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A 51-Year-Old Man With Seizures and Progressive Behavioral ChangesMan With Seizures and Behavioral Changes FREE TO VIEW

Casey A. Cable, MD; William D. Freeman, MD; Mark N. Rubin, MD; Andras Khoor, MD, PhD; Lioudmila V. Karnatovskaia, MD, FCCP
Author and Funding Information

From the Department of Internal Medicine (Dr Cable), Department of Neurology (Drs Freeman and Rubin), Department of Neurosurgery (Dr Freeman), Department of Critical Care (Dr Freeman), and Department of Pathology (Dr Khoor), Mayo Clinic, Jacksonville, FL; and Departments of Pulmonary and Critical Care Medicine (Dr Karnatovskaia), Mayo Clinic, Rochester, MN.

CORRESPONDENCE TO: Casey A. Cable, MD, Department of Internal Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: Cable.Casey@mayo.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(3):e86-e89. doi:10.1378/chest.14-1572
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A 51-year-old man was admitted for evaluation of new-onset generalized seizures in the context of progressive and significant behavioral change. His medical history was only notable for previous outbreaks of genital herpes. He took no medications. He had occasional social alcohol use and no illicit drug use but was a 35-pack-year current smoker. The patient had no relevant occupational exposure history but had recently traveled to Panama. Initially, the patient’s significant other noticed a progressive flattening of his affect. The patient then started to experience episodes of “passing out” that led to injuries prompting ED visits. He was prescribed antiseizure medications and scheduled for an outpatient workup. However, with progressive gait instability, lethargy, and an increase in frequency of generalized seizures, the patient was admitted for treatment of suspected viral encephalitis. Despite initiation of antimicrobial and antiviral therapy, the patient’s level of alertness continued to decline, ultimately leading to intubation for airway protection.

Figures in this Article

On admission, the patient was normotensive and afebrile with sinus tachycardia at 114 beats/min. He was well developed, awake, but not oriented. He was unable to follow commands, although he was moving all extremities spontaneously. He had no nuchal rigidity. The remainder of the physical and neurologic examination was unremarkable. As the patient’s level of alertness declined to stupor, no other new neurologic signs were appreciated.

The patient’s CBC and electrolyte levels were normal. Serum alcohol and urine toxicology screen tests were negative. MRI of the brain showed a focal intracortical T2 hyperintense signal abnormality in the right-side cerebellar hemisphere that contained a punctate focus of enhancement (Fig 1A). The patient continued to have encephalopathy and seizures; a second MRI showed a small focus of enhancement in the right-side superior frontal gyrus (Fig 2A). An EEG captured left-sided frontotemporal rhythmic discharges leading up to a clinical seizure.

Figure Jump LinkFigure 1 –  A, Initial MRI fluid-attenuated inversion recovery sequence showed a focal intracortical T2 hyperintense signal abnormality in the right cerebellar hemisphere, which contained a punctate focus of enhancement (arrow). B, Follow-up sequence after treatment, with the resolution of the right cerebellar lesion.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, Initial MRI fluid-attenuated inversion recovery sequence showed a small focus of enhancement in the right superior frontal gyrus indicating an inflammatory lesion (arrow). B, Follow-up sequence after treatment, with resolution of the lesion.Grahic Jump Location

Results of cerebrospinal fluid (CSF) analysis were as follows: WBC count, 36/μL with lymphocytic predominance (93%); RBC count, 19/μL; glucose level, 75 mg/dL (normal); and protein level, 29.8 mg/dL (normal). CSF Gram stain and blood cultures were negative for bacteria, fungus, and mycobacteria. Additional serum and CSF serologies were negative for cysticercosis, Lyme disease, syphilis, legionella, Bartonella, Brucella, Q fever, Ehrlichia, and Rocky Mountain spotted fever. Viral serologies were negative for herpes simplex, cytomegalovirus, John Cunningham virus, Epstein-Barr virus, varicella-zoster virus, West Nile virus, HIV, and Saint Louis and eastern and western equine encephalitis. Histoplasma urine antigen test results were normal.

