Metastases to the meninges

General

Carcinomatous meningitis
Leptomeningeal metastasis (LM)

As cancer patient living longer, number of LM cases increasing.

Incidence of LM in small cell lung cancer (SCLC) over time, from 0.5% at diagnosis to 25% after 3 years of survival

Numbers

5% of all patients with cancer

Can be as high as 20% with many solid tumours in autopsy series

Cerebral involvement

Present in 40-75%

Spine involvement

Present in 15-25%

Aetiology

Solid tumours > hematologic malignancies

Solid malignancies

Breast Ca 12-34%
Lung Ca 10-26%
Melanoma 17-25%
Gastric cancer 4-14%
Adenocarcinoma of unknown primary 1-7%

Hematologic malignancy

Leukaemia
Lymphoma
Adenocarcinoma of unknown primary

Pathophysiology

Pathways to invade the meninges

Hematogenous spread

via the arterial circulation
Most common route
Appears less common in solid tumors compared with hematological malignancies.
Seeding of the leptomeninges via retrograde venous pathways along the valveless Batson's venous plexus has been incriminated in pelvic cancers but this hypothesis remains speculative.

Endoneural/perineural and perivascular lymphatic spread

Vertebral and paravertebral metastases
Particularly from

Breast Ca
Lung Ca
Head and neck Ca

Spread centripetally along

Peripheral
Cranial nerves

Gaining access through the dural and arachnoidal sleeves of nerve roots (spinal roots, cranial nerves) and subsequently into the subarachnoid space.

Direct spread from the brain parenchyma

Direct spread from metastases located in the brain parenchyma that is in close opposition to the CSF space
Tumors breach the subarachnoid or ventricular spaces and diffuse widely in the CSF

Frequently a peritumoral fibrotic reaction at the site of invasion often circumscribes this type of metastasis.

Particularly from primary brain tumors

Choroid plexus

Metastases to the choroid plexus and subependyma has been described with subsequent CSF dissemination
Considered an uncommon mechanism of cancer spread.

De novo tumors

Primary tumors arising in the meninges

Melanoma
Malignant peripheral nerve sheath tumors

May secondarily spread to the CSF and disseminate.

Iatrogenic spread

During invasive procedures or neurosurgery
CSF tumor spread may result through an ependymal or pial breach.

Resection of cerebellar mets
Resection of supratentorial mets involving the ventricles

When enter meninges or CSF cancer cells disseminate by

Extension along the meningeal surface
Convective CSF flow to distant parts of the CNS

Hematological malignancies,

Diffuse covering of the leptomeninges

Solid tumors

Plaque-like deposits with invasion of the Virchow–Robin spaces and nodular formations

The areas of predilection for circulating cancer cell settlement are characterized by

Slow CSF flow
Gravity-dependent effects (basilar cisterns, posterior fossa, and lumbar cistern)

Breakdown of the blood–CSF barrier in LM is incomplete and partial as manifested by the observation that only a minority of patients respond to systemic water-soluble chemotherapy, even in the instance when other extrameningeal systemic metastases demonstrate response.

Pathology

Marcoscopic

Gross inspection of brain, spinal cord, and spinal roots may be normal.
Leptomeninges are abnormal manifesting thickening and fibrosis that may be diffuse or localized in one or several distinct area(s) of the CNS

Particularly in regions with relative CSF flow stasis,

Microscopic

Diffuse or multifocal infiltration of arachnoid membranes by cancer cells, often filling the subarachnoid and Virchow–Robin spaces, and sometimes invading the underlying neuraxis, vessels, and nerve surfaces.
A pure encephalitic variant is characterized by massive invasion of the Virchow–Robin spaces, without infiltration of the sub-arachnoid spaces of the brain surface

Diagnosis

National Comprehensive Cancer Network (NCCN) guidelines: any one of the following diagnostic criteria are sufficient to diagnose LM;

CSF positive for tumour cells (positive CSF cytology)
Radiologic findings in the CNS consistent with LM irrespective of supportive clinical findings or alternatively and more controversial
Clinical signs and symptoms consistent with LM and a nonspecific but abnormal CSF analysis (high white blood cell count, low glucose, and elevated protein) in a patient known to have a cancer.

