Clinical manifestations

Presentation and course

Direct complications of leukemias

Leptomeningeal metastasis. Most commonly, leukemia directly involves the nervous system by way of leptomeningeal metastasis (16). Presentation is often broad and nonspecific and includes headaches, confusion, seizures, cranial neuropathies, myelopathy, and radiculopathies (03; 18). Cranial nerve involvement most often manifests as diplopia, facial weakness, or hearing loss (08). Communicating hydrocephalus may also occur in certain cases presenting with headaches, altered mental status, and gait difficulties (08; 01; 03). Leukemia, especially acute myelomonocytic leukemia, can cause leukemic meningitis. The presentation includes meningismus, headache, photophobia, and sometimes increased intracranial pressure, cranial nerve, or spinal cord involvement. When cranial nerves are involved, they can affect oculomotor nerves (causing abducens palsy), the trigeminal nerve (causing numb chin syndrome), the optic nerve (causing optic neuropathy), and the vestibulocochlear nerve (causing hearing loss) (16).

Richter syndrome. Some leukemias, such as chronic lymphoid leukemia may convert to lymphoma, a phenomenon called Richter syndrome. Very rarely, cases of CNS Richter syndrome have been described as presenting with headache, confusion, vomiting, and focal neurologic symptoms (27).

Chloromas and granulocytic sarcomas. Chloroma or granulocytic sarcomas are a subset of extramedullary tumors seen in the setting of myeloid leukemias (16; 14). In the CNS, they most often occur adjacent to the skull or facial bones (16). They can also occur in the spine, especially the thoracic area, and rarely can also affect the peripheral nervous system (16; 14; 09). Presentation varies by the site affected. In the case of spinal cord compression, they can include myelopathy with motor or sensory symptoms, radicular pain, back pain, and bladder dysfunction (05; 14; 09). They sometimes also involve the orbit causing ophthalmic neuropathy (05). Much less frequently, parenchymal infiltration may occur, especially in the context of acute myeloid leukemia, resulting in cranial neuropathy, seizures, and headaches (05; 14).

Vascular complications of leukemias

Cerebrovascular complications of leukemia consist of hemorrhagic and ischemic strokes due to venous or arterial thrombosis (16). They often occur in hematological disturbances, such as disseminated intravascular coagulation in promyelocytic leukemia or hyperviscosity from hyperleukocytosis (08; 03).

Intracranial hemorrhage. Intracranial hemorrhage is the second most common complication in adult patients with hematologic malignancies and is also the second most common cause of death in acute leukemias (05; 14). Most bleeds occur in the parenchyma (16; 14; 19) and most commonly involve the cerebral matter rather than the cerebellum. Patients can present with headaches, encephalopathy, nausea and vomiting, diplopia, or hemiparesis (05). Unique intracerebral hemorrhage is most often seen in relation to disseminated intravascular coagulation or severe thrombocytopenia, whereas multiple intracerebral hemorrhages are most often seen in blast crisis (16). Rarely, and most often related to iatrogenic complications, subarachnoid and subdural bleeds may occur (05).

Intracranial thrombosis

Venous sinus thrombosis. Leukemic patients are prone to prothrombotic conditions, which can result in venous sinus thrombosis (08). Use of L-asparaginase or vincristine has also been associated with thrombosis (01). Venous sinus thrombosis most often presents with headache accompanied by seizures, focal neurologic deficits, and alteration of consciousness (08).

Ischemic strokes. Ischemic strokes from multiple micro-emboli, such as in disseminated intravascular coagulation or septic emboli, can occur in these patients (16). Leukemia has also been associated with vasculitis, which can present as focal neurologic deficits, encephalopathy, seizures, strokes, or mononeuritis multiplex (08). The types of vasculitis seen in leukemia are paraneoplastic polyarteritis nodosa and leucocytoclastic and cryoglonumemic vasculitis (08; 11).

Infectious complications of leukemias. Leukemic patients are at risk of innumerable infectious complications. Patients who have undergone splenectomy are at risk of infections from encapsulated bacteria, such as meningitis from meningococcus, pneumococcus, or hemophilus (04). Leukemic patients, especially those who have had hematopoietic stem cell transplants or have received chimeric antigen receptor therapy (CAR-T), are at high risk of viral infections, such as Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, human herpes 6 virus, and JC virus (15; 10). Infection with the zoster virus can cause vasculitis and stroke (01), and JC virus infection can cause progressive multifocal leukoencephalopathy, mostly presenting with alteration of consciousness (08). They are at high risk of developing fungal infections, such as aspergillus, mucormycosis, and candidiasis, which can all lead to cerebral infarction or hemorrhage (01). Candida can also cause abscesses in the brain, cerebellum, or basal ganglia, as well as mycotic aneurysms in various brain vessels (08; 01). Parasitic infections, such as toxoplasmosis, may also occur in these patients (10).

