Abstract | November 13, 2020

Brainstem Encephalitis as the Presenting Symptom of Pulmonary Large cell Neuroendocrine Carcinoma

Presenting Author: Heidi Anne Worth, MD, Internal Medicine Resident PGY3, Department of Medicine, UT Medical Center, Knoxville, TN

Co-authors: Kasey Helmlinger, MD, Radiology Resident PGY3, UTMCK, Knoxville, TN; Katherine Cochrane, MD, Pathology Resident PGY4, UTMCK, Knoxville, TN; Mark Rasnake, MD, Internal Medicine Program Director, UTMCK, Knoxville, TN

Learning Objectives

  1. Paraneoplastic neurologic syndromes are remote effects of malignancy involving the nervous system not related to tumor invasion, compression, or metastasis.
  2. It is not uncommon for a paraneoplastic neurologic syndrome to be the first clinical manifestation of malignancy, with as many as 80% of patients having no evidence of underlying tumor at initial presentation.
  3. Paraneoplastic neurologic syndromes should be considered in the differential for any patient presenting with unexplained neurologic symptoms.

Paraneoplastic Neurologic Syndromes (PNS) are remote effects of malignancy involving the nervous system not related to tumor invasion, compression, or metastasis. These syndromes are rare, with approximately 1% of adults with cancer having an associated PNS. They are immunologic in origin where malignancy triggers production of autoantibodies against various antigens of the nervous system, as antigens located on the tumor mimic those of the nervous system. It is not uncommon for a PNS to be the first clinical manifestation of malignancy, with as many as 80% of patients having no evidence of underlying tumor at initial presentation. Interestingly, tumors associated with these syndromes also tend to be small in size and without metastases. It is well known that there is a strong association between PNS and pulmonary malignancies; however, little knowledge exists regarding their association with pulmonary large cell neuroendocrine carcinoma. LCNEC is an aggressive malignancy associated with a poor prognosis, an estimated 5 year survival rate at 35.3% and a 5 year over all disease free survival estimated at 17.4%, warranting early diagnosis and initiation of treatment. Rarely have these tumors been associated with a paraneoplastic neurologic syndrome as the presenting symptom at diagnosis. Here we present the case of a 72-year old male who presented with new onset bulbar predominant symptoms in the setting of a presumed insignificant 1cm pulmonary nodule, who after extensive investigation was diagnosed with an Anti-Hu associated paraneoplastic brainstem encephalitis with subsequent biopsy confirming pulmonary large cell neuroendocrine carcinoma

A 72-year-old male with a history remarkable for tobacco use presented to the emergency department with complaints of generalized weakness, dysphagia, dysarthria, dysphonia, diplopia, ataxia, and unintentional weight loss, which he had been experiencing for approximately eight weeks. His primary care physician had initiated diagnostic testing with a head computed tomography (CT), chest x-ray, thyroid studies, sedimentation rate, c-reactive protein, lyme titer, and anti-acetylcholine receptor antibodies, all of which were unremarkable. Diagnostic investigation at our institution was initiated with magnetic resonance imaging (MRI) with and without contrast of the brain and stem, which demonstrated chronic microvascular changes. CT of the chest did demonstrate an irregular, branching 1 cm right upper lobe pulmonary nodule with an associated pneumonia and a few enlarged mediastinal nodes. Neurology was consulted and initially suspected a bulbar predominant neuromuscular junction disorder and a trial of pyridostigmine was initiated. This treatment was discontinued due to increased secretions and a lack of clinical response. He was started on intravenous immune globulin therapy with a 2 g/kg daily infusion given over a total of 5 days with only minimal improvement of symptoms. A trial of prednisone was then initiated. Serum testing for voltage-gated calcium channel antibodies, muscle specific kinase (MuSK) antibodies, and acetylcholine binding- blocking- and modulating antibodies were all negative. Lumbar puncture demonstrated cerebral spinal fluid that was clear in appearance, total protein of 126mg/dL, glucose 71mg/dL, 25 red blood cells, 0 white blood cell, and lactate dehydrogenase of 50 U/L. The elevated total protein was suggestive of a central nervous system inflammatory process rather than a peripheral neuromuscular junction process. Biopsy of a mediastinal lymph node confirmed a high-grade large cell neuroendocrine carcinoma. A paraneoplastic panel was obtained and was positive for anti-Hu (ANN1) antibodies.

