250 CASE REPORT CUNNINGHAM AND BURTLIMBIC ENCEPHALITIS

Ann Thorac Surg1994;58:250--1

Limbic Encephalitis Secondary toMalignant ThymomaJohn D. Cunningham, MD, and Michael E. Burt, MD, PhD

Thoracic Service, Department of Surgery, Memorial Sloan­Kettering Cancer Center, New York, New York

A 56-year-old woman presented with memory loss andan enlarging mediastinal mass on chest roentgenogram.Physical findings were normal except for an alteredmental status examination consistent with dementia.Further radiologic assessment was nondiagnostic. Surgi­cal resection of a malignant thymoma resulted in clinicalimprovement. Treatment for limbic encephalitis shouldbe directed at the underlying disease, and symptomsmay improve if the tumor is eradicated.

(Ann Thorae Surg 1994;58:250-1

Thymoma is the most common tumor of the anteriormediastinum. Limbic encephalitis is a rare paraneo­

plastic syndrome associated with thymoma [1, 2], whichcan also be seen with other malignancies and in benigndisease. This report describes a patient who presentedwith symptoms suggestive of limbic encephalitis and ananterior mediastinal mass.

A 56-year-old woman presented with a 2-week history ofprogressive loss of short-term memory, confusion, fa­tigue, and emotional lability. Physical examination find­ings were normal except for an altered mental statusexamination. A chest roentgenogram revealed an enlarge­ment of an anterior mediastinal mass discovered 2 yearsearlier before an elective surgical procedure. A computedtomographic scan of the chest revealed that the anteriormediastinal mass had doubled in size over the last 8months. A computed tomography-guided needle biopsyof the mass was performed and histology was indetermi­nate between thymoma and lymphoma. Computed tomo­graphic scan of the brain, cerebral angiography, and allblood chemistry tests were normal. A lumbar puncturerevealed an elevated protein level, whereas all otherinfectious, immunologic, and autoimmune cerebral spinalfluid (CSF) tests were normal. Anti-Hu antibody, anantibody found in the serum and CSF of paraneoplasticsyndromes associated with small cell lung cancer, wasnegative. A test of the CSF for Creutzfeldt-Jakob diseasewas negative, and the anti-acetylcholine receptor anti­body was normal. Neuropsychologic testing at the time ofdiagnosis found the patient's word knowledge and intel­lectual capacities to be superior; however, her immediatememory, visual recognition, and reasoning skills were

Accepted for publication Nov 6, 1993.

Address reprint requests to Dr Burt, Memorial Sloan-Kettering CancerCenter, 1275 York Ave, New York, NY 10021.

© 1994 by The Society of Thoracic Surgeons

severely impaired. These findings also suggested new­onset dementia .

.Mediastinal exploration was via a median sternotomyWith anterolateral thoracotomy extension. Intraoperativefindings included a large mediastinal mass, which waslocally invasive into the lingula with multiple small nod­ules noted on the parietal pleura. The tumor, lingula, andpleural implants were resected. Histology was consistentwith a lymphoepithelial thymic carcinoma, stage IVA.Sampled mediastinal lymph nodes were not involvedwith tumor.

.Postoperatively, the patient was treated intrapleurallyWith 15 mCi of radioactive chromic phosphate. Subse­quent treatment included 5,040 cGy of external beamradiation to the mediastinum and left chest to enhancel~cal tumor ~ontrol. Three cycles of cisplatin and etopo­Side were given to prevent distant recurrence. Serialmagnetic resonance imaging scans showed gradual im­provement in the left temporal lobe cortical and subcorti­cal lesions noted on T2-weighted images. The patient'sclinical course improved dramatically over the next 6months, and she was able to return to work. She remainswithout evidence of recurrent disease 16 months after theoperation.

Comment

Overall, 15% to 20% of patients with a malignant neo­plasm will exhibit neurologic symptoms secondary tometastases during their illness, whereas 1% to 2% ofpatients have neurologic symptoms due to paraneoplasticsyndromes [3]. Paraneoplastic syndromes need to bedifferentiated from metastatic central nervous system dis­ease because the treatment differs. Limbic encephalitis isan example of a paraneoplastic syndrome that has beendescribed in patients with thymoma [1, 2].

The clinical presentation of limbic encephalitis is vari­able, but common features include those symptoms foundin our patient, primarily an abrupt change in mentalstatus, a dramatic loss of short-term memory, confusion,and a history of or a newly diagnosed malignancy [1-3].In this case, the patient's lack of a previous history ofneurologic or psychiatric problems coupled with a suddenchange in mental status focused attention on the anteriormediastinal mass as a possible source of her symptoms.

