INTRODUCTION — Involvement of the central nervous system (CNS) at the time of acute myeloid leukemia (AML) diagnosis is uncommon, and routine evaluation is not recommended for asymptomatic patients. Clinically overt CNS involvement developing at some point later during the course of treatment is also uncommon, perhaps related to the administration of high dose cytarabine as post-remission therapy.

This topic will discuss the epidemiology, clinical presentation, diagnosis, and treatment of CNS involvement in patients with AML. The clinical features, diagnosis, classification, treatment, and overall prognosis of AML are discussed separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●(See "Induction therapy for acute myeloid leukemia in medically-fit adults".)

●(See "Acute myeloid leukemia: Management of medically-unfit adults".)

●(See "Acute myeloid leukemia in children and adolescents".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately.

●(See "COVID-19: Considerations in patients with cancer".)

EPIDEMIOLOGY

Incidence — The incidence of central nervous system (CNS) involvement in patients with acute myeloid leukemia (AML) is not well-defined, and estimates vary widely. Estimates of incidence differ, in part, because diagnostic lumbar puncture (LP) is not routinely performed in all patients with AML and detection methods vary between studies.

In one study, CNS involvement was detected in 32 percent of 103 consecutive adult patients with newly diagnosed AML who underwent routine diagnostic LP (regardless of neurologic findings), using flow cytometry and/or cytology [1]. In another study, CNS involvement was identified in 19 percent of 42 patients with AML who underwent routine LP; however, the same group detected CNS involvement in only 3 percent of 1370 consecutive patients with AML when an LP was performed only for findings suggestive of CNS disease [2]. Another study reported CNS involvement in <1 percent of 3261 adults with newly diagnosed AML and CNS symptoms who were enrolled in a series of clinical trials; the rate was 3 percent in patients with relapsed AML [3]. Among 1344 children with AML, 395 (29 percent) had evidence of CNS involvement at presentation; 217 met CNS2 criteria (ie, ≤5 white blood cells with blasts) and 178 had CNS3 disease (ie, >5 white blood cells with blasts or CNS symptoms) [4].

The incidence of CNS leukemia appears to have decreased since the incorporation of high dose cytarabine (HiDAC; which can penetrate into the CNS) into initial induction and/or post-remission therapy. Prior to the use of HiDAC, meningeal disease developed in up to 20 percent of children and 16 percent of adults with AML [5].

Risk factors — CNS involvement is more common in patients with AML with the following features [3,4,6,7]:

●Prominent monocytic component (eg, acute monoblastic/monocytic leukemia or acute myelomonocytic leukemia)

●Acute promyelocytic leukemia (APL) with PML/RARA in relapse

●Certain molecular/cytogenetic findings (eg, FLT3-internal tandem duplication; AML with inv(16) or chromosome 11 abnormalities; complex karyotype)

●Expression of CD56 adhesion molecule on the surface of leukemia blast cells

●Hyperleukocytosis (>100,000/microL)

●Patients <2 years of age

●Elevated lactate dehydrogenase (LDH)

PATHOGENESIS — How AML seeds the CNS is incompletely understood. Possible mechanisms include [8]:

●Extension from the bone marrow of the skull through bridging veins into the subarachnoid space

●Contamination of the cerebrospinal fluid (CSF) via the choroid plexus

●Invasion of the cerebral parenchyma by way of brain capillaries

●Direct infiltration of the leptomeninges through bony lesions of the skull

●Extension along nerve roots through the neural foramina and into the extradural space

●Hemorrhage into the CNS with blood containing blasts

●Iatrogenic introduction of blasts into the CSF at the time of lumbar puncture

CLINICAL PRESENTATION — Patients with CNS involvement may be asymptomatic [9]. The vast majority of asymptomatic patients do not have CNS involvement.

