Homonymous hemianopia

Authors

Valérie Biousse, MD

Sachin Kedar, MD

Xiaojun Zhang, MD, PhD

Nancy J Newman, MD Section Editor

Paul W Brazis, MD Deputy Editor

Janet L Wilterdink, MD

Last literature review version 17.1: January 2009 | This topic last updated: January 30, 2009 (More)

INTRODUCTION — Homonymous hemianopia is a visual field defect involving either the two right or the two left halves of the visual fields of both eyes. It is caused by lesions of the retrochiasmal visual pathways, ie, lesions of the optic tract, the lateral geniculate nucleus, the optic radiations, and the cerebral visual (occipital) cortex (show figure 1) [1-4] . Characteristics of the visual field abnormalities (type, form, size, and congruity), along with associated neurologic signs and symptoms, have been traditionally used for localizing pathologic lesions in the brain (show table 1) [1-6] .

Homonymous hemianopia is often disabling, causing difficulties with reading and visual scanning. Patients may fail to notice relevant objects or avoid obstacles on the affected side, causing collisions with approaching people or cars. They are not legally allowed to drive in most states. This has dramatic consequences on their vocational and private lives [1,7] .

This topic will discuss homonymous hemianopia as a fixed deficit; it may be a transient phenomenon resulting from migraine, transient cerebral ischemia, or seizure. This is discussed separately. (See "Amaurosis fugax (transient monocular or binocular visual loss)", section on Transient binocular visual loss).

ETIOLOGY — Any type of intracranial lesion in the appropriate location can cause a homonymous hemianopia; however, vascular causes (cerebral infarction and intracranial hemorrhage) are the most frequent in adults, ranging from 42 to 89 percent, followed by brain tumors, trauma, surgical interventions, and other central nervous system diseases [1,8-13] . In children, neoplasms are the most common cause of homonymous hemianopia (39 percent), followed by cerebrovascular disease (25 percent) and trauma (19 percent) [14] . Homonymous hemianopia after head trauma may be under recognized; multifocal brain injury is more common in this setting, contributing to other neurologic deficits that may overshadow the visual field defect [13] .

Uncommon causes of homonymous hemianopia include multiple sclerosis, infections (encephalitis, abscess), degenerative dementia (posterior cortical atrophy), Creutzfeldt Jakob disease, adrenoleukodystrophy, seizures, and severe hyperglycemia [12,15-17] .

NEUROANATOMY OF THE VISUAL PATHWAYS — There is a retinotopic arrangement of the nerve fibers in the visual pathways, which is responsible for the specific patterns of visual field defects. A homonymous hemianopia points to unilateral lesions of the visual sensory pathways posterior to the optic chiasm (show figure 1).

Optic chiasm and tracts — At the optic chiasm, the nerve fibers from the temporal retina (nasal visual field) maintain their relative position in the lateral chiasm before passing into the ipsilateral optic tract, while the nerve fibers from the nasal retina (temporal visual field) decussate in the chiasm and pass into the contralateral optic tract.

Each optic tract contains crossed and uncrossed nerve fibers subserving the contralateral visual field; the fibers in the left optic tract contain fibers carrying information for the right half of the visual field from both the right and left eyes. Lesions of the optic tract affect the temporal fibers and nasal visual field of the ipsilateral eye and the nasal fibers and temporal visual field of the contralateral eye, giving rise to homonymous visual field defect of the contralateral visual field (show figure 1). The optic tract lies in close proximity to the internal capsule, cerebral peduncle and basal ganglia.

The separation of the two hemifields occurs at the vertical raphe of the retina (through the fovea centralis retinae), implying that the visual field is split at the point of fixation into the right and the left halves. Thus, macular fibers are also both crossed and uncrossed in the optic chiasm.

Lateral geniculate nucleus — Most (80 percent) of the nerve fibers in the optic tract project into the ipsilateral lateral geniculate nucleus in the midbrain. Other optic tract fibers innervate the Edinger-Westphal nuclei in the pretectum, providing the afferent limb for the pupillary light reflex. The axons from the ipsilateral eye terminate in the second, third, and fifth laminae of the lateral geniculate nucleus, while the axons from the contralateral eye terminate in the first, fourth, and sixth laminae. The nerve fibers are believed to form a precise retinotopic map in the lateral geniculate nucleus.

Optic radiations — The neurons originating from the lateral geniculate nucleus form the optic radiations or the geniculocalcarine tract and end in the primary visual cortex in the occipital lobe.

The superior fibers of the optic radiations subserve the inferior visual field and pass posteriorly through the parietal lobe. The inferior fibers, which subserve the superior visual field, initially course anteriorly, superior to, and around the temporal horn of the lateral ventricle. They then pass laterally and posteriorly to the striate cortex, forming Meyer's loop (show figure 1). It is believed that as these fibers approach the occipital cortex, their retinotopic order increases, and the left and right eye fibers representing common visual loci fall into closer register and ultimately into ocular dominance columns in the striate cortex [18] .

