Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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This article includes discussion of visual agnosias, apperceptive visual agnosia, associative visual agnosia, prosopagnosia, simultanagnosia, object agnosia, topographagnosia, topographical disorientation, pure alexia, and cortical dyschromatopsia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Agnosia is a group of neurologic disorders in which a person cannot recognize or identify an object, face, sound, word, or environment despite intact consciousness, language, memory, and fundamental sensory functions (45). Visual agnosia is a subtype of the agnosic syndromes where the deficit is specific to a visual target. In this article, the authors review different types of visual agnosia with respect to clinical characteristics, pathogenesis, structural localization, differential diagnosis, diagnostic evaluation, and rehabilitation.
• Visual agnosia is a rare neurologic deficit in recognizing or identifying a visual target despite intact consciousness, language, memory, and fundamental sensory functions.
• The 2 main streams of visual pathway from the primary visual cortex to its associative cortex are the dorsal stream (“where” pathway) and the ventral stream (“what” pathway).
• Visual agnosia is classified into 2 major categories: apperceptive visual agnosia and associative visual agnosia.
• Subtypes of visual agnosia are named according to the deficit in different visual targets.
• Specific rehabilitation programs targeting visual training improve ability in visual processing among persons with visual agnosia.
One of the first descriptions of a visual agnosia was provided by Munk in 1881. Munk noted that following bilateral partial occipital lobe ablation, a dog had a change in his responsiveness to familiar objects such that the dog could see but could not recognize. In 1890 Lissauer distinguished between 2 forms of visual agnosia: apperceptive and associative (70). In 1891, Freud introduced the term "agnosia," which was later defined as failure to recognize objects, not attributable to a defect in visual acuity, impaired cognition, or aphasia (08).
The ability to recognize objects is a sophisticated process that requires multiple stages of visual processing. In the first stage of the visual pathway, light stimulus is transformed into a neural signal at the retina. Then the neural signal passes through different structures in the visual pathway from the optic nerve, optic tract, lateral geniculate nucleus in the thalamus, to the optic radiations, and finally to the primary visual cortex or striated cortex, resulting in the ability to perceive fundamental visual information. The primary visual cortex then connects to its surrounding visual association cortex and further networks to other higher cortical areas to link the basic and complex visual information to previously learned semantic knowledge. The 2 main streams of visual pathway from the primary visual cortex to its associative cortex are termed the dorsal stream (“where” pathway) and the ventral stream (“what” pathway).
As shown in the diagram, visual agnosia is classified into 2 major categories, apperceptive visual agnosia and associative visual agnosia, depending on the stage in visual processing in which impairment occurs.
Apperceptive visual agnosia. In apperceptive visual agnosia, a person has an inability to recognize fundamental visual components of objects such as shape, color, motion, form, brightness, distance, and depth. This process is the fundamental step required for further association between the visual perception and an individual’s semantic knowledge.
Associative visual agnosia. In associative visual agnosia, a person has inability to integrate visual information with previously stored semantic knowledge. The person can perceive basic visual information and semantic knowledge of objects but cannot link them together. However, when the patient relies on other sensory modalities of an object such as touch, odor, taste, or sound, the person can correctly identify the objects. Associative visual agnosia is further subcategorized into subtypes related to impairment in specific visual targets such as faces or landmarks.
Prosopagnosia. Prosopagnosia is the prototype of associative visual agnosia and is characterized by an inability to recognize familiar faces from visual guidance. However, with preserved semantic information, the person can recognize people from other aspects of the person such as voice, written name, or distinctive features such as mole, nose, hairstyle, or gait. The person with prosopagnosia may have difficulty recognizing facial emotions and tends to look at other less informative facial parts, such as the mouth, than more helpful structure facial structures, like the eyes, when looking at a picture with static facial expression (31).
In general, there are 2 subtypes of prosopagnosia (21):
Acquired prosopagnosia. Acquired prosopagnosia is a consequence of structural brain lesions from many etiologies such as cerebrovascular insults, neurodegenerative diseases, limbic encephalitis, central nervous system infections, posttemporal lobe surgery, migraine with and without aura, tumors, or trauma (05; 63; 68; 03; 75; 02; 72; 20). A deficit in the perception of eye target configuration is commonly reported in patients with acquired prosopagnosia (05).
