with cortical disturbances, usually bilateral, in these regions due to strokes, traumatic brain injury, seizure, and Alzheimer’s disease. Patients with unilateral V5 lesions have been shown to have defective motion perception in just the contralateral hemifield (hemiakinetopsia) and also the entire visual field. Two patients with the visual variant of Alzheimer’s disease were described as having a hemiakinetopsia, although presumably both of these patients have bilateral disease with a more prominent deficit in one region of the visual field.

Some drugs have been reported to cause akinetopsia. Two cases of akinetopsia, best described as akinetopsic palinopsia, related to use of nefazodone, an antidepressant that blocks serotonin (5-HT2) receptors and the reuptake of 5-HT, have been described. Other conditions that may be associated with decreased motion perception include Williams syndrome, lesions of the cerebellar vermis, amblyopia, schizophrenia, Alzheimer’s disease, and Down syndrome. V5 activity may be suppressed as an adaptive measure in patients with oscillopsia due to unilateral vestibular failure.

Riddoch phenomenon, blindsight, and V5. The preservation of retinotectal pulvinar connections with V5 is one possible explanation for the Riddoch phenomenon (ability to perceive motion) and for blindsight (unconscious vision) in individuals with field loss due to striate cortex damage (for discussion of these phenomena see Chapter 8 ). In one study, a patient with a left occipital lesion who perceived fast- but not slow-moving stimuli within an otherwise blind hemifield underwent visual-evoked potential testing that demonstrated V5 activation, suggesting the existence of another pathway to V5, which bypassed V1. Another study suggested that in patients with visual field loss but preserved motion detection due to cerebral hemispheric lesions, lateral temporooccipital cortex tended to be spared, while those without motion detection usually had involvement of this area. In PET and functional MRI studies of patients with unilateral occipital lobe infarction, ipsilateral lateral temporooccipital cortex is still activated during optokinetic stimulation and when moving stimuli are presented in the blind hemifield. In support of extrastriate projections that bypass V1, human diffusion tensor imaging reveals connections between the lateral thalamus and area V5. Furthermore, in a study of transcortical magnetic stimulation with inactivation of V1, retinal signals reached V5 by a faster pathway that did not include V1.

Visual Neglect (Hemi-Inattention)

The term unilateral visual hemi-inattention describes the neglect of visual stimuli in a homonymous half-field despite an intact geniculostriate system. Clinically, patients with this phenomenon may be difficult to distinguish from those with a homonymous hemianopia, but unlike the latter, those with hemi-inattention are more likely to detect the stimulus if their attention is directed to the neglected side (assuming central fixation is maintained). In more subtle cases the visual fields will be normal to confrontation, but if comparable visual stimuli are presented simultaneously in right and left hemifields (double simultaneous stimulation), the one contralateral to the lesion will be ignored (visual extinction). When the neglect is dense, however, the absence of a hemianopia is frequently difficult to prove. If the parietal lesion is large enough, often both the neglect and a hemianopia are present.

Bedside tests for hemi-inattention, such as line or letter cancellation, line bisection, and figure and clock drawing, are reviewed in Chapter 2 . In line or letter cancellation, patients with left neglect tend to identify targets only in their right hemispace. During line bisection, when patients are asked to identify the middle of a horizontal line, those with left neglect often pick a point that is on the right side of the line. When copying figures or the numbers of a clock, they may be drawn only on the right side (see Figs. 2.16 and 2.17 ). Patients with both left hemi-inattention and hemianopia tend to do more poorly on these tests than those with hemi-inattention alone.