25-30% pt with LM defined by a clinical syndrome,

But normal neuraxis imaging, and persistently negative CSF cytology.

Clinical presentation

Solid malignancies

Presenting mostly with

Spinal symptoms
Radicular symptoms

Compression or invasion of peripheral nerve roots.

Hematologic malignancy

Presenting more frequently with

Cranial nerve dysfunction

Compression or invasion of the cranial nerve roots.

Multifocal neurologic symptoms

Headache

Malignant cells frequently accumulate sufficiently in the subarachnoid or ventricular compartment → tumor adhesions in Subarachnoid space → obstruct CSF flow
Patients with CSF flow interruptions have been shown to have a decreased survival compared with those with normal CSF flow.

Mental alteration

Ataxia

Strokes

Invasion, compression, or spasm of blood vessels located on the brain convexity or in the Virchow-Robin spaces may interfere with the blood supply and oxygenation of neurons and may produce

ㅤ	Symptoms	%	Signs	%
Cerebral	Headache	51-75	Mental status change	27-65
ㅤ	Mental change	26-33	Seizure	11-18
ㅤ	Gait difficulty	27	(Focal/generalized)	(11/6)
ㅤ	Nausea and vomiting	22-34	Papilloedema	11
ㅤ	Unconsciousness	4	Sensory disturbance	11
ㅤ	Dysphagia	4	Insipid diabetes	4
ㅤ	Coordination disorders	20-34	Hemiparesis	2
ㅤ	Loss of consciousness	4	Cerebellar disorder	15
ㅤ	Dizziness	4	ㅤ	ㅤ
Cranial nerve	Diplopia	20-36	Ocular motor paresis III, IV, VI	5-36
ㅤ	Visual loss	9-10	Facial paresis VII	10-27
ㅤ	Hearing loss	5-14	Visual loss II	5-19
ㅤ	Decreased hearing	5	Optic neuropathy	8
ㅤ	Tinnitus	3	Diminished hearing VIII	7-18
ㅤ	Facial numbness	8-10	Trigeminal neuropathy V	6-10
ㅤ	Hypoguesia	4	Diminished gag reflex IX, X	2-6
ㅤ	Dysphonia/dysphagia	2-7	Hypoglossal neuropathy XII	5-10
ㅤ	Hoarseness	3	ㅤ	ㅤ
ㅤ	Vertigo	2	ㅤ	ㅤ
Spinal	Lower motor neuron weakness	34-46	Reflex asymmetry	86
ㅤ	Paresthesias	33-42	Nuchal rigidity	9-13
ㅤ	Back/neck pain	31-37	Weakness	73
ㅤ	Radicular pain	26-37	Sensory loss	32
ㅤ	Bladder and bowel dysfunction	16-18	Straight leg raising	15
ㅤ	Upper motor neuron weakness	14	Decreased rectal tonus	5-14

Investigation

T1+C and FLAIR MRI Brain and spine

Most sensitive sq
MRI should be obtained preferably prior the LP

Lumbar puncture itself can cause a meningeal reaction, leading to leptomeningeal enhancement.

Perineural spread of tumour cells along the subarachnoid spaces may be detected
Cerebral involvement

Subarachnoid nodules (35-50%)
Pial enhancement (15-50%).
HCP

Spine involvement

Subarachnoid and parenchymal enhancing nodules (10-35%)
Diffuse or focal pial enhancement (10-20%).

Radionuclide studies

Using

111Indium-diethylene-triamine pentaacetic or
99Tc macro-aggregated albumin

Techniques of choice for the evaluation of CSF flow interruption.
CSF flow blocks in 30-70% of patients,
Location of CSF Flow blocks

Occurring at the

Skull base,
Spine
Cerebral convexities

LP-CSF

Abnormalities of the standard CSF analysis are observed in more than 90% of the cases of LM.

