Introduction

Classic and enduring percepts of albinism include pale-skinned, white-haired, dancing pink-eyed individuals. It is now well established, however, that the albino phenotype per se ranges from extreme hypopigmentation of the hair, skin, and ocular fundi, oculomotor instabilities (e.g., idiopathic congenital nystagmus), and interocular misalignments to the albino phenotype of dark skin pigmentation (including black skin or ready ability to tan), dark brown or black hair, ocular pigmentation, and absence of ocular motor instabilities and/or misalignments (figure 25.1). Basically, and despite the wide range of albino genetic features within and between phenotypes, inherited albino abnormalities of melanin metabolism and synthesis result in two major visual pathway anomalies: foveal hypoplasia (figure 25.2) and misrouted optic nerve fibers (figures 25.3 and 25.4).^44,45 While foveal hypoplasia is a consistent and obligate albino feature, as reflected by the absence of a foveal reflex, albinos may present, albeit rarely, with normal fundus pigmentation, normal iris pigmentation, and/or ocular stability. Diagnostic ambiguity arises under these conditions and is further exacerbated in the normal infant or young child whose visual systems, including foveal hypoplasia, reflect normal fundus immaturity. In general, full foveal development, under normal conditions, is not reached before 45 months of age.⁵⁰ Therefore, a poorly defined or absent foveal reflex may simply reflect normal visual system immaturity rather than foveal hypoplasia. Diagnostic ambiguity can be resolved by noninvasive electrophysiological assessment of the visual pathways. That is, pathognomonic to albinism per se is primary optic pathway misprojection with a preponderance of misrouted temporal retinal fiber projections that erroneously cross at the optic chiasm. Thus, in albinism, regardless of genotype or phenotype, a dominant portion of temporal retinal fibers erroneously decussate at the chiasm rather than maintaining appropriate ipsilateral projections and organization (figures 25.3 and 25.4). Of interest is that albino mammals of all species have this remarkable anomalous optic pathway feature.^74,79

Figure 25.1.  

Variable genotype and phenotype in a representative sample of albinos including autosomal-recessive oculocutaneous, tyrosinase-negative albinism (left column), X-chromosomal ocular albinism, and autosomal-recessive oculocutaneous, tyrosinase-positive albinism (right column). Foveal hypoplasia, reduced visual acuity, and VEP optic pathway misrouting are common features regardless of inheritance mode or phenotypic expression.

Figure 25.2.  

Fundi of left and right eye (A) of an 18-year-old albino and (B) of a 16-year-old achiasmat. For comparison, note the presence of foveal hypoplasia only in the albino fundi; foveal hypoplasia, pathognomonic to albinism, is absent in the achiasmat.

Figure 25.3.  

Simplified schematic of the primary visual pathways emphasizing normal organization of retinal-fugal projections within the chiasmatic region compared to abnormal projections characteristic of albinos and achiasmats.

Figure 25.4.  

Simplified schematic of the visual field representation onto two adjacent right dorsal LGN layers. Normally, LGN layers receive, in strict alignment of visual space coordinates, nasal retinal projections from the contralateral eye (LGN layer A) and temporal retinal projections from the ipsilateral eye (LGN layer A1). Note also that the representation in laminae A and A1 are in register. For the albino, a central segment of temporal retinal fibers erroneously decussate. As a result, the medial portion of layer A1 representing a part of the ipsilateral visual field is misaligned with the corresponding projections of layer A and is also represented in mirror reversal. The order of the abnormal projections is reversed as indicated by the descending numbers (dark sections reflect abnormal ipsilateral field representation). In comparison, for the isolated achiasmat, all nasal fibers fail to decussate, and the entire ipsilateral hemifield is represented in LGN layer A; temporal retinal projections from the same eye project, as under normal conditions, to ipsilateral LGN layer A1. However, with both nasal and temporal retinal projections from a single retina projecting ipsilaterally, the entire visual field now is represented in layers A and A1 in complete mirror reversal; congruency is present only at the vertical midline (VM). (Source: Adapted from Williams et al., 1994, figure 4, page 639.)

Regarding ipsilateral projections, it is also of interest to note that most recently, an inborn, isolated achiasmatic syndrome (figures 25.2B, 25.3, 25.4) also was identified in humans via the albino visual evoked potential (VEP) misrouting test,^11,13,14 albeit in this instance, following monocular, full-field stimulation, the achiasmatic evoked potential responses reflect significant ipsilateral asymmetry rather than the classic albino contralateral asymmetry (e.g., figure 25.3). Such unusual ipsilateral VEP distributions following full-field stimulation reflect a unique achiasmatic condition; VEP ipsilateral misrouting results indicating an isolated achiasmatic condition were confirmed and defined via magnetic resonance imaging.^11–13 Within the same time period, the isolated achiasmatic condition with an autosomal-recessive genotype⁷³ also was reported in a breed of achiasmatic Belgian sheepdogs.⁷⁸