Several theories have attempted to explain neglect. Bisiach et al. attributed unilateral neglect to a defect in the internal mental representation of the external world, as some patients with left hemineglect have defective mental imagery of the left side of space ( representational neglect; see Visual Imagery ). Others have proposed that an interruption in the corticolimbic–reticular loop causes a defect in the orienting response toward stimuli in the contralateral hemispace. Mesulam hypothesized that a cortical network involving posterior parietal lobe, frontal lobe, and cingulate gyrus mediates directed attention. Damage to any one or more components could lead to a neglect syndrome (see Frontal Lobe Disturbances ). In Mesulam’s scheme, the posterior parietal component provides an internal sensory map of extrapersonal space, the frontal component a mechanism for scanning and exploring, and the cingulate a spatial map for motivation. More recent studies have distinguished between personal neglect resulting from lesions of the right parietal lobe and extrapersonal neglect due to a disruption in a network involving right frontal regions and superior temporal gyrus. Because these proposed mechanisms are not mutually exclusive, a combination of them may also apply. Diffusion tensor imaging reveals that cortical damage involving the inferior parietal and superior temporal regions may not be sufficient to produce visual neglect, and additional interruption of fascicular connections between posterior and frontal cortical regions may be necessary.

Visual extinction may be the result of an imbalance in the interhemispheric rivalry that occurs with asymmetric injury to the posterior parietal regions.

Other cortical and subcortical lesions . Neglect may also occur in association with lesions affecting the frontal lobe (see below), right superior temporal gyrus, and parahippocampus. Unilateral neglect behavior less commonly may result from subcortical lesions. Examples include damage to the thalamus, striatum (putamen and head of caudate) and adjacent deep white matter, and corpus callosum. These lesions may cause neglect by indirect effects on the parietal lobe by, for example, disrupting subcortical–cortical connections. Diaschisis, a poorly understood transient depression of function elsewhere in the brain due to a focal cerebral lesion, may be another explanation.

Treatment . Patients with severe left-sided neglect can be some of the most difficult to rehabilitate, and their functional disability and prognosis for recovery is often poorer than individuals with global aphasia or hemiplegia. Many patients with neglect are difficult to help because they are unaware of or deny their deficit. One study found that those with larger right-sided lesions and with preexisting cortical atrophy had a poorer prognosis for recovery. Metaanalyses of cognitive rehabilitation trials for stroke-induced spatial neglect found no immediate or lasting effect on activities of daily living outcomes but some immediate effects on assessments of neglect.

The treatment of visual hemi-inattention is largely adaptive. Like in patients with hemianopias, those with hemi-inattention should have their bed within their room arranged to face their nonneglected side. Similarly, family and friends should be instructed to approach the patient from the intact side. Visual hemi-inattention precludes driving, cooking, crossing the street unaided, or working with machinery that could injure the patient. A vertical colored strip of paper can be placed along the left margin of text to facilitate reading, with instructions given to the patient to find the paper when moving down to the next line.

Other treatment options, although touted because of their positive results during neuropsychological testing, are either unsatisfactory or unproven when improvement in activities of daily living is the goal, or the effects are temporary. We have found hemianopic prisms (see Chapter 8 ) relatively unhelpful in patients with left-sided neglect, particularly because of the confusion they cause in patients who likely also have visual disorientation. Prism adaptation, in which subjects are trained to point straight ahead while wearing base-out left eye and base-in right eye prisms, thus shifting vision to the right, has been studied extensively and shown to improve neglect in some individuals, albeit transiently. The positive effects of training with virtual reality are also only temporary. The use of hemispatial sunglasses, which shade the nonneglected side of each eye and force viewing into the neglected side, has been reported anecdotally as effective. Another technique involves the use of visual imagery and trains the patient to pretend their eyes are like the light of a lighthouse, sweeping far to the left and right. An alternative strategy, which trains patients to turn their heads to the left, utilizes the intact right visual field for scanning. Phasic alerting, which uses a warning sound, can correct visual awareness but is impractical outside of the experimental setting.

In addition, vestibular stimulation by cold water, for instance, may have some efficacy in patients with visual neglect. This maneuver may train patients how to orient toward the affected hemispatial field. Noradrenergic agents and dopamine agonists have been shown anecdotally to improve neglect. However, these therapies have not been evaluated in a controlled fashion, and in one study bromocriptine actually worsened some aspects of hemispatial neglect. Transmagnetic stimulation of the left hemisphere in a small study of left hemispatial neglect in acute right hemisphere stroke showed promising results but requires further study.

