Cerebral leukostasis occurs at blast counts exceeding 400,000/mcl and results in diffuse cerebral edema and increased intracranial pressure. Most commonly afflicted are patients with AML. Higher counts are usually required in lymphoblastic leukemia (ALL) since cells are smaller and less adherent than myeloid blasts [67]. Clustered cells within capillaries produce localized ischemic events at the same time as leukemic nodules appear in the white matter surrounding vessels. Patients complain of symptoms indicative of microcirculatory collapse such as transient hearing and vision loss. Treatment consists of leukapheresis, rapid initiation of chemotherapy and low-dose whole brain radiation therapy [68].

Leukemia patients are at higher risk for cerebrovascular accidents from various mechanisms, including infective or non-bacterial thrombotic endocarditis, thrombocytopenia, dysfunctional platelets, coagulopathies and cerebral leukostasis [69, 70] (Fig. 30.2b). Chemotherapy regimens with L-asparaginase predispose to both venous and arterial thrombosis. Disseminated intravascular coagulopathy (DIC) is most common in acute promyelocytic (M3) or monocytic leukemia (M5) [71].

Paraneoplastic immune dysfunctions in the wider sense of the word are common among patients with CLL (10–25%) [72] and myelodysplastic syndrome (MDS) (10%) [73], in particular in MDS-derived chronic myelomonocytic leukemia (CMML) . Presumably, leukemic cells [74, 75] can serve directly as immature antigen presenting cells or interfere with regulatory T-cell function [76]. The majority of cases are hematological disorders such as hemolytic anemia or thrombocytopenia. Anecdotally, paraneoplastic syndromes affecting the nervous system have been reported, including: acute demyelinating encephalomyelitis (ADEM) preceding pediatric ALL [77] and an aggressive case of CLL (Ki-67 > 30%) [78]; fulminant myopathy over 1 week with transient bone pain and fever [79] leading to diagnosis of ALL; limbic encephalitis associated with voltage-gated potassium channel antibody prior to relapsed AML [80]; and chronic inflammatory demyelinating polyneuropathy heralding transformation of MDS-chronic anemia to CMML and AML [75]. Almost all cases responded to leukemia treatment suggesting that indeed there was a pathogenetic link between the neurologic illness and leukemia. However, given the rarity of these disorders, coincidental occurrence cannot be excluded.

Neurologic toxicities to chemotherapeutic agents are rather common in the setting of leukemia. As treatment involves various modalities and chemotherapy combinations, the effect of any single agent is difficult to ascertain.

Methotrexate neurotoxicity is dependent upon mode of administration, dose and association with other neurotoxins, especially ionizing radiation. Within hours, IT methotrexate may cause chemical meningitis. Within hours to days of immediate-to-high IV doses or IT injection, patients can develop delayed leukoencephalopathy with stroke-like presentation manifesting as seizures, severe headache or transient focal neurological symptoms (sensory disturbance, aphasia, weakness) (Fig. 30.3a). Complete recovery is the rule. Re-exposure to methotrexate is possible without recurrence of the neurological syndrome. However, the dose is frequently reduced, or leucovorin rescue is intensified [81]. A chronic leukoencephalopathy with MRI evidence of demyelination is seen in recipients of IT or HD-MTX administered after cranial irradiation.

Cytarabine induces cerebellar and spinal cord toxicity [82]. The gait instability and incoordination, within weeks of therapy, is more pronounced in recipients of high-dose cytarabine, elderly patients and those with impaired renal function. Therapy should be ceased.

L–asparaginase has been linked to thrombotic and hemorrhagic cerebrovascular complications in 1–2% of patients. Patients are at risk for arterial and venous thrombosis [83]. These complications are likely due to depletion of plasma proteins involved in coagulation and fibrinolysis. Fresh frozen plasma is provided as an emergency treatment but also as prophylaxis in patients who suffered a complication during a previous cycle. Dural sinus thrombosis (Fig. 30.3b) is treated with anticoagulation, often combined with fresh frozen plasma or antithrombin III concentrate.

