A Veteran Presenting With Altered Mental Status and Clonus

►Dr. Reese : The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months). ^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years). ⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese : Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari : Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%. ⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach. ^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years. ¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.