Balint Syndrome

Balint first analyzed this symptom complex, and Holmes later elaborated his description. It results most frequently from bilateral symmetric parietooccipital cortical or white matter injury ( Figs. 9.9 and 9.10 ). In the minority of cases there is additional frontal lobe involvement. In its most severe form, patients with Balint syndrome appear disabled and almost completely blind except for macular sparing: They bump into objects and often require assistance while walking in the room, they do not refixate on novel stimuli in their visual periphery, they do not blink to threat, and they become tremendously visually fixated on single objects. The full syndrome (Video 9.2 ) consists of simultanagnosia (or simultaneous agnosia), ocular apraxia (a deficit in shifting gaze), and optic ataxia (a defect in reaching under visual guidance) . Each of these elements, which may be seen alone or in combination, are briefly considered in this section.

Location of lesions in Balint’s original patient. The two largest areas of damage were in the parietal lobes bilaterally, but there was also a lesion near the left central sulcus.

Balint syndrome due to acute hemorrhagic leukoencephalitis. Magnetic resonance fluid attenuated inversion recovery axial image demonstrates bilateral parietooccipital lesions ( arrows ). In addition to simultanagnosia, optic ataxia, and ocular apraxia, the patient had a right homonymous hemianopia.

Simultanagnosia . A striking deficit in Balint syndrome, simultanagnosia is the element seen most often in isolation. It is defined as an inability to grasp the entire meaning of a picture despite an intact capacity to recognize the picture’s individual constituent elements. Thus, affected patients may be unable to identify a picture of a landscape but are able to recognize a small tree within it. Such patients may be able to read single 20/20 letters but can read words only by spelling them out loud. Despite normal color vision, patients with simultanagnosia may have difficulty with Ishihara color plates (see Chapter 2 ), which requires identification of colored numbers created by small dots. The Navon figure test (see Fig. 2.14 ) is also an excellent method for assessing simultanagnosia, and attempts at drawing clocks ( Fig. 9.11 ) and other figures will often reveal the individual’s inability to appreciate an entire scene.

Disorganized clock drawn by a patient with Alzheimer’s dementia, simultanagnosia, and spatial disorientation. The examiner drew the circle, and then the patient was asked to draw in the numbers of a clock face within the circle.

Simultanagnosia may reflect bilaterally defective visual attention, as the lesions in Balint syndrome typically involve Brodmann areas 7 (superior parietal lobule), 19 (dorsorostral occipital lobe), and sometimes 39 (inferior parietal lobule). These are areas important for visual attention. Several authors have offered the absent “blink to visual threat” response as evidence for decreased visual attention in this disorder. One authority attributed the visual behavior to an “extreme narrowing of attention,” referring to an inability to notice any object outside foveal vision. Impaired shifting of attention; defective visual exploration of extrapersonal space, leading to deficits in visual scanning ; and an impairment in linking structural descriptions and object location, a deficit of binding ventral and dorsal stream information, have also been implicated.

Ocular apraxia . Patients with ocular apraxia are unable to generate voluntary saccades, but their involuntary reflexive saccades are normal. The term psychic gaze paralysis has often been used in association with Balint syndrome, and spasm of fixation is a term that indicates a patient is unable to initiate saccades away from a fixation target until the target is removed. Possible mechanisms include a disconnection of the occipital lobe from the frontal eye fields or uncertainty about the target’s location. In its purest form, ocular apraxia is associated with normal pursuit eye movements, but in fact many patients have defective pursuit as well. Other clinical features and mechanisms of ocular apraxia, which is also seen in other disorders, are reviewed in Chapter 16 .