Other indirect complications of leukemia

Encephalopathy. Encephalopathy can result from various conditions, such as electrolyte anomalies, metabolic derangements, vascular complications, secondary effects of treatment, or infections (05). Notably, posterior reversible encephalopathy syndrome has been associated with leukemia from treatment-induced hypertension (17), use of corticosteroids (17; 01), cyclosporine (01), calcineurin inhibitors such as cytarabine and tacrolimus (17; 10), and the use of methotrexate (05; 01). These patients will typically present with seizures, headache, nausea, vomiting, alteration of consciousness, and visual dysfunction (17; 01).

Paraneoplastic involvement. Paraneoplastic involvement is rare and mostly reported in chronic lymphocytic leukemia (11). Few cases of myasthenia gravis and Lambert-Eaton have been described (11), and a limited number of case reports have described a paraneoplastic progressive necrotizing myelopathy (16). Rarer forms of leukemia, such as hairy-cell leukemia and large granular lymphocytic leukemia, have respectively been associated with inflammatory myopathy and polyneuritis (11).

Peripheral nervous system involvement. Peripheral nervous system involvement is much rarer in leukemia. One of the most common peripheral nervous system complications is herpes zoster radiculopathies (16), presenting as a pain syndrome or further disseminating infection, causing encephalitis, meningitis, or even motor neuropathy (05). Infiltration of the peripheral nerves and roots by leukemic blasts is called neuroleukemiosis (13). Neuroleukemiosis usually presents as axonal polyradiculoneuropathy, ataxic neuropathy, or, rarely, axonal sensorimotor polyneuropathy with paresis, paresthesia, hypoesthesia, and pain with or without subcutaneous myeloid sarcoma (16; 13). It can affect any nerve of the brachial or lumbar plexus and can even affect multiple nerves at once (13). Chronic demyelinating neuropathy can also rarely be seen in patients with chronic lymphoid leukemia (16).

Iatrogenic complications of leukemias

Chemotherapy. The use of chemotherapeutic agents can result in various toxicities, from renal or hepatic failure to cerebellar dysfunction (03). Methotrexate can cause significant encephalopathy (05), headaches, seizures, cranial and peripheral neuropathy (25), and subacute myelopathy (16; 25), typically characterized by back pain, hypoesthesia, and paresis (16). Cytarabine can also cause encephalopathy, demyelinating neuropathy, and cerebellar dysfunction. Vinca alkaloids can cause peripheral axonal sensorimotor neuropathy, resulting in stock-glove paresthesia and weakness. It can also cause autonomic neuropathy (05). Another debilitating effect of chemotherapy is chemotherapy-related cognitive impairment, which can affect attention, memory, and executive functions (03). The complications of various chemotherapeutic agents are detailed in Table 1.

Radiotherapy. Early complications of radiotherapy include a form of the benign steroid-responsive demyelinating condition that usually presents as hypersomnolence (05; 01). Late complications include a mineralizing arteriopathy due to dystrophic calcifications presenting with focal seizures, ataxia, and behavioral problems (16) and a necrotizing leukoencephalopathy (05; 01). A radiation-induced asymptomatic vascular malformation may also occur, but they can also present as headaches and seizures (01). Radio-induced tumors, such as meningiomas and glioblastomas, also increase following cranial radiotherapy (08).

Graft-related complications. Graft-related complications are reported in lymphoma patients as well. Central nervous system graft-versus-host disease presents either as a cerebrovascular disease, a demyelinating disease, or an immune-mediated encephalitis involving another organ. It is usually associated with the taper of immunosuppressive therapy. Grafted patients also seemed to have a higher prevalence of metabolic syndrome and atherosclerosis, therefore predisposing them to strokes (10).

CAR-T cell therapy. Lastly, patients who have received CAR-T cell therapy, such as in acute lymphoid leukemia, may develop immune effector cell-associated neurotoxicity syndrome. This syndrome often develops in association with cytokine release syndrome (23). It occurs on average 5 days following CAR-T cell infusion (20). The clinical presentation varies but usually includes encephalopathy, altered consciousness, seizures, tremors, focal neurologic signs, dysphasia or aphasia, and headache (10; 23; 24). The earliest manifestations include anomia, dysgraphia, apraxia, and attention deficits (24). The most severe cases can present with fatal cerebral edema (23).