Patients with the following symptoms should be evaluated further for possible CNS involvement:

●Symptoms of increased intracranial pressure (constant headache, lethargy, or other mental changes)

●Cranial nerve palsies (most commonly cranial nerves III, V, VI, or VII). There are few, if any, other causes of palsies of nerves III, V or VI in patients with AML, but it can be difficult to clinically distinguish "Bell's palsy" (cranial nerve VII; which occurs frequently in the normal population) from leukemia involvement in patients with AML; magnetic resonance imaging (MRI) may be helpful in this circumstance.

●Symptoms of CNS hemorrhage (seizure, altered mental status, headache, neurological deficits)

●Symptoms of spinal cord compression (back pain, weakness, paresthesias, bladder dysfunction)

●Visual changes

EVALUATION — Patients with suspected CNS involvement should be evaluated with a lumbar puncture. Imaging studies are selected based upon the symptoms present. A careful retina exam may demonstrate leukemic infiltrates.

Lumbar puncture

Overview — Diagnostic lumbar puncture (LP) is not recommended for most patients with AML in the absence of CNS symptoms. Patients who should be considered for LP include those with symptoms suggesting CNS or ocular involvement and patients with acute promyelocytic leukemia (APL) in systemic relapse. In patients with APL, LP should be deferred until correction of the coagulopathy and, in the absence of symptoms, can usually be done after a second complete response is achieved. Even if the cerebrospinal fluid examination is negative, many experts recommend prophylactic treatment with intrathecal chemotherapy in patients with APL in second remission. (See "Lumbar puncture: Technique, indications, contraindications, and complications in adults", section on 'Complications' and "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

The most serious complication of LP is cerebral herniation. Patients with the following clinical risk factors should have a computed tomography or magnetic resonance imaging scan of the head prior to LP to identify a possible mass lesion and other causes of increased intracranial pressure:

●Altered mentation

●Focal neurologic signs

●Papilledema

●Seizure within the previous week

Technique — Every effort should be taken to avoid a traumatic LP in patients with leukemia since this can lead to seeding of the leukemic blasts into the cerebrospinal fluid (CSF). In addition, there is concern about bleeding at the site of the LP with the potential for spinal cord impingement. Thus, the most experienced clinician available should perform the LP. Many centers now refer patients to radiology to have the procedures done with the aid of fluoroscopy, which will presumably decrease the incidence of local tissue injury, although data to this effect are lacking. Prior to LP, an effort should be made to correct any underlying coagulopathy and thrombocytopenia. We generally advise not performing an LP in patients with coagulation defects who are actively bleeding, have severe thrombocytopenia, or an international normalized ratio (INR) >1.4, without correcting the underlying abnormalities.

There is some controversy and relatively little data about the minimal platelet count at which an LP can be performed safely. A large study in children demonstrated the safety of LPs at platelet counts >10,000/microL, although a larger study by the same group suggested that the rates of traumatic and bloody taps were higher with lower platelet counts [10,11]. Because of the concern about the introduction of circulating leukemia cells into the CSF, many centers routinely administer a dose of intrathecal chemotherapy when LPs are done in patients at diagnosis or in relapse.

It is difficult to extrapolate studies of children to adults because, unlike adults, most of the children were sedated during LP and because of physical differences between adults and children. Adults have a longer length of tissue that must be traversed to access the lumbar space. This general concern is magnified in the setting of obesity resulting in difficulties in the identification of the lumbar space. Based on an experience with 195 LPs in 66 patients with acute leukemia, it was suggested that a minimal platelet count of >20,000/microL is desirable [12]. These authors also noted an increase in the incidence of traumatic taps at lower platelet counts. A more recent review summarized the conundrum with the statement that "40,000 x 10⁹/L is a 'safe' count for lumbar puncture. It is likely that lower platelet counts may also be safe but there is insufficient published evidence to make recommendations for lower levels at this stage" [13]. (See "Lumbar puncture: Technique, indications, contraindications, and complications in adults".)