Optic ataxia . Although patients with optic ataxia can see an object of regard, they cannot reach for it accurately ( Fig. 9.12 ). Optic ataxia, also known as visuomotor ataxia, is unassociated with cerebellar dysfunction or motor weakness. Instead, optic ataxia may result from a disconnection of the occipital lobe from anterior motor centers in the frontal lobe, where the reaching is programmed. A defect in the internal representation of extrapersonal space, or damage to areas responsible for integrating panoramic visual information with proprioceptive information relating to the upper extremity, or a specific impairment in visuomotor control without deficits in perception, are alternative explanations.

Optic ataxia in a patient with Balint syndrome due to Alzheimer’s disease. Visual fields were normal, but the patient reached inaccurately when asked to touch the examiner’s finger.

Other neuro-ophthalmic signs . The blink to threat response may be absent even within intact visual fields. Spatial or visual disorientation, a difficulty in localizing and finding objects in extrapersonal space by sight alone, is another prominent feature in a number of cases. Although the visual fields may be normal, often bilateral inferior altitudinal defects are present owing to the frequent involvement of the superior banks of the occipital lobes.

Etiology. The usual etiology is watershed infarction in the setting of hypoperfusion following cardiac or respiratory arrest, but patients with cardiogenic emboli, Alzheimer’s disease, Creutzfeldt–Jakob disease, and progressive multifocal leukoencephalopathy (see Chapter 8 ) may also present with complex visual disturbances manifesting with any or all of the elements of Balint syndrome. Less common but other reported causes include angiography, central nervous system vasculitis, adrenoleukodystrophy, perinatal hypoxic ischemic encephalopathy, posterior reversible encephalopathy syndrome, and reversible cerebral vasoconstriction syndrome. In addition, we have seen a case of Balint syndrome caused by acute hemorrhagic leukoencephalitis (see Fig. 9.10 ).

Treatment . Aside from treating the underlying condition, the management of patients with Balint syndrome is largely adaptive. Like patients with parietal hemispatial neglect, visual cues such as colored strips of paper can be used to help them read and scan pages. Some patients, however, are so severely affected that they are rendered visually disabled.

Posterior Cortical Atrophy

The label posterior cortical atrophy has been applied to a progressive dementing syndrome characterized primarily by higher cortical visual disorders. Typically patients exhibit some combination of homonymous visual field defects, alexia with or without agraphia, visual agnosia, components of Balint syndrome, prosopagnosia, Gerstmann syndrome (left–right confusion, finger agnosia, acalculia, and agraphia), oculomotor dysfunction, and transcortical sensory aphasia (fluent aphasia with intact ability to repeat). Visual hallucinations can also occur. Memory and frontal lobe functions, such as judgment and insight, are not significantly affected early in the course. Neuroimaging reveals cerebral atrophy, more severe posteriorly.

Etiologic considerations include Alzheimer’s disease, dementia with Lewy bodies, Creutzfeldt–Jakob disease, and corticobasal degeneration. Posterior cortical atrophy is felt to be a unique presentation of these conditions. Similarly, a focal cortical atrophy of the left, greater than right, temporal lobe can present as primary progressive aphasia, and patients may eventually develop memory loss, a dementing illness due to Alzheimer’s disease, or frontotemporal lobar degeneration.

Visual Imagery

Although visual imagery is not solely a parietal lobe function, lesions in this area may affect this cognitive function. Numerous neuropsychological and functional neuroimaging studies have suggested that many of the same areas of the brain that are responsible for viewing and interpreting an object are also important for imagining it. For instance, patients with occipital lobe lesions and a contralateral hemianopia or quadrantanopia can have defective visual imagery on the side of the field defect. In addition, PET studies have demonstrated that patients with acquired blindness due to anterior visual pathway lesions activate visual cortex during mental imagery. Patients with prosopagnosia and achromatopsia can have an imagery disorder involving faces and colors of objects. Individuals with visual agnosias for particular objects, living versus nonliving, for example, might have selective loss of visual imagery for the same types of items.

