1124 PART 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

tral and dorsal roots, and dorsal root ganglia and

along the entire length of the peripheral nerves.
Sparse focal infiltrates of inflammatory cells (lym-
phocytes and other mononuclear cells) may also be
found in lymph nodes, liver, spleen, heart, and other
organs. Swelling of nerve roots at the site of their
A dural exit has been emphasized by some authors and
theorized to cause root damage.
Variations of this pattern of peripheral nerve
damage have been observed, each perhaps repre-
senting a different immunopathology. Rarely, in a
clinically typical case, there may be widespread de-
myelinative changes and only a paucity of perivas-
cular lymphocytes. In patients whose electrophysi-
ologic tests display severe axonal damage early in
the illness as discussed later, the pathologic findings
B corroborate the predominantly axonal nature of the
disease with secondary myelin damage and little in-
flammatory response. An occasional case has shown
an inflammatory process with primary axonal dam-
age rather than demyelination (Honovar et al).

Pathogenesis and Etiology Most of the evidence

supports a cell-mediated immunologic reaction di-
rected at peripheral nerve. Waksman and Adams
demonstrated that experimentally induced periph-
eral nerve disease (experimental allergic neuritis, or
C
EAN), clinically and pathologically indistinguish-
able from GBS, develops in animals 2 weeks after
immunization with peripheral nerve homogenates.
Brostoff and colleagues suggested that the antigen
in this reaction is a basic protein, designated P2,
found only in peripheral nerve myelin. Subsequent
investigations by these authors indicated that the
neuritogenic factor might be a specific peptide in the
P2 protein. However, it has become evident that
there is no dominant antigen-antibody reaction in
D GBS and that any number of myelin and axonal el-
ements may be involved in inciting the immune re-
action. The pathologic steps in this proposed reac-
tion are diagrammatically illustrated in Fig. 46-3.
Figure 46-3. Diagram of probable cellular events in acute inflammatory polyneuropathy Hartung and colleagues have found high levels of
(Guillain-Barré syndrome). A. Lymphocytes attach to the walls of endoneurial vessels and soluble interleukin (IL)-2 receptors, that is shed
migrate through the vessel wall, enlarging and transforming as they do so. At this stage no
from activated T cells, and IL-2 itself in the serum
nerve damage has occurred. B. More lymphocytes have migrated into the surrounding tissue.
of patients with acute GBS, reflecting activation of
The first effect on the nerve is breakdown of myelin, the axon being spared (segmental
demyelination). This change appears to be mediated by the mononuclear exudate, but the these cells. As noted below, complement also seems
mechanism is uncertain. C. The lesion is more intense, polymorphonuclear leukocytes being to be a necessary factor in the initial attack on my-
present as well as lymphocytes. There is interruption of the axon in addition to myelin sheath elin.
damage; as a result, the muscle undergoes denervation atrophy and the nerve cell body shows Although the transmission of EAN by T cells
central chromatolysis. If the axonal damage is distal, the nerve cell body will survive, and sensitized to myelin is strong evidence of their role
regeneration and clinical recovery is likely. If, as in D, axonal interruption has occurred in GBS, antimyelin antibodies are probably involved
proximally because of a particularly intense root or proximal nerve lesion, the nerve cell body in the initial part in the disease. The serum from
may die and undergo dissolution. In this situation, there is no regeneration, only the possibility patients with GBS causes damage to myelin in tissue
of collateral reinnervation of muscle from surviving motor fibers. (From Asbury et al, 1969,
cultures and induces a characteristic (“vesicular”)
by permission.)
form of myelin destruction. Subepineural injection
of serum from GBS patients into the sciatic nerve of
virtually all cases show perivascular (mainly perivenous) lympho- rats leads to local demyelination and electrical conduction block.
cytic infiltrates. Later, the characteristic inflammatory cell infil- The studies by Koski and associates of complement-dependent my-
trates and perivenous demyelination are combined with segmental elin damage by IgM antimyelin antibodies in GBS provided evi-
demyelination and a variable degree of wallerian degeneration. The dence that antimyelin antibodies are able to initiate myelin destruc-
cellular infiltrates are scattered throughout the cranial nerves, ven- tion even though T cells and that macrophages are the ultimate
1150 PART 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

