Axonal transport is essential for the growth, development, and function of the vertebrate nervous system. Retinal ganglion cells (RGCs), like many neurons, have relatively small cell bodies where manufacture of necessary proteins, enzymes, and mitochondria occur and are then distributed to their long peripheral extensions (axons) ( Figure 1 ). ^, RGCs measured in Epon plastic-embedded 1-μm sections to minimize artifact demonstrate variable cell body diameters averaging 18 to 20 µm with peripheral extensions to the lateral geniculate nucleus, the first synapse of the lower visual pathway, at a distance of approximately 75 mm in a normal adult. Conversion to inches and miles provides a more easily understood comparison of a typical RGC of 0.0007-inch diameter maintaining an array of peripheral membranes extending for approximately 6 miles in addition to synaptic functions. The importance of axonal transport to neurologic disease, including 5 ophthalmology-related issues, has been summarized recently, identifying 41 recognized disorders due to gene defects related to transport machinery including motor proteins, motor adaptors, and micrcotubules. Figure 2 .

Diagram illustrating features of both orthograde (toward synapse) and retrograde (toward cell body) axonal transport, including the molecular motors that move intraaxonal materials in both directions. Mitochondria, produced in the cytoplasm, move in an oscillating manner with a net orthograde flow.

A. Typical end bulb sausagelike swelling demonstrated at autopsy in axons after shearing injury to the central nervous system (CNS) myelinated white matter tract. This male construction worker had survived a severe blunt head injury from a crane hook for many months although mentally impaired. (photomicrograph, APP toluidine blue, immunohistochemistry, original magnification × 400). APP = amyloid precursor protein; TBI = traumatic brain injury.

Slow orthograde transport (0.4-0.5 mm/d) toward the synapse is thought to primarily subserve maintenance and repair of the long peripheral processes of RGCs and many other neurons with even longer extensions such as motor horn cells of the spinal cord. The rapid phase of orthograde transport (100-500 mm/d) supports growth when occurring and supplies the needed materials to maintain synaptic function. Intermediate-speed orthograde transport (5-50 mm/d) has been described, but intermixing with retrograde transport in this speed range has caused confusion in defining its speed. Mitochondria have a rapid oscillating motion but a net orthograde motion that ensures necessary energy for all required functions. Retrograde transport (50-200 mm/d) provides brain-to-RGC feedback and carries reusable materials back to the ganglion cell soma for sequestration of nonreusable items into lysosomes.

Numerous experimental studies in foveated monkeys with optic nerve anatomy identical to humans have demonstrated that both orthograde and retrograde transport are sharply interrupted in the lamina cribrosa (LC, aka lamina scleralis; zone 4 in Figure 3 ) by elevation of intraocular pressure (IOP), establishing that relatively precise location as the likely initial site of nerve injury in glaucoma. The relatively rigid glial-collagenous structure of the LC which thickens and becomes less pliable with age likely renders its component of axonal bundles increasingly vulnerable to pressure-induced distortion. ^{, ,}

Rhesus monkey optic nerve head with miniaturized anatomy identical to humans demonstrating zones histologically recognizable by light and electron microscopy. Zone 1 is the nerve fiber layer at the disc edge still containing retinal vasculature and Mueller cells in addition to a small interaxonal glial component (5%±4% by tissue volume). Zone 2 (the optic disc as seen clinically) lacks Mueller cells and can swell markedly as in hypotony or papilledema. The percentage of tissue volume occupied by interaxonal glial processes, measured in transmission electron micrographs (TEMs) increased gradually from zone 1 (5%±4%) through zone 2 (lamina retinalis) and zone 3 (lamina choroidalis) to a maximum in zone 4 (the lamina cribrosa, at (21%±9%). As is obvious in the figure, the diameter of the nerve increases dramatically posterior to the line of myelination. Zone 4 is the lamina cribrosa or scleral portion of the optic nerve head, with astrocytic columns forming the vertical boundaries of axonal bundles coursing toward the optic nerve posteriorly. The percentage interaxonal glial component in this zone increases to 23±7 not counting the boundary astrocytes lining the axonal pores. The collagen beams oriented perpendicularly to the axonal bundles are all lined by glial cell cytoplasm. The line of myelination is distinctly marked by myelin sheaths around axons staining blue in this preparation. (1-μm Epon-embedded section, toluidine blue, original magnification × 31.25).

Hypotony and increased intracranial pressure cause remarkable axonal swelling with orthograde transport block both in the LC and disc tissues. ^, Retrograde transport is more sensitive (observed at lower IOP than orthograde block) in the same animal models. The anatomy of the LC, especially the relatively dense neural tissue packing of interaxonal glial processes within the axonal columns demonstrated by morphometric measure in transmission electron micrographs, renders the region the most congested in the anterior optic nerve.

