Laryngeal paralysis (LP) is the inability of the laryngeal musculature to abduct and adduct the arytenoid cartilage. Upper airway signs caused by narrowing or obstruction of the laryngeal cavity are most prominent, particularly when there is an innervation abnormality in the cricoarytenoideus dorsalis, which has an abductor function (24). Affected animals have inspiratory dyspnea, but respiratory distress, cyanosis, and collapse are possible in severely affected animals. In some cases, increased respiratory distress is caused by one or more episodes of aspiration, resulting in pneumonia (9).

The most common form of LP is the acquired idiopathic form observed in older dogs (9); however, it is uncommon in cats. In a review of 35 cats with a laryngeal disease, the incidence of LP was approximately 40% (n = 14) in a decade (21). Congenital LP in cats is very rare, and most cases are the acquired form (10,18,21). Although the specific cause of LP in cats is often unknown, there are case reports that presumably involve trauma, neoplastic infiltration, and iatrogenic injuries (11). Since LP can also be induced by tumor metastasis or invasion of laryngeal musculature or nerves, tumors should also be considered as a differential diagnosis in cats with LP (11). The fundamental treatment for LP is to resolve the underlying disease, and tracheostomy tube insertion may be required in an emergency for patients with severe clinical signs due to upper airway obstruction.

Malignant thymoma in cats is an uncommon malignant tumor originating from the neoplastic thymic epithelium. The paraneoplastic syndrome of the malignant thymoma can present with exfoliative dermatitis, paraneoplastic pemphigus, polymyositis, and autoimmune disease such as granulocytopenia, and can cause acquired myasthenia gravis (MG) (16,20,22). Among cats diagnosed with MG, a large proportion (up to 52%) have an underlying mediastinal mass, and most of that is thymoma (8).

Here, we report a case of paraneoplastic syndrome-induced MG and acute LP in a cat with a malignant thymoma.

A 10-year-old neutered male Domestic Short-haired cat visited a veterinary medical teaching hospital for emergency dyspnea. The cat was anorexic and showed regurgitation before presentation; however, the respiratory distress suddenly progressed. Obstructive respiratory distress associated with stridorous respiratory noise (Supplementary Video 1) was remarkable. Depression, generalized weakness, and hypothermia were also identified in the primary survey. Upper airway obstruction, especially laryngeal disease, was strongly suspected, and a direct visual inspection was immediately performed under light sedation (butorphanol 0.3 mg/kg IV, Butophan_®, Myungmoon Pharm., Seoul, Korea) with oxygen supply. Lack of mobility on both sides of the larynx during all phases of respiration confirmed laryngeal paralysis in a cat. Physical examination did not reveal any other structural abnormalities such as neoplasm, inflammation, edema, or trauma.

The following diagnostic plans were established to identify the underlying cause of LP: polyneuropathy, polymyopathy, iatrogenic trauma to one or both recurrent laryngeal or vagus nerves, neoplastic, secondary to inflammatory laryngeal disease, and idiopathic. Given that there was no history of surgery or trauma, direct damage to the larynx or laryngeal nerve could have been ruled out in this cat. Visual inspection revealed no visible mass or inflammatory changes. Radiography, computed tomography (CT), and laboratory tests were performed to confirm the underlying diseases that could cause the paraneoplastic syndrome, polyneuropathy, or polymyopathy. In addition, it is necessary to identify the causes of regurgitation and generalized weakness.

Megaesophagus, aspiration pneumonia in the right caudal lung lobe, and soft tissue opacity in the cranial mediastinum were found on thoracic radiography (Fig. 1). The cranial mediastinum mass was identified as a well-defined, 1.6 × 1.8 × 2.2 cm in size, heterogenous mass lesion with contrast enhancement on CT scanning. Cytological analysis of the mass revealed an epithelial cell-originated tumor with highly malignant cells (anisocytosis, pleomorphism, coarse chromatin, nuclear molding, multi-nucleoli, and high nuclear/cytoplasm ratio) (Fig. 2A, B). Mitotic figures were not observed in the cytological analysis. The thymic mass was surgically removed and submitted to the pathology laboratory for histopathological examination. Neoplastic epithelioid cell infiltration was observed in normal small lymphocytes in the thymus (Fig. 2C). The tumor cells had round to oval-shaped nuclei, which were usually pale stained and vesicular, with a single prominent nucleolus (Fig. 2D). Mitotic figures were observed less frequently. Consequently, the tumor was diagnosed as a malignant thymoma. Laboratory analysis, including feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) serostatus, was unremarkable.