Visual cortex — The primary visual cortex (also called the calcarine cortex, striate cortex, Brodman area 17) is believed to be retinotopically organized based on visual information from the corresponding retinal loci from the two eyes. The upper lip of the calcarine cortex receives projections from the inferior visual field, while the lower lip of the calcarine cortex receives information from the superior visual field. The posterior pole of the occipital lobe is concerned with the central visual field, while the peripheral visual field is represented in the most anterior part of the striate cortex.

The striate cortex is surrounded by the visual association areas (Brodman areas 18 and 19). These areas are also believed to be retinotopically arranged with significant representation for the central visual field, as in the primary visual cortex [1-4] .

COMMON VISUAL FIELD DEFECTS — The visual cortex receives a point-to-point projection that corresponds to the retinal image of the visual fields. The fields are divided into temporal and nasal halves that respect the vertical meridian; the temporal field is somewhat larger than the nasal field. The point of visual fixation is represented centrally. The blind spot represents the optic disc and is located 15 degrees temporal to fixation.

Terminology — A homonymous hemianopia is complete when the visual field defect respects the vertical meridian, has macular splitting, and involves the entire hemifield on the affected side (show figure 2). All other visual field defects are defined as partial or incomplete (show table 1).

Incomplete homonymous hemianopias are defined as congruous if the homonymous defects in fields of the two eyes are identical in shape, depth, and size (show figure 3). Other incomplete homonymous hemianopias are called incongruous (show figure 4). It is important to emphasize that the concept of congruency applies only to incomplete homonymous hemianopias. Because of the anatomical organization of the visual pathways, congruous homonymous hemianopias are usually related to lesions involving the most posterior part of the visual pathways (ie, the occipital lobe). Lesions of the anterior radiations and optic tract are usually incongruous (show figure 1 and show figure 4).

Congruency is a helpful but not always reliable feature for localizing lesions to the anterior versus posterior portions of the visual pathways. In one case series, congruency of incomplete hemianopias was seen in 83 percent of lesions attributed to occipital lobe lesions and 50 percent of those with optic tract pathology [19] .

Incomplete homonymous hemianopias include: homonymous quadrantanopia; homonymous hemianopia with macular sparing; homonymous scotomatous defect; homonymous sectoranopia; unilateral loss of temporal crescent; and temporal crescent-sparing homonymous hemianopia.

Complete homonymous hemianopia — A complete left or right visual field defect can occur with complete lesions anywhere along the retrochiasmal visual pathway (show figure 2). In one study of 852 patients with homonymous hemianopia, 38 percent were complete [12] .

Homonymous quadrantanopia — Superior and inferior homonymous visual field defects respecting the vertical and sometimes the horizontal meridians (show figure 5) were the most common incomplete homonymous hemianopias in one large case series [12] . These defects occur when lesions (especially

infarcts) selectively damage either the inferior or superior banks of the occipital cortex (show figure 6). Less commonly, a quadrantanopia represents a lesion in the optic radiations in the temporal or parietal lobe [20] .

Homonymous hemianopia with macular sparing — Homonymous visual field defects sparing the central 5 to 25 degrees of visual field on the affected side (show figure 7) are common when the posterior half of the occipital region has been at least partially spared by the lesion. Because of the dual vascular supply of the occipital pole in many individuals (by branches of both the middle and posterior cerebral arteries), macular-sparing homonymous hemianopia is more likely to occur with stroke than with other occipital lesions. While classically associated with occipital lobe injury, macular sparing may also represent incomplete damage to the optic radiations, and less commonly, to the optic tracts [12] .

It is important to emphasize that macular sparing of 3 degrees or less is not clinically meaningful, as it may be the result of wandering fixation. Also, macular sparing should be diagnosed only when there is good fixation on visual field testing [12] .

Homonymous scotomatous defect — Homonymous visual field defects respecting the vertical meridian and limited to the central 30 degrees are usually enclosed within an area of normal peripheral visual field (show figure 8). These defects are the converse of macular-sparing homonymous hemianopia. The cause is most commonly occipital tip injury, most frequently due to stroke or trauma (show figure 9). However, larger lesions involving the occipital cortex and lesions in the occipital radiations and optic tract have also been associated with this defect [12,21] .

Homonymous sectoranopia — Wedge-shaped defects located near the horizontal meridian, either pointed at fixation or sparing fixation (show figure 10), are characteristic of lesions involving the lateral geniculate body (usually infarctions). These are relatively unusual visual field defects. The visual field patterns are based on the lateral geniculate body's dual blood supply from the anterior and posterior choroidal arteries.

