CASE REPORT

Small cell lung cancer presenting with paraneoplasticlimbic encephalitisajco_1374 180..184

Samantha BOWYER,1 Suzanne WEBB,1 Michael MILLWARD,1,2 Kevin JASAS,1

David BLACKER3 and Anna NOWAK1,2

Departments of 1Medical Oncology and 3Neurology, Sir Charles Gairdner Hospital, 2School of Medicine and Pharmacology,University of Western Australia, Perth, Western Australia, Australia

Abstract

We report two cases of the rare neurological paraneoplastic syndrome, limbic encephalitis, as the initialpresentation of small cell lung cancer. The first case responded to treatment of the underlying malignancy,while the second required more acute treatment in the intensive care setting. In this case, initial treatmentwas with immunosuppression to achieve a degree of stability before the underlying malignancy could betreated. Both cases had significant improvement in neurological function. These cases highlight the impor-tance of directed investigation to try and identify an underlying malignancy in patients in whom a diagnosisof limbic encephalitis is made, and the difficulty in managing such patients.

Key words: limbic encephalitis, paraneoplastic, small cell lung cancer.

INTRODUCTION

Limbic encephalitis is a rare neurological paraneoplasticsyndrome. It is most commonly associated with smallcell lung cancer, but can be a feature of several othermalignancies, including breast and testicular cancer.Clinical presentation can be with subacute confusion,short-term memory impairment, psychiatric disturbanceand seizures. Neurological symptoms might precedethe clinical diagnosis of an underlying malignancy byseveral months.1 Treatment essentially is that of themalignancy, but there might also be a role for immuno-suppression in the short term as a temporizing measure.Due to this, it is imperative that when the clinicaldiagnosis is suspected, a search for the underlyingmalignancy is undertaken to allow appropriate moredefinitive management.2 Diagnostic criteria are based onan appropriate clinical picture, supported by serology,electroencephalogram (EEG) and magnetic resonanceimaging (MRI) findings.

CASE REPORT 1

Case 1 is a 66-year-old man presenting with confusion,personality change and a possible seizure leading tocollapse. During this collapse, he sustained a fracture toL1. The history was acute in onset over a 1-week period.His collapse prompted admission and further investiga-tion. He had no significant past medical history, but didhave an 80-pack per year history of smoking.

Examination revealed tenderness over the L1 verte-brae and a Glasgow Coma score of 14 due to confusion.Other findings were unremarkable, including a full neu-rological examination. Standard initial investigationsto determine a cause for confusion in the emergencydepartment were essentially normal. This included anormal chest X-ray and computed tomography (CT)scan of the brain. He did have an elevated white cellcount of 18.0 ¥ 109, with an associated neutrophilia(normal 4.0–11.0 ¥ 109). His C-reactive protein wasnormal. The L1 fracture was confirmed on X-ray and asubsequent CT scan of the lumbar spine.

Following admission, he displayed impairment ofhigher cognitive function, lack of insight and recurrentgeneralized tonic clonic seizures. The seizures were notcontrolled with several anti-epileptics, despite thera-peutic doses and blood levels. An MRI of the head

Correspondence: Professor Michael Millward, Department ofMedical Oncology, Sir Charles Gairdner Hospital, Perth6009, WA, Australia. Email: millward@cyllene.uwa.edu.au

Accepted for publication 12 November 2010.

Asia–Pacific Journal of Clinical Oncology 2011; 7: 180–184 doi:10.1111/j.1743-7563.2010.01374.x

© 2011 Blackwell Publishing Asia Pty Ltd

demonstrated an altered signal in the left hippocampus,and an EEG showed background slowing consistentwith a mild encephalopathic state. A lumbar punctureshowed a mildly elevated protein of 0.47 g/L (normal0.1–0.47). Cerebrospinal fluid was negative for evidenceof bacterial or viral infection (Figs 1,2).