Developmental prosopagnosia. Developmental prosopagnosia was first reported in 1976 by McConachie (50). This condition is characterized by lifelong difficulty in facial recognition without obvious memory, visual defect, or structural brain lesion to explain the deficits. The prevalence of developmental prosopagnosia is reported around 2% to 3% (14) of the adult population and 1.2% to 4% of primary school children (10). The proposed criteria for developmental prosopagnosia require both subjective and objective evidence of facial recognition impairment on standardized face familiarity tests. Autism spectrum disorder must be excluded prior to the diagnosis of this condition (06; 22). This condition may cooccur with object agnosia; however, prosopagnosia without object agnosia is also not uncommon (24; 33; 35). Children with developmental prosopagnosia tend to spend less time examining the internal facial content and the eyes but use more time examining the mouth compared to controls (12). Facial motion can sometimes be used as a cue to improve facial recognition (09; 48). Persons with developmental prosopagnosia may have difficulty matching the same person with variations in appearance or grooming (74). Apart from impairment in facial recognition, the person with developmental prosopagnosia also requires more effort and time to accurately recognize other nonfacial body parts (66).
Interestingly, developmental prosopagnosia has been reported to have familial transmission as a continuous trait (42). This condition also increases risk of nonface visuospatial deficits in the family with prosopagnosic members (42). There is a genetic association with single-nucleotide polymorphisms in the oxytocin receptor gene (15). Individuals who were small for gestational age are at increased risk of showing low performance in facial recognition (60). Developmental prosopagnosia condition can cause short- and long-term psychosocial consequences for patients and their families (25).
Object agnosia. In object agnosia, a person has difficulty identifying or recognizing objects from visual input despite intact visual acuity; however, identification of objects is still preserved through use of other sensory modalities such as sounds, odors, or tactile sensation. At the level of the retina, object recognition occurs in mid-periphery whereas facial recognition occurs in the fovea. Limitation of eye movement is associated with impairments in object recognition but not face or letter recognition (36). From a series of 147 patients, this condition cooccurred with acquired prosopagnosia in 11.6% (69). Although this relationship between object agnosia and prosopagnosia is observed, the connection between the neural pathways and these 2 conditions is still uncertain (34).
Simultanagnosia. In simultanagnosia, a person cannot recognize a whole scene or picture but can identify individual objects from the scene. This condition can be associated with optic ataxia (difficulty reaching to visual guided goals in periphery) and oculomotor apraxia (difficulty initiating volitional gaze), which is known as Bálint syndrome. Simultanagnosia is classified as:
Dorsal simultanagnosia. In dorsal simultanagnosia, a person cannot see more than 1 object at a time. For example, in the Boston Cookie Theft picture, the person may report only seeing a boy in the picture. When attention is redirected, the person may report seeing a lady washing something but the boy disappears from the individual’s view. In everyday life, a person with dorsal simultanagnosia may run into objects that are spaced close together while walking due to visual perception of only 1 object.
Ventral simultanagnosia. In ventral simultanagnosia, a person can see more than 1 object at a time but can only recognize 1 object and cannot identify other objects in a scene. For example, in the Boston Cookie Theft picture, the person may report that he/she sees a boy in the picture and identifies the overflowing sink as a waterfall. In addition, the person cannot provide the meaning of the whole scene. Unlike dorsal simultanagnosia, persons with ventral simultanagnosia do not usually bump into objects while walking as they can see many objects at a time.
Pure alexia. In pure alexia, patients are unable to read but have preserved writing skills. They have difficulty recognizing letters or assembling letters into words or sentences. Though writing skill is preserved, they are unable to read what they have written. Other components of language, including naming, fluency, repetition, and verbal comprehension are intact. This syndrome is often associated with right homonymous hemianopia/quadrantanopia or right hemi-dyschromatopsia as a consequence of left occipital lobe damage. However, the visual field defect is not severe enough to account for the compromised reading ability. Some individuals may have pure alexia without hemianopia if the lesion involves only the visual word form area. From a series of 147 patients with acquired prosopagnosia, combined alexia with agraphia and pure alexia cooccurred with acquired prosopagnosia in 4.7% and 2.7%, respectively (69).
