Review
The Immunopathogenesis of Guillain-Barré Syndrome
Sindhu Ramchandren, MD, MS, and Robert P. Lisak, MD
Department of Neurology, Wayne State University- Detroit Medical Center, Detroit, Michigan
Seffo and Daw report a case of Guillain-Barré syndrome (GBS) in a patient with T/NK-cell non-Hodgkin lymphoma (NHL), stage Ie-A, after her sixth treatment cycle with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.1 The diagnosis was based on ascending motor weakness proximally and distally with cranial nerve involvement and nearly complete areflexia, albuminocytologic dissociation on cerebrospinal fluid (CSF) analysis, and electrodiagnostic studies demonstrating bilateral acute sensory motor polyneuropathy. Details of the therapy that was initiated are not provided; however, the patient reportedly had continued disease progression, and was discharged to hospice.
The diagnosis of GBS is clinical and is based on presentation, electrodiagnostic findings, and CSF analysis, as well as exclusion of other etiologies. In their discussion, Seffo and Daw have provided a succinct summary of clinical and electrodiagnostic features of GBS; readers are further advised to read the comprehensive review of GBS by Hughes and Cornblath.2 GBS is an acute illness; the duration of symptoms from onset to nadir should be 4 weeks or less; if longer than 8 weeks, the diagnosis is probably chronic inflammatory demyelinating polyneuropathy (CIDP) or its variants. We are not provided with details on the progression of symptoms in the case report to know which category it belongs to. The clinical picture of GBS can be produced by several pathologic subtypes, often distinguished electrodiagnostically. The most common subtype of GBS in Europe and North America is acute inflammatory demyelinating polyradiculoneuropathy (AIDP); the acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) subtypes are more prevalent in Asia and Central and South America, especially following Campylobacter jejuni infections. We are not provided sufficient detail on the clinical electrophysiologic studies to distinguish between the axonal and demyelinating forms in the case report. CSF evaluation should show elevated protein concentration with normal CSF white blood cell count (typically <5 cells/mm3); variations should prompt investigations such as cytology for alternate etiologies. In the case report, the 11 cells/mm3 and the degree of asymmetry, while not excluding GBS, is somewhat atypical.
Some researchers describing rare occurrences of GBS in patients with Hodgkin lymphoma3,4 and NHL5-8 have attributed the GBS presentation either to the underlying disease or its therapy, specifically vincristine, a key component of CHOP therapy. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most important dose-limiting toxicities seen with vincristine exposure.9-11 CIPN manifests as painful dysesthesias, length-dependent sensory loss to pain, temperature and proprioception (legs worse than arms), suppression of deep tendon reflexes in proportion to sensory loss, difficulty with balance and coordination, and distal muscle weakness, consistent with nerve pathology.12 Patients with pre-existing neuropathies can develop life-threatening paralysis, even with low doses of vincristine.13 Electrophysiologic studies show a distal axonal sensory-motor neuropathy,14,15 but demyelination has also been seen.16 This makes it difficult at times to separate a GBS presentation in malignancy from, or superimposed on, CIPN. Only 1 patient with NHL has been reported to develop GBS before the diagnosis and initiation of chemotherapy5; the rest developed GBS after initiation of CHOP or other chemotherapies. Nerve biopsy may sometimes be needed to distinguish the 2: neurofilamentous accumulations within axons are considered characteristic for vincristine neuropathy,17 whereas GBS is characterized by intense lymphocytic inflammatory infiltrates in nerve roots and peripheral nerves (demyelinating type),18 or macrophages invading the periaxonal space of myelinated nerve fibers (axonal type).19
Besides CIPN, direct lymphomatous infiltration of the nerve, vasculitis, paraproteinemic deposition, and paraneoplastic syndromes have all been postulated as the underlying etiology of acute neuropathies in NHL; these can be confirmed by morphologic and immunologic analysis.5 Paraneoplastic neuropathy is a heterogeneous group of conditions that often presents as a subacute sensory neuronopathy. Less frequently seen paraneoplastic presentations include motor-sensory neuropathies, autonomic neuropathies, and lower motor neuron syndromes. The diagnosis is based on serum testing for known antineuronal antibodies (antibodies that react with antigens common to the peripheral nerve and the neoplasm).20 It is not clear if GBS associated with lymphoma should be considered classically paraneoplastic, since the target antigen in most cases of AIDP is not known.
The pathogenesis of GBS is unclear, although there is strong evidence of immune dysfunction with delayed hypersensitivity to components of peripheral nervous system myelin.21,22 In AIDP, macrophages invade intact myelin sheaths. This has been postulated to be due to a T-cell mediated process against one of the myelin proteins,23 as seen in the animal model of GBS-experimental allergic neuritis24-26; a secondary enhancement of demyelination by an antibody-mediated process may be involved. Alternatively the initial event may be binding of antibodies to the Schwann cell surface and demyelination, perhaps prior to the cell invasion by macrophages.27 On the other hand, in AMAN, there is strong evidence to support axonal destruction by antibodies to gangliosides on the nerve axolemma that target macrophages to invade the axon at the node of Ranvier as the result of molecular mimicry.28,29
Although the development of an immune-mediated disorder such as GBS in an apparently immunosuppressed individual may appear paradoxical, animal models such as the NZB mouse demonstrate that the depression of cell-mediated immunity and the T-cell system are associated with a humoral-mediated increase in autoantibodies and autoimmune diseases.30-33 It is possible that selective depression of cell-mediated immunity of any etiology might allow the development of a humoral and/or cellular immune reaction directed against peripheral nerve antigens. However, given the rare association between lymphoma (Hodgkin lymphoma or NHL) and GBS, we postulate that there must be other epigenetic factors that contribute to the development of GBS in any particular immunosuppressed patient.
Treatment of the patient with GBS requires a multidisciplinary approach, given the potentially fatal complications in patients with rapidly progressive disease and autonomic dysfunction.34 In the acute phase, plasma exchange was accepted as the gold standard 20 years ago.35,36 Studies done in the 1990s established the equivalence of plasma exchange with intravenous immunoglobulin (IVIg); no significant improvement was noted with the combination of both treatment modalities.37,38 A Cochrane Database Review of 6 trials utilizing corticosteroids failed to show any benefit in GBS.39 The American Academy of Neurology has published practice parameter guidelines recommending either plasma exchange or IVIg for the treatment of patients with GBS who have lost the ability to walk.40 However, available treatment options still leave 20% of patients disabled, and persistent milder symptoms remain. Controlled clinical trials comparing best therapeutic options or developing new, targeted agents are needed. There is no mention in the case report of whether IVIg or pheresis was initiated in the patient; the fact that the patient continued to progress (potentially increasing the duration of symptoms to over 8 weeks) also raises the possibility of CIDP. Regardless, the above treatments are efficacious in CIDP as well as GBS.
In conclusion, although immune dysfunction is clearly associated with GBS, the underlying immunopathogenesis of its various subtypes are still being elucidated. The case reports of GBS associated with various immunosuppressed states such as lymphoma may provide further insight into the underlying etiology of this syndrome and lead to the development of targeted immunomodulatory therapies that are more specific, less toxic, and more beneficial than those currently available.
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