ANNA-1 Paraneoplastic Encephalomyelitis Presenting as Rapidly Progressing Dementia in a Man With Undiagnosed Small Cell Lung Cancer

“Mr. B” is a 64-year-old man with a past medical history of hypertension presented to our emergency department with his wife for safety concerns in context of rapid behavioral changes, mood lability, impulsivity, and memory problems. Review of his outside records showed that he initially presented to his primary care physician 2 months prior due to a 1-month history of memory deficits, confabulations, confusion, and executive function deficits in the context of an unintended 20-pound weight loss. Additionally, he had alternating irritability and euphoria, psychomotor agitation, nonspecific paranoia, increased speech, and impaired judgment. Neurologic examination was concerning for frontal and temporal lobe deficits. The patient’s Montreal Cognitive Assessment score was 12/30. His vitamin B12 and thyroid-stimulating hormone levels were normal. His primary care physician started him on bupropion (150 mg twice daily) and mirtazapine (7.5 mg at night) for mood. An MRI of the patients’ head revealed several foci of T2 hyperintensity within the periventricular white matter and centrum semiovale. Subsequently, an [¹⁸F]FDG PET [¹⁸F-fluorodeoxyglucose positron emission tomography] scan of the brain showed reduced metabolic activity in the posterior cingulate, precuneus, and lateral temporal-parietal lobes suggestive of Alzheimer’s disease. Two days prior, the patient was seen at an outside emergency department because he was becoming too difficult to manage; olanzapine (5 mg a day) was added to his medication regimen.

The patient is a former smoker with a 50-pack/year history and drinks alcohol occasionally. He lives at home with his wife and worked as a repairman until 2 months prior when he had to resign due to cognitive decline. His family history is significant for a mother with depression, anxiety, and acute lymphoblastic leukemia as a child, as well as a sister with depression and anxiety.

Laboratory investigation in the emergency department revealed a hemoglobin level of 12.1 g/dl with normal mean corpuscular volume, hyponatremia with a sodium level of 134 mEq/L, a negative toxicology screen, an unremarkable urinalysis, and Montreal Cognitive Assessment score of 12/30. The patient was admitted for further workup. The consulting psychiatry service recommended discontinuing bupropion, mirtazapine, and olanzapine in favor of 50 mg of quetiapine at night.

Initially, the patient had episodes of increasing agitation and confusion that was managed with an as-needed quetiapine dose of 50 mg. About a week into his hospitalization, his agitation worsened, necessitating the addition of haloperidol (2 mg p.r.n.) to control his agitation. As his delirium was subsequently better controlled, it remained clear that his major neurocognitive disorder remained, with serial Montreal Cognitive Assessment examinations demonstrating consistent levels of cognitive impairment.

An initial EEG demonstrated focal spike and wave discharges from the right temporal chain, but a 24-hour video EEG re-demonstrated epileptiform abnormalities without clear electrographic seizures. Levetiracetam was loaded but discontinued after the results of the video EEG. Initial head CT was unremarkable, and a head MRI showed T2-fluid attenuated inversion recovery hyperintensity in the bilateral mesial temporal lobes. Initial laboratory workup included a heavy metal screen that was negative; iron studies demonstrating elevated ferritin, normal iron, total iron binding capacity, and transferrin indicating anemia of inflammation; and CSF analysis. Basic CSF analysis demonstrated normal cell count and glucose and an elevated level of CSF protein to 75 mg/dl. CSF gram stain and cultures were negative. CSF polymerase chain reaction tests were negative for herpes simplex virus, enterovirus, and Epstein-Barr virus. CSF angiotensin converting enzyme levels were normal. CSF serology demonstrated positive anti-neuronal nuclear antibody-1 (ANNA-1), with a titer of 1:512, no anti-N-methyl-d-aspartate receptor antibodies, and a normal Creutzfeldt-Jakob screen. A prostate-specific antigen screen was normal. Given the positive ANNA-1 antibody, a CT of the chest, abdomen, and pelvis was performed, which showed enlarged right paratracheal lymph nodes but no other abnormalities. Subsequent bronchoscopy with endobronchial ultrasound-guided fine-needle aspiration of the paratracheal lymph nodes was performed. Initial cytology smear was suspicious for malignancy. Final pathology demonstrated cells positive for synaptophysin, chromogranin, and thyroid transcription factor-1 consistent with small cell lung carcinoma. A subsequent PET-CT performed showed hypermetabolic activity in the right paratracheal lymph nodes, mildly hypermetabolic nodes involving the right hilum, pretracheal, and paraesophageal nodes, and moderate uptake in the right fourth and tenth rib with sclerosis, suggestive of extensive-stage small cell lung carcinoma.

