Auditory system. a, b Audiogram along with a quantitative analysis of neurosensory elements within the cochleae. Audiometric thresholds in the right and left ears at age 17 are shown in (a) and (b), respectively. Speech discrimination was 96% in both ears (normal). The cytologic alterations are displayed below the audiogram in a series of parallel bar graphs, with distance in millimeters from the basal end on the x axis from right to left, and magnitude of pathologic changes on the y axis (black) from bottom to top. The composite graph is known as the cytocochleogram [24]. This method allows depiction of the pathologic changes and its correlation with the associated audiogram. By displaying the pathology and the audiometric results on the same scale, the tonotopic organization of the cochlea is incorporated, and one can correlate the site of pathology (e.g., hair cell loss) with the frequency distribution of the hearing loss (on the audiogram). The black areas in the cytocochleogram represent missing or abnormal elements. The inner and outer hair cells are shown as present (white) or absent (black). Vertical axes of the cytocochleogram for the stria vascularis and cochlear neurons represent percentage of loss. The cochlear neuronal counts were compared with mean counts from normal newborns as well as age-matched control samples. It is evident that there was complete loss of inner hair cells and outer hair cells in the basal 0–13 mm of both cochleae, which corresponds well with the high-frequency sensorineural hearing loss. Note that the atrophy of the stria vascularis was focal and restricted mainly to the apical turn. The cochlear neurons were intact except in the base, where there was a mild loss. c A medium magnification H&E view of the cochlea at the mid-modiolar level, showing the basal, middle and apical turns. Note that the turns are fully developed. d, e Higher power H&E views of two of the cochlear turns. d The lower basal turn where the organ of Corti is completely atrophic with missing hair cells and missing supporting cells. The cochlear neurons innervating this part of the organ of Corti are also reduced in number with absence of the dendrites between the cell bodies and the organ of Corti. e A higher power view of the upper basal turn where the organ of Corti is intact, including outer and inner hair cells and supporting cells. There is neural innervation of the organ of Corti and the cochlear neurons are present, with dendrites extending from the cell bodies to the organ of Corti

Olivopontocerebellar system. a An H&E/LFB-stained section that compares the patient’s rostral medulla with a control. The patient’s entire medulla is small. Volume has been lost in the inferior olivary nucleus (ION) and reticular formation, and the medial vestibular nucleus (MVN) is slightly red, which represents a gliotic reaction to neuron loss. A higher magnification view of the ION in (b) reveals many remaining neurons; however, they are at a lower density than normal (see “Results”). They appear more spread out and do not show large patches of loss. Rare axons immunostain for amyloid precursor protein (APP) in (c). Similar to the medulla, the pons from the patient in (d) is small compared to the control. The tegmentum (Teg) has nearly the same size in both, but the base is moderately shrunken. The trigeminal nerve (V) is similar in both. To illustrate the patchy pattern of loss in the pontine base, the more gliotic regions were color-selected and then blackened (e). In these patches of gliosis, neurons are lost; in adjacent gray matter regions, they are spared. Notice that the dorsal aspect of the pontine base displays only slight involvement. As in the medulla, a few APP-immunoreactive axons are present in the pontine base white matter (f); these are rare. g, h H&E/LFB stains that illustrate the normal histology of the cerebellar gray matter. The molecular layer (ML) is not atrophic, the Purkinje neurons layer (PNL) has an appropriate number of large neurons, and the internal granular layer is normal. The dentate nucleus has a normal contingent of neurons. Correlating with the normal dentate nucleus, the superior cerebellar peduncle (scp) in (d) is fully myelinated, compared to the control. A neurofilament immunostain in (i) highlights only very rare axonal torpedoes in the IGL (brown-staining oval)

Pancreas pathology. a Medium magnification view of the pancreas stained with hematoxylin and eosin (H&E). The organ has a normal lobular architecture; however no small, pale islands containing islets cells are visible. This is confirmed in panel (b), which has been immunostained with synaptophysin; no islands of islets cells are identified

