Rapidly Progressive Dementia and Plateau Waves: A Rare Presentation of Leptomeningeal Disease

Case Presentation

RP, in the mid-50s, presented with decline in short-term memory, behavioral change, and visuospatial disorientation over a 3-month period. Two months previously, RP had experienced an episode of transient faciobrachial weakness lasting 30 minutes, suggesting a probable transient ischemic attack. After a few days of this transient weakness, a severe throbbing holocranial headache of episodic nature occurred. An initial brain MRI and magnetic resonance venography tests had unremarkable results and did not show features of raised intracranial pressure (ICP). The headache kept worsening and became continuous over the next 30 days, leading to presentation at the authors’institution.

Cognition was assessed using the Montreal Cognitive Assessment (MoCA) and a detailed higher mental function test for lobar function, which revealed mild cognitive impairment involving the cognitive domains of complex attention, recent memory, and new learning ability, without any focal neurologic deficit or meningeal signs. There was no papilledema observed on funduscopy.

Diagnostic Process

Contrast-enhanced brain and spine MRI scans repeated at our institute showed diffuse leptomeningeal enhancement with enhancement of bilateral cranial nerves V, VI, and VII (Figure 1, A–D). Hematologic and biochemical investigations, including thyroid profile, vitamin B12 levels, kidney and liver function tests, and sodium level, had normal results. Erythrocyte sedimentation rate was elevated (37 mm/h). Lumbar puncture revealed normal opening pressure (14 cm H₂O), clear cerebrospinal fluid (CSF), elevated protein level (155 g/dL), reduced glucose level (53 mg/dL), and mild pleocytosis (25 cells/uL, lymphocytic predominant). Other tests, including CSF cytology for malignant cells, CSF cartridge-based nucleic acid amplification test, India ink test, cryptococcal antigen test, and galactomannan test were negative. Aerobic, fungal, and mycobacterial cultures were sterile. Contrast-enhanced CT of the thorax and abdomen showed an ill-defined consolidation in the superior segment of the right lower lobe and lateral segment of the right middle lobe with extension into segmental bronchi (Figure 1E). Bronchoscopy and bronchoalveolar lavage were negative for fungal, mycobacterial, and other infective etiology. Scrub typhus and Lyme serology tests were also negative.

Considering the possibility of an atypical bacterial infection, RP was given a trial of antibiotics (ceftriaxone and doxycycline), without any response and with subsequent worsening of headache. RP’s cognitive function continued to worsen, with involvement of executive dysfunction causing difficulty in carrying out activities of daily living (eg, bathing, toileting, eating). At this time, an additional differential diagnosis of autoimmune or paraneoplastic encephalitis was considered, and injectable corticosteroids were started on the seventh day of hospitalization. Immediately after starting corticosteroid treatment, RP exhibited nonsensical speech and hallucinations. Considering the possibility of corticosteroid psychosis, corticosteroids were stopped. Fifteen days later, corticosteroids were restarted at a very low dose (dexamethasone 4 mg twice daily), resulting in improvement in headache and psychosis.

Fifty days after headache onset (and after 20 days of hospitalization), RP developed intermittent episodes of severe vertigo with impaired awareness and generalized hypotonia. The initial possibility of focal seizures with impaired awareness was considered. However, later it was observed that the events were mostly associated with a change in posture, and RP was extremely unsteady and needed support to stand and walk during the episodes. Change of posture was not associated with a substantial decrease in blood pressure. RP was started on the anticonvulsant oxcarbazepine (900 mg per day) orally without response. Electroencephalography (EEG) showed diffuse, generalized 5- to 6-Hz theta activity with intermittent increased high-amplitude 3- to 4-Hz delta range slowing, which was more prominent on changing posture (Figure 2, A and B). Therefore, the possibility of electrographic correlate of plateau waves associated with leptomeningeal disease was considered. However, invasive ICP monitoring could not be performed; RP’s relatives denied consent for the procedure in view of preserved consciousness and absence of deficits.

Case Resolution

Whole-body [¹⁸F]fluorodeoxyglucose positron emission tomography was performed and showed a metabolically active nodular opacification in the right lung (Figure 1F) as well as hypometabolism in the bilateral prefrontal and parietal regions with relative hypermetabolism in the mesial temporal lobes and cerebellum (Figure 1G). The presence of rapidly progressive dementia (RPD), focal impaired awareness seizures, behavioral changes and plateau waves, along with focal hypermetabolism in mesial temporal regions, strengthened the possibility of paraneoplastic autoimmune encephalitis. Intravenous immunoglobulin was started at 400 mg/kg of body weight daily for 5 days, but no substantial improvement in symptoms occurred. A paraneoplastic antibody panel including anti-Hu, anti-Ri, anti-CRMP5, and anti-Yo had negative results. CT-guided biopsy of the lung lesion revealed nonmucinous lung adenocarcinoma with a lepidic pattern. On immunohistochemistry, the atypical cells lining the alveolar spaces (lepidic pattern) showed nuclear positivity for thyroid transcription factor-1 (TTF-1) (Figure 2, C–E). Because a localized lung malignancy causing leptomeningeal disease without any regional spread was unusual, a repeat CSF lumbar puncture was performed to investigate for malignant cytology, but results were negative. Brain biopsy was planned, but the relatives did not consent to this test. Considering the available data, a diagnosis was made of leptomeningeal carcinomatosis causing RPD and plateau waves.