A total of 8 to 15 mL of CSF is typically removed during routine LP. Up to 40 mL of fluid can safely be removed if needed. CSF should be sent for cell count and differential, protein and glucose concentrations, gram stain and culture (if infection is suspected), cytology (examination of stained cytospin slides) and flow cytometry or immunohistochemistry if needed to identify blasts that cannot be characterized with certainty by morphology. (See "Treatment of leptomeningeal disease from solid tumors".)

Findings — Blast cell counts can vary from as few as 5 to >1000/microL. Most patients have moderate elevations in CSF protein with a moderate decrease in glucose. Some patients with clinical signs of cranial nerve involvement or masses demonstrated by imaging studies can have relatively benign appearing CSF without detectable blasts, but treatment should not be delayed in such patients. (See 'Treatment' below.)

After the administration of intrathecal therapy, cytocentrifuge preparations can demonstrate reactive ependymal cells that, particularly if the leukocyte count is low, can be difficult to distinguish from leukemic cells.

Imaging — Imaging studies used to evaluate a patient with suspected CNS involvement of AML are selected based upon the symptoms. Mass lesions are unusual in patients with CNS involvement by AML, although they have been reported in patients with inv(16) [6].

●Magnetic resonance imaging (MRI) of the brain may be useful in excluding acute or subacute stroke and multifocal inflammatory lesions or when posterior fossa or vascular lesions are suspected. In patients with cranial nerve palsies, careful examination with thin sections of the course of the nerve roots is often helpful since the spinal fluid can be "negative" in patients with isolated nerve involvement by leukemia.

●MRI of the spine is indicated if there are concerns of spinal cord compression. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)

●Computed tomography (CT) of the brain may be used to evaluate for signs of stroke, tumor, hemorrhage, or infection. A subset of patients with symptoms concerning for increased intracranial pressure should also undergo CT scan of the head prior to lumbar puncture. (See 'Overview' above.)

DIAGNOSIS — The diagnosis of CNS leukemia is confirmed by the identification of leukemic blasts on cytocentrifuge preparations of cerebrospinal fluid (CSF) after lumbar puncture [14].

Flow cytometry and/or molecular genetic analysis can confirm the presence of malignant cells, if diagnostic abnormalities are present.

TREATMENT — There have been no prospective studies comparing the use of intrathecal (IT) chemotherapy, systemic chemotherapy, and cranial radiation in patients with involvement of the CNS with leukemia. Most of the evidence comes from clinical experience, retrospective analyses, and the extrapolation of data from other types of carcinomatous meningitis.

For patients with involvement of the CNS with AML without signs of cranial nerve impairment, we suggest initial treatment with IT chemotherapy rather than cranial radiation or systemic chemotherapy designed to penetrate the blood brain barrier. This preference is largely based on the known ability of IT chemotherapy to clear cerebrospinal fluid (CSF) involvement in most patients relatively quickly and a desire to avoid the potential acute and long-term complications of cranial irradiation. Radiation therapy is administered in addition to IT chemotherapy for patients with cranial nerve involvement or with a tumor mass that impinges on important structures (eg, the spinal cord). Radiation therapy may also be given to patients who fail to respond completely to IT chemotherapy.

Patients who develop CNS and systemic relapse simultaneously require both CNS directed therapy and systemic chemotherapy. However, even when there is no evidence of systemic relapse, systemic disease will inevitably develop if systemic therapy is not delivered.

Intrathecal (IT) chemotherapy — IT chemotherapy involves the injection of chemotherapy into the CSF, either directly into the lateral ventricle through a subcutaneous reservoir and ventricular catheter (eg, an Ommaya reservoir) or into the lumbar thecal sac by lumbar puncture (LP). If possible, CSF pressures should be measured in patients receiving therapy in the lumbar space. As fluid is removed, many patients will have a rapid relief of symptoms that were related to increased intracranial pressure.

An Ommaya reservoir is often placed, either because of difficulties in performing repeated lumbar punctures or because of concern that the CSF flow does not deliver sufficient amounts of the drug from the lumbar space to the entire CNS in some individuals. Typically, the flow of CSF is from the choroid plexus in the lateral ventricles down through the aqueduct to the base of the spine and then back up along the spinal cord until it is reabsorbed over the surface of the brain. Usually the dose of chemotherapy is reduced when given directly into the ventricles (figure 1).