Furthermore, imagining an object or scene requires the ability to generate an internal representation of objects and scenes in extrapersonal space and relies upon the inferior parietal lobule. Thus patients with right parietal lobe lesions may neglect the left side during visual imagery (so-called representational neglect). For instance, Bisiach and Luzzatti asked patients with left hemineglect to imagine they were looking at the Piazza del Duomo in Milan. When asked to describe the view from the side of the square opposite the cathedral, patients described fewer landmarks on the left side of their imagined scene. When asked to recall the view of the square from the other side on the cathedral steps, again patients neglected more details on their left, but they described correctly objects on the right they had previously ignored from the other side. Other patients with visual disorientation and defective visuospatial imagery have been reported.

Several cases have shown that perception and imagery can be dissociated. For instance, patients with hemianopias and cortical blindness have been reported with intact visual imagery. Some patients with cerebral achromatopsia have preserved color imagery. In addition, a patient with a right parietal lesion and left-sided representational neglect without visual perceptual neglect, and others with visual agnosia but intact visual imagery, have been reported.

Alzheimer’s Disease

This neurodegenerative condition is highlighted by a gradually progressive, age-related dementia, which in turn is characterized by (1) a loss of intellect sufficient to interfere with social or occupational functions, (2) memory loss, and (3) a clear sensorium. The disease is considered probable if these features are present, the age of onset is between 40 and 90 years, and other neurologic diseases that could account for the deficits are absent.

Alzheimer’s disease is the most common cause of dementia in North America and Europe, accounting for at least half of cases. One study revealed that 47.2% of those older than age 85 years are affected by the disorder. Commonly, patients present with an amnestic mild cognitive impairment and later develop Alzheimer’s disease.

Primary risk factors for the disease include family history, presence of the apolipoprotein E ∈4 allele, and trisomy 21. Less common are autosomal dominant forms of early onset Alzheimer’s disease that are associated with mutations in the amyloid precursor protein gene on chromosome 21 and presenilin 1 and 2 genes on chromosomes 14 and 1, respectively. Possible risk factors include a history of head trauma and low intelligence.

Neurologic symptoms and signs . In addition to insidious memory loss, patients with Alzheimer’s disease may develop language deficits, particularly word-finding difficulties. Personality and affect changes, problems with concentration, and psychosis and agitation with deterioration in social skills and motor impairment can be evident in later stages. In general, noncognitive functions are normal. Extrapyramidal signs such as bradykinesia and tremor may be observed, as some patients have coexisting Parkinson’s disease or cortical Lewy bodies. Job loss, home care, nursing home placement, and eventual demise occurs between 5 and 12 years following dementia onset.

Differential diagnosis . Depression, multiinfarct dementia, extrapyramidal disorders, hypothyroidism, and toxic-metabolic disorders, for instance drug toxicity and B ₁₂ deficiency, are the conditions most commonly mistaken for Alzheimer’s disease. Neurosyphilis should also be excluded. The reader is referred to reviews and practice guidelines for a complete differential diagnosis of dementia.

Neuro-ophthalmic symptoms and signs . Visual deficits are the initial complaints and findings in the synonymous “visual,” “posterior,” or “posterior cortical atrophy” variants of Alzheimer’s disease and occasionally in the typical variant. In one study of community-based patients with Alzheimer’s disease, approximately one-half had a visual object agnosia, while one-fifth had Balint syndrome. Prosopagnosia, visual hallucinations (see Chapter 12 ), defective visuomotor perception, abnormal form perception, decreased visual attention, poor performance on visuospatial tasks, right-sided neglect, alexia without agraphia, poor visual memory, and diminished curiosity of novel or unusual visual stimuli may also occur. Because patients with Alzheimer’s disease and higher cortical visual disturbances usually have normal visual acuity and eye examinations, many patients return for repeated examinations and changes in eyeglass prescriptions before they are recognized to have higher cortical visual dysfunction. However, patients with Alzheimer’s disease may have deficits in visual acuity ; visual fields, including hemianopic field loss ; contrast sensitivity ; stereoacuity ; and color vision. Primary visual function abnormalities are not always observed.