A CT scan of the chest showed three pulmonarynodules, the largest measuring 11 ¥ 10 mm. There weremultiple subcentimeter axillary and mediastinal lymphnodes also (Fig. 3).

An endoscopic bronchial ultrasound and biopsy of theright paratracheal lymph nodes confirmed a high-gradeneuroendocrine carcinoma consistent with small celllung cancer. Anti-GAD 65 antibodies were >30 (<1.0).Anti-Hu antibodies were not present. Other staginginvestigations, including a bone scan, did not demon-strate any extrapulmonary disease. He was diagnosed ashaving limbic encephalitis based on a compatible clinicpicture and investigations in the setting of untreatedsmall cell lung cancer.

Following the biopsy results, he began chemotherapywith carboplatin (area under the curve [AUC] = 5 mg/

mL.min) on day 1 and etoposide (100 mg/m2) on days1–3 with a 21-day schedule. He required a 3-monthinpatient hospital stay, as initially he was not able to beplaced in a care facility due to his behavioral problems.He went on to complete four cycles in total. His CT scanafter two cycles demonstrated improvement in appear-ances with resolution of two of the pulmonary nodules.The third remained stable and was thought not malig-nant in etiology. The mediastinal lymphadenopathy alsoshowed improvement. On completion of his chemo-therapy, he had 50 Gy in 25 fractions of radiotherapy tothe chest and mediastinum, and prophylactic cranialirradiation.

With the treatment of his underlying malignancy, hiscognitive and functional status improved and his sei-zures were controlled. He remained on levetiracetam1000 mg BD and phenytoin 400 mg nocte. Followingcompletion of his treatment, he had no recollection ofthe 3 months he spent in hospital. Following treatment,he made slow improvements and was able to returnhome to live with his wife after temporary placement ina transitional care facility.

Figure 1 Magnetic resonance imaging head case 1. Axialsection T2-weighted images showing altered signal in the lefthippocampus.

Figure 2 Magnetic resonance imaging head case 1 demon-strated on the coronal section FLAIR images.

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CASE REPORT 2

Case 2 is a 51-year-old woman who presented with a3-week history of multiple seizures associated with aprolonged postictal phase. Her past medical historyincluded a significant smoking history (30–40 cigarettes/day) in association with alcohol excess of up to twobottles of wine per day. Her initial blood tests revealedhyponatremia with a sodium of 124 mmol/L (normal134–146) and a slightly elevated white cell count of14.0 ¥ 109/L (normal 4–11). A CT scan of the brainshowed no abnormality.

She continued to deteriorate following admission withincreasing frequency of seizures, progressive confusionand slurred speech. Her seizures were not controlled,despite therapeutic levels of sodium valproate. She wascommenced on phenytoin, but continued to deteriorate,and developed status epilepticus requiring intubationand ventilation in the intensive care unit.

She underwent a lumbar puncture, and examination ofthe cerebrospinal fluid (CSF) showed an elevated proteinof 0.5 g/L (normal 0.15–0.45). EEG was mildly abnor-mal and demonstrated generalized slowing without focalor epileptiform activity at the time of investigation. AnMRI showed no evidence of a focal lesion and no evi-dence of encephalitis. Limbic structures were normal.Anti-GAD 65 and anti-Hu antibodies were negative.

A CT chest showed significant lymphadenopathy atthe left hilar and precarinal (mediastinal) regions. A CTof the abdomen and pelvis were normal. A transbron-chial fine-needle aspiration of the precarinal lymph noderevealed small cell lung carcinoma. The patient wasstaged as having limited stage disease (Fig. 4).

She spent several days in the intensive care unit whileher seizures were being managed. She was commenced onhigh-dose methylprednisolone (500 mg i.v. daily), andunderwent plasma exchange. Once she was stable, che-motherapy was commenced with carboplatin (AUC =4.5 mg/mL.min) on day 1, and etoposide (100 mg/m2) ondays 1–3. Her condition improved slowly and sheremained seizure free after initial immunosuppressionand commencement of chemotherapy. The second cycleof chemotherapy was given as inpatient, and she wasdischarged home after spending 2 months in hospital.