Increased opening pressure	(>200 mm of H2O)	46%
Increased leukocytes	(>4/mm3)	57%
Elevated protein	(>50 mg/dl)	76%
Decreased glucose	(<60 mg/dl)	54%

Although indicative of LM, these CSF abnormalities are nonspecific. Identification of cancer cells in the CSF by cytological analysis is the key diagnostic feature of LM.

Identification of neoplastic cell by CSF cytological study is the key feature determining LM.
The initial cytology is falsely negative in up to 40–50% of patients with pathologically proven leptomeningeal carcinomatosis.
Diagnostic yield improves with

Repeated sampling (50% for the first to 90% for the third spinal tap)
CSF sample volume (10 mL at least)

CSF Volume	Sensitivity of CSF cytology
3.5 ml	68%
10.5 ml	97%

Avoiding delays in (i.e., immediate) processing and cytospin of the samples in the laboratory

30 min	50% of cells remain viable
90 min	10% of cells remain viable

Sampling site (LP provides a higher yield than ventricular CSF)
Nonhemorrhagic CSF specimen.

CSF biomarkers are still being investigate (CA125, EGFR, VEGF etc)

Radionuclide CSF flow studies

Meningeal biopsy from an enhancing region on MRI, in cases where CSF exams remain inconclusive

Management

Generally it is Palliative

Improve or stabilize the neurological status
Maintain neurological quality of life
Prolong survival

Monitoring Treatment success:

CSF cytology (conversion from positive to negative) AND/OR
Clinical response (improved or stable)

Palliative/Symptomatic treatment

Pain

Headache, back, or radicular pain, frequently necessitates using opioid analgesics.
Neuropathic pain

Tricyclic antidepressants (such as amitriptyline or nortrptyline) OR
Antiepileptic drugs (such as gabapentin, pregabalin, carbamazepine, and lamotrigine).

Corticosteroids

Radicular pain.
Headaches due to oedema and inc. ICP

Focal irradiation of symptomatic sites is often quite efficient in relieving pain.

Seizures

If seizure present give anticonvulsant drugs (AEDs)
Not for prophylactic AEDs

Course of steroids during whole brain
Skull-base radiotherapy
Repeated lumbar punctures

An alternative method to relieve temporarily headache in patients declining CSF diversion.

CSF shunting

Depression or fatigue

SSRI
Stimulant medication (modafinil, methylphenidate)

Surgery

Main surgical intervention

For symptomatic hydrocephalus
Complication

Tumour seeding into the abdomen
Device failure
Infection

Evidence

Bander 2021
Dhaliwal Et al 2023

Meta analysis
Shunting does not improve OS
Shunting does relieve symptoms

Suggesting that individuals who exhibit certain symptoms should be considered for CSF diversion
Symptoms

Headache
N/V
Focal neurological deficits (including cranial nerve palsies, visual deficits, and hemiparesis)
Encephalopathy (confusion, altered mental state, cognitive disturbance)
Gait disturbance
Urinary incontinenc

Placement of a ventricular (rarely lumbar) access device (e.g., an Ommaya or Rickham reservoir)

Facilitate administration of intra-CSF chemotherapy.
Post op confirmation of correct intraventricular (IVent) placement requires a

Brain CT OR
A radio-isotope CSF flow study

Complication

Hemorrhage at the time of device placement occurs < 1%
Infection (4-10%)

Micro

Staphylococcus epidermidis

Due to

Initial implantation
Contamination at the time of device access.

Management if infected

IVent device may be left in situ and treated with both intravenous and IVent antibiotics.
Removal and if indicated, replacement of the reservoir.