Unilateral loss of temporal crescent — The most peripheral 30 degrees of the temporal field viewed by each eye is not overlapped by a corresponding nasal field in the other eye. This portion of the field is called the temporal crescent and has monocular representation in the anterior part of the contralateral visual cortex.

These rare visual field defects are secondary to lesions involving the anterior ten percent of the primary visual cortex (show figure 11). The lesion is usually an infarction [22] . Unilateral loss of temporal crescent is the only example of a monocular visual field defect caused by a retrochiasmal lesion (all other defects are bilateral and homonymous).

Temporal crescent-sparing homonymous hemianopia — When the anterior portion of the primary visual cortex is spared by an occipital lesion producing a homonymous hemianopia, there is sparing of the temporal crescent on the contralateral eye visual field (show figure 12). A small percentage (<20 percent) of individuals with this pattern of vision loss will have lesions of the optic radiations instead [23] . The temporal crescent is particularly sensitive to moving stimuli, making this lesion somewhat less disabling.

The unilateral loss of, or preservation of, the temporal crescent is more likely to be detected with Goldmannn perimetry rather than automated perimetry (eg, Humphrey visual fields or the Octopus), which concentrates on the central 30 percent of the visual field.

CLINICAL FEATURES — Patients with homonymous hemianopia may not complain specifically of visual field loss. They may complain instead of monocular vision loss or of an ill-described difficulty with seeing or reading (dyslexia). Unilateral retrochiasmal lesions producing homonymous hemianopia do NOT affect visual acuity. Complaints of visual impairments, therefore, should prompt an examination of the visual fields as well as of visual acuity. (See "The detailed neurologic examination in adults", section on Visual fields).

Characteristics of the visual field defect as described above, along with accompanying neurologic signs, help to localize the lesion within the brain; occipital lobe lesions are most common [12] .

Lesions of the optic tract — Lesions of the optic tract account for 3 to 11 percent of all homonymous hemianopias. Optic tract lesions produce characteristic clinical features, which are exquisitely localizing (show figure 1) [1,24,25] . Lesions of the optic tract produce either complete or incomplete homonymous hemianopia. When incomplete, the visual field defect is often (but not always) incongruous [19] . Rarely, small lesions of the optic tract may produce congruent homonymous scotomatous defects [26] . Isolated lesions of the optic tract produce a relative afferent pupillary defect in the eye contralateral to the side of the lesion (eye with the temporal field loss). Another pupillary phenomenon commonly ascribed to lesions of the optic tract is pupillary hemiakinesia (hemianopic pupillary reaction or Wernicke's pupil). When a sharp focused beam of light is projected onto the retina

from the intact hemifield, the pupil is found to constrict normally. However, when light is shone from the blind hemifield, the pupillary reaction is either decreased or absent [1] . In practice, it may be difficult to demonstrate the hemianopic pupillary reaction; light often scatters across the iris, stimulating the intact field and producing pupillary constriction. Lesions of the optic tract cause a characteristic pattern of optic atrophy. While the eye ipsilateral to the side of injury develops diffuse pallor, the contralateral optic disc develops a horizontal band of pallor in a "bow-tie" configuration within four to six weeks after the injury (show figure 13 and show figure 14). Patients with optic tract lesions may also show neurologic deficits related to hypothalamic signs and symptoms and contralateral hemiparesis from contiguous internal capsular damage.

Lesions of the lateral geniculate nucleus Visual field defects resulting from lesions of the lateral geniculate nucleus are of variable nature because of the intricate retinotopic organization of the lateral geniculate nucleus. The nature of the visual field defect is also influenced by the underlying cause. Vascular lesions of the lateral geniculate nucleus usually produce congruous and characteristic visual field defects [1-4,27,28] . Occlusion of the posterior choroidal artery causes a wedge defect that straddles the horizontal meridian region (sectoranopia), while occlusion of the anterior choroidal artery spares that sector of visual field (sector-sparing) (show figure 10) [1-4,27,28] . The pupillary reactions in patients with lesions of the lateral geniculate nucleus are normal, unless there is involvement of the optic tract or the brachium of the superior colliculus, which produces a contralateral relative afferent papillary defect. Patients with lesions of the lateral geniculate nucleus may also show signs and symptoms suggestive of damage to the ipsilateral thalamus (contralateral hemihypoesthesia, abnormal referred pain on the contralateral side) and/or pyramidal tract (contralateral motor weakness).