Vincristine produces a cumulative dose-related disorder of sensory nerves in the face or extremities giving rise to tingling or burning paresthesia or jaw pain. Autonomic involvement leads to gastrointestinal dysmotility and abdominal cramping. Some improvement is noted with cessation of treatment and with neuropathic pain medications such as gabapentin or amitriptyline. Once weakness (e.g., foot drop) ensues, the drug has to be discontinued.

Fludarabine affects the peripheral and central nervous system at high doses. A highly morbid acute toxic leukoencephalopathy with cognitive dysfunction, decreased levels of consciousness and vision changes has been described [84, 85]. Risk factors include older age, decreased renal function, previous fludarabine-based transplant [85] and polymorphisms leading to high activity of the pro-drug-converting enzyme deoxycytidine (CdR) kinase in the brain [86].

All–trans retinoic acid treatment can be complicated by pseudotumor cerebri (Fig. 30.3c).

Increasing emphasis has been placed on substitution of “safe” chemotherapeutic agents for whole brain radiation for CNS prophylaxis and treatment of CNS disease in leukemia patients. Depending on total and single fraction dose, WBRT alone or combined with intrathecal or systemic methotrexate is associated with irreversible white matter changes and cognitive dysfunction [87, 88]. This dysfunction likely reflects the underlying calcific microangiopathy affecting the white matter [89, 90]. WBRT is also associated with aresorptive hydrocephalus poorly responsive to ventriculoperitoneal shunting.

Neuroendocrine difficulties are dependent on dose and age at the time of exposure. The growth hormone (GH) axis is most sensitive and can be the only axis affected following irradiation of less than 30 Gy [91]. Even at 18 Gy, a subtle insufficiency of the GH axis during the puberty growth spurt is observed [92]. Treatment is available with early hormone replacement therapy.

A seven-fold excess of all cancers and a 22-fold increase in the risk of central nervous system tumors have been observed among leukemia patients [93]. Radiation-induced tumors occur at a median latency of 6 years (range 0.9–15 years) [32]. High-grade glioma (median latency 9 years) and meningioma (median latency 19 years) arise with equal frequency (Fig. 30.4). The risk is dose dependent [94].

In general, B-lymphocyte dysfunction predisposes the host to encapsulated bacterial infections (e.g., Streptococcus, Hemophilus, Klebsiella). Rituximab, a CD-20 specific monoclonal antibody that is effective in treating CLL, is also known to reactivate viral infections such as hepatitis B, cytomegalovirus, herpes simplex virus, varicella zoster virus, West Nile virus and JC virus (Fig. 30.5a) [95]. Allogeneic stem cell transplantation requiring immunosuppressive therapy results in T-lymphocyte dysfunction, which predisposes to infections with fungi (Fig. 30.5b), viruses (e.g., human herpesvirus 6, JC virus), parasites (toxoplasmosis) or fastidious organisms (listeria, mycobacteria) [96]. Routine screening and prophylactic administration of acyclovir or ganciclovir for high-risk patients have essentially eliminated cytomegalovirus encephalitis [97]. Diagnosis of OI can be challenging, as clinical and radiographic presentations may be atypical. An example is cerebral toxoplasmosis, which may lack characteristic features such as rim-enhancement and vasogenic edema on MRI (Fig. 30.5c).

Among patients with AML, invasive fungal infection is a leading cause of mortality [98, 99]. Systemically, the most common organisms are mold (64% of cases; 90% aspergillus, <5% zygomycetes) followed by yeast (35% of cases; 90% candida, <5% cryptococcus) [99]. CNS aspergillosis or zygomycosis can present as abscesses or hemorrhagic strokes from angioinvasive fungal hyphae causing mycotic aneurysm, vasculitis and venous occlusion [100]. Candida and cryptococcus have a predilection for the meninges and present as meningitis or diffuse cerebral micro-abscesses [101]. For candida meningitis, the IDSA Practice guidelines [102] recommend intravenous amphotericin B plus flucytosine. However, treatment success with liposomal amphotericin for aspergillus [103] and zygomycetes [104] has been limited. Voriconazole is now considered first-line therapy for CNS aspergillosis [105]. Posaconazole has shown some promise against zygomycetes [106, 107].