Gross pathology. a Ventral view of the brainstem and optic nerves. The optic nerve (II) has a light brown color, rather than white, and has shrunken almost to the size of the oculomotor nerve (III). The remaining cranial nerves are unremarkable (IV–VIII). However, both the medulla (white arrowheads) and pons (black arrowheads) are significantly shrunken. b The diminution of the pontine base compared to a normal control. While the tegmentum (teg) has a normal height, the base is significantly smaller in all dimensions. c Similarly illustrates changes in the rostral medulla at the level of the inferior cerebellar peduncle (icp). The inferior olivary (ION) bulge is flattened and the medullar reticular formation (RF) is small. d A normal lateral geniculate nucleus (LGN) and medial geniculate nucleus (MGN) at the level of the posterior commissure (pc). e In the patient, the MGN has the same light gray color as the control; in contrast, the LGN completely lacks the darker brown color of the control. The coronal section in (f), which includes the LGN in (e), illustrates the essentially normal telencephalon. The lateral ventricles (lv) are not dilated, the corpus callosum (cc) is not atrophic or discolored, the thalamus (Th) is of normal size and configuration (except for the pallor in the LGN), and no hippocampal (Hip) shrinkage is present. Similarly, the radial section of the cerebellum in (g) displays no atrophy of the folia, and the dentate nucleus (DN) has a normal size and color

Hypothalamus–pituitary axis. a–c H&E/LFB stains, c, e are H&E stains, d an immunostain for glial fibrillary acidic protein (GFAP). The coronal section of the hypothalamus in panel (a) is a field view showing the locations of the paraventricular (PVN) and supraoptic (SON) nuclei. The median eminence (ME) is preserved while the optic tract (OT) has lost most of its central myelinated axons. The large neurons with peripherally marginated Nissl that characterized the PVN (b1) and SON (b2) are absent in these sites. The pituitary in (c) lacks a normal neurohypophysis; serial sections through the remaining pituitary were similar. Immunostains for GFAP in (d) show that the small rim of eosinophilic material in (c) represents a remnant of the posterior pituitary. The entire neurohypophysis is confined to a narrow band (between the arrowheads) at the posterior of the adenohypophysis. A small area of the pituitary that lacks normal architectural nesting in (c) (origin of arrow) still retains a normal complement of eosinophilic, basophilic and amphophilic cells (e)

Eye. a, b Compare the retinal histology (H&E) in the patient and a control retina. They are at the same magnification, as determined by the similar width of the rod inner and outer segment layers. The patient’s retina has very few remaining retinal ganglion neurons (RGN) in the ganglion cell layer (GCL). Neurons in the inner (INL) and outer (ONL) neuronal layers are relatively preserved, while both the inner (IPL) and outer (OPL) plexiform layers are greatly diminished. c Stained for calretinin and shows an occasional RGN in the GCL (black arrowhead). Some calretinin-positive cells lie within the inner aspect of the INL. The Neu-N immunostain in (d), which reacts with a subset of neurons, reveals more RGN (black arrowheads), several of which are small or shrunken. e is an H&E-Luxol fast blue (H&E/LFB) stain of the head of the optic nerve. Many of the ganglion neuron axons have degenerated, resulting in pale myelin staining. Calretinin immunostains in (f) highlight remaining retinogeniculate axons

Lateral geniculate nucleus. a A low-magnification view of the hippocampus and lateral geniculate nucleus (LGN). For orientation, the inset shows a normal LGN. Notice that the LGN lies medial to the attachment point (ap) of the choroid plexus (cp), while the tail of the caudate nucleus (CN) is lateral to this point. In the control, the LGN is completely surrounded by myelinated axons; a myelin boundary (mb) separates the LGN from the surface of the brain. b A higher magnification view of the LGN, from the box in (a). This image is a composite of multiple smaller images taken at higher magnification and then combined to give higher resolution. The LGN lacks any discernable six-layer structure (see the control LGN). The optic radiation (or) is completely devoid of myelinated axons. A small amount of myelin is present in the myelin boundary (mb). c A higher magnification view from the box in (b). A few remaining magnocellular neurons (MCN, arrows) lie immediately superior to the myelinated axons; however, most neurons in the LGN are absent

Primary visual cortex. The coronal section of the primary visual cortex, stained with H&E/LFB, is illustrated in a field view in (a). The prominent white matter band within area 17 on gross inspection is composed of well-myelinated axons (line of Gennari or outer band of Baillarger). The optic radiation, which arose from the LGN and traveled lateral to the occipital horn of the lateral ventricle, exhibits pale myelin staining in this section, in keeping with the loss in the LGN. In this patient, the posterior recesses of the lateral ventricle had closed and left a line of ependymal rests (er). The small box in (a) is magnified in panel b to show the cortical layers. The outer band of Baillarger, representing intracortical connections, is well myelinated in layer IV-B. Small stellate or granular neurons in IV-C are present. Layer IV-C is illustrated at high magnification in (c) and (d). Radially oriented myelinated axons are identified on both the LFB (c) and Bielschowsky (d) stains. Neither stain shows myelin ovoids or axonal spheroids. Layer IV-C (and less so layer IV-A) is the major input lamina for the LGN; in this patient within the scope of this analysis, they are histologically normal