Lesions of the optic radiations — The optic radiations project from the lateral geniculate nucleus to the striate cortex (show figure 1). The first part of the optic radiations makes up the most posterior limb of the internal capsule. Here, the optic radiations lie in close proximity to the corticospinal and corticobulbar tracts, as well as the thalamocortical fibers. Lesions of the optic radiation in this location typically produce a contralateral, usually complete, homonymous hemianopia, associated with contralateral hemianesthesia and hemiplegia. A relative afferent pupillary defect may also be observed in lesions that are proximate to the lateral geniculate body [29] . Involvement of the optic radiations in the temporal lobe produce a homonymous defect, which is usually incomplete, incongruous, either confined to the superior quadrants or more dense superiorly than inferiorly and often called "pie-in-the sky" defect [1-4] . Temporal lobe lesions also produce other neurologic manifestations, including aphasia, memory deficits (dominant hemisphere lesions), complex seizures, and auditory and visual hallucinations. Evaluations of visual field defects after temporal lobectomy in patients with epilepsy demonstrate 15 percent greater loss in the nasal than the temporal field, and considerable interindividual variance, especially as regards the anterior extent of Meyer's loop [30] . Involvement of the optic radiations in the parietal lobe usually produce incomplete, mildly incongruous homonymous hemianopia, which is either limited to the inferior visual fields or is more dense inferiorly than

superiorly. However, large lesions may produce a complete homonymous hemianopia. Contralateral hemifield neglect is also seen in lesions of the nondominant hemisphere and can be difficult to distinguish from a visual field defect. Since the parietal lobe is the principal sensory area of the cerebral cortex, lesions often produce sensory deficits [1-4] . Lesions extending to the dominant angular gyrus lobe may also produce Gerstmann's syndrome (finger agnosia, agraphia, acalculia, and right-left disorientation), while lesions of the nondominant parietal lobe may cause inattention or neglect and impaired constructional ability [1-4] .

Lesions of the occipital lobe — Occipital lobe lesions are the most common cause of homonymous hemianopia and are most often vascular in origin [8-10] . Lesions of the occipital lobe tend to produce an isolated homonymous hemianopia (ie, not associated with other neurologic deficits). Depending on the location of the lesion, various visual field patterns are seen. Lesions of the occipital pole (most posterior aspect of the striate cortex) typically cause congruous homonymous scotomas (show figure 1 and show figure 8). Lesions extending to the dominant angular gyrus lobe may also produce Gerstmann's syndrome [1-4] . Lesions of the most anterior part of the striate cortex produce homonymous defects involving the peripheral visual field (temporal crescent) (show figure 11). Conversely, large lesions of the posterior occipital lobe may produce a homonymous hemianopia with sparing of the contralateral crescentic temporal visual field (show figure 12). Unilateral temporal crescent may be missed if only the central visual field is tested, as is common with automated perimetry. In cases with unilateral temporal visual field defects, the nasal retinal periphery should be carefully examined, as lesions in this location may also produce unilateral temporal visual field defects [1-4] . Homonymous hemianopia due to occipital lesions often have macular sparing (sparing of the central visual field) (show figure 7). Explanations for this phenomenon include bilateral representation of the macula in the occipital cortex, incomplete damage to the striate cortex on the affected side, and, more commonly, dual blood supply of the occipital pole by middle and posterior cerebral arteries [1-4] . Bilateral homonymous hemianopias are produced by bilateral lesions of the occipital lobe, either simultaneously or consecutively. The extent of the visual field defect depends on the extent of involvement of the striate cortex and can include a combination of visual field defects such as bilateral complete hemianopias (cortical blindness), "checkerboard" field defects, and combinations of complete homonymous hemianopia, scotomatous, and altitudinal defects (show figure 15 and show figure 16). In cases with bilateral homonymous hemianopia, visual acuity may be reduced. It is important to emphasize that the amount of visual loss should be symmetric in both eyes, unless the patient has another anterior visual pathway cause for his decreased visual acuity. Cortical blindness may be accompanied by a striking anosognosia, in which the patient is unaware of his deficit; this is called Anton's syndrome. A lesion involving the extrastriate cortex produces congruous quadrantic visual field defects (show figure 5).

DIAGNOSIS — Confrontation testing of the visual fields is the usual screening test for visual field defects. Techniques are described separately. (See "The detailed neurologic examination in adults", section on Visual fields). A comparison of these techniques found that they had poor sensitivity (35 to 73 percent)

for the detection of visual field abnormalities, but the test population included relatively few patients with homonymous hemianopia [31] . Use of a small, red target gave the most sensitive results.

In addition to increased sensitivity, visual field perimetry gives more information regarding the type, size, and form of the visual field loss. These tests include automated static perimetry as well as manual kinetic perimetry (eg, Goldmann, tangent screen). These are similarly reliable in their ability to detect the presence of a homonymous hemianopia. However, the manual kinetic techniques are more precise in providing information regarding the type, size, and form of the visual field defect and in one study, were more predictive of the lesion location on magnetic resonance imaging (MRI) [32] .

Perimetry should be performed in all patients with neurological lesions that may produce a visual field defect. Confrontation perimetry at bedside is insufficient to identify and follow visual field changes. Formal visual fields are important from a medicolegal point and are also useful prior to allowing a stroke patient to drive or return to work (see "Driving" below).