Topographagnosia (landmark agnosia) and topographical disorientation. In topographagnosia, patients have impairment in the more ventral “what” visual stream and therefore have difficulty identifying buildings, landscapes, and scenes. Conversely, a person with topographic disorientation is more affected on the dorsal “where” pathway and thus can perceive buildings or landscapes but is unable to navigate in a larger scale environment. Both conditions can be either acquired or developmental. In daily tasks, the person with topographagnosia or topographical disorientation usually encounters difficulty in directions. Topographic memory may partly contribute to topographic disorientation (44). These conditions can occur with prosopagnosia, although they are less frequently found in persons with development prosopagnosia than in acquired prosopagnosia (21). From a series of 147 patients, this condition occurred with acquired prosopagnosia in 29% (69).
Cerebral dyschromatopsia. Cerebral dyschromatopsia is a deficit in discriminating hues, color saturation, and color constancy (52; 55). This condition is different from color anomia, in which the person usually has preserved color recognition but cannot name the colors. Unlike congenital dyschromatopsia due to inherited deficits in cone pigments, this condition is usually not specific to a particular color and seems to involve all ranges of the color hues (55). From a series of 147 patients with acquired prosopagnosia, cerebral dyschromatopsia occurred in 30% (69).
The prognosis of visual agnosias varies according to the type of visual agnosia (developmental or acquired agnosia) and the specific agnostic syndrome. In the acquired type, the etiology is the major factor in prediction of the prognosis. Reversible or treatable conditions may only cause transient episodes of agnosia, such as migraine with aura. More static etiologies such as posttemporal lobectomy, ischemic or hemorrhagic stroke, or damage from limbic encephalitis may contribute to long-term consequences. Cognitive rehabilitation programs improve the opportunity for recovery.
Prosopagnosia. A 39-year-old man suffered an infarction of the right mesial occipital lobe, noted on MRI. On examination, the patient had normal visual acuity and a dense left homonymous hemianopia.
Over a 2-week period, the patient began noting the inability to recognize the faces of family members. He described their faces as looking the same. He made an analogy that it was like “looking at the faces of monkeys; they all appear similar.” He could only recognize his wife by the sound of her voice and color of her clothes. He recognized his physicians only by their white coats and distinguishing characteristics like facial hair and spectacles. A repeat brain MRI revealed a mesial right occipital lobe infarction extending anteriorly to the parahippocampal gyrus.
Pure alexia. A 57-year-old woman noted the inability to read but retained the ability to write. Examination revealed that she correctly wrote a sentence, but could not read what she had written. Her visual acuity was 20/25 in both eyes and Goldmann visual fields revealed a dense right homonymous hemianopia.
An MRI scan of the brain showed a left occipital lobe infarction.
Apperceptive visual agnosia. Apperceptive visual agnosia occurs from disconnection between the primary visual cortex and visual association cortex. Lesions in the inferior occipital-temporal region cause this condition (28).
Prosopagnosia. From functional MRI studies, the neural network functioning in perception of facial configuration is confined in the posterior half of the ventral occipitotemporal cortex (inferior occipital gyrus or occipital face area) and in the middle and posterior fusiform gyrus (fusiform face area) (32; 76). In addition, an occipitotemporal lesion was found to be associated with partially selective processing loss for eye information in a patient with acquired prosopagnosia (71). The key area for face perception is the right fusiform cortex (76; 59). Beyond perception of facial configuration, facial memory or recognition is more confined to the right anterior temporal lobe. In a study on right-handed normal subjects, the right anterior temporal area was activated during the discrimination between familiar and unfamiliar faces (59). Thus, this area is responsible for the recognition of previously learned visual information. This supports the idea that apperceptive variant of prosopagnosia is related to the damage in the right fusiform and occipital face area whereas the associative variant links to a right anterior temporal lesion (05). However, a study on healthy subjects found that the gray matter volume of the right ventral anterior temporal lobe, but not the right occipital face area and the right fusiform face area, positively correlated with the performance in the Cambridge Face Memory test (56).
