Chemotherapy can cause encephalopathy in a dose-dependent fashion. Onset can be acute or delayed. Table 18.2 provides a list of chemotherapies commonly used in HSCT associated with encephalopathy. Acute encephalopathy may present within days of receiving chemotherapy. Pyramidine analogues 5-FU (fluorouracil) and cytarabine (cytosine arabinoside, Ara-C) are associated with a dose-dependent acute encephalopathy that can resolve over several weeks. For example, high-dose cytarabine (HIDAC) may cause an acute cerebellar syndrome occurring after 3–8 days and (less commonly) acute onset generalized encephalopathy characterized by somnolence, disorientation, headache, and psychosis [13]. Delayed encephalopathy, occurring months after undergoing HSCT, can occur with purine analogues such as fludarabine, which are often used in preparative regimens [14, 15]. Imaging may demonstrate white matter changes similar to posterior reversible encephalopathy syndrome (discussed further below) or toxic leukoencephalopathy. In one series, the incidence of severe CNS toxicity associated with fludarabine conditioning was 2.4%, with cases presenting approximately 2 months after starting fludarabine and evolving over 1 month. Common presenting symptoms included confusion, generalized seizure, severe headache, and blurred vision.

Because of the increased risk of infection, especially prior to engraftment, many patients will require prophylaxis and/or treatment with antimicrobial agents. The Centers for Disease Control (CDC) recommends preventing cytomegalovirus (CMV) disease with prophylactic or preemptive gancyclovir, herpes simplex virus (HSV) disease with prophylactic acyclovir, candidiasis with fluconazole, and Pneumocystis jirovecii pneumonia (PJP) with trimethoprim–sulfamethoxazole. While an infection is more likely to be the underlying cause of encephalopathy, some antimicrobial agents may directly cause encephalopathy with or without seizures (Table 18.3) [16, 17]. Acyclovir can cause acute neurotoxicity in rare patients, particularly in older patients with renal dysfunction [18]. Symptoms may include confusion, tremor, hallucinations, coma, ataxia, and seizures. Cases of acyclovir-associated neurotoxicity have been reported even after standard oral doses. CSF is typically normal. Complete neurologic recovery after stopping acyclovir is observed in most cases.

Encephalopathy may rise in the setting of liver, lung, or kidney dysfunction. Hepatic veno-occlusive disease (VOD) , also known as sinusoidal obstruction syndrome (SOS) , is characterized by tender hepatomegaly, fluid retention, weight gain, and hyperbilirubinemia following high-dose myeloablative conditioning therapy [19]. VOD occurs in approximately 14% of patients undergoing HSCT (in modern series), typically within the first month after HSCT, and is associated with cyclophosphamide-based conditioning regimens either with total body irradiation or with busulfan [20]. CNS dysfunction may also be an early manifestation of multiple organ dysfunction syndromes (MODS) associated with severe forms of VOD. HSCT patients presenting with either pulmonary or CNS dysfunction are up to 18 times more likely to die from MODS than patients without pulmonary of CNS dysfunction [21]. Treatment is required for severe VOD and includes rigorous fluid management, pharmaceutics such as defibrotide, coagulolytic agents, or methylprednisolone, and liver transplantation [20].

Posterior reversible encephalopathy syndrome (PRES) in the HSCT population has been associated with chemotherapies such as fludarabine [22], hypertension, renal disease (Fig. 18.1a, b), fluid weight gain, hypomagnesemia, and calcineurin inhibitors such as cyclosporine and tacrolimus [23]. The calcineurin inhibitors are often used to prevent GVHD following allogeneic transplants. Most cases occur in the early post-transplantation period [24, 25] with the median time to onset of tacrolimus-associated PRES onset 61–85 days post-transplant [23]. Patients may present with headache, seizures, visual changes, and encephalopathy. MRI may demonstrate vasogenic cerebral edema, predominantly involving the white matter but can also involve the gray matter. PRES is often reversible with supportive care and removal of the offending agent. While stopping a calcineurin inhibitor may help reverse PRES, some patients may need to remain on a calcineurin inhibitor or switch to another immunosuppressant to prevent or manage GVHD.

Aspergillus fumigatus and Aspergillus flavum are the most common fungal CNS infections in HSCT patients [35]. The lungs are the most common site of involvement. Retrospective studies of CNS involvement in allogeneic SCT patients with invasive aspergillosis report rates as high as 40% [36] and as low as 3% [37]. Infection usually occurs following engraftment and typically occurs through inhalation of excessive Aspergillus spores in contaminated air. Following hematogenous dissemination, invasion of cerebral arteries eventually leads to occlusion by hyphal elements, infarction, and frequently secondary hemorrhagic conversion. These lesions may be localized in the subcortical areas of the cerebral hemispheres, the cerebellum [38], or the basal ganglia [39]. Rarely, patients may develop fungal vasculitis or mycotic aneurysms with resultant subarachnoid hemorrhage. Involvement of the meninges in the inflammatory process is distinctly uncommon.

Clinical and laboratory diagnosis of aspergillosis is difficult. Presenting symptoms are nonspecific and may include hemiparesis, unilateral cranial nerve palsies, intention tremor, seizures, headaches, or dysmetria [38, 39]. Fever and nuchal rigidity may be absent. There is a relative paucity of CSF abnormalities. Pleocytosis (usually a mix of polymorphonuclear and mononuclear cells) is usually less than 100/mm³; CSF protein content is only mildly elevated; and glucose level is normal or mildly decreased. CSF cultures for Aspergillus are rarely positive [39]. Serologic testing in immunocompromised patients yields inconclusive results. Several MRI patterns have been described: (a) nonenhancing lesions located in the basal ganglia and thalami representing small infarctions of the lenticulostriate and thalamoperforator arteries and (b) large cerebral artery infarctions with early intravascular and meningeal enhancement [39]. Most cases do not demonstrate contrast enhancement, but ring or nodular enhancement has been described in patients who survived [40].