All patients with homonymous hemianopia require neuroimaging, usually MRI study, to define the underlying etiology (see "Etiology" above). In cases in which there is no underlying MRI abnormality, neurodegenerative disease is often the underlying cause [15] .

PROGNOSIS — The rate of spontaneous improvement of homonymous hemianopia varies greatly, between 18 to 67 percent, and depends to a large extent on the time period after the brain injury when the visual fields were tested as well as the underlying lesion [1-4,9,13,33-35] . One study reported 46 percent spontaneous improvement of homonymous hemianopia within three weeks from onset of ischemic stroke event [35] . Another study reported 67 percent spontaneous recovery of homonymous hemianopia (by confrontation method) within one month of a stroke [34] . Spontaneous improvement of the visual field defect is unlikely after six months from the injury unless there is an improvement of the underlying disease, such as can occur in multiple sclerosis [1,13,36] .

In one study of 113 patients with homonymous hemianopia from a variety of causes, no patient, lesion, or visual field characteristic was found to correlate with the final visual outcome [36] .

DRIVING — Most patients with homonymous hemianopia secondary to a stroke are unaware of their visual field defect and may continue to drive, if not otherwise disabled from doing so [37] . Patients should be aware that driving abilities are compromised by a homonymous hemianopia [38] . In most

states of the United States, patients with a complete homonymous hemianopia are not legally allowed to drive.

Medically, it is intuitive that if a person misses large parts of his visual field especially an entire half, then he would not be safe on the road. Decisions regarding the legality to drive are solely based on prescribed visual criteria which differs for each state in the USA. It is the responsibility of the treating physician to counsel the patient regarding driving once it is determined that the patient no longer meets the minimum required vision criteria. However, it is not incumbent upon the treating physician to notify the Department of Motor Vehicles.

The following link summarizes the vision criteria for each state in the USA: http://www.icoph.org/standards/drivingapp2.html

TREATMENT AND REHABILITATION — In most patients with homonymous hemianopia, no or few treatments are usually offered. Some rehabilitation techniques have been suggested over the past decade, but remain controversial [39] . They are based upon three principles: Compensation (use of intact function) Substitution (adapt the patient's environment to the patient's functional impairment) Restitution (retraining the impaired function; ie, expanding the visual field)

One approach includes the use of hemianopic mirrors or prisms. The principle is to project the images from the blind hemifield onto the intact hemifield. However, these techniques may cause significant spatial disorientation and confusion for some patients [7,40] .

Patients with homonymous hemianopia experience considerable difficulty reading, especially when the visual field defect is complete or involves fixation. Patients with right-sided defects cannot see the letters immediately following the ones that they have read, while patients with left-sided defects have problems returning to the next line, as it falls in the blind hemifield [41,42] . These patients notice benefit in reading if they use their finger or a ruler positioned under each line of text, so that they do not lose the position while reading the text, or if they train themselves to read vertically.

Computerized saccadic training programs may improve patients' visual function by training patients with homonymous hemianopia to make saccades into their blind hemifield [43-45] . A systematic review reported that results of small studies suggest modest benefits in increased reading times and decreased reading errors using this approach [46] .

Restorative methods are based upon the stimulation of a transition zone adjacent to the blind hemifield, resulting in visual field expansion, presumably due to cortical plasticity [40,47] . Although this concept remains debated [48,49] , visual restoration therapy has been approved United States Food and Drug Administration (FDA) and is used at some centers in the United States and in Europe [47] .

SUMMARY — Homonymous hemianopia represents a visual field defect relating to loss of vision in all or part of the left or right visual field in both eyes. Stroke is the most common etiology in one-half to two-thirds of patients, followed by traumatic brain injury, brain tumors, and other structural brain lesions. (See "Etiology" above). Homonymous hemianopia occurs with lesions in the retrochiasmal visual pathways: the optic tracts, lateral geniculate body, the optic radiations, and the occipital cortex. (See "Neuroanatomy of the visual pathways" above). Specific features of the visual field defect (type, form, congruity, and size), along with other neurologic symptoms and signs, help to localize the underlying lesion (show table 1). (See "Common visual field defects" above and see "Clinical features" above). While homonymous hemianopia may frequently go unrecognized by patients and clinicians, it is nonetheless disabling, impairing visual scanning and reading, and restricting driving. (See "Treatment and rehabilitation" above). Many patients will recover spontaneously, over half within the first month. Recovery after six months is unlikely. (See "Prognosis" above). Treatment options are limited and include rehabilitation techniques aimed primarily at compensation and accommodation. (See "Treatment and rehabilitation" above).