Figure 1. (A) Megaesophagus and cranial mediastinal mass (asterisk) is confirmed in radiographs. (B) The cranial mediastinum mass was identified as a well-defined, 1.6 × 1.8 × 2.2 cm sized, heterogenous mass lesion with contrast enhancement on CT.

Figure 2. Cytologic and histologic evaluation of the mass. (A, B) Epithelial cell origin and highly malignant cells (anisocytosis, pleomorphism, coarse chromatin, nuclear molding, multi-nucleoli, and high nuclear/cytoplasm ratio) were identified in cranial mediastinum mass FNA. ×100 (A), ×400 (B) Diff-Quik stain. (C) Neoplastic epithelioid cells (left area) infiltrate remained normal small lymphocytes (right area) in the thymus. H&E stain, scale bar = 100 μm. (D) Round to oval nuclei of the tumor cells is pale-staining and vesicular with a single prominent nucleolus. H&E stain, scale bar = 100 μm.

Acquired MG secondary to malignant thymoma in cats can explain the following symptoms: laryngeal paralysis, megaesophagus, aspiration pneumonia, and generalized weakness. A Tensilon test using neostigmine 0.02 mg/kg IV (Neostigmine Methylsulfate Injection, Jeil Pharmaceutical Co., Ltd., Seoul, Korea) was performed, and the motility of the bilateral larynx following respiration was reversed 10 min after administration (Supplementary Video 2). The cat was tentatively diagnosed with acquired MG; however, a confirmative acetylcholine receptor antibody titer test using a blood sample on admission was below the cut-off value (IDEXX Laboratories, Westbrook, ME, USA).

A tracheostomy tube was temporarily placed during the thymectomy to relieve dyspnea due to upper respiratory tract obstruction. Oral administration of pyridostigmine 2 mg/kg q 12 h PO (Mestinon, Korean Drug Co., Ltd., Seoul, Korea), which has a relatively long half-life, was intended for long-term management. However, the drug was retained in the lower esophagus and insufficiently absorbed due to the megaesophagus. Instead, additional administration of neostigmine IV was scheduled at 3 h intervals. However, the cat experienced cardiopulmonary arrest for severe bleeding after the surgery and expired. As per the owner’s request, a necropsy was not performed.

Here, we report a case of feline LP as a paraneoplastic syndrome of malignant thymoma. LP is uncommon in cats; only 57 cats were reported in 33 years (from 1979 to 2011) (10), and another study of 69 cats with feline laryngeal disease reported an incidence rate of 42% (29 cats) (10). In addition, only two of 16 cats with LP had megaesophagus and aspiration pneumonia, similar to the present case (18). The etiopathogenesis of acquired LP in cats is not clearly known; however, a possible underlying disease includes polyneuropathy/polymyopathy, tick paralysis, iatrogenic (after surgical procedures in the neck or near ligamentum arteriosus, which causes trauma to the recurrent laryngeal or vagal nerve), neoplastic invasion or mass effect, traumatic condition, secondary to inflammatory laryngeal disease, generalized toxicosis, and idiopathic (11,18). LP due to damage to the recurrent laryngeal nerve usually affects the action of the cricoarytenoideus dorsalis muscle, which abducts the arytenoid cartilage (17). Usually, iatrogenic trauma, neoplasia of the vagus nerve, or the presence of masses exerting compressive or tensile forces on the recurrent laryngeal nerves can be considered (23). Tick paralysis, iatrogenic and traumatic conditions, and generalized toxicosis could be excluded in this cat through history, including deworming, vaccination, and physical examination. Although inflammatory laryngeal disease could not be completely ruled out because cytology or histopathology of the muscles, and soft tissues of the larynx could not be performed, no inflammatory changes such as edema or erythema in the larynx were observed on visual inspection. In addition, secondary paralysis due to inflammatory laryngeal disease could be ruled out as there was no systemic inflammation or inflammatory changes in tissues around the larynx on blood tests and diagnostic imaging, respectively. Ultimately, malignant thymoma was identified as a comorbidity, and the neostigmine test showed a temporary recovery of LP, suggesting a tentative diagnosis of paralysis by acquired MG.