There is a laterality of word processing to the left cerebral hemisphere and of face processing to the right cerebral hemisphere. A lesional study in patients with acquired prosopagnosia suggested that facial recognition is more right hemispheric dominant. Isolated right-sided lesions were reported in 90% of cases whereas isolated left side lesions were found in 9% (69). Bilateral lesions produced more severe symptoms than a unilateral lesion (05).
Although the fusiform and occipital face areas are mainly responsible for facial recognition, these 2 areas alone may not be sufficient for this task. Widespread connections with other areas of the brain including the left prefrontal cortex (46) and superior temporal sulcus (47) are also crucial in this process.
In a functional magnetic resonance imaging study, activity of the fusiform gyrus, occipital face area, and lateral occipital cortex was significantly reduced in 3 family members with developmental prosopagnosia when compared to controls (40). In participants with developmental prosopagnosia, prosopagnosia and object agnosia were reported to be independently processed but both related to decreased spontaneous neural activity measured by fMRI on the right occipital face area (57). Electrical stimulation on the right anterior fusiform gyrus produced transient impairment of familial face recognition (77). This finding leads to the emerging hypothesis that the ventral anterior temporal area may connect with the core-face recognition network in the occipital and fusiform face area (43).
Local and long-range white matter tracts are also pathologically involved in these disorders (19; 38; 37). From diffusion weighted imaging studies, the tracts involved in face and in place recognition are separate (19).
Object agnosia. Object recognition is considered a component of ventral “what” stream visual processing. It is unclear whether this task relies more on the left hemisphere, right hemisphere, or symmetrical bilateral hemisphere function. The lateral occipital cortex is reported to function in object recognition (54). A unilateral lesion can suppress the neural response to object stimuli on the contralateral side, which leads to the conclusion that both hemispheres need to be functionally intact for unimpaired object processing (64; 62; 65). Furthermore, object processing of shape and surface (color and texture) activates different foci of the brain. The lateral occipitotemporal cortex is more responsible for shape recognition whereas the medial occipitotemporal cortex is more responsible in color (anterior collateral sulcus and lingual gyrus) and texture recognition (posterior collateral sulcus) (16).
Simultanagnosia. Bilateral damage to the visual pathways in the parieto-occipital cortices disconnects the cortices and white matter tracts responsible for visual processing and spatial attention and contributes to simultanagnosia (17; 23). This disconnection leads to the poor awareness to simultaneous visual stimuli. Bilateral gray matter damage within the middle frontal area (Broadmann area 46), cuneus, calcarine, and parieto-occipital fissure, as well as right intraparietal and postcentral gyri, is also associated with simultanagnosia (17). However, simultanagnosia is not solely a cortical dysfunction. Based on tractography studies, bilateral damage to the superior longitudinal, inferior fronto-occipital, and inferior longitudinal fasciculi is associated with simultanagnosia (17).
Pure alexia. In a person with left hemispheric language dominance, the left hemisphere is more responsible for reading and language skill whereas the right hemisphere more heavily functions in face recognition. Damage to the left occipital area and splenium of the corpus callosum accounts for alexia without agraphia, also called pure word blindness, an entity reported by Dejerine in 1892. Extensive damage to the left occipital-temporal area may also cause right hemianopia. In addition, damage to the splenium of corpus callosum impedes the signal from the intact right hemisphere to the dominant angular gyrus. Thus, a patient can perceive the presence of letters but cannot integrate those letters into meaningful words or sentences. The majority of reported cases have not had lesions in the classic locations. Pure alexia has, therefore, been divided into 2 types based on the location and symptoms (Rodríguez-López and Guerrero Molina 2018). The first type, or disconnection alexia, is a classic disconnection syndrome similar to the hypothesis of Dejerine. Splenium of corpus callosum and/or periventricular white matter involving visual related fibers are affected in that type. It is usually accompanied by right homonymous hemianopias and dyschromatopsia. The second type, or cortical alexia, is a result of damage to cortical visual word form area in the left inferior temporal sulcus and usually presents with isolated pure word alexia without visual field loss.