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Diseases of the central nervous system caused by prions

Authors

Henry G Brown, MD, PhD

John M Lee, MD, PhD Section Editor

Steven T DeKosky, MD, FAAN Deputy Editor

Janet L Wilterdink, MD

Last literature review version 17.1: January 2009 | This topic last updated: January 2, 2009 (More)

INTRODUCTION — Prion diseases are neurodegenerative diseases that have long incubation periods and progress inexorably once clinical symptoms appear. Five human prion diseases are currently recognized: kuru, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD also known as new variant CJD), Gerstmann-Straüssler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI) [1,2] . Bovine spongiform encephalopathy (BSE), one of a number of prion infections affecting animals, was responsible for bringing these agents to more widespread public attention with its possible link to vCJD [3,4] .

These human prion diseases share certain common neuropathologic features including neuronal loss, proliferation of glial cells, absence of an inflammatory response, and the presence of small vacuoles within the neuropil, which produces a spongiform appearance. The current theory is that prion diseases are associated with the accumulation of an abnormal form of a host cell protein, designated the prion protein (PrP) [5] .

The clinical manifestations and diagnosis of the prion diseases Kuru, GSS, and FFI will be reviewed here. CJD and variant CJD are discussed separately. (See "Creutzfeldt-Jakob disease" and see "Variant Creutzfeldt-Jakob disease").

The biology of prions and the genetics of prion diseases are discussed separately. (See "Biology and genetics of prions").

KURU — Kuru was the first transmissible neurodegenerative disease to be identified and well studied; it has served as the prototype of human prion diseases [6,7] .

Epidemiology — Kuru, which was endemic in Papua New Guinea among the Fore tribes, was felt to be transmitted from person to person by ritual cannibalism [8] . The cessation of these practices in the 1950's had been thought to end incident cases of kuru; however, increased active surveillance in Papua New Guinea led to the identification of 11 new cases of kuru between July 1996 and June 2004, with a likely incubation period of more than 50 years in some cases [9] . Kuru also remains important because of some overlapping clinical and pathologic features with iatrogenic CJD, vCJD, and GSS. Hence, it provides clues to the pathogenesis of other human prion diseases.

Clinical features — Unlike some of the other prion diseases such as CJD, kuru occurs in predictable stages [8] . The early or ambulatory phase is characterized by tremors, ataxia, and postural instability. The tremors resemble shivering, which accounts for the name of the disease (kuru = shivering). The sedentary stage follows as the disease progresses with loss of ambulation resulting from increased tremors and ataxia. Involuntary movements, including myoclonus, choreoathetosis, and fasciculations, also appear. Dementia, which usually begins as slowing of the mental processes, progresses in the late stages of the disease. Patients may exhibit indifference or seem unconcerned with their disease. Frontal release signs, cerebellar type dysarthria, and inability to get out of bed mark the terminal stage, with death typically due to pneumonia occurring within 9 to 24 months from the onset of the disease.

Diagnosis — Few laboratory studies have been performed on patients with kuru, and neuroimaging has not been reported. The cerebrospinal fluid (CSF) is unremarkable. The electroencephalogram (EEG) is abnormal, but it is not characterized by the periodic sharp wave complexes found in some of the other human prion diseases [10] .

Genetics — While limited molecular genetic studies of patients with kuru have been undertaken, no mutations in the prion protein (PRNP) gene have been reported. However, homozygosity at the polymorphic codon 129 of the PRNP gene has been detected at a higher than expected frequency in kuru and also in patients with iatrogenic CJD, sporadic CJD, and vCJD [11] . (See "Biology and genetics of prions").

Pathology — The pathologic hallmark of kuru is PrPSc-reactive plaques occurring with the greatest frequency in the cerebellum [11] . Kuru plaques are unicentric and round with radiating spicules and are periodic acid-Schiff (PAS) positive. Neuronal loss and hypertrophy of astrocytes is also observed

GERSTMANN STRAÜSSLER SCHEINKER SYNDROME — Gerstmann-Straüssler-Scheinker syndrome (GSS) is a rare human prion disease with an incidence of 1 to 10 cases per 100 million population per year.

Epidemiology and clinical features — GSS is inherited in an autosomal dominant pattern with virtual complete penetrance. At least 24 separate kindreds have been identified throughout the world.

The hallmark of the clinical disease is progressive cerebellar degeneration accompanied by differing degrees of dementia in patients entering midlife (mean age 43 to 48 years), although the onset of symptoms in older patients has been reported [12-15] . The course of the illness typically advances for approximately five years before culminating in death. Cerebellar manifestations include clumsiness, incoordination, and gait ataxia. Dysesthesia, hyporeflexia, and proximal weakness in the legs are also early signs [16] . Myoclonus is typically absent in GSS. Whether and to what degree dementia ensues varies among affected families and individuals within the same family [17,18] . Part of the variability of expression of this illness may be due to differences in the underlying PRNP mutation or the associated polymorphisms in codon 129. (See "Biology and genetics of prions").

