Paraneoplastic neurologic syndromes are a heterogenous group of neurologic disorders associated with malignancy. They are caused by a mechanism other than metastases, infections, metabolic disorder, or side effects of cancer treatment. These rare syndromes occur in about 6.6% of patients with malignancy and may affect any part of the nervous system including cerebrum, spine, neuromuscular junction and muscle, either damaging one or multiple sites2
PLE, one of the paraneoplastic neurologic syndromes, refers to an inflammatory process localized to the limbic system, which is associated with neoplasm. It is characterized by acute or subacute mood and behavioral changes, short-term memory loss, seizures and cognitive dysfunction. The symptoms typically progress over days to weeks but more indolent presentations over months have been described1
. The most frequent associated malignancy is lung cancer (especially SCLC) but testicular tumors, thymoma, breast cancer and Hodgkin lymphoma can be related with PLE2
The pathobiology of PLE is believed to be autoimmune-related. The mechanism is suggested to be triggered by autoantibodies against onconeural antigens which are common to both the cancer and the nervous system4
. Among several PAAs, the most frequent are anti-Hu and anti-Ma2 antibodies. The presence of PAA often allows early detection of the associated tumor, thus aiding the diagnosis, however these antibodies are detected in only 60% of patients diagnosed with PLE. Therefore, the absence of PAA does not exclude PLE5
. According to the detected PAA, the clinical manifestation can vary. For example, patients with anti-Hu (also known as antineural nuclear antibody type 1, ANNA-1) antibody often have multifocal neurologic involvement affecting temporal lobes, brainstem, cerebellum and dorsal roots7
. SCLC is most frequently found malignancy associated with anti-Hu antibody1
. On the other hand, testicular cancer is associated with anti-Ma2 (also called anti-Ta) antibody and the clinical presentation of Ma2-associated encephalitis differs from classical PLE in that its symptoms particularly related with brainstem and cerebellar dysfunction8
A brain MRI is helpful in that one can exclude other causes with similar neurologic symptoms. Characteristic MRI finding of patients with PLE is high signal intensity on flair or T2WI in bilateral or unilateral medial temporal lobes and/or brain stem9
. EEG has limited usefulness in making the diagnosis of PLE, but it is useful to exclude nonconvulsive seizures. In patients with PLE, nonspecific EEG abnormalities are common and include focal or generalized slowing, epileptiform activity and periodic lateralized epileptiform discharges10
. CSF tapping should be performed to exclude the leptomeningeal metastasis and to detect other inflammatory or immune-mediated neurologic disorder. CSF finding is not specific for PLE and often shows mild elevation of protein level or monocyte count11
The diagnosis of PLE is difficult to diagnose for several reasons1
. First, similar symptoms such as seizure, memory loss, irritability, depression, confusion or dementia can be caused by many other cancer-related complications, including brain metastasis, toxic and metabolic encephalopathies, infections and side effect of cancer therapy. Second, the clinical manifestation and frequently involved brain area is especially similar with those of herpes simplex encephalitis. Finally, neurologic symptoms frequently precede the detection of the tumor, further confounding the diagnosis of the neurologic disorder as paraneoplastic in origin. Gultekin et al.1
suggested the following diagnostic criteria: a compatible clinical picture; an interval of <4 years between development of neurologic symptoms and tumor diagnosis; exclusion of the other neuro-oncological complications; and at least one of the following: CSF with inflammatory changes but negative cytology, MRI demonstrating temporal lobe abnormalities or EEG showing epileptic activity in the temporal lobe. In the current case, the patient had neurologic symptoms and brain imaging findings suspicious of limbic encephalitis, and we could exclude other causes by CSF analysis. Although the PAAs were negative, we suspected underlying hidden neoplasm and finally diagnosed PLE with SCLC.
Unlike most paraneoplastic syndromes of the central nervous system, which do not improve with treatment, PLE is well- known for its good response to therapy. In a case series of 50 patients of PLE, the response rate of neurologic manifestation to the treatment was over 60%1
. Immnunosuppression with methylprednisolone, intravenous immunoglobulin can be available. Kobayakawa et al.12
reported that plasma exchange could be useful to control symptoms by reducing the titer of PAA. However, treatment of associated tumor is more important in neurologic improvement and prognosis13
. Bowyer et al.14
reported two cases of PLE with SCLC which were successfully treated after chemotherapy stressing the importance of identifying underlying malignancies, while Cho et al.15
reported a case whose prognosis was poor due to delayed diagnosis. The present case also demonstrated the importance of early diagnosis and treatment of underlying cause.
We report a case of a patient admitted due to seizure and disorientation, and finally diagnosed as PLE associated with SCLC, whose neurologic symptoms were gradually improved with treatment of underlying malignancy. Although the diagnosis PLE is often difficult and exclusion of other causes of encephalitis is essential, all efforts should be made to find a hidden neoplasm when encountering symptoms compatible with limbic encephalitis. It is also important to remember that PLE is a potentially 'controllable' disorder with early diagnosis and appropriate treatment.