Shortly after diagnostic confirmation the patient underwent percutaneous endoscopic gastrostomy (PEG) tube placement for progressive worsening of his dysphagia, and shortly thereafter he required intubation for hypoxic respiratory failure. Neurology recommended starting high dose steroids and treating the underlying malignancy; however, before these measures could be initiated his neuromuscular weakness continued to progress and he passed away after comfort care measures were instituted.

After reviewing the literature, the few PNS cases associated with LCNEC that have been described include Lambert Eaton myasthenic syndrome (VGCC antibody mediated), paraneoplastic retinopathy, and Anti-Hu associated syndrome presenting with sensory neuropathy, autonomic dysfunction, and tonic pupils. LCNEC has been rarely associated with Anti-Hu positivity. In one study investigating Anti-Hu positivity in patients with paraneoplastic encephalomyelitis, only 2% were found to have an underlying LCNEC. As to the authors’ knowledge, LCNEC presenting as an Anti-Hu associated brainstem encephalitis has not been described. We suspect the rates of these malignancies are underreported given difficulty surrounding their diagnosis as well as their relatively recent recognition as their own separate entity. Unfortunately, limited data exists regarding their association with PNS. This is likely related to the rarity of these tumors. We suspect the frequency of these tumors to increase as we develop more efficient ways to diagnosis them and with this, we suspect there will likely be increased rates of their association with PNS.

Given their rapid progression in addition to frequent delay in their diagnosis, patients with PNS often have irreversible neurologic damage once their diagnosis is finally confirmed. Unfortunately, Anti-Hu positive PNS generally do not respond well to immunotherapy compared to other antibody associated PNS as the associated antigens are intracellular in location. Treatment is generally directed toward treating the underlying malignancy. In a study involving 63 patients followed for 1 year, the only therapy that demonstrated clinical stability or improvement involved treating the underlying malignancy. Thus, prompting the need for earlier tumor detection.

Unfortunately, the initial diagnosis of a PNS is often difficult and even overlooked when the presenting symptoms are non-specific and there is no evidence of underlying malignancy. [8] Diagnostic criteria and clinical situations where the evaluation for PNS should occur have been published in Graus et al. Our case met criteria for “definite” diagnosis for PNS given the presence of a classical syndrome and a well characterized onconeural antibody. As previously described and supported by this case presentation, it is not uncommon for a paraneoplastic syndrome to develop before a cancer is identified; therefore, as supported by Graus et al. and others when suspicion is high, investigations for tumor identification should be initiated. Specific paraneoplastic antibodies and clinical syndromes are often used to guide investigations of identifying the occult malignancy such as the use of mammogram, breast MRI, or ultrasound of the pelvis or testes, when clinically indicated. If otherwise unspecified, CT of the chest, abdomen, and pelvis may be utilized. Some studies have suggested the use of Whole-body FDG-PET combined with CT, with improved sensitivity and specificity for identifying an occult malignancy when compared to CT alone. Even in the setting of a negative evaluation, it has also been recommended to continually repeat cancer screening approximately every 3 to 6 months for up to 4 years.

Identification of these syndromes is challenging and often overlooked, especially when the primary nodule is inconspicuous and the presenting symptoms highly variable. We present this case in an effort to increase awareness of this rare and likely underrecognized malignancy and knowledge of PNS as a potential presenting symptom. In addition, we hope to promote that PNS be considered in the differential for any patient presenting with unexplained neurologic symptoms.

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Posted in: Medical Oncology17 Neurology1 Pulmonary Disease6