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Complex neurological paraneoplastic syndrome in lung cancer with myastheniform syndrome and mononeuritis multiplex

Pedro J Modrego*, Leyre Diaz de Cerio.

Department of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain

*Corresponding author

*Pedro J Modrego, Department of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain.

Abstract

Overlapping of neurological paraneoplastic syndromes occurs rarely in patients with cancer. We report the case of a 66-year old patient with lung adenocarcinoma who presented with ocular myastheniform syndrome and multineuritis multiplex. Onconeural antibodies and voltage-dependent calcium channel antibodies were negative, which made the diagnosis more difficult. After complete surgical resection of cancer and the help of diaminopyridine the patient improved remarkably, but some residual symptoms remain after two year follow-up period.

Introduction

Paraneoplastic syndromes (PNS) pose diagnosis challenges when the underlying cancer is not visible with the usual ancillary tests. Lung cancer is one of the cancers that cause paraneoplastic symptoms most frequently, especially small cell subtype. Several neurological symptoms have been reported such as sensory neuronopathy, limbicencephalitis, Eaton-Lambert syndrome, retinopathy, myasthenia gravis, cerebellar degeneration, opsoclonus-myoclonus, and others, and they occur in less than 1/10,000 cases of patients with cancer [1]. The most frequent neurological PNS is EatonLambert syndrome, which appears in around 1% of patients with small cell type lung cancer [1].

The presence of specific anti-neuronal antibodies can help greatly in the diagnosis [2]. Early detection and treatment of the cancer may improve or stabilize the syndrome, but it is not always possible, with irreversible neuronal damage [3]. In the era of checkpoint inhibitors we can expect an increased occurrence of PNS [4]. We report a case of overlapping neurological PNS in a patient with lung cáncer and that posed some diagnostic difficulties at onset.

Case Report

A 66 year old man was referred to the neurology department in January, 2021 because of sub-acute vertical dyplopia, bilateral complete palpebral ptosis, and tingling in the left hemifacies and arm since 3 months earlier. He was a heavy smoker in the past, but he had no hypertension, hyperlipidemia nor diabetes. In the clinical examination it was observed a complete bilateral ophthalmoplegia and bilateral palpebral ptosis that hampered vision; there was no sensory or motor impairment, the osteotendinous reflexes were symmetric; finger clubbing was remarkable in both hands; the gait was normal; swallowing was intact. In the standard blood tests the red and white cell count was normal, ESR was normal, glucose, and creatinine were normal. In the study of autoimmunity in the serum there was positivity for the SSA (anti-Ro52; 47.3 IU/mL) antibodies, ANA at titre 1/80, weakly positive anti M2; and antiMPO: 88.6 IU/mL In the CSF protein level and glucose were normal, no cells were found. The X-ray of the chest showed diffuse interstitial pattern, without effusions or masses (Figure 1). A brain MRI carried out on two occasions did not show abnormalities. In the EMG-ENG, repetitive stimulation on the frontal and facial muscles did show neither decrement or increment in the amplitude of muscle action potential; signs of axonal asymmetric sensory-motor neuronopathy were seen in both arms (normal nerve conduction plus decreased amplitude of the sensitive and motor potentials), with more damage in the left arm, The lower limbs were spared. The F-wave was normal. Figure 2 shows the values of CMAP in the different peripheral nerves, with lower amplitudes in the left arm and ulnar nerve. Anti-AchR, anti-Musk, and Voltage-dependent calcium channel antibodies were negative. Onconeural antibodies were negative (Hu, Yo, Ri, CV2, Ma2/Ma1, Tr, anphiphisin, SOX1, GFAP, ZIC4, GAD, AK5).

Figure 1: Chest X ray: diffuse interstitial pattern.

Figure 2: CMAP potentials decreased in both arms in an asymmetric way. Ulnar nerves (A and B), median nerves (C and D). The values are normal in the legs: tibial nerves (E and F), and peroneal nerves (G and H).

Figure 3: CT of the chest; nodule of 19 mm in the posterior region of the left.

The symptoms did not improve with piridostigmine and prednisone at doses of 1 mg/kg weight. With all data we retained the diagnosis of paraneoplastic myastheniform syndrome (not fulfilling criteria of Lambert-Eaton syndrome), and mononeuritis multiplex of paraneoplastic nature. Then, the patient underwent a Chest-CT revealed a pulmonary nodule of 19 mm with malignant aspect in the left inferior lobe (Figure 3), with a left paratracheal enlarged lymph node. PET-scan confirmed malignancy of the nodule and the malignant lymph node. Complete resection of the left inferior pulmonary and 5 lymph nodes lobe was performed with favorable outcome. The biopsy showed an adenocarcinoma with a molecular profile negative for the mutations EGFR, BRAF, ALK and ROS-1, PDL-1 lower than 1%. Only one lymph node showed malignancy, After surgery, four cycles of cisplatin plus pembrolizumab were administered, with tolerable side-effects (fatigue). Two months after surgery, the patient developed weakness and asymmetric atrophy of the intrinsic muscles of the hands  predominantly in the left hand and interosseous muscles. The ophthalmological symptoms improved remarkably with 3-4-diaminopirydine, ptosis resolved in two weeks, but ocular motility took one year toresolve. Diaminopiridine was tapered. Sensory and motor symptoms in the face and arms improved after surgical resection, but some residual symptoms remain after two-year follow-up period.

Discussion

PNS are a rare condition that results from remote immune-mediated damage caused by the underlying tumor. Specific antibodies are an essential tool to diagnose PNS, and to detect early the primary tumor even when there is no overt evidence of it. Multiple neurological PNS in the same patient have been reported rarely, but the presence of two or more antibodies is possible [5]. A patient had, at the same time, limbic encephalitis, opsoclonus-myoclonus, sub-acute cerebellar degeneration, brain-stem encephalitis, and sensory-motor neuropathy, without finding any tumor in autopsy; onconeural antibodies on the CSF were negative [6]. Another patient with malignant thymoma developed gastrointestinal suboclusion, muasthenia gravis, Lambert-Eaton syndrome, and polymyositis; onconeural antibodies were negative [7]. Lambert-Eaton syndrome and dermatomyositis were found in a patient with squamous lung cancer, and in another one with adenocarcinoma, but onconeural antibodies were not searched [8, 9]. It is also noteworthy that the patient had interstitial lung disease, another autoimmune disease with antinuclear antibodies, which was diagnosed in the wake of cancer. This association suggests propensity to autoimmune phenomena. However it is surprising that onconeural antibodies were not present, although it may happen in 30% of neurological PNS [1]. The clinical manifestations of peripheral nerves in the arms and in the trigeminal nerve, along with the asymmetric presentation, underpin the syndrome of mononeuritis multiplex, which has not previously reported. From the treatment viewpoint PNS are an untoward condition whose symptoms may or may not resolve with the appropriate treatment of the underlying cancer.

Conflicts Of Interest: The authors have no competing interests to declare. No financial aid was received.

References

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Journal of Clinical Case Reports, Medical Images and Health Sciences (ISSN 2832-1286) is a peer-reviewed journal dedicated to publishing clinical images from all sectors of medicine. The goal of this magazine is to disseminate information about new discoveries and treatments in science and medicine.

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