What is the diagnosis?
Diagnosis: Paraneoplastic limbic encephalitis PLE secondary to small cell lung cancer diagnosed by serum paraneoplastic panel testing, chest imaging, and tissue sampling

The combination of a clinical scenario that includes progressive psychiatric changes, encephalopathy, and new-onset seizures in a setting of small cell lung cancer suggests paraneoplastic limbic encephalitis (PLE). The presence of γ-aminobutyric acid (GABA) B-receptor antibody and N-type and P/Q-type calcium channel antibodies can confirm the diagnosis.

Neurologic paraneoplastic syndromes are rare, occurring in < 0.01% of patients with cancer. Symptoms result from the autoimmune response induced by antibodies and directed at antigens shared by the tumor and the CNS. Severe neurologic sequelae often follow. Neurologic symptoms typically progress over the course of weeks. Numerous autoantigen targets have been identified and include neuronal surface receptors and synaptic proteins. For example, antineuronal nuclear antibody-1 (ANNA-1 or anti-Hu) is associated with small cell lung cancer, anti-Ma2 with germ-cell testicular tumors, and anti-N-methyl-D-aspartate receptor antibodies with ovarian tumors. GABA B-receptor antibodies, as detected in the present patient, have been reported in PLE associated with small cell lung cancer accompanied by new-onset seizures.

N-type and P/Q-type calcium channel antibodies are rare and have been described in very few patients with PLE. Their presence has been associated with cerebellar dysfunction in paraneoplastic encephalomyelitis and can be seen with Lambert-Eaton myasthenia syndrome and paraneoplastic cerebellar degeneration.

Diagnostic criteria for PLE were originally published by Gultekin and colleagues after a review of 50 cases. According to these authors,

diagnosis of PLE required neuropathological examination (biopsy or autopsy), or all four of the following criteria: (i) a clinical picture of short-term memory loss, seizures, or psychiatric symptoms suggesting involvement of the limbic system; (ii) an interval of <4 years between the onset of neurological symptoms and the cancer diagnosis; (iii) exclusion of other cancer-related complications (metastasis, infection, metabolic and nutritional deficits, cerebrovascular disorder or side-effects of therapy) that may cause symptoms of limbic dysfunction; and (iv) at least one the following: CSF with inflammatory changes (pleocytosis, oligoclonal bands, increased immunoglobulin content or increased protein content in the absence of measured immunoglobulin); MRI showing unilateral or bilateral temporal lobe abnormalities on T2-weighted images or atrophy on T1-weighted images; and [electroencephalography] showing slow- or sharp-wave activity in one or both temporal lobes.

Contrast enhancement on imaging studies is seen less frequently but has also been reported. Neurologic symptoms may precede cancer diagnosis in 60% of patients. Brain imaging findings vary based on the tumor type and involve the limbic system in about two-thirds of diagnosed cases. Therefore, PLE should be considered in patients with known malignancy or at high risk for one who present with subacute progressive neurologic and psychiatric changes. In patients with positive antibodies and features suggestive of PLE, appropriate malignancy workup is indicated because the presence of cancer affects treatment and prognosis of the neurologic syndrome.

Unlike many paraneoplastic syndromes involving the CNS, PLE is more likely to respond to therapy. Because PLE appears to be mediated by tumor-induced autoimmunity, treatment includes immunomodulators and chemotherapy. Close airway monitoring and use of antiseizure medications are important aspects of care. High-dose IV steroids may be tried, but evidence of benefit is limited. Use of plasma exchange, IV immunoglobulin, cyclophosphamide, and rituximab has been reported with variable results. Systemic chemotherapy or surgery to treat the underlying malignancy appears to be more effective at improving neurologic symptoms than any other therapy. However, even after tumor resection or chemotherapy, neurologic symptoms may gradually improve over weeks to months but usually do not resolve completely. The presence or absence of certain antibodies appears to be of prognostic significance: Patients with small cell lung cancer and PLE but without ANNA-1 antibodies have more symptomatic improvement following chemotherapy than those with ANNA-1 antibodies. Ultimately, long-term prognosis of the neurologic syndrome is contingent on the underlying malignancy and available treatment.