Table 1. Neurologic Side-Effects or Complications from Chemotherapeutic Agents

Prognosis and complications

Nervous system involvement at diagnosis or during relapse usually confers a poor prognosis (03). It is estimated that the median survival at the time of leptomeningeal metastasis discovery ranges from 3 to 6 months (18).

The presence of chloromas usually signifies an aggressive underlying systemic disease (16) and neuroleukemiosis is thought to be a predictor of systemic relapse with a poor prognosis (13).

Intracranial hemorrhage in patients with hematological malignancies has a poor survival rate due to the presence of associated thrombocytopenia, leukocytosis, hyperfibrinolysis, and disruption of the coagulation cascade, which favor the expansion of the hemorrhage. Survival at 7 days varies from 17% to 65%, and survival at 30 days varies from 33% to 56.6% (19).

The prognosis of central nervous system infections is based on clinical presentation, etiology, and effective treatment (06).

Clinical vignette

A 52-year-old woman was receiving chemotherapy for recurrent acute lymphoblastic leukemia. During chemotherapy, she experienced a seizure. A brain MRI was performed.

The T1-weighted images showed evidence of an area of hyperintense signal without contrast enhancement in the bilateral occipital lobes and possibly in the right thalamus. Hyperintense signal was evident in these areas on FLAIR images. Diffusion-weighted images revealed no obvious abnormality with the exception of a subtle, hyperintense signal along the cortex of the right occipital and temporal lobes and left occipital lobe. A lumbar puncture was performed and was negative. She was hypertensive and was treated with the belief that this may have represented posterior reversible encephalopathy syndrome. Seven days later, the patient underwent a repeat brain MRI because of a progressive decline in mental status and possible cortical blindness.

Again, there was no evidence of enhancement on pre- and postcontrast T1-weighted images, though there was evidence of increased hypointense signal surrounding the sulci. On FLAIR, there was increased signal in the right and left occipital lobes and left temporal lobe. This correlated with an area restricted to diffusion on diffusion-weighted images. Because of progressive neurologic decline, she underwent a repeat brain MRI approximately 4 days later.

Hypointensity was increased on T1-weighted images, and sulcal and meningeal enhancement was evident. There was evidence of worsening of the abnormalities previously noted on FLAIR and diffusion-weighted imaging and a new area of restricted diffusion in the left thalamus. A lumbar puncture was performed and was positive for leukemia.

This clinical vignette characterizes the presence of meningeal disease and resulting stroke. In this case, the patient was initially believed to have posterior reversible encephalopathy syndrome based on the initial MRI findings and the lack of any significant abnormality on FLAIR testing. However, subsequent evidence of ischemia and local enhancement indicated that this patient was experiencing progressive meningeal disease, resulting in infarction. She was treated with radiation therapy but did not recover any neurologic function.

Biological basis

Etiology and pathogenesis

Leptomeningeal metastasis disease mechanism consists of direct invasion of the surrounding structures, hematogenous spread, or entry through the fenestrated pores of the choroid plexus (18). It is believed that the overexpression of adhesion molecules in leukemia may enhance endothelial permeability and allow CNS penetration (18).

Hemorrhage can occur due to disseminated intravascular coagulation, disseminated infection (such as aspergillosis and mucormycosis), vascular leukemic cell infiltrate, or severe thrombocytopenia (platelets < 25 000/mm³) (05; 16; 14). Hemorrhage can also be a result of thrombosis secondary in the setting of chemotherapy-induced hyperfibrinogenemia (14) or hyperviscosity in blast crisis with extreme leucocytosis (leucocytes > 100 000) (16). Nonhemorrhagic strokes most often occur in the setting of venous sinus thrombosis due to either leukemic infiltration or L-asparaginase-induced hyperfibrinogenemia. Multiple micro-arterial infarcts should raise suspicion for disseminated intravascular coagulation or septic emboli (16).

Immune effector cell-associated neurotoxicity syndrome occurs after CAR-T cell therapy, but its pathophysiology is not clearly established (23). Systemic inflammation may allow for inflammatory cytokines to enter the CNS due to increased permeability of the blood-brain barrier from endothelial damage resulting in multifocal microhemorrhage and microglial inflammation (15; 23).

Epidemiology

CNS involvement is more commonly seen with acute leukemias, but each leukemia subtype has the potential to affect the nervous system (03; 07).

Acute myeloid leukemia has an incidence of 4.1 per 100,000 per year and is predominantly diagnosed in adults. Neurologic complications of acute myeloid leukemia are seen in 5% of diagnosed cases. Certain characteristics, such as younger age, trisomy 8, certain chromosomic and generic anomalies, or complex cytogenetics seem to confer a higher risk (03). Some studies also show that in hyperleukocytosis, male sex has been associated with an increased risk of CNS involvement (07). When CNS involvement occurs in these patients, it is most often due to vascular complications or myeloid sarcomas (03).