Topographagnosia. In right-handed normal subjects, the bilateral parahippocampal gyri and parieto-occipital junctions are involved in processing scene perception (59).
In addition to this area, the anterior half of the lingual gyrus and the adjacent fusiform gyrus are involved in the identification of familiar buildings and landscapes (Takahashi and Kawamura 2002). Lesions in the right temporal and occipital lobes account for landmark agnosia (18).
Topographic disorientation. The posterior parietal lobe is responsible for egocentric orientation, or the representation of the location of objects with respect to self (01; 18). Due to the complexity and heterogeneity of the task, it is challenging to pinpoint a clinical-anatomical correlation (49), though lesions commonly involve the superior parietal lobule (01).
Cerebral dyschromatopsia. From a metaanalysis of 92 case reports, cerebral dyschromatopsia can be caused by lesions in the ventral occipital cortex (13). Another study showed that a lesion in the fusiform gyri, but not in anterior temporal cortex, can lead to cerebral dyschromatopsia (55).
Visual acuity and visual field defects may impair recognition of objects, written words, or faces. Semantic dementia and memory impairment can mimic or partially contribute to visual agnosia. Anomia secondary to language impairment can manifest similarly to visual agnosia. Delirium due to general medical conditions needs to be excluded because delirious persons will have impaired attention which leads to inability to assess other cognitive functions. Psychiatric conditions such as Capgras syndrome can sometimes be confused with prosopagnosia.
The first step to assess for visual agnosia is evaluation of global cognitive function to assure that other cognitive domains, including attention, memory, and language, are intact. Mini Mental State Exam or Montreal Cognitive Assessment are the 2 widely used screening instruments for global cognitive function. It is not uncommon for patients to have poor insight and not to report their deficits (58). These global cognitive tests sometimes unmask such impairment and lead to further evaluation. Impairment in naming, cube copying, or clock drawing may be a clue for further evaluation for a visual agnosia.
An ophthalmological examination should include visual acuity, color testing, and naming, visual fields (may be confrontational), and ocular motility. These exams aim to rule out optical or primary visual pathway abnormalities that may cause visual deficits. Testing for apperceptive visual agnosia can be relatively simple by testing ability to copy simple figures, to match, or to self-draw pictures.
For associative visual agnosias, examiners should look for deficits related to specific subtypes. For prosopagnosia, there are various standardized tests for facial recognition such as Cambridge Face Memory test (14; 51), Glasgow Face Matching test (30), or the Benton Face Recognition test (11). Further details on the guideline for studying developmental prosopagnosia in children and adults is available (26). After confirming impairment in facial recognition, the examiner should also assess if the person has preserved basic information about people or can recognize people from voice or distinctive features, which helps in differentiation of prosopagnosia from semantic dementia (04; 53).
In a patient with alexia, both reading and writing should be assessed for differentiating pure word blindness from alexia with agraphia, which aids in neurologic localization. In a patient with new visual agnosia, structural brain lesions need to be evaluated by neuroimaging.
For cerebral dyschromatopsia, color-naming tasks (Ishihara charts), color discrimination tasks, and color matching can be tested (39).
Developmental prosopagnosia can be improved by teaching individuals to identify and discriminate facial features from other facial components (61). A 3-week online face-training program targeting holistic face processing was reported to improve face perception among 24 adults with developmental prosopagnosia (29). A randomized, controlled trial demonstrated that intranasal inhalation of oxytocin could improve facial processing in developmental prosopagnosia (07), but the therapeutic effect of oxytocin on this condition needs to be further explored. In acquired prosopagnosia, improvement in face discrimination after 11 weeks of perceptual learning is described (27). The neuropsychological rehabilitation in visual agnosia was extensively reviewed by Heutink and colleagues, finding that compensatory strategies can be beneficial in most cases, but efficacy of restorative therapies are limited (41).
Jonathan D Trobe MD
Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.See Profile
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