Exemplary of the tight confines of passage through the region, some relatively fragile intraocular tumor cells (including lymphoma and retinoblastoma) can often be observed accumulated in axons just anterior to the LC beams some demonstrating rupture as they transit through the LC (D.S.M., personal microscopic observation in intraocular lymphoid lesions and retinoblastoma during extension into the optic nerve).

Amyloid precursor protein (aka APP-A4, amyloid beta A4 protein, β pre-amyloid human protein, or Alzheimer precursor protein) has been studied since the 1980s and is regarded as a reliable, highly sensitive marker of axonal injury in both myelinated and nonmyelinated axons. Neuropathologists use it regularly to identify shearing injury to the central nervous system myelinated tracts, where it demonstrates sausage-like swellings within axons at the injury site ( Figure 1 ).

Herein we report illustrative cases demonstrating APP-A4 accumulations especially within LC axons in 62 suspected abusive head trauma (AHT) eyes referred for pathology study as suspected shaken baby cases. At least 4 prior publications summarized the rationale for APP-A4 as a marker of optic nerve injury in AHT. We speculate that AHT may include transient elevation of IOP as an explanation for APP-A4 accumulations in the LC similar to that demonstrated experimentally.

APP-A4 is an evolutionarily preserved molecule, the precursors of which are generated in the cytoplasm of neuronal cells that are then transported as large complex molecules in the rapid orthograde stream to the site of axonal injury presumably to help with tissue repair, APP-A4 antigens are remarkably durable in formalin-fixed tissue and still demonstrable 40 years after formalin fixation and paraffin embedding. To our knowledge, APP-A4 is the only immunohistochemical (IHC) marker of axonal transport so far applied to human autopsy ocular tissue. Bais and associates recently reported IHC findings in AHT including amyloid precursor protein, ubiquitin, a regulatory protein, and glial fibrillary acid protein, a common component of retinal architecture. To our knowledge, their study was the first to emphasize APP-A4 block in the lamina cribrosa of AHT victims besides including a large control group and exhaustive histopathologic correlations with retinal hemorrhages.

Although seldom recorded and not previously reported, elevation of IOP in AHT is likely for several reasons, including frequent retinal and vitreous hemorrhages and possible clogging of outflow pathways by red cells, macrophages, or fibrin. In addition, constriction of ocular venous outflow by subdural blood expanding the optic nerve sheath, inflammation from retinal trauma debris, vitreous hemorrhage, angle contusion injury, and tears in anterior segment structures or retina from associated blunt trauma and secondary uveitis may contribute.

METHODS

The University of California, Irvine, institutional review board acknowledged that our study posed no risk to human subjects and qualified as exempt from institutional review board approval. Over a 4-year period, the University of California, Irvine, Ocular Pathology laboratory received 36 sets of suspect AHT eyes from the Los Angeles Coroner in 10% neutral buffered formalin, all of which were eventually studied with APP-A4 IHC ( Tables 1 and 2 ). All globes were opened, after laterality was confirmed and standard globe measurements and transillumination completed. Orbital optic nerve segments were separated from the globes, leaving a 5-mm attached stump. Cross and longitudinal optic nerve sections were submitted for paraffin processing separately.

TABLE 1

APP-A4 in Abusive Head Trauma Suspect Eyes With LC Block and Known Survival After Injury

Case no.	LC block R/L	Survival Days	Age, mo	LC present	Comment
1	+/+	3	13	2	High ICP; cerebral hemorrhage
2	+/+	3	47	2	ON infarct OD >ICP RH
3	+/+	4	5	2	SDH multiple injuries
4	+/+	1	12	2	Extensive RH
5	0/+	4	7	1	OD lost; mild RH OS
6	+/+	191	10	2	SDH; multiple fractures
7	+/+	4	12	2	SDH, midline shift
8	+/0	70	7	1	SBS; SDH, optic atrophy; ROP
9	+/+	6	11	2	28-wk premature DIC, RH
10	+/+	1	7	2	Skull and rib fracture
11	0/+	1	7	1	OD lost, Massive RH
12	+/+	1	9	2	Developmental delay; SID in bed
13	+/+	16	3	2	Foster child SBS diagnosis
14	+/+	382	7	2	Pierre-Robin, a optic atrophy
15	+/+	1	12	2	Skull fracture at home
16	+/+	3	12	2	Home skull fracture
17	+/+	1588	48	2	SBS; SDH, VP shunt
18	+/+	3	11	2	Obtunded, rib fractures
19	0/+	2	12	1	SDH, RH, RD, contusion
20	+/+	1	24	2	Massive RH and RD
21	+/0	3	144	1	OS disc lost
22	+/+	19	24	2	SDH cerebral hernia
23	+/+	1	48	2	Skull fracture, ON hemorrhage
				42

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