A 48-year old woman was diagnosed with metastatic colon cancer in December 2017. She underwent right hemicolectomy and left hepatectomy. From February to August 2018, the patient received 10 cycles of adjuvant chemotherapy with FOLFOX-4 (oxaliplatin,
5-fluorouracil, folinic acid) regimen. Since the first cycle, she has developed moderate signs of acute sensory neuropathy. However, after the tenth cycle, and an oxaliplatin cumulative dose of 850 mg/m2, she suffered persistent diarrhea followed one week later by an acute increase of distal dysesthesia accompanied by weakness of the four limbs. Electrodiagnostic (EDX) was in accordance with an inexcitable form of Guillain-Barré syndrome (GBS) (Table 1, Figure 1). Five days after first symptoms, distal compound muscle action potential (CMAP) size were low, around 10 % from normal values, and motor excitability evaluated by iMAX (1) was diffusely decreased. Moreover, while distal motor latencies and F-wave latencies remained within normal limits, there wasone motor conduction block on the left ulnar nerve at the forearm (75 % in amplitude). Sensory nervous conduction in upper and lower limbs was within normal limits in velocity and amplitude. The patient soon started treatment with intravenous immunoglobulin (0.2 g/kg/die for 5 days) and showed in 3 weeks remarkable recovery with significative weakness improvement (Figure 1). Onconeural antibodies were negative. There was no raise of protein in the cerebrospinal fluid. Anti-campylobacter jejuni (CJ) antibodies were not initially checked. Antiganglioside GM1 antibodies, IgM more than IgG, were positive.
Discussion
We reported a case of an acute polyneuropathy with conduction blocks occurred in a patient with colorectal cancer receiving FOLFOX chemotherapy. EDX was in favor of a
nodo-paranodopathy mechanism (2). To our knowledge this is the first report of an “axonal” GBS in a patient receiving oxaliplatin-based chemotherapy. From the physiopathological point of view, three possibilities have to be discussed: an acute toxic neuropathy, a paraneoplastic disorder or an infectious cause.
Oxaliplatin used for patients with colorectal cancer, is well known to be neurotoxic. Two different forms of neurotoxicity are described. The acute one with cold-induced paresthesias and peri-oral numbness is transient and occurs in nearly all patients. The chronic one with loss of sensation and functional impairment is dose-cumulative (> 780 mg/m2), persistent and develops progressively in approximately 10-15 % of patients. Some motor clinical manifestations and neurophysiological changes are described in the acute toxic neuropathy: cramps, fasciculations, neuromyotonic discharges, multiplets, repetitive CMAPs (3). Recently, studies provided evidence for slowing of sodium channel inactivation in acute neurotoxicity of oxaliplatin, particularly in motor axons (4). We hypothesize that in most patients, motor manifestations result from an excess-of-function defect. In some very rare conditions, possibly in relation to a voltage-gated sodium channel polymorphism (5), motor symptoms, including weakness in the four limbs, might be due to a loss-of-function defect responsible for conduction blocks.
Paraneoplastic GBS is not a classic disorder in patients with colorectal cancer. As onconeural antibodies were negative and as the neurological findings improved without remission of cancer, paraneoplastic disorder was very unlikely.
Anti-CJ antibodies were tardively tested and were positive. By comparison with a frozen serum, dating from early GBS, it was proven that the CJ infection was acute. We knew from Hadden et al work (6) that when GBS was related to CJ infection, IgM (but not IgG or IgA) antibodies to ganglioside GM1 were more frequent in the axonal and inexcitable forms. The latter was in agreement with our observation. Despite the likely infectious mechanism in the present clinical case, we suggest that oxaliplatin might be a triggering agent for autoimmune disorder by inducing either production of various cytokines as tumor necrosis factor alpha and interleukin 6 (7) or reduction of immune response facilitating CJ infection that might induce an immune response to GM1 leading to the neuropathy. Such causal relationship has been already discussed between GBS development and a paradoxical effect of monoclonal antibody therapy (8). Oxaliplatin might also contribute to motor axonal hypoexcitability which characterizes some GBS with a nodo-paranodopathy mechanism (2, 4).
References
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2. Uncini A, Susuki K, Yuki N. Nodo-Paranodopathy: Beyond the Demyelinating and Axonal Classification in Anti-Ganglioside Antibody-Mediated Neuropathies. Clin Neurophysiol 2013;124(10):1928–1934.
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Figure 1 : left tibialis anterior muscle recordings (5, 14, 28, 56 and 150 days after the beginning of symptoms) following fibular nerve stimulation above fibula
At day 150, compound muscle action potential (CMAP) amplitude was within normal limits (5.6 mV). We retrospectively expressed amplitude data as a percentage of CMAP obtained at day 150 (black columns, left y-axis). By doing so, we estimated the percentage of inexcitable motor axons (grey columns). iMAX (stars, black broken-line, right y-axis) which is the minimal current intensity evoking a motor response of maximum amplitude (1), was clearly increased at each exam, particularly at day 28 and day 56 (upper limit of normal for the fibular nerve at the knee: 9.7 mA). From these data and given a recovery in a few weeks, we concluded a peripheral neuropathy with motor axon hypo-excitability and a great number of inexcitable motor axons at the beginning of the disease.