Returning to the albino mammalian primary visual pathways per se, the anomalous albino optic pathway condition was initially described in rats.⁶² Thereafter, the aberrant albino visual pathways were confirmed across several albino mammalian species, including mice, mink, monkeys, and humans.^43,67 Within this period, studies of melanin metabolism during embryogenesis also began to demonstrate the prominent role of melanin in normal retinal neurogenesis and axonal trajectory along the immature optic cup and stalk.^71,72 Preclusion of normal melanogenesis of neural ectoderm derivatives, as in albinism, was found to result in abnormal histogenesis of retinal pigment, abnormal retinal ganglion cell metabolism, and differentiation and the consequent inappropriate guidance, projection, and organization of retinal-fugal fibers. The deleterious effects of abnormal melanin metabolism that disturb the delicate embryological processes that are involved in retinal differentiation and patterning of chiasmal decussation are evident at birth and predetermine the final course of visual pathway maturation.^49,70 Recent magnetic resonance imaging (MRI) assessment of the albino visual pathways also has demonstrated that the size and configuration of the optic chiasm, reflecting aberrant optic fiber decussation, differs significantly in albinos compared to normal age-matched controls. Compared to normal controls, the albinos showed significantly smaller chiasmal widths, smaller optic nerves and tracts, wider angles between nerves and tracts, and a distinctly different size and configuration of the optic chiasm.⁶⁸ In addition, ascending further along the primary visual pathway, anatomical studies have shown via the lateral geniculate nuclei (LGN) of albinos that near the vertical meridian, a central segment of temporal retinal fibers erroneously terminates within contralateral rather than ipsilateral projection sites. As a result of the misrouting, the medial portion of LGN layers A1, representing a portion of the ipsilateral visual field, is misaligned. The albino LGN receives aberrant crossed input from temporal fibers, thus displacing portions of the normal ipsilateral temporal projections. Each albino hemiretina maps to the appropriate LGN layer: however, the abnormal segment represents the mirror symmetric portion of the visual field, disrupting normal alignment from layer to layer (see figure 25.4).

Adaptation to these and various other LGN layer incongruencies demonstrates remarkable plasticity of the albino visual system. For example, given the albino mismapping of retinal projections, albino visual field loss also is expected. However, if visual field testing in a given albino is performed accurately (i.e., account is taken of accompanying albino ocular motor instabilities, misalignments, and reduced acuities), the albino visual fields prove perfectly normal.

While optic pathway misrouting including an abnormal preponderance of contralateral retinal fiber projections defines the albino condition via molecular, biological, and genetic assessment, two primary genetic forms of albinism have been defined: autosomal-recessive albinism and X-linked albinism. Autosomal-recessive albinism, is further subdivided into tyrosinase-positive albinism with melanin pigment present in hair, skin, and ocular structures; tyrosinase-negative albinism with melanin pigment sparse or absent; and brown oculocutaneous albinism. Brown oculocutaneous albinism is phenotypically distinct from tyrosinase-related oculocutaneous albinism (OCA1) and genetically distinct from protein P-gene-related oculocutaneous albinism (OCA2). The occurrence of OCA1 and OCA2 in the general Western population is approximately one in 40,000 individuals. The majority of affected individuals are compound heterozygotes with distinct maternal and paternal mutations. Of clinical relevance, however, is that regardless of albino genotype or phenotype, albinism, as was stated above, fosters two primary pathognomonic albino features: foveal hypoplasia with corresponding visual acuity reduction and misrouted temporal retinal projections with corresponding high incidence of ocular motor misalignments and instabilities. In addition to reduced visual acuity due to albino fovea hypoplasia and misrouted primary optic pathway projections, auxiliary albino ophthalmic features include photophobia, iris transillumination, and refractive errors.

For clinical albino diagnosis, regardless of genotype or phenotype and across the age range from neonate to the elderly, the obligate albino optic pathway misrouting of retinal fugal fibers can be readily recorded from the surface of the scalp via appropriate VEP testing (figure 25.5). Protocol details of the VEP misrouting test protocol are described in more detail below in the section on optic pathway misrouting detection. In general, however, the albino VEP response demonstrates contralateral hemispheric response lateralization following full-field monocular stimulation. That is, with right eye viewing, albino VEP topography across the electrode array shows a relatively early latency window of left hemispheric response dominance; with left eye viewing, an early latency window of right hemispheric response dominance is effected. Thus, via appropriate and age-dependent stimulus profiles, monocular albino VEPs measured across the electrode array demonstrate contralateral interocular asymmetry. This pattern of lateralization is specific to albinism and should not be confused with VEP asymmetries resulting from optic pathway lesions, malformations, or tumors. Nor should this form of interhemispheric and/or interocular asymmetry be confused with normally occurring hemispheric response dominance, which, in normal controls, can reflect remarkable intersubject variability. That is, VEP topography across the occiput, in any given test group and regardless of age, can alter from midline dominance, midline attenuation, left hemispheric response dominance, or right hemispheric response dominance. However, of direct relevance to VEP albino misrouting detection is that in nonalbinos, the recorded interhemispheric asymmetry remains constant with either left or right eye viewing. In addition to the relevance of interhemispheric response profiles, it is of considerable significance to note that the VEP misrouting test protocol is age dependent. The age variable has proven critical in optimizing the VEP misrouting test across the age span.

