Anti-Amphiphysin-associated limbic encephalitis in a 72-year-old patient with aortic angiosarcoma

Abstract

Paraneoplastic autoimmune encephalopathic syndromes have been described most often in association with small cell lung cancer or breast cancer, tumours of the ovaries, testes, lymphoma and thymoma. Antibodies associated with paraneoplastic encephalopathies are, among others, anti-Hu, anti-Ma2 and, in part, anti-N-methyl-D-aspartate(NMDA)-receptor antibodies. Here, we present the case of a 72-year-old patient hospitalised due to progressive cognitive decline and disorientation. Diagnostic workup revealed paraneoplastic anti-amphiphysin associated limbic encephalitis on the basis of an aortic angiosarcoma with metastases to kidney, muscle and bones. Highly aggressive chemotherapy as well as immunosuppressive therapy and cytoreductive laparoscopic nephrectomy were initiated. However, follow-up revealed further tumour progress and a worsening of neurological symptoms.

Background

Encephalopathic syndromes such as limbic encephalitis, caused by immune-mediated interaction at the synaptic level, are a rare symptom of neoplastic diseases and might precede the diagnosis of the neoplasia for years. Limbic encephalitis may present with a variety of symptoms including epileptic seizures, cognitive and memory deficits, agitation, sleep disturbances and other psychiatric symptoms such as depression and affective disturbances.

Antibodies against the synaptic protein amphiphysin have previously been described in conjunction with breast cancer and small cell lung cancer (SCLC) and are known to cause stiff person syndrome and limbic encephalitis.

Here, we report on a 72-year-old male patient presenting with amphiphysin-mediated limbic encephalitis. Diagnostic workup revealed no breast or lung neoplasia but an angiosarcoma of aortic origin with metastases to kidneys and bones.

Case presentation

A 72-year-old male patient was admitted to hospital because of confusion and cognitive decline within the last weeks. He had an academic background and profession but was now unable to manage the activities of daily living. Next to being recently diagnosed with mild anaemia, case history included recurring embolic strokes of unknown source.

Neuropsychological testing revealed a severe dysexecutive syndrome with an impairment of both verbal and non-verbal memory function and a manifest reduction of cognitive flexibility. Electroencephalography showed discrete subcortical dysfunction. Cerebrospinal fluid analysis resulted in a normal cell count, and ß-amyloid, tau protein and phospho-tau were within normal ranges. Further testing revealed highly positive anti-amphiphysin antibodies whereas anti-N-methyl-D-aspartate (NMDA), anti-LGI1 and anti-Hu/Ma/CV2 antibodies were negative.

Positron emission topography (PET)-CT conducted to detect tumour resulted in hypermetabolic foci in the descending thoracic aorta, the left kidney, the right iliac bone and the right paraspinal musculature suspicious of a metastasised renal cell carcinoma (see figure 1).

Figure 1.

Imaging findings from PET-CT (A, B, E and H) and CT for further evaluation of hypermetabolic masses in the aorta (A–D), the left kidney (A, E–G) and the right iliac bone (A, H–J). The initial working hypothesis was a metastasised renal cell carcinoma. However, diagnosis of an angiosarcoma was established through CT-guided samples of the right iliac bone and the renal mass. Fused=overlay of PET information on CT images. ceCT, contrast-enhanced CT; Cor, coronal; non-ceCT, non-contrast-enhanced CT; tra, transversal.

However, biopsy of the right iliac bone revealed an undifferentiated sarcomatoid carcinoma and an additional sample taken from the renal tumour confirmed the diagnosis of an angiosarcoma. Hence, the aortic hypermetabolism was considered to reflect the primary tumour site.

To address the paraneoplastic neurological symptoms that had led to hospitalisation, the patient was treated with high-dose glucocorticoids (methylprednisolone 1000 mg/day intravenous for 3 days) followed by immunoglobulins (30 g/day intravenous for 5 days). Under immunosuppressive therapy, a temporal clinical improvement of neurological symptoms was achieved.

For treatment of the angiosarcoma and the metastases, cytoreductive laparoscopic nephrectomy was performed, and a chemotherapy with weekly application of docetaxel (30 mg/m²) was established. The patient could be discharged to his home.

Outcome and follow-up

After five cycles of docetaxel therapy, reassessment via PET-CT revealed a massive progress with increasing volumes of both the aortic and the renal lesion as well as new hepatic and muscular metastases. Clinical neurological symptoms had worsened as well; the patient was disoriented and near to bed-ridden.

In light of the progressive disease, the poor prognosis and the patient’s severely limited clinical status, best supportive care therapy was initiated in close contact with the patient’s family. The patient died at home about 4 months later.

Discussion

Paraneoplastic encephalopathies such as limbic encephalitis are a rare symptom of malignoma, although recent data suggest that the true incidence might be higher than previously thought.^1–4 About 60%–70% of cases of limbic encephalitis are suspected to be of paraneoplastic origin.²

Among the antibodies known to be associated with paraneoplastic encephalopathies are anti-Hu, CV2, as well as Ma2 and GABAb-receptor antibodies, which are mostly associated with SCLC, but can be observed in malignomas of the breast, ovaries and testes, as well as thymoma. Anti-NMDA-receptor antibodies are partly (9%–55%) associated with ovarian teratomas.³ The anti-amphiphysin antibodies observed in the present case can cause various paraneoplastic neurological syndromes including autoimmune encephalitis and cases of stiff person syndrome and are most often seen in breast cancer and SCLC.1 3 5–7 A case of anti-amphiphysin associated encephalomyelitis in a patient with ovarian carcinoma has also been described.⁷

In our case, anti-amphiphysin antibodies linked to aortic sarcoma with renal and osseous metastases caused a severe autoimmune encephalopathic syndrome with disorientation and progressive cognitive decline. The recurring embolic strokes, which had occurred over the past 4 years, might have been the first symptom of the aortic neoplasia. Two cases of angiosarcomas in the aortic arch presenting as recurring strokes have been reported.^{8 9}

Angiosarcomas are rare malignant tumours with only few cases of paraneoplastic syndromes being described. In a patient with cardiac angiosarcoma, a case of paraneoplastic membranoproliferative glomerulopathy has been reported.¹⁰ A patient with renal angiosarcoma showed paraneoplastic cutaneous manifestations with erythrodermic dermatitis, eruptive seborrhoeic warts and acral hyperkeratosis.¹¹ An early report describes a case of paraneoplastic syndrome in adrenal gland angiosarcoma.¹² Paraneoplastic antibodies were not detected.

To the best of our knowledge, no previous cases of anti-amphiphysin associated encephalitis in patients with angiosarcoma have been described before.

Learning point.

• Anti-Amphiphysin-associated paraneoplastic encephalopathic syndromes do occur in cases of breast or lung cancer and in other neoplastic diseases such as angiosarcoma