An endoneurial mononuclear cell infiltrate composed of macrophages and lymphocytes (chiefly CD4⁺) is often present (Fig. 9.1), and although the predominant cell type may depend on the stage of evolution of nerve damage, macrophages are usually most numerous (Figs. 9.1, 9.2, and 9.3) (Wisniewski et al. 1969; Brechenmacher et al. 1987; Pollard et al. 1987). The prominence of lymphocytes varies widely in the literature. Asbury and colleagues commented on the “primacy of lymphocytic lesions in idiopathic polyneuritis” (Asbury et al. 1969), but most studies have shown few or no lymphocytes even with immunohistochemistry (Honavar et al. 1991; Mancardi et al. 1988; Hughes et al. 1992; Kanda et al. 1989; Berciano et al. 1993). It is worth noting that only 5 of 57 specimens in the largest GBS nerve biopsy study reported to date demonstrated an increase in endoneurial lymphocytes (Brechenmacher et al. 1987), despite the presence of active demyelination in most of these specimens. It has been argued that the absence of lymphocytes in sural nerve biopsies is due to the limited sampling inherent therein, but several autopsy studies included a close examination of the nerve roots (Honavar et al. 1991; Kanda et al. 1989; Berciano et al. 1993) and did not support this notion. When present, lymphocytes may be perivascular or randomly distributed in the epineurium and endoneurium (Fig. 9.1). Debris-filled macrophages can be seen in association with axons (vide infra), in a perivascular or subperineurial distribution, or randomly dispersed throughout the nerve fascicle (Fig. 9.3). Schwann cells are typically free of myelin debris in AIDP, which differs from typical demyelination in which Schwann cells are the initial degradative site. Schwann cells separate from their myelin sheaths, reenter the cell cycle, produce daughter Schwann cells outside the original basal lamina, and reenter and remyelinate the denuded internode. Axonal loss or axonopathy may represent a “bystander effect” due to endoneurial toxic cytokines (e.g., TNF-α) or edema-induced local ischemia and compression. It is surprising for a demyelinative condition that AIDP often shows considerable loss of axons (Fig. 9.2). Schwann cell proliferation begins at 1–2 weeks after the onset of disease (Asbury et al. 1969) and contributes to endoneurial hypercellularity. Polymorphonuclear infiltrates have been reported in early fulminant disease (Asbury et al. 1969), but we have not observed this in the sural nerve nor has it been noted in other large series (Prineas 1972; Brechenmacher et al. 1987). Plasma cells are infrequently seen. Endoneurial edema is often present but we have never seen it in the absence of other pathology, contrary to the initial reports of Haymaker and Kernohan (1949). Months and even years after the acute illness, inflammatory cells may still be seen in peripheral nerve (Asbury et al. 1969).

The predominant pathological process in AIDP is segmental demyelination and remyelination. The entire spectrum of normally myelinated, thinly myelinated, and denuded axons can be seen (Figs. 9.2 and 9.3). A longitudinal section shows a long expanse of naked axon (arrow, Fig. 9.3d) surrounded by multitudes of closely applied, myelin-containing macrophages. The severity of these changes often depends on the duration of the disease. Some cases may show selective involvement of large myelinated fibers. Active axonal degeneration is not uncommon, but this is usually minor relative to the demyelinating changes. A demyelinated axon with an adjacent macrophage filled with myelin debris may be mistaken for a myelin ovoid of axonal degeneration if the attenuated axon is not visualized by light microscopy. As Schwann cells do not accumulate large amount of debris, any cell laden with myelin breakdown products is likely to be a macrophage. Axonal degeneration should not dominate the picture if a diagnosis of “primary demyelination consistent with GBS” is to be made (however, exceptions exist, vide infra).

Widening of the nodal gap, best seen on teased fiber preparations, is an early but nonspecific alteration, whether in GBS (Asbury et al. 1969) or in other demyelinating or axonal neuropathies. Onion bulbs have been seen in cases reported as GBS (Prineas 1972), but their presence suggests chronicity and that the patient more likely suffers from CIDP presenting with an acute exacerbation of previously subclinical disease.

In the initial case of axonal GBS (AMAN) studied at autopsy, peripheral nerve showed only axonal degeneration and scanty inflammation (Feasby et al. 1986) which overlaps with some cases of clinically typical GBS (Prineas 1972; Hughes et al. 1992; Vallat et al. 1990). Although typical cases of AMAN show mild sensory axon degeneration, some cases of axonal GBS may show extensive sensory changes which are designated acute motor sensory axonal neuropathy (AMSAN). These cases are thought to represent a spectrum of a single type of immune attack on the axon differing in severity, immunologic presentation, or distribution of a critical epitope (Griffin et al. 1996, vide infra). Since the recognition of additional cases of AMAN/AMSAN, it has become clear that the most striking differences between AIDP and AMAN/AMSAN are the paucity of lymphocytic inflammation and the lack of demyelination and a variable increase in the number of degenerating axons in AMAN/AMSAN. Axonopathy ranges from diffuse axonal degeneration to distal axonal damage, with denervated neuromuscular junctions; the latter changes may be reversed rapidly.