A CT scan after two cycles of chemotherapy showed aresponse to treatment. A repeat MRI scan did not showany evidence of limbic encephalitis and was unchangedfrom the prior scan. Her cognition and confusion contin-ued to improve during chemotherapy, and she completedfour cycles. She did, however, have some persistentmemory loss and cognitive difficulties, and was emotion-ally labile. She required ongoing antiseizure medication,although her regimen was rationalized. She went on tohave radiotherapy to the precarinal and left hilar regions

Figure 3 Computed tomography (CT) chest case 1. CT dem-onstrating a pulmonary nodule in the posterior segment of theright upper lobe.

Figure 4 Computed tomography (CT) chest case 2. CTshowing paratracheal lymphadenopathy.

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(65 Gy in 25 fractions), followed by prophylactic whole-brain radiotherapy (30 Gy in 15 fractions).

Nine months, later positron emission tomography andCT imaging confirmed recurrent small-volume disease inthe right paratracheal node and left hilar region. Inaddition to this, she had hyponatremia for which sherequired escalating doses of demeclocycline. With pro-gression of her disease, however, her symptoms of limbicencephalitis did not recur. She was retreated with afurther four cycles of carboplatin/etoposide, with areduction in her paratracheal node and stable disease atthe left hilum. After a further year, a restaging CT scanshowed right supraclavicular nodes and an increase in themediastinal and left inferior hilar nodes. She was symp-tomatic with neck pain, weight loss and had recurrenthyponatremia. Again she was retreated with three cyclesof carboplatin/etoposide, with imaging demonstratingstable disease. Over 2 years following diagnosis, shepassed away secondary to disease progression.

DISCUSSION

Limbic encephalitis is a rare neurological paraneoplasticsyndrome. It is not caused directly by the tumor or by itsmetastases, but as a response to onco-antigens producedby the tumor, which share similarities with antigensfound within the central nervous system. This leads to anautoimmune attack, likely involving cellular immunity,on neuronal tissue and resultant clinical presentation.3,4

Limbic encephalitis is a neurological syndrome charac-terized by the subacute onset of confusion, impairment ofshort-term memory and psychiatric symptoms.1,5 Sei-zures are a common feature and might predate the onsetof other neurological symptoms.5 The inflammationwithin the central nervous system resulting in symptomsis usually centered around the medial temporal lobes,brain stem and hypothalamus.3 In addition to this, theneurological presentation with limbic encephalitis mightproceed the diagnosis of cancer in up to 60% of the cases,with a median time frame of 3.5 months. Thus, when theclinical diagnosis is suspected, a search for the underlyingmalignancy should be undertaken (Table 1).1

The Mayo Clinic, in a review of 24 patients withsuspected limbic encephalitis, aimed to determine poten-tial diagnostic criteria based on the presentation andabnormal investigations. These investigations includedEEG, MRI, serology and CSF examination. They foundcommon clinical manifestations were cognitive dysfunc-tion (92%), seizures (58%) and psychiatric symptoms(50%). EEG showed focal or generalized slowing and/orepileptiform activity, maximal in the temporal regions in

all patients tested. MRI revealed increased T2 signalinvolving one or both temporal lobes in 83% of thecases. Paraneoplastic auto-antibodies were found in64%. CSF results were abnormal in 78% of the cases.6

In a case series of 50 patients with paraneoplasticlimbic encephalitis, lung, testicular and breast cancerswere the three main malignancies associated with limbicencephalitis. Together, they accounted for 80% of thecases. Small cell lung cancers alone accounted for 40%of all cases.1

