Clinical Reasoning: An 81-year-old woman with confusion, weakness, and left-sided hemineglect

Section 1

An 81-year-old right-handed woman presented to the emergency department (ED) with confusion, generalized weakness, and difficulty ambulating. In addition to several cardiovascular comorbidities (hypertension, hyperlipidemia, peripheral arterial disease, coronary artery disease, chronic kidney disease, and renal artery stenosis), her medical history was significant for stage IV carcinoma of the urinary bladder. She had been in her usual state of health until 1 week prior to her presentation when she began experiencing generalized weakness in her legs, requiring more frequent use of a walker as well as intermittent headaches and increasing forgetfulness. Two to 3 days prior to presentation, her husband noted that she was increasingly getting confused. On the day of presentation, she woke up disoriented and was too weak to get out of bed, prompting her husband to bring her to the ED. In the ED, she was afebrile, hypertensive (180/90 mm Hg), and tachycardic (heart rate 120–130/min). On mental status examination, she was intermittently oriented to time and place and unable to follow complex instructions. Her score on the Montreal Cognitive Assessment (MoCA) was 9/30. Other pertinent examination findings included left facial weakness (lower face) and left upper and lower extremity weakness (3/5). Sensory examination revealed left-sided hemineglect. The patient was unable to ambulate as she could not stand without assistance.

The patient had been diagnosed with stage IV metastatic transitional cell carcinoma of the urinary bladder 2 years before the current admission and had gone into remission following therapy with gemcitabine and cisplatin. Eight months prior, she began immunotherapy with pembrolizumab infusions every 3 weeks after a follow-up PET scan showed nodal metastases, indicative of probable disease progression. Her most recent PET scan (2 weeks before the current admission) revealed interval improvement of the nodal metastases with pembrolizumab and absence of any new lesions. Her husband reported that she had experienced pembrolizumab-related adverse effects such as rash and colitis several months prior which resolved with steroids. She had otherwise been tolerating the immunotherapy well and had received her last infusion 2 weeks prior to presentation.

Questions for consideration:

1. What is the differential diagnosis given the presentation and history?

2. What diagnostic tests would you perform?

GO TO SECTION 2

Section 2

This presentation of altered mental status with acute/subacute-onset focal neurologic deficits certainly indicates a CNS pathology. Stroke remains at the forefront of the differential diagnoses, primarily because of the fast onset of the neurologic deficits in the background of multiple cardiovascular risk factors, including the history of myocardial infarction. However, it is important to keep the differentials wide and resist the temptation to anchor only towards stroke. Infections of the CNS (meningitis or encephalitis) remain an important differential here because of the acute to subacute onset of confusion and neurologic deficits. The patient's history of metastatic cancer makes paraneoplastic disease process and new metastasis to the meninges or brain parenchyma a reasonable differential diagnosis. Although not supported by the rapid onset of the symptoms, altered mental status and gait impairment in an elderly patient prompts the inclusion of normal-pressure hydrocephalus (NPH) into the list of differentials. Given the history of transitional cell carcinoma of the urinary bladder, cancer-associated Wernicke-Korsakoff syndrome is reasonable to consider as it may present with ataxia, altered mental status, and weakness.¹ Finally, as checkpoint inhibitors are rarely associated with autoimmune neurologic side effects including encephalitis, aseptic meningitis, and hypophysitis,² pembrolizumab-associated adverse effects are important to consider.

Among the differential diagnoses mentioned above, it is essential to evaluate for stroke first. Investigations for stroke include noncontrast CT of the head, CT angiogram, CT perfusion, and MRI of the brain (noncontrast). These investigations did not reveal any evidence of acute stroke. MRI brain (without contrast), however, revealed ventriculomegaly out of proportion to the cortical atrophy.

Because of the ventriculomegaly, a high-volume CSF tap was essential in this case as the patient also had 2 cardinal symptoms of NPH, i.e., cognitive dysfunction and gait impairment. Opening and closing pressure, while not obtained on this patient, would be useful to measure. Moreover, CSF analysis (routine cell counts, cytologic, biochemical, and microbiological examinations) is necessary to investigate 2 differential diagnoses, i.e., CNS infection and metastasis to the meninges. MRI of the brain was repeated (with contrast) as it was essential for the remaining differential diagnoses, i.e., CNS infections, metastasis, and immunotherapy adverse effects such as aseptic meningitis or hypophysitis. In addition, the patient's lower extremity weakness and ataxic gait warranted MRI of the whole spine. Considering the history of cancer, serum paraneoplastic panel is of paramount importance. Although we did not check thiamine level to evaluate for Wernicke encephalopathy (as onset was rapid), this should be regarded as one of the important differentials in the background of advanced cancers. In addition to these targeted investigations, complete blood count, comprehensive metabolic panel, vitamin B₁₂, folate, and workup for syphilis and HIV are crucial.

A high-volume lumbar puncture (24 mL) did not result in substantial improvement in gait or cognition (MoCA remained unchanged). MRI brain (with contrast) was motion-degraded, which made visualization on any contrast enhancement difficult. However, there was leptomeningeal enhancement in the cauda equina and conus (figure, A and B). CSF analysis was significant for lymphocytic pleocytosis (18/mm³), low glucose (<1 mg/dL), and elevated protein (114 mg/dL). Infectious workup (herpes simplex virus, Venereal Disease Research Laboratory, bacterial culture) of CSF was unremarkable. Subsequently, cytology examination of CSF revealed scattered malignant cells with enlarged nuclei and a high nucleocytoplasmic ratio in a background of reactive lymphocytes, consistent with metastatic urothelial carcinoma. Serum paraneoplastic panel was negative, and the rest of the laboratory investigations mentioned above were within normal limits. The table summarizes the differential diagnoses for this case, pertinent investigations, and their results.

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Figure MRI abnormalities in the lumbar segment of the spinal cord

(A) Sagittal T2 sequence of the lumbar spine demonstrating hyperintense signal changes in the L1-L2 level. (B) Sagittal T1 (postcontrast) sequence of the lumbar spine demonstrating contrast enhancement around the L1-L2 level.

Section 3

CSF investigation was the key in this case. CSF glucose was very low (hypoglycorrhachia) in the background of elevated protein and lymphocytic pleocytosis. The major differential diagnoses for this CSF profile are tubercular meningitis (TBM) and carcinomatous meningitis. The patient did not have any signs or symptoms of TBM. She had no cough, fever, night sweats, neck stiffness, or photophobia. Importantly, T-spot was negative, and the X-ray of the chest was unremarkable, making a diagnosis of tuberculosis unlikely. Hence, the suspicion for carcinomatous meningitis became stronger. Later, positive cytology examination tilted the diagnosis in favor of carcinomatous meningitis. Enhancement of the conus medullaris and cauda equina further reinforced this diagnosis.

Carcinomatous meningitis is rare and typically occurs late in the course of the disease. It is most often a result of hematogenous spread of tumor cells to the subarachnoid space and into the CSF. Diagnosis is usually based on imaging and CSF analysis.³ The condition is most commonly associated with primary tumors of the breast or lung, as well as with melanoma.^3,4 Carcinomatous meningitis secondary to bladder cancer is rare, and to date, only 33 case reports are available in the literature.⁵ The majority of these cases involved transitional cell carcinoma, as observed in our patient.