Acute lymphoid leukemia has an incidence of 1.9 cases per 100,000 and is the most common pediatric malignancy. Although mostly diagnosed in children, acute lymphoid leukemia in adults is associated with the highest rate of CNS involvement. In acute lymphoid leukemia, younger age, mature B or T cell phenotype, and Philadelphia chromosome positivity confer a higher risk (03). Some studies also suggest elevated lactate dehydrogenase, and certain cytogenetic anomalies may confer a higher risk (07). CNS involvement in these patients is mostly due to leptomeningeal metastasis (03).

Chronic lymphoid leukemia and myeloid leukemia have an incidence of 4.6 per 100,000 and 1.8 per 100,000, respectively. CNS involvement is much rarer in these two types (03).

Prevention

Leptomeningeal involvement most often occurs during acute lymphoid leukemia relapses (14). Intrathecal prophylaxis has reduced the rate of CNS involvement from 30% to 50% down to 5% to 10% (25). CNS prophylaxis using a regimen of intrathecal and systemic chemotherapy with or without craniospinal radiation is, therefore, recommended in all patients with acute lymphoid leukemia (14). No specific regimen has been defined, and no specific indications exist for other types of leukemias (14).

Intracerebral hemorrhage is a feared complication of acute myeloid leukemia (16). Due to the high risk of disseminated intravascular coagulation, patients with acute promyelocytic leukemia are increasingly being treated with arsenic trioxide and all-transretinoic acid to prevent intracerebral hemorrhage (16). All-transretinoic acid as induction therapy for promyelocytic leukemia has resulted in great response rates, but intracranial hemorrhage continues to be the most common cause of mortality among these patients (19). Hyperviscosity in blast crisis is another cause of intracerebral hemorrhage that can be prevented with oral hydroxyurea, leukapheresis, and whole-brain radiation (16).

Precautions, such as proper immunization, are recommended to prevent serious infectious complications (04). Antibiotic and antifungal prophylaxis can be considered in certain patients, such as those with persistent neutropenia, prolonged or high-dose corticotherapy, and undergoing active lymphodepletion or anti-cytokine therapy (15).

No specific prophylaxis is recommended to prevent immune effector cell-associated neurotoxicity syndrome, but it is thought that a lower CAR-T cell dose in acute lymphoid leukemia patients with greater than 25% abnormal B cells in their bone marrow might reduce the risk of severe immune effector cell-associated neurotoxicity syndrome (23). Studies are evaluating the use of anakinra as a prevention agent (15).

Differential diagnosis

Neurologic disease in leukemic patients can have a broad range of clinical presentations and can be from various etiologies. Certain types of leukemia might raise suspicion for more specific etiologies, such as in patients with acute myeloid leukemia, for whom vascular complications or myeloid sarcomas are more common, or in patients with acute lymphoid leukemia, for whom leptomeningeal metastases are more common (03). In all cases however, neoplastic, vascular, metabolic, infectious, immunological, and iatrogenic causes should be considered.

Special attention should be given to the differential diagnosis of leptomeningeal infiltration of leukemic cells. It should evoke a broad differential diagnosis, including cancerous causes, such as leptomeningeal metastasis or carcinomatosis, or noncancerous causes, such as inflammatory or infectious causes. Importantly, it should be differentiated from neurosarcoidosis, neuroborreliosis, and giant cell arteritis (18). Neurosarcoidosis can present with headaches, diplopia, and vertigo. If pulmonary involvement and elevated angiotensin-converting enzyme are found, sarcoidosis should be suspected rather than leptomeningeal infiltrate. Neuroborreliosis can present with meningitis, cranial nerve deficits, and radiculopathy. In the presence of erythema, rash, and positive Lyme antibody serological testing, borreliosis should be suspected. Giant cell arteritis should be suspected with ischemic optic neuropathy and should be confirmed by temporal artery biopsy.

Because peripheral nervous system involvement is rarer in leukemic patients, it should also raise a broad differential diagnosis, which includes neuropathy due to vasculitis, secondary effects of chemotherapy, demyelinating conditions such as Guillain-Barre syndrome (13), infections such as herpes zoster (16), and leukemic cell infiltration of the peripheral nerves (13).