Early diagnosis and treatment is important since mortality is almost 100% in most series with only a few case reports of HSCT patients surviving CNS aspergillosis [38–42]. Survival is usually only 2 days to 3 weeks after onset of neurologic symptoms [40]. Therefore, a positive test for galactomannan antigen or clinical signs and symptoms compatible with invasive aspergillosis should trigger further workup [43]. Patients with pulmonary aspergillosis and neurologic deficits should be treated as CNS aspergillosis. Diagnosis of CNS aspergillosis in a patient with characteristic neuroimaging may be established by direct detection of mold from the lungs, but occasionally biopsy of a cerebral lesion may be necessary to document CNS infection [41, 42].

Prevention of aspergillosis is very important and includes clear air supply by high-efficiency particulate air filters on the hospital ward, prevention of CMV infection (which seems to predispose to invasive aspergillosis), and preemptive antifungal therapy once colonization of airways with Aspergillus species is found. Treatment consists of intravenous amphotericin B or intravenous voriconazole [43]. Duration of treatment is unknown, but treatment should probably be continued for two to three months after the MRI scan has normalized.

Candidiasis is a common systemic infection in HSCT patients but rarely leads to CNS involvement [35]. The risk of candidal infection is high during the pre-engraftment period due to neutropenia and severe mucositis, which facilitates Candida colonization and subsequent invasion [44, 45]. In granulocytopenic HSCT patients, candidiasis is often disseminated, involving the liver, spleen, kidney, heart, gastrointestinal tract, lungs, skin, and brain [46]. Mortality rates with disseminated Candida may be as high as 90% and is almost always fatal when brain parenchyma is involved [32]. Candida can lead to meningitis, meningoencephalitis, vascular complications such as mycotic aneurysms, or cerebral abscesses. One retrospective series of 58 HSCT patients identified 19 patients with Candida abscesses (15 Candida albicans, 2 Candida tropicalis, 2 unknown species) [47]. Only one patient survived but ultimately died from congestive heart failure. Twelve of these 19 patients had positive blood cultures. Another study by Maschke and collaborators reported one patient with Candida encephalitis occurring 24 days after HSCT [31]. Brain MRI demonstrated multiple lesions in the basal ganglia and cerebellum that were hypointense on T1-weighted images, intermediate signal on T2-weighted images, and ring-enhancing after gadolinium administration. The patient died after 19 days from respiratory failure. All allogeneic recipients and select autologous recipients should receive fluconazole prophylaxis (400 mg per day) during neutropenia to prevent invasive disease [48]. In patients who develop candidiasis, early treatment with antifungal therapy such as amphotericin B and reversal of underlying host defects are critical to good outcomes [45].

Toxoplasmosis is caused by Toxoplasma gondii, an obligate intracellular protozoan parasite, and most often affects immunocompromised patients or pregnant women. Transmission may occur transplacentally, via ingestion of raw or undercooked meat containing T. gondii cysts, or by exposure to oocytes from cat feces. The incidence of toxoplasmosis following allogeneic stem cell transplantation varies between 0.1 and 6.0% depending on the series [49].

Clinical disease usually results from reactivation of latent disease during immunosuppression , particularly with concurrent GVHD. Rarely, it occurs as a primary infection acquired from the allograft into the seronegative recipient [50]. Following a mononucleosis-like prodromal stage, toxoplasmosis disseminates to the lungs, liver, bone marrow, and brain. Encephalitis is the most common CNS presentation. Symptoms and signs include headaches, low-grade fever, lethargy, focal seizures without or with secondary generalization, and focal neurologic deficits depending on the location of the lesions. Clinical onset usually occurs between the second and sixth months following transplant, but may occur as early as nine days. Most patients present within three months of transplant [51–55].

Definitive diagnosis may be difficult to achieve. Polymerase chain reaction (PCR) testing for T. gondii DNA is the main method of diagnosing toxoplasmosis in HSCT patients [56] although a negative blood PCR should not rule out disease [57]. Serological tests measuring IgG antibodies against T.gondii in blood are of limited value given the prevalence of latent infection. Increased IgM levels may indicate recent activation of infection, but false-positive and false-negative cases have been reported [50, 53, 58, 59]. Routine CSF parameters such as cell count and protein level are either normal or mildly elevated due to the immunosuppressed state of the patient. PCR assay in CSF may be a useful diagnostic tool in the early detection of T. gondii [60, 61]. However, even PCR assay in CSF may be negative, at least early in the infection [52]. Proof of CNS toxoplasmosis relies upon histologic demonstration of tachyzoites of T. gondii from brain biopsy [53, 54, 60].

Multiple lesions in the basal ganglia and at the corticomedullary junction are usually present [54] (Fig. 18.2a–d). Enhancement after gadolinium administration may or may not be present, depending on the ability of the patient’s immune system to muster a meaningful inflammatory response [54]. Unlike the HIV population, toxoplasmic lesions in the HSCT population may be initially hemorrhagic [62]. Differential diagnosis based on MRI characteristics would include other opportunistic infections such as aspergillosis, mucormycosis, as well as progressive multifocal leukoencephalopathy and post-transplant lymphoproliferative disorders/primary CNS lymphoma.