Diagnosis — A diagnosis of GSS cannot be made from laboratory or imaging studies. The cerebrospinal fluid (CSF) is normal in GSS. The electroencephalogram (EEG) may show slowing, but does not typically show the periodic sharp wave complexes characteristic of sCJD. (See "Creutzfeldt-Jakob disease", section on Electroencephalogram). The magnetic resonance imaging (MRI) is not specific or sensitive but may show areas of decreased T2 signal in the striatum and midbrain in some patients [19] . Single photon emission computed tomography (SPECT) may demonstrate diffusely decreased blood flow; in one study, findings on SPECT that were very sensitive for GSS early in the disease course included decreased flow in the occipital lobe and spinal cord [16] .

Demonstration of PRNP gene mutations appears to be a sensitive and highly specific way to diagnose GSS since the vast majority of cases are familial, and all patients with definite GSS have been found to have PRNP mutations. (See "Biology and genetics of prions"). Neuropathology can be useful, and immunostaining of brain tissue for PrPSc is positive.

Neuropathology — GSS displays neuropathologic features consistent with other forms of human prion diseases. However, the presence of kuru-like plaques in highest density in the cerebellum but also elsewhere in the brain is a common finding [20] . These plaques are often multicentric with radiating spicules and are accompanied by microglial changes; they stain for PrPSc and are PAS (periodic acid-Schiff) positive. Neurofibrillary tangles and neuropil threads, identical to those seen in Alzheimer disease, have been seen in brains from several kindreds [21] .

FATAL FAMILIAL INSOMNIA — Fatal familial insomnia (FFI) was first identified in Italian families, but kindreds have now been reported throughout the world. Sporadic cases are also described [22-24] .

Epidemiology and clinical features — FFI is a rapidly fatal disease with a mean duration of 13 months, which generally occurs in midlife, median age at onset 56 years (range 23 to 73 years) [25,26] . Disease onset is earlier and duration is shorter in those who are homozygous for methionine at codon 129. (See "Biology and genetics of prions").

Patients characteristically develop progressive insomnia with loss of the normal circadian sleep-activity pattern, which may manifest as a dream-like confusional state during waking hours [27] . Mental status and behavioral changes include inattention, impaired concentration and memory, confusion, and hallucinations, but overt dementia is rare [28] . As the disease progresses, motor disturbances such as myoclonus, ataxia, and spasticity can occur [28,29] . Methionine-homozygous patients are more likely to have hallucinations and myoclonus as prominent disease features, while methionine-heterozygous patients are more likely to develop early problems with ataxia, bulbar signs, and nystagmus [26] .

FFI is the only prion disease to produce dysautonomia and endocrine disturbances [25,29,30] . Dysautonomia may induce hyperhidrosis, hyperthermia, tachycardia, and hypertension. Endocrine disturbances include decreases in ACTH secretion, increases in cortisol secretion, and loss of the normal diurnal variations in levels of growth hormone, melatonin, and prolactin.

Diagnosis — Laboratory testing and routine imaging with CT or MRI are not helpful in making the diagnosis of FFI. The CSF is unremarkable, and 14-3-3 protein is usually not detectable in the CSF [31] . EEGs do not show periodic sharp wave complexes, and MRI shows no distinctive abnormalities. Fluorodeoxyglucose PET has been reported to show decreased glucose utilization in the thalamus, which may be detectable even before the development of clinical symptoms [32-34] . Sleep studies demonstrate a dramatic reduction in total sleep time and disruption of the normal sleep architecture [26] .

While FFI like other prion diseases has been transmitted to experimental animals, genetic studies are now the diagnostic procedure of choice. Most cases are associated with the D178N PRNP gene mutation. (See "Biology and genetics of prions").

Pathology — Spongiform degeneration, which is a characteristic feature of most of the human prion diseases, is rarely detected in FFI, particularly in those with the methionine-homozygous genotype [26] . Neuronal loss and gliosis that is maximal within the thalamus are consistent findings [25,26,29] . These changes can also occur in the cerebellar cortex, cerebellar nuclei, and olivary nuclei. Brain tissue stains for PrPSc, but the intensity of staining, which correlates with the amount of protein present, appears to be reduced compared with most other human prion diseases [26,29,35] .

CJD AND VARIANT CJD — Creutzfeldt Jakob Disease (CJD) and variant CJD are discussed separately. (See "Creutzfeldt-Jakob disease" and see "Variant Creutzfeldt-Jakob disease").

