Page 944 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 67 Autoimmune Peripheral Neuropathies 911

4. Systemic transfusion of anti-MAG IgM paraproteins produces vasculitis, Raynaud phenomenon, renal involvement with pro-
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segmental demyelination in chickens, with deposition of teinuria, and polyneuropathy. Type II cryoglobulinemia may be
IgM on to the outer lamellae of the myelin along with splitting associated with an underlying lymphoproliferative process. There
of the myelin lamellae, similar to that observed in the human is an increased incidence (up to 90%) of hepatitis C virus infection
neuropathy. in patients with mixed cryoglobulinemia. The nerve biopsy shows
5. Immunization of cats with purified SGPG causes an ataxic perivascular inflammatory cuffing with axonal degeneration.
neuropathy, similar to the one seen in humans, with involve-
ment of the dorsal root ganglia including inflammation within PARANEOPLASTIC PERIPHERAL NEUROPATHIES
the ganglionic neurons. 32 WITH ANTI-HU ANTIBODIES

Peripheral neuropathy is not an uncommon complication of
POLYNEUROPATHY, ORGANOMEGALY, cancer, related either to the systemic effects of the tumor or,
ENDOCRINOPATHY, MYELOMA, AND more often, to various neurotoxic chemotherapeutic agents. It
SKIN CHANGES usually affects the small nerve fibers causing numbness or painful
dysesthesias. The most distinct immune-related neuropathy in
A subset of patients with malignant IgG or IgA monoclonal patients with cancer is paraneoplastic sensory neuronopathy
proteins have polyneuropathy with osteosclerotic myeloma. Most (PSN), often associated with small cell lung cancer, and to a
of them have POEMS syndrome (polyneuropathy, organomegaly, lesser degree with breast cancer or other neoplasms, such as
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endocrinopathy, M protein, and skin changes). Not included lymphoma or thymoma. It might be the presenting symptom
in the acronym are several features, such as sclerotic bone lesions, preceding the discovery of the tumor by months. PSN has a
giant lymph node hyperplasia (Castleman disease), papilledema, unique clinical picture, characterized by burning or aching
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pleural effusion, edema, ascites, and thrombocytosis. More than paresthesias; sensory loss of the large fibers, causing profound
50% of patients with osteosclerotic myeloma of the IgA or IgG sensory gait ataxia and choreoathetotic movements related to
type have a sensorimotor, symmetric polyneuropathy with mixed loss of proprioception in the feet and hands; normal strength;
demyelinating and axonal features and high (usually 200 mg/ and areflexia. Some patients may have autonomic dysfunction,
dL) CSF protein. Pure axonal neuropathies can be also seen. In encephalopathic symptoms, or cerebellar disturbances. CSF
POEMS, the neuropathy tends to be associated with edema in protein is increased, electrophysiological testing shows an axonal
the legs, with hyperpigmentation, sclerodermatous thickening, sensory neuropathy, and nerve biopsy demonstrates axonal
or papular angiomas of the skin, and hypertrichosis with dark degeneration with rare mononuclear cell infiltrates. PSN is a
hair. Endocrinopathy most often includes gonadal failure, ganglionopathy (sensory neuronopathy) caused by a variable
amenorrhea, impotence, gynecomastia, hypothyroidism, diabetes, degree of inflammation in the dorsal root ganglionic neurons.
or elevated prolactin levels. The IgG class is slightly more common These patients have specific IgG anti-Hu autoantibodies directed
than the IgA class, with λ light chain present in the majority of against a closely spaced group of proteins with a molecular weight
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the patients. Bone lesions can be sclerotic, solitary, or multiple, of 35–40 kDa. The antibodies are found in higher titers in CSF,
sparing the skull and the extremities. Pathological changes in suggesting intrathecal synthesis. The Hu protein is also present
lymph nodes resemble those of Castleman disease, which can in the tumors of patients with PSN. Further, low titers of anti-Hu
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also be associated with polyneuropathy. In POEMS, there is antibodies can be seen in up to 20% of patients with small cell
an imbalance of proinflammatory cytokines with increased IL-1β, lung cancer, even without neurological symptoms, suggesting
IL-6, and tumor necrosis factor-α (TNF-α). Vascular endothelial that PSN may be the result of an autoimmune reaction against
growth factor (VEGF) may play a major role because it induces antigens shared by both the tumor cells and the dorsal root
a rapid increase in vascular permeability and is a growth factor ganglionic neurons. Although the role of anti-Hu antibodies in
important in angiogenesis and endothelial cells. 34 the causation of PSN is unclear, these antibodies are specific
In some patients, the neuropathy responds to steroids, markers to detect an occult small cell lung cancer in patients
tamoxifen, or alkylating agents. In others, it may respond to the who present with sensory ataxic neuropathy. Some patients may
removal or irradiation of the solitary sclerotic lesion, suggesting have other paraneoplastic antibodies, such as collapsing response
that the tumor may secrete neurotoxic factors. IVIG and plas- mediator protein (CRMP-5) often referred to as anti-CV2. 36
mapheresis are ineffective. The median survival is 165 months. 35
Recently, autologous peripheral blood stem cell transplantation AUTOIMMUNE AUTONOMIC NEUROPATHIES
has been shown to result in significant improvement with reduc-
tion of VEGF, improved nerve conduction velocity, and increased Autoimmune autonomic neuropathy (AAN) is highlighted by
survival. 35 circulating antibodies against the ganglionic nicotinic acetyl-
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choline receptors (AChRs). These patients present with a
Cryoglobulinemic Neuropathy subacute (within 4 weeks) or chronic (within months) onset of
Cryoglobulins are proteins that precipitate in the cold and neurogenic orthostatic hypotension, defined as a systolic blood
redissolve when heated (Chapter 58). There are three types of pressure reduction of at least 30 mm Hg or mean blood pressure
cryoglobulin: type I, which is monoclonal, often of the IgM and reduction of at least 20 mm Hg that occurs within 3 minutes
IgG class; type II, which is mixed polyclonal, with one monoclonal of head tilting. The subacute onset is often preceded by a viral
(often monoclonal IgM with polyclonal IgG); and type III, which infection. In addition, patients demonstrate three or four
is polyclonal (often IgM and IgG). Polyneuropathy occurs most parasympathetic/enteric symptoms: sicca (dry eyes and dry
often with mixed cryoglobulinemias and presents as distal, sensory, mouth); abnormal pupillary response to light; upper gastro-
symmetrical polyneuropathy or as mononeuropathy multiplex. intestinal symptoms (early satiety, postprandial nausea, and
These patients also have purpura, polyarthralgias, cutaneous vomiting that lead to severe weight loss); and neurogenic bladder.