Clinical Course

The patient’s serum paraneoplastic panel was positive for several neurally directed autoantibodies, including GABA B receptor and N-type as well as P/Q-type calcium channel autoantibodies. Testicular ultrasound was unrevealing. CT scan of the chest was unremarkable except for several small areas of atelectasis and an enlarged subcarinal lymph node. Endobronchial ultrasound-guided transbronchial aspiration of the lymph node was performed; histopathology findings are shown in Figure 3.

Figure Jump LinkFigure 3 –  Aspirate smear of the subcarinal lymph node. The cells exhibited irregular nuclei with stippled “salt-and-pepper” chromatin, nuclear molding, and very little cytoplasm (Diff-Quick and Papanicolaou , original magnification × 63).Grahic Jump Location

Once paraneoplastic autoantibody panel results were known, IV steroids were started. Two days later, results of the endobronchial biopsy confirmed the diagnosis of small cell lung cancer. Systemic chemotherapy was then initiated with cisplatin and etoposide. The patient’s mental status and motor skills gradually improved. His seizures recurred during the treatment course, but he continued to make clinical progress. Repeat MRI after treatment revealed that the previously noted abnormalities had completely resolved (Figs 1B, 2B), and no new lesions were identified. The patient is expected to make continual slow progress over the following weeks to months.

  • 1. Paraneoplastic neurologic symptoms are rare, occurring in < 0.01% of patients with cancer.

  • 2. Small cell lung cancer is the most common malignancy associated with PLE.

  • 3. PLE is considered in clinically appropriate patients with acute or subacute neurologic and psychiatric changes in the absence of a clear alternative etiology; evaluation for underlying malignancy even in the absence of obvious imaging findings may be warranted.

  • 4. Although the role of immunomodulating therapies is unclear, treatment of an underlying malignancy, once identified, offers a better and faster chance of neurologic improvement.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Alamowitch S, Graus F, Uchuya M, Reñé R, Bescansa E, Delattre JY. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain. 1997;120(pt 6):923-928. [CrossRef] [PubMed]
 
Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123(pt 7):1481-1494. [CrossRef] [PubMed]
 
Messori A, Lanza C, Serio A, Salvolini U. Resolution of limbic encephalitis with detection and treatment of lung cancer: clinical-radiological correlation. Eur J Radiol. 2003;45(1):78-80. [CrossRef] [PubMed]
 
Tüzün E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist. 2007;13(5):261-271. [CrossRef] [PubMed]
 
Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology. 2011;76(9):795-800. [CrossRef] [PubMed]
 
Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology. 2013;81(17):1500-1506. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  A, Initial MRI fluid-attenuated inversion recovery sequence showed a focal intracortical T2 hyperintense signal abnormality in the right cerebellar hemisphere, which contained a punctate focus of enhancement (arrow). B, Follow-up sequence after treatment, with the resolution of the right cerebellar lesion.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, Initial MRI fluid-attenuated inversion recovery sequence showed a small focus of enhancement in the right superior frontal gyrus indicating an inflammatory lesion (arrow). B, Follow-up sequence after treatment, with resolution of the lesion.Grahic Jump Location
Figure Jump LinkFigure 3 –  Aspirate smear of the subcarinal lymph node. The cells exhibited irregular nuclei with stippled “salt-and-pepper” chromatin, nuclear molding, and very little cytoplasm (Diff-Quick and Papanicolaou , original magnification × 63).Grahic Jump Location

Tables

Suggested Readings

Alamowitch S, Graus F, Uchuya M, Reñé R, Bescansa E, Delattre JY. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain. 1997;120(pt 6):923-928. [CrossRef] [PubMed]
 
Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123(pt 7):1481-1494. [CrossRef] [PubMed]
 
Messori A, Lanza C, Serio A, Salvolini U. Resolution of limbic encephalitis with detection and treatment of lung cancer: clinical-radiological correlation. Eur J Radiol. 2003;45(1):78-80. [CrossRef] [PubMed]
 
Tüzün E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist. 2007;13(5):261-271. [CrossRef] [PubMed]
 
Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology. 2011;76(9):795-800. [CrossRef] [PubMed]
 
Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology. 2013;81(17):1500-1506. [CrossRef] [PubMed]
 
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