There have been no prospective trials comparing chemotherapy agents in this setting. Either methotrexate (15 mg/dose when administered via an LP or 12 mg when administered via an Ommaya) or cytarabine (50 mg/dose via LP or 40 mg via Ommaya) can be used as the initial IT chemotherapy in an adult with a planned crossover to the other agent in the event of refractory disease or relapse. Young children may need a dose calculated on body weight.

A typical schedule includes treatment two to three times per week until the CSF has cleared of leukemic cells, generally occurring after a few injections. Treatment is then given at weekly intervals for two more doses, to be followed by monthly administration, for a total of one year. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Intrathecal therapy'.)

Administration — As mentioned above, IT chemotherapy can be administered into the CSF via an Ommaya reservoir or by LP. Once access to the CSF is attained, the administration of chemotherapy is essentially the same. The details of accessing an Ommaya reservoir are described in detail separately. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Technique of administration'.)

Perhaps one of the most important details to consider when administering IT chemotherapy is the volume of chemotherapy to be instilled. Careful attention must be paid to minimizing any change in CSF volume. Thus, equivalent volumes of CSF (usually 7 to 10 mL) should be removed prior to instilling IT chemotherapy.

Methotrexate — IT methotrexate (MTX) is administered at a fixed dose of 15 mg (12 mg if administered via Ommaya), initially two to three times weekly. A variety of neurologic complications can result from IT MTX therapy. These include chemical (aseptic) meningitis, delayed leukoencephalopathy, acute encephalopathy, and transverse myelopathy. These issues are discussed in detail separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Methotrexate'.)

Cytarabine — Cytarabine is administered intrathecally at a fixed dose of 50 mg/dose (40 mg if administered via Ommaya), initially two to three times weekly. IT cytarabine may be associated with chemical (aseptic) meningitis and, less commonly, with encephalopathy, seizures, and myelopathy as discussed separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Cytarabine'.)

A liposomal formulation of cytarabine has been removed from the market because of excessive toxicity.

Thio-TEPA — Thio-TEPA is an alkylating agent that can also be administered into the CSF. It is more often used to treat carcinomatous meningitis, but may also have benefit against CNS leukemia.

Cranial radiation — As described above, IT chemotherapy is the preferred treatment for patients with AML and involvement of the CNS. We generally reserve radiation therapy (RT) for patients with cranial nerve involvement (CNI) or with a tumor mass that impinges on important structures (eg, the spinal cord) or for patients who fail to respond completely to IT chemotherapy. Failure should be suspected if the CSF does not clear after four to five injections or if there are increasing numbers of blasts with or without worsening symptoms. Usually, an alternative IT chemotherapy agent is attempted prior to adding external beam RT.

To avoid excess myelosuppression, cranial rather than craniospinal RT is preferred. It is important that the treatment field include the base of the brain (typically down to C2) in order to adequately cover the foramina for the cranial nerves. Patients with lower extremity weakness, or bladder or bowel dysfunction, may receive lumbosacral spine irradiation in addition to cranial irradiation, particularly if an MRI demonstrates nerve involvement at this level.

For patients with CNI or a tumor mass that impinges on important structures, we suggest initial RT rather than IT chemotherapy alone. We initiate RT (18 to 25 Gy for the brain) as soon as CNI is suspected because the effect of IT therapy alone on CNI is unpredictable and the chance of nerve recovery decreases substantially the longer the deficit has been present. Magnetic resonance imaging can be helpful in confirming the presence of CNI, but treatment should not be delayed if there is a strong clinical suspicion and the imaging study cannot be obtained expeditiously.

While cranial radiation is an effective form of CNS-directed therapy, its use is limited by acute and long-term toxicities [15-18]. Major acute toxicities include myelosuppression, mucositis, and esophagitis. Long-term toxicities include secondary neoplasms, endocrine diseases, neurocognitive dysfunction, neurotoxic effects, and growth retardation in children. These are discussed in more detail separately. (See "Delayed complications of cranial irradiation".)

