Polymyositis with too Many Associations: A Paraneoplastic Syndrome.

Sir,

Polymyositis is characterized by symmetrical proximal weakness. Asymmetry and associated neuropathy are rare. It may be associated with interstitial lung disease (ILD), and a paraneoplastic association is known as well. The disease is usually amenable to treatment with corticosteroids and immunosuppression. Some patients may have refractory disease and may develop complications of the disease and treatment and may be challenging to manage.

Here, we present a patient who presented with asymmetric weakness, coexistent demyelinating neuropathy, muscle biopsy-proven polymyositis, and a fulminant refractory course. These features may be diagnostic cues to a paraneoplastic etiology. Paraneoplastic association of polymyositis is less common than dermatomyositis and association of anti Ma-2 with polymyositis has not been reported so far.

A 55–year-old man presented with 1 year history of cough and scanty mucoid expectoration. He also had New York heart association Class II exercise intolerance, without fever or constitutional symptoms. Investigations revealed ILD on high-resolution computed tomography (CT) chest. Echocardiography revealed normal biventricular function and no pulmonary hypertension. Transbronchial lung biopsy revealed chronic inflammatory infiltrate.

Around 10 months after the onset of pulmonary symptoms, he developed subacute onset progressive pure motor weakness of both lower limbs proximal more than distal, followed by proximal right upper limb weakness without wasting or fasciculations. After 1 month, he developed weakness of the left upper limb. One month later, he developed swallowing difficulty, neck drop and facial weakness without extraocular muscle weakness.

Since he had pure motor weakness, clinical differential diagnoses considered were anterior horn cell disorders, myasthenia gravis, inflammatory myopathy, and chronic inflammatory demyelinating neuropathy. He was evaluated at a private hospital and was treated with intravenous immunoglobulin (IVIg) 150 g over 5 days with a provisional diagnosis of myasthenia gravis before he presented to our center. Creatine phosphokinase was 10,328 U/L and nerve conduction study revealed asymmetrically prolonged distal latency, reduced conduction velocity and compound muscle action potential amplitude without conduction block. Sensory nerve conductions revealed absent sural sensory nerve action potential on the left side. Electromyography revealed spontaneous activity in the form of positive sharp waves and fibrillations. The motor unit action potentials were of low amplitude with polyphasia. Interference pattern was complete with early and full recruitment. These features were suggestive of an inflammatory myopathy. A diagnosis of polymyositis was made; muscle biopsy was done and was treated with IV methylprednisolone, 1 g/day for 5 days. On the 10th day after admission, he was intubated in view of poor respiratory effort. The muscle biopsy showed loss of fascicular architecture, variation in fiber size with atrophic fibers, and degenerating and regenerating fibers with adipose tissue infiltration within the perimysium. There was myonecrosis and myophagocytosis with major histocompatibility complex (MHC) II upregulation seen on immunohistochemistry. These features were suggestive of polymyositis as well as necrotizing myopathy [Figure 1]. A paraneoplastic etiology was suspected in view of significant necrosis and absence of MHC Class I upregulation.

Figure 1

(a and b) (×20) Marked variation in fiber size with adipose tissue infiltration within the perimysium (long black arrow), dense perimysial lymphocytic infiltrate (long red arrow), degenerating and regenerating basophilic fibers (small black arrows), myonecrosis (red arrow head,) and myophagocytosis (red small arrow). (c) (×10) Major histocompatibility complex II upregulation seen in immunohistochemistry. (d) (×10) Immunohistochemistry for CD56 staining the regenerating fibers

The vasculitic profile, viral markers, and malignancy screening were negative; CSF showed raised proteins [Table 1]. Serum protein electrophoresis and acetylcholine receptor antibody were negative.

Table 1

Results of investigations

Paraneoplastic antibody panel revealed anti Ma-2 positivity by immunoblot assay. Ultrasound of the testes and whole body positron emission tomography (PET) CT did not reveal any malignancy.

He was started on rituximab weekly infusions. After 48 h of administration of the second dose, he developed thrombocytopenia with normal prothrombin time, activated partial thromboplastin time, thrombin time, and raised D-dimer. Since there was temporal association with rituximab, further doses were withheld. Peripheral smear showed thrombocytopenia, microangiopathic hemolytic anemia with schistocytes and increased reticulocyte count suggestive of thrombotic thrombocytopenic purpura (TTP). Bone marrow examination was done, to look for malignant infiltration. It was consistent with TTP with no atypical cells or suggestion of malignant infiltration. CD20 cell count was 0. Renal function tests were normal. The patient developed hypogammaglobulinemia, hypoalbuminemia with preserved albumin-to-globulin ratio, and no proteinuria, suggesting rituximab-induced lymphopenia.

