Weakness and numbness after chemotherapy for metastatic non-seminoma testis: A new neurological complication

To the Editor

Germ cell tumors have been associated with paraneoplastic neurological syndromes, mainly encephalitis, and its treatment with peripheral neuropathy. We present a 41-year-old male treated with chemotherapy for a germ cell tumor who developed a Guillain-Barré syndrome, an acute demyelinating neuropathy. This is the first case of Guillain-Barré potentially related to a germ cell tumor described in the literature to date.

Case presentation

A 41-year-old man of Arabic descent was admitted to the Department of Medical Oncology. Physical examination at another hospital had revealed a tumor of the left testis, and a supraclavicular mass. An inguinal orchidectomy was performed and pathological examination showed embryonal cell carcinoma and diffuse embryoma. Further work-up revealed a stage IV non-seminoma of the left testis with a good risk according to the IGCCG [1]. The patient was referred to our hospital for chemotherapy. Two months before the current admission three courses of BEP chemotherapy (Bleomycin 30 mg/day on day 2,8 and 15, Etoposide 100 mg/m² on day 1–5 and Cisplatin 20 mg/m² on day 1–5) were given at an interval of 3 weeks, without any substantial toxicity, besides some symptoms of coughing after the last course.

One week after the last dose of Bleomycin of the third cycle the patient was seen at the outpatient clinic because of fatigue, generalized weakness and numbness in the feet and hands. Laboratory investigation was unremarkable with normal tumor markers, blood count, electrolytes, kidney and liver function. Examination by a neurologist revealed normal cranial nerve function and no weakness of his arm muscles. There was an inconsistent weakness of the iliopsoas, quadriceps and hamstrings grade 4 of 5 on the MRC-scale (Medical Research Council). Achilles tendon reflexes were absent. There was a subtle decrease in vital sensibility of the peripheral limbs. Diagnosis at that time was a cisplatin-induced polyneuropathy with aggravation. No specific treatment was given. Two days later the patient was admitted with progression of malaise, dyspnea, weakness and difficult micturition. Cardiopulmonary examination, chest x-ray, electrocardiogram and extensive laboratory studies did not reveal any abnormalities. Neurological examination was repeated, and now showed a paresis grade 4 of the hand muscles and a progressive paresis of the legs: proximal strength 2/5, distal 4/5. All tendon reflexes were abolished. Hypoesthesia was present in the proximal limbs. Straight leg raising was very painful. The differential diagnoses were infectious polyradiculoneuropathy, leptomeningeal metastases, Guillain-Barré syndrome or a paraneoplastic phenomenon. The clinical picture was too severe for chemotherapy-induced polyneuropathy. MRI of the total spine was normal. Analysis of the spinal fluid showed an a-cellular fluid with markedly increased protein content: 2.8 g/l (Normal <0.5 g/l). Malignant cells were not seen. Nerve conduction studies showed normal motor conduction velocities but a conduction block in the ulnar nerve. Dispersal of the compound muscle action potential (CMAP) was seen in multiple nerves. Sensory nerve conduction velocities were slightly reduced in the arms, and sensory nerve action potential (SNAP) were absent in the superficial peroneal nerves. Lower extremity F-waves were absent. Needle electrode examination showed normal motor unit potential number and reduced recruitment in both examined leg muscles. These changes are consistent with early Guillain-Barré syndrome [2].

At that time the diagnosis of Guillain-Barré syndrome was made. The patient was treated at the department of Neurology with intravenous immunoglobulins. Analysis for specific antibodies associated with paraneoplastic syndromes (anti-Hu, Yo, Ri, Tr, Amphysine, CV2, Ma2) tested negative. The clinical course was that of a slow but gradual improvement without any respiratory failure.

Discussion

The present report is first in the literature suggesting a relationship between a germ cell tumor during chemotherapy treatment and Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating neuropathy characterized by acute onset of peripheral and cranial nerve dysfunction. It can present with both sensory and motor disturbances. The incidence is 1.2–1.9 per 100 000 in Europe [3]. Although pathogenesis is incompletely understood, most likely there is a humoral and cellular immune-reaction aimed at the myelin or the axon of peripheral nerves. Molecular mimicry after a previous bacterial of viral infection is probably an important precipitating factor, with a previous Campylobacter jejuni-infection most commonly mentioned [3]. Patients present with pain, numbness and weakness in the limbs. Facial and respiratory nerves can be involved leading to respiratory insufficiency in up to 25% of cases. Treatment is with intravenous immunoglobulins or plasmapheresis.

Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic disorders. In some cases a relationship with a specific antibody can be established, a so-called anti-onconeural antibody [4].

Germ cell tumors have been associated with these syndromes, especially encephalitis. In most cases this encephalitis is related to anti-Ma2-antibodies [5].

Neurological symptoms can also occur due to anti-cancer treatment. Chemotherapy-induced polyneuropathy has been shown to occur in up to 29% of patients undergoing BEP-chemotherapy [6]. Cisplatin may cause an axonal, predominantly sensory polyneuropathy [7].

GBS has also been associated with malignancies. Patients experiencing this syndrome have an odds-ratio of 2.4 of suffering from a malignancy compared to the general population [8]. No specific antibody has been identified to date. GBS associated with lung cancer, lymphoma, esophageal cancer and other solid organ malignancies have been reported [8].

A number of pathogenic factors may have played a role in the development of GBS in this particular patient. Although the co-occurrence can be mere chance, we feel there is an actual relationship between the tumor, its treatment and the GBS. First, it could be related to the germ cell tumor as a ‘genuine’ paraneoplastic syndrome. The short interval between the diagnosis of non-seminoma and GBS are strongly suggestive for this explanation [4]. Secondly, the GBS could be related to the chemotherapeutical treatment. GBS occurring during or shortly after treatment with platinum-containing compounds has been described in patients with cancer of the endometrium, lung or colon [9], [10]. The pathogenesis could involve increased amounts of circulating tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) known to occur during treatment with these compounds [9], [10]. IL-6 and TNF-α are elevated in patients with active GBS. A third possible mechanism is the immunosuppressed state during chemotherapy. A generalized immuno-depressed state may lead to loss of immuno-regulatory mechanisms, predisposing to the inflammation known to occur with GBS [3]. Finally, the symptoms of a potential respiratory infection after the last course of BEP could be involved. This however seems less probable considering the short interval between coughing symptoms and first manifestation of GBS (<5 days) and the absence of fever, inflammatory parameters and x-ray abnormalities.

In conclusion, we present the first case of Guillain-Barré syndrome associated with chemotherapy treatment for a germ cell tumor. Potential pathogenic factors are tumor-induced antibodies against myelin, use of cisplatinum or a generalized immunosuppressed state.