Diagnostic studies . CT and MRI are helpful in excluding other disorders and are usually normal or reveal diffuse cortical atrophy. PET, single photon emission computed tomography (SPECT), and perfusion studies may demonstrate decreased rates of glucose metabolism and blood flow in the posterior cingulate, parietal, parietooccipital, temporal, and prefrontal regions. When the symptoms are primarily visual, the abnormalities on anatomical and functional imaging tend to be more posterior. Amyloid PET imaging is a ligand-based imaging mechanism that provides a measure of β-amyloid deposits in the living brain and is a marker of the pathology associated with Alzheimer’s disease, but it is not specific for Alzheimer’s disease; as such, it is not part of the routine clinical evaluation for Alzheimer’s disease, but will likely be used in the near future.

Spinal fluid levels of tau may be elevated and those of β-amyloid protein (see Pathology) may be decreased. Sometimes an electroencephalogram, which is either normal or shows diffuse slowing in Alzheimer’s disease, is performed when Creutzfeldt–Jakob disease is also considered. Although their significance is unclear, abnormal visual-evoked potentials and electroretinograms and reduction in nerve fiber layer and macular thickness demonstrated by optical coherence tomography have been reported in patients with Alzheimer’s disease.

Pathology . The diagnosis of Alzheimer’s disease is confirmed histologically, by biopsy or postmortem examination. The pathologic features include neurofibrillary tangles, which are characterized by paired helical fibers composed of altered forms of the microtubule-associated protein tau; senile plaques, consisting of insoluble β-amyloid protein; neuron degeneration; and loss of synapses. Also seen are granulovacuolar degeneration, amyloid (congophilic) deposition in vessel walls, and Hirano bodies, which are eosinophilic filaments. Cell loss in the basal forebrain cholinergic complex and decreased choline acetyltransferase activity suggest defective cholinergic transmission is associated with the disease.

The visual deficits in Alzheimer’s disease are usually attributed to neurofibrillary tangles in visual association areas or striate cortex. Levine et al. described a patient with Alzheimer’s, visual object agnosia, visual field constriction, and impaired contrast sensitivity. The postmortem examination revealed the density of tangles was highest in the occipitoparietal areas and lowest in the frontal lobes. A similar distribution of lesions was found in a group of Alzheimer’s patients presenting with Balint syndrome. Alzheimer’s patients who are visually symptomatic are more likely to demonstrate tangles in the occipitoparietal regions than those who have normal visual function.

Pathologic findings in the primary visual pathways have also been found, but inconsistently. For instance, the density of retinal ganglion cells subserving the central 11 degrees of vision was reduced in patients with Alzheimer’s disease as well as in age-matched control patients.

Treatment . For further details regarding pharmacologic agents used in Alzheimer’s disease, the reader is referred to detailed reviews. In general, there is no cure and no method for halting disease progression, and medications are only mildly effective. To enhance central cholinergic neurotransmission, cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine can be used. Gastrointestinal side-effects such as nausea and diarrhea can limit dosing. Memantine, an N-methyl- d -aspartate (NMDA) antagonist, is effective in later stages of Alzheimer’s disease by interfering with glutamatergic excitotoxicity or its effect on hippocampal neurons. Medical treatment of agitation, depression, and psychosis, including visual hallucinations (see Chapter 12 ), can be necessary in later stages.

Dementia With Lewy Bodies

Dementia with Lewy bodies is a slowly progressive, dementing neurodegenerative disorder that is distinct from Alzheimer’s disease. It accounts for up to 30% of all dementias and is associated with disturbances in attention, executive function, and visuospatial processing and later development of parkinsonism, neuropsychiatric symptoms, autonomic dysfunction, and sleep disturbances.