Figure 25.5.  

Schematic of an optimum electrode montage for VEP assessment in albinos. Ag/AgCl electrodes are positioned with an equal spacing of 3cm in a horizontal row 1cm above the inion. Reference is either linked ears or Fz.

With positive results from VEP detection of albino pathognomonic contralateral VEP response dominance, initial queries during establishment of the albino VEP misrouting test protocol concerned the optimum surface electrode loci as well as the minimum number of electrode derivations. To address these issues, principal component analysis was applied to the monocular VEP profiles of several normal controls as well as albino patients; VEP recordings were performed with 24 electrode derivations (figure 25.6). Basically, the multielectrode dipole studies revealed that a primary, five-channel, albino optic pathway misrouting response with pattern onset stimuli reflected both striate and extrastriate VEP components. With aberrant retinogeniculate projections and abnormal visual field representation identified within cortical areas 17 and 18,⁶¹ it is of interest to note that in clinical practice, the albino VEP “signature” is found consistently for the VEP component from cortical area 18. The latter is due to the fact that cortical area 18 is more accessible than cortical area 17 to scalp electrodes;⁶⁰ area 17's contribution to the albino VEPs is generally reduced. As a result, responses generated from cortical area 18 constitute (at least in adults) the most likely indicator for albino VEP asymmetry. Of practical relevance in the multielectrode tests was that the results accurately defined the optimum electrode montage, including number and loci of recording channels, for application of the albino VEP misrouting test across the age range.

Figure 25.6.  

Principal component analysis (PCA) applied to the VEP response with monocular (OS) stimulation. Left and right panels show the VEP pattern-onset response of an oculocutaneous and an ocular albino, respectively. PCA with a time interval of 71–179ms was used to identify cortical sites of albino asymmetry with a 24-electrode derivation. Contralateral VEP asymmetry within this early time window clearly is demonstrated by the equipotential lines (faded contours) and the fitted equivalent dipole potential distributions (darker contours). Location and orientation of the equivalent dipoles are indicated by the dots with arrow. In albinism, the strongest contralateral asymmetry generally is obtained from the extrastriate component (as shown in the left panel). The albino VEP response at the right panel also demonstrates contralateral asymmetry for the striate component. Horizontal and vertical axes are at 0° azimuth and elevation angles. Electrodes, in both horizontal and vertical planes are spaced 3cm apart. The lowest row of electrodes is positioned 1cm below the inion; the second row of electrodes is positioned 2cm above the inion. (See also chapter 15.)

While the precise electrical sources and loci of the recorded VEPs remain under investigation, it is understood that, in general, the VEPs are derived from extracellular field potentials of the apical dendrites of pyramidal cells. The dendridic trees that generate the evoked potentials that are recorded at the scalp surface are parallel to each other and are also oriented perpendicularly to the cortical surface. Therefore, electrical activity in the neurons causes current to flow in the extracellular medium over considerable distances. VEPs that are recorded at the scalp therefore reflect the summed ion current that is generated from a plethora of synchronously activated neuronal assemblies, including retinogeniculocortical, intracranial, and corticocortical processing. Although VEP measures are generated within different brain regions, it is also of interest to note that VEPs reflect not only retinogeniculate cortical processing (figure 25.6), but also intracranial and corticocortical processing. As such, if the anatomic structures and underlying extracellular electrical field potentials are defined, VEP evaluation serves as a noninvasive probe for characterizing and localizing maturational and/or anomalous developmental processes throughout the primary visual pathways. As a caveat, however, it is of clinical relevance to acknowledge that the albino VEP misrouting test protocol per se is both age dependent and stimulus specific.

Via indexes of interhemispheric asymmetry derived from interocular comparisons of VEP profiles across the electrode array, the presence or absence of albino misrouting can be reliably determined. Note, however, that until proven otherwise, the degree of asymmetry does not reflect or demonstrate any relationship with the percentage of erroneously crossed chiasmal fibers and/or various phenotypic characteristics such as cutaneous pigmentation.

While the present study promotes albino assessment via VEP testing, most recently, the abnormal visual pathway projections associated with albinism also have been investigated via nonfunctional⁶⁸ as well as functional magnetic resonance imaging.^49,64 The latter has revealed that the albino visual cortex is activated by both the contralateral visual field and by abnormal input representing the ipsilateral visual field.