Plasma exchange (PLEX) was initiated, and following this, upper limb power started improving; however, the asymmetry of weakness persisted. Thrombocytopenia persisted, and he received 125 g or IVIg over 5 days after PLEX, along with single and random donor platelet infusions. Subsequently, platelet count started improving, and there was no further fall. He developed bilateral pleural effusion when on mechanical ventilation, and pleural fluid was transudative.

Doppler ultrasound of the lower limbs did not reveal deep venous thrombosis. Echocardiography revealed ejection fraction of 50% and could not explain the pleural effusion. Cause of effusion was presumed to be hypoproteinemia. Twenty-four hour later, he developed sudden cardiac arrest and could not be revived. His troponin level was normal, and there were no preceding ST-T changes on electrocardiogram. Throughout the course of illness, he did not have fever. The cause of death was likely occult sepsis although we could not isolate any organism, as the patient was immunosuppressed and was on continuous empirical antibiotics. The clinical course of the patient is summarized in [Figure 2].

Figure 2

Clinical course of the patient

Polymyositis is characterized by symmetric proximal muscle weakness, no rash, with raised muscle enzymes, myopathic pattern on electromyography, and biopsy suggestive of inflammatory changes with MHC Class I upregulation and other characteristic features. Polymyositis may be associated with other connective tissue diseases and extramuscular involvement such as ILD.

Polymyositis is characterized by symmetrical weakness. Association of neuropathy with polymyositis is very rare and is limited to a single case report.[1] There are very few case reports, regarding asymmetric weakness.[2]

ILD has been found to be associated with polymyositis, in isolation or as a part of antisynthetase syndrome. In our patient, there was no Raynaud's phenomenon, fever, or rapid onset symptoms. Anti-Jo-1 antibody was negative, which was the most common associated antibody. Rest of the antisynthetase antibodies were not tested.

Anti-Ma-2 has been associated with neurologic conditions including limbic encephalitis, cerebellar dysfunction, seizures, extrapyramidal syndrome with vertical gaze palsy and multiple mononeuropathies and may mimic frontotemporal dementia or multisystem atrophy. Peripheral nerve syndromes have also been reported.[3] However, association of polymyositis with anti Ma-2 has not been reported so far.

Development of thrombocytopenia in this patient was temporally related to rituximab. It is ironical that rituximab, which is used in the treatment of immune thrombocytopenic purpura, is also associated with thrombocytopenia in up to 30% cases including hematological as well as nonhematologic indications.[4] Other causes of thrombocytopenia such as, sepsis, other drugs, immunemediated, infiltraion of bone marrow and TTP were still possible in a patient with autoimmune disease on immunosuppression. Rituximab was stopped; peripheral blood smear revealed schistocytes with anemia and thrombocytopenia suggestive of TTP.

Polymyositis is a rare disease and association with TTP is rarer, and PubMed search revealed only 6 cases reported so far.[5] Our patient had microangiopathic hemolytic anemia and thrombocytopenia and fulfilled the criteria for TTP. There was no renal failure, fever, or central nervous system involvement. Our patient was started on PLEX; there was improvement in muscle power in upper limbs, with no improvement of thrombocytopenia. Inspite of platelet transfusions, counts never improved suggesting rapid peripheral destruction of the transfused platelets.

Our patient was on mechanical ventilation and nasogastric tube feeds. He developed hypoalbuminemia and hypoglobulinemia, with preserved albumin-to-globulin ratio. This was likely due to rituximab-induced lymphopenia. He had symptomatic hypoproteinemia, and the patient developed sudden cardiac arrest, and though electrolyes and platelets were normal at the time of arrest could, not be revived. He most likely succumbed to occult sepsis and did not mount an immune response as he was immunosuppressed and cultures were persistently sterile probably because of continuous antibiotic administration.

This case represents a rare association of asymmetric demyelinating neuropathy with polymyositis, who developed TTP, and was refractory to corticosteroids, rituximab, PLEX, and IVIg, and is an example of resistant form of disease. He may have had an underlying malignancy, which was not picked up on PET and other imaging and also had positive anti Ma-2 antibody, which is reported for the first time in polymyositis.

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Conflicts of interest

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