Leptomeningeal carcinomatosis, known by a variety of names, including leptomeningeal metastases and neoplastic meningitis, indicates spread of tumor to the cerebrospinal fluid (CSF) and invasion of the subarachnoid space. The term leptomeningeal (from the Greek lepto, meaning “fine” or “slight”) describes the thin meninges, the arachnoid and the pia mater, between which the CSF is located. Although CSF metastases are a subtype of central nervous system (CNS) metastases, it is important to differentiate them from other CNS metastases such as brain or dural metastases, as both prognosis and management differ significantly between these neuroanatomic locations. We will discuss key concepts in the diagnosis, prognosis, and management of leptomeningeal carcinomatosis in a case-based format.
Clinical Vignette #1
A 65-year-old woman with non−small-cell lung cancer diagnosed 11 years earlier (stage IB at diagnosis) developed bony metastases 1 year prior to the current presentation. A thoracic vertebra metastasis was treated with focal radiation therapy (RT; 60 Gy). Later on, the patient developed unilateral facial weakness. Her symptoms were initially thought to represent idiopathic Bell’s palsy, but remained refractory to treatment with steroids and acyclovir. Brain MRI at that time demonstrated ipsilateral cranial nerve VII enhancement (Figure 1). Her CSF was noninflammatory, without evidence of malignant cells. Subsequently, over a 4-month period, the patient developed bilateral facial weakness, unilateral tinnitus, dizziness, hyperacusis, and abnormal sensations in the right upper extremity. Electromyography and nerve conduction studies of facial nerves revealed an axonal degenerative process, without evidence of demyelination. Repeat CSF studies demonstrated lymphocytic pleocytosis with malignant cells on cytology, and a diagnosis of leptomeningeal carcinomatosis was made. An MRI of the spine revealed nodular enhancement at the conus medullaris.
The patient’s leptomeningeal disease was treated with whole-brain radiotherapy (WBRT) plus focal RT to the lumbosacral region (total, 28 Gy), and intrathecal (IT) liposomal cytarabine (50 mg in 5 mL preservative-free solution) was delivered every other week via an intraventricular catheter, along with oral dexamethasone (4 mg twice a day 2 days prior, day of, and 2 days post liposomal cytarabine injections). Tinnitus and sensory symptomatology improved, but the patient’s facial diplegia remained. After 8 doses (4 months) of liposomal cytarabine, follow-up CSF cytology was negative and repeat MRI imaging revealed no further evidence of leptomeningeal enhancement. Two months after starting IT chemotherapy, the patient again presented with severe headache and repetitive extremity movements that were indicative of seizures, but electroencephalogram did not show epileptiform activity. She was found to have focal edema near the intracranial catheter on imaging. She was then started on levetiracetam prophylactically and continued to receive IT liposomal cytarabine for 2 additional months, during which her functional status rapidly deteriorated, and she transitioned to hospice care.
What Are the Presenting Symptoms of Leptomeningeal Carcinomatosis?
Patients with leptomeningeal carcinomatosis may present with a wide range of clinical symptoms that can vary from barely perceptible to profoundly debilitating; they can be categorized as neuroanatomically localizable or nonlocalizable (Table 1). These symptoms may represent the initial manifestation of cancer or they may occur years after the initial diagnosis, as in Clinical Vignette #1.[3-5] The nonlocalizable symptoms arise from an increase in intracranial pressure (ICP) that manifests as headaches, which most commonly occur after prolonged time in a supine position, for example, upon awakening in the morning. This is different from many primary headache syndromes, such as migraine, which often resolve after a night’s sleep. Headaches that result from increased ICP can awaken patients from sleep, and in turn should be differentiated from primary headache disorders such as trigeminal/autonomic headaches (eg, cluster headaches) and hypnic headaches, all of which can have a similar presentation. Additional symptoms associated with trigeminal/autonomic headaches and hypnic headaches can include manifestations of autonomic dysfunction (unilateral lacrimation, rhinorrhea, and diaphoresis). However, they lack the nausea, vomiting, and diplopia which, when present, should raise concern for increased ICP.
The localizable symptoms relate to the specific neuroanatomy involved. The presence of symptoms that localize to multiple nonconfluent areas in the nervous system should raise the suspicion of a pathologic process within the CSF, which bathes the surface of the entire CNS. Symptoms can be broadly divided into two categories: intracranial and spinal. Intracranial symptomatology most commonly arises from dysfunction of cranial nerves. This can cause extraocular movement deficits leading to binocular diplopia, which resolves with single eye closure. Motor and sensory facial deficits can also develop. The sensory symptoms would be anterior to the ear, limited to the distribution of the fifth cranial nerve. The facial weakness would most likely involve the forehead in addition to the lower face, clinically resembling Bell’s palsy. Clinicians must pay careful attention to the patient’s history, and findings on the physical examination may alter one’s suspicion of leptomeningeal carcinomatosis as the underlying etiology for facial weakness. In the case described here, the known history of stage IV lung cancer should raise concern for leptomeningeal carcinomatosis as the underlying etiology of the patient’s initial facial weakness. Spinal symptomatology can manifest as weakness, due to involvement of the motor nerve roots. There may also be a loss of sensation, but more often radicular pain that radiates along a dermatomal distribution is observed. Cauda equina syndrome is another common presentation of leptomeningeal carcinomatosis. This involves sensory loss in a saddle distribution, radicular pain of the lower extremities, bladder incontinence, and constipation. In comparison to conus medullaris syndrome, which involves the lower portion of the spinal cord parenchyma, cauda equina syndromes are more likely to have asymmetric presentations and radicular pain. Electromyography and nerve conduction studies often reveal an axonal pattern of injury, as was noted in Clinical Vignette #1. This differs from immune-mediated processes, where a demyelinating pattern would more likely be expected. Once the diagnosis of leptomeningeal carcinomatosis is established, prognosis is poor and clinical deterioration can progress rapidly.
What Is the Discrepancy Between Radiologic and CSF Findings in the Setting of Leptomeningeal Carcinomatosis?
Classic radiographic findings of neoplastic meningitis include the presence of enhancement between cerebellar folia, deep in the brain sulci, and over the convexities. Enhancement can also be present on the surface of the spinal cord or on the nerve roots of the cauda equina. However, these findings are nonspecific and can also be seen in infectious diseases (tuberculosis, for example) and autoimmune conditions (sarcoidosis, for example), and oftentimes as an artifact following lumbar puncture. Thus, the timing of radiographic evaluation and lumbar puncture is important: imaging should always precede spinal tap whenever possible. It should be emphasized that radiographically evident disease may not always be symptomatic in patients with leptomeningeal carcinomatosis. The wide range of reported negative imaging in the setting of positive CSF findings (30% to 70%) arises at least in part from the varying methodologies utilized to evaluate the incidence of leptomeningeal carcinomatosis. The explanation for negative CSF studies in the setting of abnormal imaging suggestive of leptomeningeal carcinomatosis may be even less clear. This may be due to some patients being diagnosed with leptomeningeal carcinomatosis radiographically and not being optimal candidates for lumbar puncture due to noncommunicating hydrocephalus, large intracranial metastases, thrombocytopenia, or other medical issues.
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