The anti-Hu antibody is an antineuronal antibodyand is the most common auto-antibody seen in paraneo-plastic limbic encephalitis. It is not only associated withlimbic encephalitis, but also paraneoplastic cerebellardegeneration and sensory neuropathy.2,7 Anti-GADantibodies, as found in our first case, have also beenimplicated in limbic encephalitis. They are thought tointerfere with g-aminobutyric acid synthesis or its exo-cytosis in the central nervous system.8

Other auto-antibodies are also found in associationwith this paraneoplastic syndrome and are associatedwith different underlying malignancies. An example isanti-Ta (or anti-Ma2) found in testicular cancer. Theirpresence might guide the search for the underlyingprimary malignancy and assist directed therapy.However, no auto-antibodies are detectable in approxi-mately one-third of patients, and up to 10% might havean atypical antibody. Therefore, their presence is notnecessary for diagnosis.5,9,10

Several studies have suggested that cellular immunityis involved in the pathogenesis of paraneoplastic syn-

Table 1 Diagnostic criteria for paraneoplastic limbicencephalitis

Clinical picture compatible with a diagnosis of limbicencephalitis

Less than 4 years between symptoms and the diagnosis of amalignancy

Exclusion of other differential diagnosis such as brainmetastases, toxic and metabolic encephalopathies andinfections

At least one of:• CSF: inflammatory changes but negative cytology• MRI: temporal lobe abnormalities• EEG: epileptic activity in the temporal lobes

Diagnosis supported by:• The presence of onconeural antibodies• A response to anticancer treatment in the absence of

immune modulation

Adapted from2,7. CSF, cerebrospinal fluid; EEG, electroencephalogram;MRI, magnetic resonance imaging.

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dromes associated with anti-Hu antibodies.4 Studieshave shown the infiltration of CD-8 positive T cells intumors and affected nervous system tissues, suggestingthat these cells might be responsible for the inflamma-tion and neuronal damage.11

Early diagnosis and exclusion of other causes isessential in the diagnosis and initial management ofthese patients. Patients without a known malignancyshould have investigations directed at identifying anunderlying primary tumor, as well as helping to estab-lish the diagnosis. In the first instance, supportivetreatment is required, including anti-epileptics forseizure control and antidepressants for depressivesymptoms.2

In general, the earlier the treatment of the primarytumor can be commenced, the more likely a clinicalimprovement will be seen. Other treatments availableinclude immunosuppression with high-dose methyl-prednisolone or intravenous immunoglobulin. In asmall, uncontrolled, unblinded trial, it was suggestedthat rituximab was beneficial for the treatment ofanti-Hu-positive paraneoplastic limbic encephalitis.12

Plasma exchange to reduce the titer of auto-antibodiesmight also be of benefit in helping to control seizuresin the short term.8 Previous studies have shown treat-ment of the underlying malignancy to be more effectivethan immunosuppression alone; however, it may beuseful as a temporizing measure, as in our second casereport.1,2

The absence of anti-Hu antibodies has also beenassociated with an improved chance of neurologicalimprovement with treatment of the underlying malig-nancy.2,9 Anti-Ta antibodies found in patients with tes-ticular cancer were also associated with a poorerneurological outcome.1

Limbic encephalitis is a rare neurological paraneo-plastic syndrome associated with several malignancies,but most commonly, with small cell lung cancer. It ischaracterized by clinical features, such as confusion,personality changes and short-term memory loss. Neu-rological symptoms might precede diagnosis of theunderlying malignancy by weeks or even months. Inves-tigations which aid establishment of the diagnosis andexclude other differentials include MRI, EEG, auto-antibody serology and CSF analysis.

We described two case reports of paraneoplasticlimbic encephalitis presenting with seizures and confu-sion in patients with previously undiagnosed small celllung cancer. Both cases had resolution of their paraneo-plastic neurological symptoms with treatment of theirunderlying malignancy. Interestingly, our second case

did not have recurrence of her symptoms when shedeveloped recurrent disease; however, neurological dete-rioration might recur if the primary tumor progressesafter initial treatment.13

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