Epidermal growth factor receptor (EGFR) testing of the biopsied specimen was positive for a T790M variation in the EGFR gene. Based on this report, RP was started on osimertinib (Tagrisso; AstraZeneca Pharmaceuticals, Wilmington, DE), a third-generation tyrosine kinase inhibitor (TKI), resulting in some improvement in symptoms. At 1-month follow-up, RP had reduced frequency of episodes of impaired awareness and reduced headache. RP did not return for any follow-up visits.

Discussion

Leptomeningeal metastasis (LM), also known as carcinomatous meningitis or leptomeningeal carcinomatosis, is a rare and usually late complication of different malignancies. Its incidence is higher in hematologic malignancies (5%–15%) than in solid organ malignancies (5%–8%).¹ Most solid organ malignancies metastasize to the leptomeninges, the most common being breast, lung, and melanoma malignancies.² LM is observed in 9% to 25% of lung cancers and is less common in lung adenocarcinoma.³ Clinical features of leptomeningeal carcinomatosis are variable and multifocal, mostly due to cranial and spinal nerve dysfunction, increased ICP, or meningeal irritation.² RPD, described as a substantial decline in cognitive function leading within weeks to months to impairment of activities of daily living, is an uncommon feature of LM.⁴ The definition varies on the basis of etiologic background and relates to the speed of cognitive decline.⁵ Common causes of RPD include immune-mediated, infectious, or metabolic diseases, and neoplastic entity is a rare etiology of RPD (3.4% of cases).⁶ LM of neoplastic origin is even more uncommon in cases of RPD, and is usually seen in established and metastatic cancers. One study reported 2 cases of RPD with LM due to gastric carcinoma. Another case described RPD with extrapyramidal syndrome as the first presentation of LM.^4,7 Jadav et al⁸ and Francolini et al⁹ reported 1 case each of leptomeningeal disease presenting as RPD.

Many people with LM experience intermittent neurologic episodes characterized by transient severe vertigo and unresponsiveness, attributed to episodic increases in ICP upon postural changes, known as “plateau waves”.¹⁰ It is challenging to differentiate these episodes from focal seizures with impaired awareness. RPD and plateau waves may be caused by LM with advanced malignancies. However, it has never been documented as an initial manifestation. A case series revealed that 26% of individuals with LM experienced elevated ICP, with or without hydrocephalus.¹¹ Among various explanations for the pathogenesis of plateau waves, the most accepted is a transient change in ICP, with sudden increase and decline of ICP.¹⁰ Because seizures are also a typical manifestation of LM that are observed in 14% of individuals, it is essential to differentiate plateau waves from seizures. Video EEG is a helpful tool which aids in the differentiation of plateau waves and seizures.¹² Various EEG findings of plateau waves detected in a case series including mild to moderate diffuse slowing similar to the diffuse slowing seen in RPD have been reported.¹³

MRI and CSF cytology are valuable tools for the diagnosis of LM, but the sensitivity of CSF cytology is low. A single CSF examination may be positive for malignant cells in ~50% of cases, increasing to 85% to 90% after 3 lumbar punctures.¹⁴ However, MRI findings alone in the presence of clinical features and background of malignancy is sufficient to establish the diagnosis of LM.¹⁵

Adenocarcinoma of the lung with EGFR positivity, even if associated with LM, is treated with TKIs. Erlotinib and gefitinib are first-generation TKIs that cannot readily cross the blood–brain barrier in non-small cell lung cancer, and may be actively eliminated by drug efflux proteins.¹⁶ Second- and third-generation EGFR TKIs are thought to penetrate the blood–brain barrier more effectively.²

In an individual with RPD and transient episodes of impaired sensorium along with diagnostic possibilities of Creutzfeldt-Jakob disease and autoimmune or paraneoplastic encephalitis, LM as a severe and rare differential diagnosis should be considered. Neuroimaging, including nuclear imaging studies, CSF cytology tests, and an extensive workup for primary malignancy, is required for diagnosis. The presence of plateau waves may indicate LM, and although the prognosis is poor, early diagnosis and appropriate management may help improve the outcome.