Leptomeningeal Metastases Clinical Presentation

Updated: Oct 27, 2021
  • Author: Herbert H Engelhard, III, MD, PhD, FACS, FAANS; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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Meningeal symptoms are the first manifestations of leptomeningeal metastases (LM) in some patients; however, by the time LM is detected, most patients already have widespread and progressive cancer.

A high index of suspicion is necessary, and involvement of multiple anatomic sites in the CNS should raise the suspicion for LM, although multiple metastases are statitically more likely with that presentation.

The symptoms are protean and can include the following:

  • Headaches (usually associated with nausea, vomiting, lightheadedness)

  • Memory problems, confusion (dementia)

  • Double vision, facial numbness and/or facial weakness (cranial neuropathies)

  • Gait difficulties from weakness or ataxia

  • Neck, back, or radicular pain

  • Incontinence

  • Sensory abnormalities

Pain and seizures are the most common presenting complaints.


Physical Examination

Signs of leptomeningeal metastases (LM) generally exceed patient-reported symptoms.

Involvement of the CNS is divided into the following 3 broad anatomical groups:

  • Cerebral involvement results in headache, lethargy, papilledema, behavior changes, and gait disturbance (the latter can be due to either cerebellar or cauda equina involvement). Major dysfunction, such as hemiparesis and hemisensory loss or visual field defects, is rare and more indicative of parenchymal metastasis.

  • Cranial nerve involvement  presents with impaired vision, diplopia (most common), hearing loss, and sensory deficits, including vertigo. Palsies of cranial nerves III, V, and VI are most common; palsy of nerve VII is less common. Isolated VII nerve palsies may occur however, and may be hard to differentiate from idiopathic facial nerve (Bell's) palsies. [14]  Solid tumor-derived LM has a greater affinity for the optic and extraocular nerves, while leukemic meningitis preferentially affects the facial nerve. Involvement of multiple cranial nerves is the rule rather than the exception.

  • Spinal root involvement is caused by either meningeal irritation, presenting with nuchal rigidity (15%) and neck and back pain (rare), or invasion of the spinal roots. The latter can cause leg weakness, radiculopathy (usually lumbar, mimicking a herniated disk), reflex asymmetry or loss (most common, noted in 70% of patients), sphincter incontinence (less common), positive Babinski reflexes, paresthesias, and numbness. Asymptomatic bladder enlargement can occur from spinal cord compression. Spinal-root symptoms are usually followed by cranial-nerve symptoms. Nuchal rigidity, positive results on the straight-leg raising test, and decreased rectal tone are rare.

Over the course of the disease, cranial-nerve deficits are the most frequent signs, occurring in 94% of patients. Although these are seldom the presenting complaint (30% of patients), mild cranial-nerve abnormalities are usually present on physical examination; the abnormalities typically include diplopia, dysphagia, dysarthria, and hearing loss. However, most patients do not have isolated cranial-nerve deficits; rather, they have a combination of cranial-nerve, cerebral, and spinal signs.




The most common complication of leptomeningeal metastases (LM) is hydrocephalus, which results when tumor cells occlude the CSF outflow foramina of the fourth ventricle or over the convexities of the brain, decreasing CSF reabsorption.

Hydrocephalus causes ventricular dilatation and increased ICP, occasionally leading to brain herniation and death.

Even in the absence of hydrocephalus, CSF flow abnormalities are present in 70% of patients with LM, and this adversely affects the distribution of intrathecal chemotherapy.

Other complications of the disease

LM may cause seizures or other neurologic dysfunction by invading the parenchyma of the brain or Virchow-Robin spaces or cause areas of ischemia or infarction by interfering with blood supply.

Competition for glucose between malignant cells and neurons can lead to hypofunction in affected areas. For example, in hypothalamic leukemia, weight gain in patients in leukemic remission can signify relapse because hypothalamic hypoglycorrhachia is induced by local competition for glucose by metastatic tumor cells.

LM also causes partial disruption of the blood–brain barrier once the tumor size has increased enough to stimulate growth of its own vasculature.

Treatment-related complications can result from catheter placement, chemotherapy, or radiation.

Catheter placement causes perioperative complications (1% of patients), and after placement, the catheter tip can migrate into the brain tissue, obstruct the shunt, or, more commonly, cause infection (usually Staphylococcus epidermidis, in 5% of patients).

Complications of treatment

MTX administration can cause acute arachnoiditis (nausea, vomiting, mental status changes), seizures, mucositis, or myelosuppression (mitigated with folinic acid coadministration, 10 mg q6h for 24 h).

Meningeal irritation, characterized by headache, fever, stiff neck (sometimes), confusion, and disorientation, often develops several hours following intrathecal MTX administration but is self-limiting and resolves within 24–72 hours. This can be treated on an outpatient basis with antipyretics, antiemetics, and corticosteroids.

Transverse myelitis is a rare idiosyncratic reaction to MTX that begins 30 min to 48 h after intrathecal treatment and presents with paraplegia, leg pains, and development of a sensory level and bladder dysfunction; it should be distinguished from traumatic spinal subdural hematoma. Again, no specific treatment is available but some improvement can occur over days to months.

Leukoencephalopathy is the most serious complication; it appears a year after treatment and is more likely in those who have also undergone cranial radiation. It presents as a progressive encephalopathy, often with ataxia, dysarthria, and focal findings.

Cytarabine, like MTX, also may cause meningism, headache, and fever.

Thiotepa causes less neurologic toxicity than MTX; the most common effect is transient limb paresthesias. Unlike MTX, there is no way of mitigating the resultant myelosuppression.

Radiation can cause myelosuppression and increase the neurotoxicity of intrathecal chemotherapy. Necrotizing leukoencephalopathy is most common after a combination of MTX and cranial irradiation. Initial findings are changes in the white matter on neuroimaging after 6 months of therapy; progressive dementia and other neurologic complications develop later. Other complications are delayed cerebral radiation necrosis, acute transverse myelopathy, chronic progressive myelopathy, and acute brachial plexus lesions.

The syndrome of inappropriate diuretic hormone secretion (SIADH) may occur with LM. [3]