CSF tracking along the catheter

Due to raised ICP
Causing subgaleal or intraparenchymal collections of CSF,
If symptomatic willl require revision or replacement with a VPS

If both VPS and Ommaya ventricular access device are needed,

An on–off valve may be placed but this necessitates that the patient can tolerate having the VPS placed in the off position so as to permit drug installation into the ventricles and time for ventricular transit and distribution into the nonventricular CSF compartments.

General

Does not prolong survival
Aim

To relieve CSF block
To decompress nerve (spinal/cranial)
To relief pain

Involved-field radiotherapy

To sites of

Symptomatic disease,

Whole brain irradiation (WBRT)

Dose: 30 Gy delivered in 10 fractions over 2 weeks.
Provides effective relief of pain and stabilizes neurological symptoms
Rarely leads to significant neurological recovery (due to demyelination, axonal and neuronal injury, and injury by infiltrating cancer cells),

Reasons why need for early treatment of LM.

Bulky disease observed on MRI

Skull-base radiation therapy (RT)

Used in patients with cranial neuropathies.

Sites of CSF flow block

Defined by radioisotope ventriculography.
Via WBRT

Allows tumor masses not treated by intra-CSF chemotherapy (due to limited diffusion of intra-CSF chemotherapy) to receive palliative radiotherapy.
Administration of involved-field radiotherapy to the site of CSF flow obstruction restores flow in

30% of patients with spinal involvement
50% of patients with intracranial involvement.

After reestablishment of CSF flow, the survival of patients with pretreatment CSF flow interruption is similar to patients without flow abnormalities.

Craniospinal axis irradiation (CSI)

Is the only method of radiotherapy that treats the entire neuraxis and that may be reasonably considered as a single modality of treatment for LM.
Majority of adults CSI is rarely considered as most patients have

Previously had some region of the neuraxis irradiated
Poor bone marrow reserve as a consequence of prior exposure to cytotoxic chemotherapy

Toxicity

Myelosuppression
Enteritis

Complications

Radiation-associated fatigue
Myelosuppression
Mucositis
Esophagitis
Leukoencephalopathy

More often asymptomatic
More likely to occur with radiation

Chemotherapy

Only modality aside from CSI allowing simultaneous treatment of the entire neuroaxis

Intrathecal

Intra-CSF chemotherapy

Reasons intra CSF chemo is used:

Bypass BBB →

Normal blood–brain and blood–CSF barriers limit penetration into the CNS of most systemically administered anticancer agents. → CSF exposure to most cytotoxic agents is <5% of the plasma concentration.

The blood–CSF barrier in LM is compromised but the disruption is partial, varies from one region to another such that with few exceptions (e.g., high-dose MTX discussed later for breast cancer-associated LM) is rarely a primary treatment of LM.

Increase drug exposure and reducing systemic toxicity
Increase drug half life

In the presence of CSF flow blocks, intra-CSF treatment has reduced efficacy and increased toxicity due to impaired intra-CSF drug distribution

Route of administration

Lumbar intrathecal (IT)

Repeated LP
Lumbar catheter

Pt needs to remain flat for at least an hour post treatment.

Intraventricular

Ommaya reservoir
Rickham reservoir

Pros

Painless after insertion
More efficient use of time for the administering physician
Provides certainty that the drug has not been administered in the epidural or subdural space (up to 10% of all IT injections)
Can be used safely with a platelet count as low as 20,000 cell/mm3, thus avoiding the significant risk of epidural or subdural hematoma after lumbar puncture
IVent CSF drug concentration following IT injection is only 10% of these achieved after an equivalent IVent dose.
Offers the possibility of delivering frequent small doses of drug to reduce high peak drug concentrations → limit total cumulative drug dose → reduce neurotoxicity.

Cons

Risks for GA

Can also be performed with local anaesthesia.