Acquired MG occurs as a paraneoplastic syndrome in dogs and cats with a malignant thymoma (8,15). The exact mechanism of autosensitization remains unknown; however, several theories have been proposed. The thymus may be the site of initial autosensitization against acetylcholine receptors, and the thymus maintains an immune response against these receptors (19). When neoplastic thymic epithelial cells express antigenic epitopes similar to acetylcholine receptors in skeletal muscle, paraneoplastic MG can occur (19). However, there haven’t been any cases of LP in cats caused by acquired MG. In acquired MG, there are many cases in which the laryngeal skeletal muscle is affected in a focal form, although it rarely progresses to paralysis (6). In addition, it could be possible that tumor cells from malignant thymoma were directly infiltrated into structures of the recurrent laryngeal nerve or larynx or the esophageal muscle itself.

There are several reasons for the seronegative acetylcholine receptor antibody titer (below the cut-off concentration) of MG: all of the available antibodies are bound to the muscle endplate region with undetectable levels of circulating antibody (antigen excess), damaged to certain antigenic epitopes of the acetylcholine receptor, and fail to recognize some antigenic variations of the acetylcholine receptor antibodies, directed against antigenic proteins of the endplate region other than the acetylcholine receptors, immunosuppressive therapy for longer than 7 to 10 days, and early in the course of the disease (4). The diagnostic criteria for seronegative MG include consistent clinical signs, a positive pharmacological response, suggestive electrophysiological findings (i.e., decremental response), and a negative acetylcholine receptor antibody titer. Although the incidence rate of seronegative MG in both dogs and cats is now known, it has been classified as a subgroup of acquired MG in recent review papers because there are often case reports of dogs (15). However, to date, there have been no reports of cats (5,14). Given the unclear history of prior medication, steroid administration could not be completely excluded in this cat. Since the clinical signs of regurgitation, weakness, and dyspnea presented a subacute onset (within a week), it could be an early phase of the disease to detect antibodies (10). The clinical signs worsened until neostigmine administration, and eventually, the laryngeal movement was responsive to neostigmine, which supports that this case could be a seronegative MG subclass.

Another limitation of this case is that the possibility of polyneuropathy or polymyopathy cannot be definitively ruled out. There have been several cases of generalized polyneuropathy diagnosed in dogs with megaesophagus and laryngeal paralysis (1,2,7,12), and paraneoplastic myositis caused by thymoma has also been reported in cats (3,13,25). To differentiate between polymyopathy or polyneuropathy and acquired MG, muscle biopsy, electromyography, and other tests that can diagnose MG are necessary; however, only the acetylcholine receptor antibody test was performed in this cat. Nevertheless, the typical clinical signs of polymyositis, such as weakness, muscle wasting, progressive pain, stiffness, and lameness that worsens with exercise other than LP and generalized weakness, were not present; acquired MG was prior to myopathy in this case.

In summary, LP was strongly suspected due to acquired MG, based on 1) laryngeal mobility was confirmed immediately after administration of neostigmine, 2) most other diseases that could cause LP were excluded, 3) malignant thymoma was present as a comorbidity, and 4) clinical signs of MG, such as megaesophagus and generalized weakness, were confirmed. However, a more accurate diagnosis could have been made if additional tests such as acetylcholine receptor antibody retesting at intervals of several weeks, electromyography, and muscle biopsy or necropsy were conducted.

In conclusion, acquired MG should also be considered a differential diagnosis in cats with concurrent LP and thymoma, as MG may appear as part of a paraneoplastic syndrome. It is recommended to conduct a thoracic radiograph or CT to check for tumors such as malignant thymoma.

This research was supported by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) through Companion Animal Life Cycle Industry Technology Development Program, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (322092-04-1-HD030).

The authors have no conflicting interests.