Neurologic symptoms and signs . Patients present with cognitive decline associated with fluctuations of intellectual function and alertness that precede signs and symptoms of parkinsonism, often by at least 1 year. Other findings include rapid eye movement (REM) sleep behavior disorder and autonomic dysfunction. Neuropsychiatric and neurobehavioral changes due to delusions, apathy, depression, and anxiety can result in considerable burden for caregivers.

Differential diagnosis . At onset, patients can be misdiagnosed as having Alzheimer’s disease, while later in the course they are often incorrectly diagnosed with Parkinson’s disease. Differentiating these conditions can be difficult, but cognitive decline that precedes parkinsonism by 1 year, frequent visual hallucinations, REM sleep disturbances, and autonomic dysfunction are important clues to the diagnosis.

Neuro-ophthalmic symptoms and signs . Visual hallucinations and higher order visual dysfunction are characteristic of dementia with Lewy bodies. These two features are independent, although Mosimann et al. found that visual perceptual dysfunction was worse in patients with visual hallucinations. Visuospatial and perceptual abnormalities include impaired visual construction, angle matching, color matching, form matching, and simple motion perception. These symptoms support involvement of both the dorsal (visuospatial) and ventral (recognition) streams in dementia with Lewy bodies.

Diagnostic studies . Routine neurologic evaluation with neuroimaging, neuropsychological assessment, and polysomnography for evaluation of REM sleep behavior disorder are indicated. Brain CT and MRI are often normal early in the disease. CT SPECT studies reveal low dopamine transporter uptake in the striatum and 18F-fluorodeoxyglucose PET studies reveal low glucose metabolism in the occipital regions with relative sparing of the medial temporal lobes.

Pathology . The hallmark pathology is Lewy bodies throughout the cortex, limbic regions, and brainstem. Lewy bodies are proteinaceous material composed of alpha-synuclein, which is aggregated into fibrils. Some patients have evidence of overlap of Alzheimer’s disease pathology, which is often referred to as the Lewy-body variant of Alzheimer’s disease.

Treatment . Symptomatic treatments can be effective, but there are no treatments available for slowing or preventing neurodegeneration. Neuroleptics used to treat visual hallucinations and other neuropsychiatric symptoms can result in severe side-effects with worsening parkinsonism and confusion in patients with dementia with Lewy bodies and are generally to be avoided. Symptoms of parkinsonism can respond to levodopa or dopamine-receptor agonists, and acetylcholinesterase inhibitors and NMDA-receptor antagonists may provide benefit for visual hallucinations and cognitive and neuropsychiatric symptoms. The presence of visual hallucinations predict a better response to acetylcholinesterase inhibitors and has been linked to low acetylcholine states.

Creutzfeldt–Jakob Disease

Creutzfeldt–Jakob disease, a relatively uncommon neurodegenerative disorder in adults, is characterized by rapidly progressive dementia and myoclonus worsening over weeks to months. In one large study, the range of age of onset was wide, 16–82 years, but the most frequent age group affected was between 60 and 64 years.

Creutzfeldt–Jakob disease, along with kuru, Gerstmann–Sträussler–Scheinker syndrome, and fatal familial insomnia, constitute a group of dementing illnesses known as human transmissible spongiform encephalopathies. Clinically, kuru and Gerstmann–Sträussler–Scheinker syndrome present primarily with cerebellar syndromes, and dementia occurs at later stages. Scrapie and bovine spongiform encephalopathy (mad cow disease) are related neurodegenerative diseases seen in animals. The responsible agents in these conditions are proteinaceous particles called prions (PrP, prion protein), which are devoid of nucleic acids. Disease results when the normal (cellular) prion protein PrP ^C misfolds into the pathologic (scrapie) form, PrP ^Sc .