OTHERS — A new prion disease, proteinase-sensitive prionopathy, was described in a 2008 case series of 11 patients identified by the National Prion Disease Pathology Surveillance Center [36] . Patients presented at a mean of 62 years with a dementia with prominent neuropsychiatric manifestations and progressive motor decline (ataxia and/or parkinsonism). Death followed symptoms onset within a mean of 20 months. A family history of dementia was present in seven patients, suggesting a possible genetic origin. CSF 14-3-3 was negative in the five patients in whom it was tested, MRI demonstrated diffuse atrophy without restricted diffusion, and EEGs were normal or showed only diffuse slowing. Neuropathologic examination revealed spongiform degeneration in the cerebral cortex, basal ganglia, and thalamus with relative sparing of the brainstem and cerebellum. There was a similar anatomic distribution of PrP immunostaining that was characterized by a distinctive pattern of cluster-forming granules. Immunoreactivity was virtually abolished by protein digestion.

TREATMENT OF PRION DISEASES — No effective treatment has been identified for human prion diseases, which are universally fatal [37] . Care for patients with prion disease is supportive. Isolated case reports of stabilization or improvement following treatment with amantadine [38] , vidarabine [39] , and methisoprinol [40] have not been confirmed. Reports of treatment with acyclovir, interferons, polyanions, and amphotericin B have also failed to show benefit in human cases [41-43] .

Animal models and cell culture systems that are used for studying prion diseases may assist in the testing of new agents for the treatment of prion diseases. The dye Congo red, anthracyclines, DMSO, glycerol, polyene antibiotics, and copper chelation with penicillamine have all shown efficacy in delaying PrPSc accumulation or disease development in cell culture or animal models, but none have been tried in human disease [44-47] .

Flupirtine — Flupirtine maleate is a centrally acting, nonopioid analgesic that has displayed cytoprotective activity in vitro in neurons inoculated with a prion protein fragment [48] . The mechanism of neuroprotective action is unknown, but it may involve up-regulation of the anti-apoptotic protein bcl-2 [48,49] . Alternatively, its N-methyl-D-aspartate antagonist properties might limit glutamate-mediated neurotoxicity [50] .

Flupirtine is not currently available in the United States. In a European study, 28 patients with CJD were randomly assigned to treatment with flupirtine (n=13) or placebo (n=15) [51] . One patient in each group had familial CJD, the remainder were sporadic cases. Diagnosis was based upon the World Health Organization (WHO) criteria for "probable" CJD. Flupirtine treatment was initiated at 100 mg per day, and increased over three days to a maintenance dose of 300 to 400 mg per day, which was continued for a median treatment duration of 29 days. There was no significant effect of flupirtine treatment on survival time compared with placebo. However, the patients treated with flupirtine performed significantly better on the cognitive part of the Alzheimer Disease Assessment Scale (ADAS-Cog). Flupirtine-treated patients also did better on the Mini Mental Status Examination, but the difference did not reach statistical significance. Caregiver's impressions were also significantly better in the flupirtine-treated group.

Chlorpromazine and quinacrine — Specific derivatives of acridine and phenothiazine were found to inhibit PrPSc formation in a cultured neuroblastoma cell line (ScN2a) chronically infected with prions [52] . Effective compounds included chlorpromazine and quinacrine. Quinacrine was approximately 10 times more potent than chlorpromazine in inhibiting scrapie formation in culture.

Despite the promise of quinacrine in cell models of infection, subsequent studies did not show benefit in animal models of CJD [53,54] . Similarly, early results in humans have been disappointing. In an uncontrolled observational study of 32 patients with either sporadic CJD or variant CJD, treatment with quinacrine resulted in no significant benefit [55] .

Three groups are investigating quinacrine in the treatment of CJD in clinical trials [50] .

New targets — The scientific advances in the understanding of the molecular pathogenesis of prion diseases have led to the identification of new targets for therapy. Some of these potential targets include the steps in the conversion of PrPC to PrPSc, binding of PrPSc with PrPC, binding of protein X, removal of PrPC, or the steps in the transport of PrPSc to the nervous system [50,56] . Immunotherapeutic approaches have also shown promise. As examples: iPrP13, a peptide that can break a beta-sheet conformation, was shown to reduce the protease resistance of PrPSc and to delay the onset of symptoms in transmission experiments in mice [57] . Depletion of endogenous PrPC in mice with established prion infection reversed spongiform change, prevented neuronal loss, and prevented progression to clinical disease [58] . Another study reported a prion protein epitope that is selectively exposed in the pathologic conformation (tyr-tyr-arg), opening the possibility that antibodies could be used as therapeutic agents [59] . In a murine scrapie model, anti-PrP monoclonal antibodies reduced PrPSc levels and prion infectivity [60] . High throughput drug screening to isolate small molecules with potential therapeutic action is also ongoing [61] . (See "Biology and genetics of prions").

Passive immunization with monoclonal antibodies

ACKNOWLEDGMENT — The authors and editorial staff at UpToDate, Inc. would like to acknowledge Kenneth L Tyler, MD, and C Alan Anderson, MD, who contributed to an earlier version of this topic review.

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