In the diagnostic work-up of limbic encephalitis, thephysical examination with the exception of the mentalstatus examination is usually unrewarding [1-5]. Themental status examination and neuropsychiatric testingmay show marked impairment of mental function, yetthese tests are not diagnostic. Serum laboratory abnormal­ities are uncommon, although examination of the CSFreveals a mildly elevated protein level [1, 2, 4] withoutcytologic [1, 2, 4], immunologic [1], or infectious [1, 2]abnormalities. In patients with cerebral or cerebellar para­neoplastic syndromes associated with small cell lungcancer, an antibody known as anti-Hu has been identifiedin the serum and CSF that is associated with but notdiagnostic for paraneoplastic syndromes [6]. In this case,the anti-Hu antibody was not identified in the serum or

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Ann Thorae Surg1994;58:250--1

CASE REPORT CUNNINGHAM AND BURTLIMBIC ENCEPHALITIS

251

CSF. Further work-up is needed to make the diagnosis oflimbic encephalitis.

Neuroimaging for limbic encephalitis includes com­puted tomography and magnetic resonance imaging ofthe brain and four-vessel cerebral angiography, yet it israrely diagnostic. Initially, the computed tomograms maybe normal, as in this case, or show mild ventriculardilatation [2, 3]. Magnetic resonance imaging scans mayreveal hyperintense T2-weighted images in the temporallobes early in the course of the disease while the com­puted tomograms are normal [7]. The improvement in theserial magnetic resonance images in this case has beenseen by others [7]. Thus, computed tomography does notappear to be helpful in the diagnosis of limbic encephali­tis, but magnetic resonance imaging is useful early inlocalizing the pathologic process to the limbic system andit appears to be useful in follow-up evaluations.

The gold standard for the diagnosis of limbic encepha­litis is histologic confirmation of extensive neuronal losswith reactive gliosis, perivascular monocytic infiltrates,and microglial nodule formation in the temporal lobe [1,2,4]. There was no brain biopsy performed in our patientdue to the rapid improvement in her clinical course. Thus,the diagnosis of limbic encephalitis in our case remainsone of exclusion.

The natural history of limbic encephalitis is one of aprogressive deterioration of function resulting in deathwithin several months from the time of diagnosis [1, 2].Burton and associates [6] showed that the neurologicsymptoms may improve with the eradication of the pri­mary disease. Our case is an example of clinical improve­ment after resection of a malignant thymoma. Therefore,a reversal of the disease process appears to be dependenton the complete removal of the primary disease and theprevention of recurrence.

Possible causes of limbic encephalitis include viral in­fection or an immune-mediated response suggesting across reactivity between tumor antigen and antigens 10-

cated in the limbic system [8]. This immune responseleads to neurologic impairment of limbic function second­ary to neuronal injury. The presence of a circulatingantibody in this case remains speculative. Support for thisantibody may exist because an extensive work-up forother causes was negative and the patient improvedsignificantly after treatment of the primary disease.

There are no clinical, laboratory, or radiographic find­ings pathognomonic for limbic encephalitis, and the diag­nosis can only be made by tissue confirmation. Treatmentfor limbic encephalitis secondary to a paraneoplastic syn­drome should be directed at the underlying disease.Control of the primary tumor may result in the reversal ofneurologic symptoms, but the natural history of thedisease in patients with persistent or recurrent disease isprogression, resulting in death.

References

1. Ingenito GG, Berger JR, David NJ, Norenberg MD. Limbicencephalitis associated with thymoma. Neurology 1990;40:382.

2. McArdle}p, MiIlingen KS. Limbic encephalitis associated withmalignant thymoma. Pathology 1988;20:292-5.

3. Henson RA, Urich H. Encephalomyelitis with carcinoma. In:Henson RA, Urich H, eds. Cancer and the nervous system:the neurologic manifestations of systemic malignant disease.Boston: Blackwell, 1982:315-45.

4. Newman NJ, Bell IR, McKee AC. Paraneoplastic limbic en­cephalitis: neuropsychiatric presentation. Bioi Psychiatry1990;27:529-42.

5. Burton GV, Bullard DE, Walther PJ, Burger rc. Paraneoplasticlimbic encephalopathy with testicular carcinoma; a reversibleneurologic syndrome. Cancer 1988;62:2248--51.

6. Furneaux HF, Reich L, Posner JB. Autoantibody synthesis inthe central nervous system of patients with paraneoplasticsyndromes. Neurology 1990;40:1085--91.

7. Kodama T, Numaguchi Y, Gellad FE, Dwyer BA, Kristt DA.Magnetic resonance imaging of limbic encephalitis. Neurora­diology 1991;33:520-3.

8. Levitt P. A monoclonal antibody to the limbic system. Science1984;223:299-301.