Ultrastructural examination shows a complex collection of pathological findings (Fig. 9.6) including naked axons, edema separating axons, a background of macrophages with debris, demyelination (arrowhead, Fig. 9.6), and remyelination (arrows, Fig. 9.6). Ultrastructural analysis is critical for establishing the diagnosis of macrophage-mediated demyelination (Figs. 9.7, 9.8, and 9.9), the hallmark of inflammatory demyelinating neuropathy, whether acute (GBS) or chronic (CIDP). The classic picture is of a macrophage penetrating the Schwann cell basement membrane (Fig. 9.7a, b, arrows), separating Schwann cell cytoplasm from its underlying intact myelin (Fig. 9.7c) and insinuating cytoplasmic fingers into the intraperiod lines of the myelin sheath. Myelin destruction may seem to occur by dissolution along the site of contact with macrophage processes or through the separation, engulfment, and removal of large segments of myelin off the axon. The invading macrophage is rich in organelles including smooth ER, mitochondria, Golgi, and ribosomes, but the processes inserted into the myelin lamellae are largely free of these. All the while, the axon maintains a relatively normal appearance. Sometimes several processes may attack the myelin sheath at once, and it is unclear if they belong to one or several macrophages. Debris may appear as pieces of normally compacted myelin, vesicular myelin, lamellar disorganized osmiophilic material, or amorphous globules (Figs. 9.8, 9.9, and 9.10). Rarely, debris that seems to be extracellular may be detected (Prineas 1972).

The picture described above is not always easy to demonstrate. A more common observation is the presence of supernumerary cell processes sharing the Schwann tube with a residual Schwann cell and a demyelinated axon (Fig. 9.8); further afield, a macrophage may be present but separated from the affected fiber. Presumably the site of macrophage penetration has occurred outside the plane of section. As Schwann cells do not commonly accumulate myelin debris in AIDP, one may infer that the cell processes harboring phagocytosed lipid debris are those of a macrophage (Prineas 1972). The Schwann cell may be absent altogether, with the axon sharing a Schwann tube only with macrophages. Demonstration of segmental demyelination alone cannot establish macrophage-mediated demyelination. In summary, what is characteristic about macrophage-mediated demyelination is separation or peeling off of normal appearing myelin by fingerlike macrophage extensions; this process cannot be visualized after myelin disintegration is complete, and in such a situation, it cannot be determined whether the macrophage is the primary effector of the damage or simply a scavenger cell (Fig. 9.10). Alterations of myelin periodicity have very rarely been reported in GBS, including both uncompacted myelin (Brechenmacher et al. 1987) and widely separated myelin involving the two or three outermost turns of the myelin sheath (Vallat et al. 1994).

Schwann cells can appear normal as they are being separated from their myelin or may show reactive or degenerative changes, with dilated ER, loss of organelles, and watery distension. Little or no myelin debris accumulates within them. Most axons appear unperturbed in the face of the myelin destruction surrounding them, but some show various stages of degeneration, ranging from loss of electron density to Wallerian degeneration. Naked axons have been said to shrink by as much as 50 % in volume as a consequence of the myelin loss, with a resulting increased density of tubules and filaments, and wrinkling of the axolemma (Prineas and McLeod 1976; Carpenter 1972; Raine et al. 1969). Evidence of recent remyelination is found in the presence of axons surrounded by very thin, poorly compacted myelin sheaths and Schwann cells rich in organelles.

A loss of unmyelinated axons may be seen but is rarely prominent and never predominant (Prineas 1972). Tubuloreticular inclusions have rarely been seen in endothelial cells and macrophages in GBS associated with HIV infection (Fuller and Jacobs 1989) but never in classic GBS. On two occasions, we have seen mononuclear cells, free of debris, within a seemingly intact myelin sheath without any detectable axon. These were cases with a particularly aggressive course and prominent axonal degeneration, but the observation has been too infrequent to allow generalization. We have never observed this finding outside of GBS. Similar observations were reported by Brechenmacher et al. (1981). A single report claims to document “viral particles” within the nerve in classic GBS (Sibley 1972), but in the absence of any corroborating observations, this must be regarded with skepticism. PCR studies have failed to demonstrate evidence of CMV genome in nerve specimens of patients with GBS (Hughes et al. 1992).

Although myelinated axon numbers are clearly decreased in GBS (Fig. 9.2b), ongoing axonal degeneration may be infrequent at any one time. Nonetheless, some cases of GBS exhibit so much axonal degeneration (Fig. 9.11a) that they can be mistaken for pure axonal degeneration. The case illustrated in Fig. 9.11 was initially thought to represent fulminant axonal degeneration alone; however, examination of other fascicles where myelinated axons were still present demonstrated macrophage-mediated demyelination (Fig. 9.11b, c).

Ultrastructural changes include penetration of macrophage processes into the periaxonal space at the paranode or more distantly (Fig. 9.12a) and demonstration of an entire macrophage within myelin sheaths adjacent to intact axons (Fig. 9.12b, different case). Altered nodal structure with widening of the nodes and distortion of paranodal myelin may be followed by degeneration of outermost myelin terminal loops, eventually causing local degeneration of Schwann cell cytoplasm but sparing the internodal myelin sheath.