Eighty-five percent of cases of Creutzfeldt–Jakob are sporadic, while 10–15% of cases are familial, caused by a mutation in the prion protein gene (PRNP). Much less commonly, Creutzfeldt–Jakob is iatrogenic due to growth hormone derived from human cadaveric pituitary glands, reuse of stereotactic electroencephalography electrodes, and corneal or cadaveric dural transplantation. New-variant Creutzfeldt–Jakob results from consumption of beef from bovines with spongiform encephalopathy.

Neurologic symptoms and signs . The disorder usually starts with gradual memory loss and behavioral abnormalities. Some patients present with additional sleep disturbances, depression, weight loss, anorexia, or anxiety. Cerebellar dysfunction, typified by ataxia and dysarthria, or pyramidal or extrapyramidal dysfunction may also be evident. Usually within a few weeks or months of onset, mental and motor functions deteriorate rapidly. Global dementia, cerebellar incoordination, rigidity, akinetic mutism, and startle-induced or spontaneous myoclonic jerks typify the later stages of the illness.

Neuro-ophthalmic symptoms and signs . Patients with the Heidenhain (occipitoparietal) variant often present with visual symptoms that predate dementia or behavioral changes, and they may have visual field defects such as homonymous hemianopia or quadrantanopia. Cortical blindness, visual hallucinations, visual agnosia, palinopsia, and Balint syndrome may also occur. Usually the fundus is normal, but rarely patients with optic atrophy have been reported. Ocular motor disturbances, including supranuclear (e.g., Parinaud syndrome) and infranuclear gaze palsies, nystagmus, and slow saccades, and eyelid abnormalities, such as ptosis and apraxia of eyelid opening, may also be observed. In other patients with Creutzfeldt–Jakob disease, by the time visual signs and symptoms develop, often they are too confused and uncooperative for careful documentation and accurate testing of their visual function.

Pathology . Creutzfeldt–Jakob disease is characterized neuropathologically by neuronal loss, prominent gliosis, and spongiosis in cortex, thalamus, basal ganglia, and cerebellum. Occasionally fine, radiating eosinophilic kuru amyloid plaques may be observed. Immunohistochemistry with antibodies against the prion protein can provide additional confirmation of the disease. In the Heidenhain variant, the neuropathologic abnormalities are most pronounced in the parietal and occipital lobes. Although tissue damage is usually confined to the central nervous system, some reports have documented involvement of the optic nerve head and retina.

Diagnostic studies . The definitive diagnosis of Creutzfeldt–Jakob disease is made with a biopsy or autopsy. However, spinal fluid analysis for the 14-3-3 brain protein is a sensitive (92%) and relatively specific (80%) laboratory test for the sporadic form of this disorder. It should be used cautiously, because autopsy-proven false negatives can occur, and false-positive 14-3-3 assay results have been reported in patients with herpes simplex encephalitis, hypoxic brain injury, intracerebral metastases, frontotemporal dementia, and Alzheimer’s disease. Recently, elevated levels of total tau in cerebrospinal fluid has been shown to be potentially superior to 14-3-3 in predicting disease status. Furthermore, a ratio of total tau to phosphorylated tau has been found to be greater than 99% specific and approximately 80% sensitive. Another study revealed that spinal fluid analysis of total prion protein can improve diagnostic accuracy in the differentiation of atypical Alzheimer’s disease and Creutzfeldt–Jakob disease.

Conventional T1-weighted MR images are frequently normal in patients with Creutzfeldt-Jakob disease, while diffusion-weighted MR sequences may demonstrate high signal abnormalities in the cortex or basal ganglia ( Fig. 9.13 ) in Creutzfeldt–Jakob disease, with a 98% sensitivity and a 94% specificity. With less sensitivity, T2-weighted and fluid attenuated inversion recovery (FLAIR) images can reveal similar changes. PET may demonstrate hypometabolism ( Fig. 9.14 ), and SPECT may show hypoperfusion in the occipital lobes in patients with the Heidenhain variant of Creutzfeldt–Jakob disease that occasionally precede abnormalities found on MRI.

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