Presentation and course
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• Presenting features of neurologic complications of leukemia are broad and vary according to the etiology and region affected. |
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• General presentation includes encephalopathy, headaches, and seizures, but patients may also present with more localizing features, such as cranial neuropathies or cerebellar dysfunction. |
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• Direct complications of leukemia include leptomeningeal metastasis, leukemic meningitis, extramedullary tumors, and CNS-Richter syndrome. |
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• Indirect complications of leukemia include cerebrovascular complications (hemorrhage, ischemia), posterior reversible encephalopathy syndrome, paraneoplastic syndromes, infections, and treatment-related complications. |
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
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Agent |
Manifestations |
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Blinatumomab |
Encephalopathy, seizures, tremor, dysphasia, dysarthria, loss of vibration sense, dizziness, confusion |
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Busulfan |
Seizures (dose-dependent risk) |
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Cisplatin |
Autonomic neuropathy, encephalopathy, cortical blindness, optic neuropathy ototoxicity, peripheral neuropathy |
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Cladribine |
Low dose: confusion, headache, neuropathy
High dose: dizziness, paraparesis, quadriparesis |
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Cyclophosphamide |
Blurred vision, dizziness, encephalopathy, seizures |
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Cytarabine |
Encephalopathy, cerebellar dysfunction, corneal toxicity, peripheral neuropathy, seizures, arachnoiditis |
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Fludarabine |
Headaches, confusion, paresthesias, posterior reversible encephalopathy syndrome, acute toxic leukoencephalopathy, leukoencephalopathy, seizures, coma |
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Ifosfamide |
Encephalopathy, extrapyramidal syndrome, peripheral neuropathy, seizures |
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Hydroxyurea |
Headaches, encephalopathy, seizures |
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Ibrutinib |
Stroke, progressive multifocal leukoencephalopathy |
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Imatinib |
Headaches, brain hemorrhage, confusion, papilledema |
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L-Asparaginase |
Hyperammonemia-related encephalopathy, seizures, cerebral hemorrhage, thrombosis, parenchymal edema |
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Methotrexate |
Transverse myelopathy, blurred vision, alteration in consciousness, seizures, leukoencephalopathy, aphasia, stroke-like episodes, ataxia, aseptic meningitis |
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Nelarabine |
Encephalopathy, leukoencephalopathy, CNS necrosis, posterior reversible encephalopathy syndrome, Guillain-Barre syndrome, cerebral edema, pyramidal tract syndrome, peripheral motor or sensory neuropathy, seizures, headaches, alterations of consciousness, cranial nerve palsies |
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Retinoic acid |
Pseudotumor cerebri, mononeuropathies |
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Rituximab |
Headaches, dizziness, myalgias, paresthesias |
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Thiotepa (intrathecal) |
Aseptic meningitis, myelopathy |
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Thiotepa (systemic) |
Encephalopathy |
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Vinblastine |
Ataxia, diplopia, peripheral neuropathy |
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Vincristine |
Ataxia, sensory, motor, or autonomic neuropathy, blurred vision, cortical blindness, seizures, diplopia, headache, jaw pain, optic atrophy, auditory disturbances, cranial neuropathy |
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Corticosteroids |
Blurred vision, insomnia, myopathy, neuropsychiatric symptoms, tremor |
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(06; 22; 02; 26; 10; 24)
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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.