Diagnostic workup

Leptomeningeal disease or leukemic meningitis diagnosis involves cerebrospinal fluid analysis with flow cytometry and cytology, contrast-enhanced brain magnetic resonance imaging, and sometimes a biopsy of the affected area (16; 14; 07; 18). Enhancement and nodular aberrancies in the cerebral convexities, basal cisterns, meninges, ventricular ependyma, cranial nerves, and cauda equina confer a probable diagnosis of leptomeningeal infiltration. Hydrocephalus can also be seen on MRI (18). It should be noted that MRI should preferably be obtained before lumbar puncture as lumbar punctures may cause dural enhancement (12). To improve the sensitivity of CSF analysis, it is also recommended to collect a minimum of 5 to 10 mL and increase the diagnostic capacity with a second sampling of CSF should the first one be negative (16; 12). CSF analysis often shows increased opening pressure, lymphocytic pleocytosis, hypoglycorrhachia, and hyperproteinorrachia (12; 18).

Extramedullary myeloid tumors are often seen on imaging. On MRI, they are usually isointense on T1 and hyperintense on T2 (13). They also typically enhance homogeneously with contrast (14).

In cerebrovascular complications of leukemia, diagnosis is made by appropriate clinical suspicion and findings on examination and with CT or MRI. Additional laboratory testing may assist in determining the etiology, such as the presence of thrombocytopenia or extreme leukocytosis (21).

Central nervous system infection diagnosis is made based on the appropriate clinical setting. Diagnosis is made by lumbar puncture, MRI or computed tomography scan, and brain biopsy if needed (06).

Peripheral nervous system involvement, although rare, should prompt investigation with electromyography to distinguish axonal from demyelinating neuropathies and imaging to confirm if a mass is present. Nerve biopsy with immunophenotyping may also be used (13).

Immune effector cell-associated neurotoxicity syndrome is a clinical diagnosis. It is graded on a clinical scale (Table 2). MRI, lumbar puncture, and EEG should be considered in all cases (20). Precautions should be taken in grades 3 and 4 to avoid complications due to intracranial hypertension during the lumbar puncture (15). Because this syndrome is strongly associated with severe cytokine release syndrome, these patients should undergo careful monitoring of serum inflammatory markers, blood count, fibrinogen, prothrombin time test, and international normalized ratio to screen for coagulopathy (15).

Table 2. Immune Effector Cell-Associated Neurotoxicity Syndrome

Management

Leptomeningeal infiltration treatment encompasses conventional leukemia treatments such as radiotherapy and chemotherapy. Radiation can be implemented in the form of whole-brain radiation therapy or traditional fractionated radiation. Studies have also explored craniospinal irradiation, which seems to be promising in hematological cancers with leptomeningeal infiltration (18). Chemotherapy can be administered systemically or intrathecally using agents like methotrexate or cytarabine (03; 07). Patients with systemic relapse may also undergo allogeneic bone marrow transplantation (13) or CAR-T (15; 23).

Chloromas and extramedullary myeloid tumors are often treated with external beam radiation therapy or chemotherapy (14). When optic neuropathy occurs, emergent radiotherapy is warranted to preserve vision (16).

As a general measure, corticosteroids can be used as an adjunct treatment for cases presenting with increased intracranial pressure or compressive myelopathy (03). Interventricular devices may be warranted in certain cases, such as hydrocephalus or increased intracerebral pressure (18). Decompressive laminectomy may also be warranted in certain compressive myelopathy cases (09).

Treatment of cerebrovascular complications is directed at symptomatic management and anti-aggregant or anticoagulant administration in the case of ischemic events (01). Most importantly, treatment revolves around reversing the underlying cause, such as correcting the coagulopathy or reducing the hyperleukocytosis using irradiation or chemotherapy (05).

Central nervous system infections should be treated accordingly with antibiotics, antivirals, or antiparasitic drugs. Treatment, such as lymphodepleting chemotherapy or CAR-T cell infusions, should be stopped until the infection is controlled (15).

Immune effector cell-associated neurotoxicity syndrome management depends on the severity grade and relies on corticosteroid therapy, symptomatic treatment, such as with antiseizure medications, or management of intracranial hypertension. For grade 1 syndromes, supportive therapy only is indicated (20). For grade 2 syndromes, dexamethasone with a rapid taper is recommended. For grades 3 and 4 syndromes, methylprednisone is recommended for at least 3 days or until symptoms improve. Seizure treatment usually consists of levetiracetam or benzodiazepines in the occurrence of status epilepticus. Tocilizumab is used to treat cytokine release syndrome but is not recommended for treating immune effector cell-associated neurotoxicity syndrome (15).

Outcomes

Outcomes are variable in function of the complication and the treatment administered for that specific complication.