The efficacy of cranial RT for the treatment of CNS leukemia was assessed in a single-center retrospective study of 163 adults with CNS leukemia treated between 1996 and 2012 [19]. Sixty-six patients had AML and some received concurrent IT treatment with chemotherapy. The most common CNS-related symptoms were headache (49 percent), cranial nerve VII deficit (28 percent), and cranial nerve II deficit (27 percent). Following RT, symptoms were resolved in 16 percent, improved in 54 percent, and stable in 15 percent. Patients received either whole brain, craniospinal, or base of skull ports. The doses administered were not mentioned. Because it is not clear how a particular port was chosen for individual patients, it is not possible to draw conclusions about which ports are appropriate for different clinical presentations. The median survival after radiation was 3.8 months. These results suggest that cranial RT often relieves symptoms, but is not sufficient treatment by itself.

Systemic chemotherapy — Systemic chemotherapy that penetrates the CNS can serve as an adjunct to IT treatment. High dose methotrexate or cytarabine have been reported to achieve clearance of the CNS tumor load [16,20]. Unfortunately, the relapse rate, even after initially rapidly successful therapy, is high, either in association with bone marrow relapse or independently [15].

Patients with ocular involvement — Direct involvement of the eye or vitreous is uncommon in AML. (See "Overview of the complications of acute myeloid leukemia", section on 'Ocular involvement'.)

RESPONSE EVALUATION — As mentioned above, the response to CNS-directed therapy is evaluated by cerebrospinal fluid (CSF) cytology at the time of each intrathecal chemotherapy treatment. Failure should be suspected if the CSF does not clear after four to five injections or if there are increasing numbers of blasts with or without worsening symptoms.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●In adults and children (>1 year of age), involvement of the central nervous system (CNS) by acute myeloid leukemia (AML) is uncommon at the time of initial diagnosis. The incidence of CNS involvement is higher at the time of relapse of AML. (See 'Epidemiology' above.)

Routine evaluation of the CNS is not recommended for asymptomatic adult patients and children (>1 year old) with AML.

All infants (≤1 year old) with a diagnosis of AML and adults with acute promyelocytic leukemia in second remission should undergo routine evaluation of the CNS because of the higher incidence of CNS involvement. (See 'Epidemiology' above and 'Evaluation' above.)

●Patients with CNS involvement are usually symptomatic, but may be asymptomatic. The great majority of asymptomatic patients with AML do not have CNS involvement.

●If CNS involvement is suspected, evaluation should include a lumbar puncture. The diagnosis of CNS leukemia is confirmed by the identification of leukemic blasts on cytocentrifuge preparations of cerebrospinal fluid (CSF). Flow cytometry and/or molecular genetic analysis can confirm the presence of malignant cells, if diagnostic abnormalities are present. (See 'Findings' above and 'Diagnosis' above.)

Imaging studies are selected based upon the nature of symptoms present. (See 'Imaging' above.)

●Treatment of CNS leukemia consists of the administration of intrathecal (IT) chemotherapy, with the addition of cranial radiation in patients who do not respond fully to chemotherapy, or in whom cranial nerve involvement is present. (See 'Treatment' above.)

●For patients with involvement of the CNS with AML, we suggest initial treatment with IT chemotherapy rather than cranial radiation or systemic chemotherapy that can penetrate the blood brain barrier (Grade 2C). Either methotrexate or cytarabine, depending on the site of administration, can be used as the initial IT chemotherapy with crossover to the other agent in the event of refractory disease or relapse. (See 'Intrathecal (IT) chemotherapy' above.)

●For patients with cranial nerve involvement or a tumor mass that impinges on important structures, we suggest initial radiation therapy (18 to 25 Gy for the brain) followed by IT chemotherapy rather than IT chemotherapy alone (Grade 2C). (See 'Cranial radiation' above.)