locities, but there is no conduction block as occurs in other acquired perature-dependent pattern is the most characteristic feature of the
demyelinating polyneuropathies. The pathologic changes are most disease as pointed out by our colleague T. Sabin. The sensory maps
intense in the distal segments of the nerves, with the expected chro- he has drawn (Fig. 46-4) are typical of established cases. The nose,
matolysis of their cell bodies. earlobes, and elbows may be affected early as a result of the cool-
The cause of uremic polyneuropathy is unknown. What has ness of the skin in those areas. The process evolves over years.
been called the “middle molecule” theory is plausible. The end Eventually the anesthesia spreads to involve most of the cutaneous
stage of renal failure is associated with the accumulation of toxic surface. Extensive sensory loss is followed by impaired motor func-
substances in the range of 300 to 2000 molecular weight. Further- tion owing to invasion of muscular nerves where they lie closest
more, the concentration of these substances, which include meth- to the skin (the ulnar nerve is the most vulnerable). There is a loss
ylguanidine and myoinositol, has been shown to correlate with the
degree of neurotoxicity (Funck-Brentano et al). These toxins (and
the clinical signs of neuropathy) are not greatly reduced by chronic
hemodialysis. In contrast, the transplanted kidney effectively elim-
inates substances of wide-ranging molecular weights, which would
account for the almost invariable improvement of neuropathy after
transplantation. As is the case with uremic encephalopathy, urea
alone given to experimental animals and in controlled studies
of humans, does not seem capable of inducing a metabolic neu-
ropathy.

Alcoholic-Nutritional Polyneuropathy (See page 989 and Chap.

41) In all patients with alcoholic-nutritional polyneuropathy who
for some reason remain untreated with vitamin and protein resto-
ration, the weakness and atrophy of the legs, and to a lesser extent
the arms, may reach an extreme degree. Thus this disease, though
subacute in its evolution as described earlier in the chapter, be-
comes a frequent cause of chronic polyneuropathy. There are usu-
ally prominent sensory features and considerable acral pain and
allodynia. Certain cases of diabetic neuropathy behave similarly.

Leprous Polyneuritis This is the classic example of an infectious

neuritis, due to the direct invasion of nerves by the acid-fast My-
cobacterium leprae. The disease is still frequent in India and Cen-
tral Africa, but there are many lesser endemic foci including parts
of South America and of Florida, Texas, and Louisiana that border
on the Gulf of Mexico.
The initial lesion in leprosy is an innocuous-appearing skin
macule or papule, which is often hypopigmented and lacking in
sensation and is caused by the invasion of cutaneous nerves by M.
leprae. In patients with a degree of immunologic resistance to in-
fection the disease may progress no further than this stage, which
is spoken of as indeterminate leprosy, or it may evolve in several
ways, depending mainly upon the resistance of the host. The bacilli
may be locally invasive, producing a circumscribed epithelioid
granuloma that involves cutaneous and subcutaneous nerves and
results in a characteristic hypopigmented patch of superficial numb-
ness and sensory loss (tuberculoid leprosy). The underlying sub-
cutaneous sensory nerves may be palpably enlarged. If a large nerve
in the vicinity of the granuloma is invaded (the ulnar, median,
peroneal, posterior auricular, and facial nerves are most frequently
affected), a sensorimotor deficit in the distribution of that nerve is
added to the patch of cutaneous anesthesia.
In contrast to the limited tuberculoid variety of leprosy, lack
of resistance to the organism permits the proliferation and hema-
togenous spread of bacilli and the diffuse infiltration of skin, ciliary
bodies, testes, lymph nodes, and nerves (lepromatous leprosy).
Figure 46-4. Patterns of sensory loss in leprosy. The localization of these
Widespread invasion of the cutaneous nerves produces a symmet- areas to cooler portions of the body is unique to this disorder. Shown in
rical pattern of pain and temperature loss involving the pinnae of the upper figure is the sparing of the palmar and antecubital surfaces and
the ears as well as the dorsal surfaces of hands, forearms, and feet variation in the sensation within the distribution of a single sensory nerve.
and anterolateral aspects of the legs— a distribution that is deter- In the lower figure, almost universal analgesia is found but there is still
mined by the relative coolness of these parts of the skin. This tem- sparing of warmer regions of skin. (From Sabin with permission.)