The patient’s paraneoplastic syndrome was initially managed with 5 daily doses of intravenous immunoglobulin (400 mg/kg/day) and five plasmapheresis treatments three times weekly. His first cycle of chemotherapy with cisplatin and etoposide was started in the hospital. He was discharged home after a 23-day hospital stay. During initial follow-up with a lung oncologist, the decision was made to pursue curative intent with chemotherapy plus radiation. The patient’s behavioral agitation is improved; however, his cognitive function remains diminished.

Paraneoplastic syndromes are autoantibody-mediated disorders associated with underlying tumors (1). Neurological paraneoplastic syndromes occur in approximately 1 in 10,000 cancer patients (2). These conditions arise when systemic tumors express antigens normally found on neural tissue. Tumor directed immune responses recognize these antigens as non-self, leading to production of antibodies against the neural antigen. Paraneoplastic encephalomyelitis symptoms are often subacute and often precede detection of the tumor (2). Cancers associated with paraneoplastic encephalomyelitis include small cell lung carcinoma, ovarian carcinoma, breast carcinoma, thymoma, Hodgkin’s lymphoma, and, rarely, prostate cancer (3).

The patient in the above case presented with records showing imaging suggestive of Alzheimer’s dementia. On PET, the metabolic pattern characteristic of Alzheimer’s disease is hypometabolism in parietotemporal areas, the posterior cingulate cortex, and the precuneus, as well as medial temporal lobes, mostly the entorhinal cortex and hippocampus (4). Interestingly, PET has utility in the diagnosis of paraneoplastic neurologic syndromes as well. In clinically suspected paraneoplastic encephalomyelitis, PET has a sensitivity and specificity of 75% and 87%, respectively, in diagnosing paraneoplastic encephalomyelitis (5). Clear indications for PET in patients with major neurocognitive disorder are not currently established, but the American College of Radiology and the American Society for Neuroradiology suggest it can be useful in patients with unexplained major neurocognitive disorder (6).

A case series of patients with ANNA-1 paraneoplastic encephalomyelitis shows similarities with the above case (7). The authors reported that the median age was 63 years old, 75% were men, and paraneoplastic encephalomyelitis preceded diagnosis of the malignancy in 73% of cases (7). Treatment of the primary tumor with or without immunotherapy was a predictor of improvement or stabilization of the neurologic sequelae (7). Similarly, in another case series of ANNA-1 paraneoplastic encephalomyelitis, tumor complete response was the only predictor of paraneoplastic encephalomyelitis stabilization, and immunotherapy did not modify the outcome regarding the tumor or paraneoplastic encephalomyelitis (8). The probability of survival at 30 months has been shown to be higher in small cell lung carcinoma patients with paraneoplastic encephalomyelitis than those without paraneoplastic encephalomyelitis (8). Similarly, a report in patients without clinically evident paraneoplastic encephalomyelitis showed that small cell lung carcinoma patients with detectable ANNA-1 antibodies in their serum were more likely to have: limited stage disease, a complete response to therapy, and longer overall survival compared with patients without ANNA-1 antibodies (9). Despite more positive prognosis for small cell lung carcinoma with ANNA-1 paraneoplastic encephalomyelitis, reports suggest that up to 65% of patients with ANNA-1 paraneoplastic encephalomyelitis and small cell lung carcinoma die of neurological complications rather than tumor progression (9). It is unclear whether paraneoplastic encephalomyelitis preceding small cell lung carcinoma diagnosis allows for earlier detection of disease and a potential survival benefit through lead-time bias or there is a biological relationship between these autoimmune processes and small cell lung carcinoma outcomes.

Despite the initial uncertainty in the above case, a relatively rapid diagnosis of small cell lung carcinoma was made. Initial diagnostic workup for rapidly progressive dementia should be broad and include testing for metabolic, infectious, and autoimmune causes through blood, urine, and CSF; neuroimaging with MRI is also recommended (10). This workup can be expanded based on results of a complete initial evaluation. Early diagnosis of paraneoplastic encephalomyelitis and tumor and early tumor treatment are necessary. However, the overall functional outcome is poor, and >50% of patients are confined to bed or a wheelchair in the chronic phase of the disease, highlighting the therapeutic challenge these patients face (7, 8).

The authors thank their mentors, Drs. Burr Eichelman and Michael Peterson, for assistance with caring for the patient in this case report, as well as for their editorial assistance. The authors also thank all medical professionals that played a role in the complex management of this patient, as well as the patient and his family for allowing us to take part in his care.