Infections
Epilepsy by extravasation of the drug into the brain
Failure to puncture slit ventricles
Hemorrhages are rare complications occurring especially with repeated puncture attempts.
Reservoir or catheter obstruction or dysfunction

Evidence

Glantz 2010

Depending on the drug's half life, some have PFS benefit some do not have

Techniques of intra-CSF administration

Ensure equal volume administration

Pt are on the edge of their “pressure-volume” compliance curve any increase in volume can cause dramatic increase in pressure.
Remove same volume of CSF that the drug is being administered (aka isovolumetric withdrawal)

During the withdrawal of a large volume of CSF from the ventricles, a transient retro-orbital or frontal headache may result.
The headache is often improved with administration of intra-CSF chemotherapy if given in 5-10 ml volume.

No prospective trials in adults with LM have proven any benefit to concomitant use intra-CSF glucocorticoids (hydrocortisone) in combination with intra-CSF chemotherapy.

Drugs available for intra-CSF treatment

Most common used:

These are not effective vs Melanoma and lung Ca
No Evidence combination use is better than single agents
Eg

Methotrexate(1st line)

Intraventricular (2mg/day for 5 days for alternate weeks for 4 treatment cycles)

Liposonal ara C (Cytosine arabinoside/Cytarabine)
Thiotepa

Biological agents being investigated

Solid tumour: The benefit of intra-CSF chemotherapy is poor. This is due to

Intrinsic chemoresistance
Limited choice of intra-CSF chemotherapeutic agents,
Poor accessibility of bulky nodules to intra-CSF chemotherapy

Haematological tumour: lymphoma and leukaemia

Prophylactic treatment (Prevention of CNS relapse)

High-dose systemic and/or intrathecal chemotherapy are used depending on the presence of risk factors for CNS involvement. Such as:

Lymphoma grade and stage
Extent of extranodal disease
Young age
Elevated serum lactate dehydrogenase levels
Presence of human immunodeficiency virus(HIV)-related NHL
Presence of a primary CNS lymphoma

Systemic

Agents

Temozolomide
High dose MTX
High dose cytarabine

Future treatment

Craniospinal radiation and intrathecal chemotherapy via a CSF reservoir are the mainstays of treatment, although outcomes remain poor (6 weeks untreated).

Patient survival with Subarachnoid seeding is <6 months

Prognosis

Without specific LM-treatment, median overall survival (OS) is 4-6 weeks.

With combined treatments, median overall survival (OS) usually less than 8 months with a median OS of 2-3 months.

From CNS national comprehensive cancer network guidelines:

Poor risk group	Good risk group
Low KPS (<60%)	High KPS (≥60%)
Multiple, serious, or major neurological deficits	No major neurological deficits
Extensive systemic disease with few treatment options	Minimal systemic disease
Bulky CNS disease	Reasonable systemic treatment options
LM-related encephalopathy	No CSF block

KPS: Karnofsky performance status; CNS: Central nervous system
Poor risk group for best supportive care and good risk group for treatment

Type of primary cancer major prognostic factor

Best to worse: Leukaemia/lymphoma > breast > Lung > melanoma

Leukaemia/lymphoma median overall survival months to years
Breast median overall survival 6 months

Intra-CSF chemotherapy appeared to improve OS in a recent case series of patients with lung cancer and LM.

Whole brain radiotherapy no change in OS

Differential diagnosis

Differential diagnosis for meningeal enhancement.

Neurogenic:

Increased CSF pressure,
Intracranial hypotension

Inflammatory:

Sarcoidosis
Infectious:

Subacute and chronic meningitis

Tuberculosis,
Fungal infection,
Granulomatous cell infiltration

Vascular:

Local ischemia,
Venous thrombosis,
Hypoxia,
Subarachnoid haemorrhage

Traumatic

Drug induced:

Chemotherapeutic agents,
Heavy metals

Neoplastic:

Local tumor infiltration,
Primary meningeal glioma,
Primitive neuroectodermal tumor,
Isolated primary meningeal melanomas,
Rhabdomyosarcoma of the leptomeninges

Other:

Ionizing radiation,
Metabolic disturbances,
Reaction to hyperventilation