Recovery of Anti-contactin-associated-protein-like-2 and Anti-leucine-rich-glioma-inactivated-1 Antibodies Related Peripheral Nerve Hyperexcitability in an Anti-acetylcholine Receptor Combined with Anti-titin Myasthenia Gravis Patient

Dear Editor, Peripheral nerve hyperexcitability (PNH) is characterized by spontaneous firing and hyperexcitability of the distal motor nerves or motor nerve terminals. It can be caused by inherited disorders, toxins, nerve injury, autoimmune disorders, and other various reasons. Among them, benign fasciculation syndrome, cramp fasciculation syndrome, Isaacs syndrome, and Morvan’s syndrome are specific entities with distinguishable clinical findings. Isaacs and Morvan’s syndromes are frequently associated with voltage-gated potassium channel (VGKC) complex antibodies and have an immune basis. Furthermore, they can be observed as a part of a paraneoplastic syndrome of thymoma or small-cell lung carcinoma. In the current literature, PNH is emphasized as a tumor recurrence marker for treated thymoma patients.[1] Herein, we present an anti-acetylcholine receptor (AChR) antibody and anti-titin antibody positive myasthenia gravis (MG) patient with malignant thymoma, who developed dual seropositive VGKC complex antibody-associated PNH and thymoma recurrence despite having adjuvant radiotherapy after nonresidual thymectomy. A 56-year-old otherwise healthy male patient was admitted to an outside hospital with fatigable fluctuating binocular diplopia and left-eyed ptosis. Single-fiber electromyography was consistent with neuromuscular blockage and his anti-AChR antibody serum level was elevated. The patient was diagnosed with MG and received pyridostigmine bromide and prednisolone 1 mg/kg PO qDay. Prednisolone was tapered slowly in about 9 months without any myasthenic symptoms. Since heterogeneously enhanced mass suggestive of thymoma without invasion was detected on thorax computed tomography (CT), he was informed and referred for thymectomy. After preoperative intravenous immunoglobulin (IvIG) infusion, he went under the thymectomy. The pathological examination was consistent with malignant thymoma. Radiotherapy was started to prevent local recurrence after 1, 5 months from thymectomy. There were no local residual mass at that time. However, 2 weeks before radiotherapy, he began to feel a tingling sensation and twitching in his calves. He did not consult any clinicians during this period because the complaints were not disturbingly intense. Meanwhile, the twitching of his calf muscles increased, became continuous, and spread to the thighs and arms. He also had cramps, stiffness, and increased sweating complaints in inquiry. Neurologic examination revealed mild proximal muscle weakness in the lower extremities with Medical Research Council scale grade 4 and visible bag-of-worms movements, especially in his calves [Video 1]. Nerve conduction studies in electroneuromyography revealed prolonged after discharges in single stimulation of tibial and peroneal nerves [Figure 1]. Needle electrode examination showed spontaneous fasciculation, doublet, triplet, and multiplet myokymic discharges, and neuromyotonic discharges in bilateral gastrocnemius medialis, tibialis anterior, and biceps muscles [Video 1]. Antibody testing and follow-up thorax CT were ordered to detect possible paraneoplastic or autoimmune etiologies of peripheral nerve excitability findings. His anti-AChR antibody was 9.44 nmol/L (ref: <0.25 nmol/L), anti-Titin antibody was 3+, anti-contactin-associated-protein-like-2 (CASPR2) was 1/1000 positive, and anti-leucine-rich-glioma-inactivated-1 (LGI1) was 1/320 positive. Thorax CT revealed a recurrent mass in the anterior mediastinum. Under the diagnosis of acquired neuromyotonia, his prednisolone treatment re-increased to 1 mg/kg PO qDay, and he received IvIG infusion. Since acetylcholinesterase inhibitors may increase neuromyotonia, pyridostigmine was decreased. Finally, he was referred to the department of thoracic surgery for the evaluation of recurrent malignant thymoma. He was symptom-free after the evaluation for malignant thymoma. {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1.","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_uggndo5b"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Figure 1: (a) Right median nerve motor conduction study, (b) Right ulnar nerve motor conduction study, (c) Right tibial nerve motor conduction study, (d) Right peroneal nerve motor conduction study. After discharges were shown with red arrow after normal compound muscle action potential in (c and d)PNH clinically consists of fasciculation, myokymia, neuromyotonia, and pseudomyotonia with its electromyographic correlates of fasciculation potentials, myokymic discharges, and neuromyotonic discharges.[2] It can be caused by many inherited or acquired conditions; among them, cramp fasciculation syndrome, Isaacs syndrome, and Morvan syndrome are distinct clinical entities with some clinical and serological overlaps.[2] PNH syndromes were reported in concurrence with autoimmune diseases such as MG and paraneoplastic conditions such as thymoma-related paraneoplastic disorders. Our patient had cramps, fasciculations, myokymia, neuromyotonia, muscle stiffness, paraesthesia, and excessive sweating which we assessed as PNH symptoms; together with the pathognomonic electroneuromyography findings, we further investigated him for possible PNH etiologies, especially paraneoplastic origin. In the first part of the investigation, we performed antibody tests that can be associated with PNH syndromes. Autoantibodies against the VGKC complex can be detected in approximately 45% of acquired neuromyotonia patients.[3] Anti-LGI1 and anti-CASPR2 double seropositivity as in our case, although much rarer, has been reported in some case reports and series.[1,3,4] One reason for its sparseness may be the inability to detect VGKC subunits in older studies. Underlying the immune etiology of acquired neuromyotonia there is a clear association with paraneoplastic origin, mostly related to thymoma and small-cell lung carcinoma.[5] The paraneoplastic mechanism is explained by the cross-reactivity of antibodies against tumor-associated epitopes with antigens at the axon or its terminal.[6] Our patient had a diagnosis of MG with positive anti-AchR and anti-titin antibodies, which supposedly were associated with thymoma. In addition, the diagnosis of peripheral hyperexcitability was considered with neurological and electrophysiological evaluation, and the etiology of PNH was strongly considered to be paraneoplastic with laboratory and imaging support. The most interesting aspect of this case was the detection of a recurrent thymic mass in the CT, which was scanned at the onset of PNH; although no residue was detected in the postoperative thorax CT. This may be due to a residual tissue which cannot be seen macroscopically during the operation or postoperative CT, or it may indeed demonstrate that de novo PNH symptoms herald thymoma recurrence as suggested recently in one study.[1] In a detailed PubMed search, there are a total of nine articles reporting single cases or case series related to PNH and thymoma recurrence as far as we could detect.[1,4,7-13] Among them, the specialty of our case is the detection and management of the malignant thymoma before its invasion at the beginning. We suggest that the disease was probably not as advanced as some other reported cases and that the symptoms were alleviated by interventions for recurrent thymoma. Our experience shows that the association between PNH and thymoma should be kept in mind even after the thymectomy and radiotherapy. In the presence of de novo PNH symptoms in a myasthenia patient, the patient should be further investigated with neuronal antibodies and imaging studies even after very successful thymoma management previously. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.