Time point
Complication
Stem cell harvest
Intracranial hypotension due to entry into subarachnoid space during bone marrow aspiration
Worsening neurologic manifestations of underlying autoimmune syndrome, possibly related to G-CSF
Conditioning
Chemoradiation toxicity (see Table 18.2)
Infusion
Encephalopathy due to DMSO
Ischemic stroke, possibly related to DMSO or debris across a PFO
Transient global amnesia
Prior to engraftment and marrow reconstitution
Cerebrovascular accidents related to aspergillus or infectious emboli
CNS infections including Aspergillus and CMV
Coagulopathies resulting in SDH
Drug toxicities including tacrolimus and cyclosporine for GVHD causing PRES as well as antimicrobials causing seizures
Idiopathic hyperammonemia
Metabolic abnormalities
Neuromuscular complications including steroid myopathy, pressure related peroneal nerve palsies, GBS
Systemic organ failure
Chronic complications (after bone marrow reconstitution)
CNS infections including toxoplasmosis, herpes viruses, and nocardia
CNS manifestations of chronic GVHD including neuromuscular complications and CNS angiitis
Drug toxicities including tacrolimus and cyclosporine for GVHD
Encephalopathy
Encephalopathy is the most common neurologic complication encountered in HSCT patients [8]. In a retrospective study of 116 adult HSCT patients, a depressed level of consciousness was a principal reason for admission to intensive care units and conferred a poor prognosis [11]. Similarly, in a study of pediatric HSCT patients, encephalopathy was associated with a poor prognosis [12]. A wide array of neurotoxic insults can cause encephalopathy and/or seizures including chemotherapy, electrolyte imbalance, infections, acid–base disorders, increased intracranial pressure, antimicrobials, organ failure, immunosuppressants, and vitamin deficiencies. Encephalopathy related to chemotherapy, organ failure, antimicrobials, and posterior reversible leukoencephalopathy (PRES) are discussed in more detail below.
Although signs and symptoms may differ depending on the etiology and severity, the hallmark of encephalopathy is an altered mental status manifesting as personality changes, inattentiveness, lack of concentration, lethargy, cognitive dysfunction, and/or depressed consciousness. Other findings that may accompany an acute confusional state include autonomic changes (fever, tachycardia, diaphoresis) and abnormal movements (tremor, asterixis, myoclonus).
Diagnosis is based on clinical history and examination. Fever suggests an infectious etiology such as meningitis or sepsis. Common etiologies that can be easily evaluated through blood or urine studies include electrolyte abnormalities, endocrine disorders, nutritional deficiencies, acid–base disorders, and alcohol/drug intoxication. Patients with an unexplained encephalopathy or with focal neurologic deficits should undergo imaging. Brain MRI with contrast is generally recommended over a head CT unless a neurologic emergency such as hemorrhage or hydrocephalus is suspected or the patient is too unstable to tolerate an MRI. Lumbar puncture is indicated if there is concern for infection, an inflammatory disorder, or neoplastic meningitis. Electroencephalogram (EEG) is useful to evaluate for nonconvulsive status epiletpicus or subclinical seizures.
Prognosis depends on the underlying etiology. Encephalopathy without focal neurologic deficits is often reversible with conservative management and removal of the offending agent or cause. However, certain types of encephalopathy can occasionally result in permanent structural changes, brain damage, and even death.
Chemotherapy – Induced Encephalopathy
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.
Table 18.2
Neurologic complications associated with chemotherapeutic agents commonly used in preparative regimens for hematopoietic stem cell transplantation
Agent | Central nervous system | Peripheral nervous system |
---|---|---|
Busulfan | • Seizures are common but preventable by seizure prophylaxis with antiepileptics • Headaches | |
Carmustine (BCNU) | • Delayed onset encephalopathy (25–47 days after treatment) with lesions in basis pontis, corpus callosum, spinal cord, cerebral hemispheres reported with high-dose BCNU | |
Cyclophosphamide | • Impaired cognition reported in breast cancer patients receiving high-dose therapy • Transient dizziness after intravenous push doses | • Guillain–Barre syndrome reported |
Cytarabine (cytosine arabinoside, Ara-C, Cytosar) | CNS effects are not common with standard doses of cytarabine, but CNS toxicity may be associated with high-dose therapy: • Acute cerebellar syndrome characterized by dysarthria, dysmetria, and ataxia occurring 3–8 days after initiation of treatment • Acute encephalopathy (with or without cerebellar toxicity) • Seizures | • Motor and sensory neuropathies reported with high-dose therapy. |
Etoposide (VP-16) | • Rarely, cerebral edema with capillary leak syndrome • Acute dystonia • Neuropathy | • Neuropathy rarely reported with high-dose therapy |
Fludarabine | • CNS toxicity infrequent with conventional doses (≤125 mg/m2 per course of treatment) • High doses can cause delayed, severe encephalopathy characterized by cortical blindness, confusion, and coma • Progressive multifocal leukoencephalopathy reported • Headaches | • Paresthesias reported |
Melphalan | • Seizures and encephalopathy in patients with renal failure receiving high-dose melphalan |
Antimicrobial – Induced Encephalopathy
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.
Table 18.3
Drugs used in HSCT that can cause encephalopathy ± seizures
Antineoplastic agents |
Cytarabine (Ara-C) |
Busulfan |
Methotrexate |
BCNU |
Mechlorethamine |
Ifosfamide |
Cisplatin |
Immunosuppressive agents |
Cyclosporin |
Tacrolimus |
Muromonab-CD3 |
Antibiotics |
Aminoglycosides (gentamicin, streptomycin, amikacin, tobramycin, neomycin, kanamycin) |
Penicillin |
Cephalosporins (cefazolin, cefoselis, ceftazidime, cefoperazone, cefepime) |
Carbapenems (imipenem, meropenem, ertapenem) |
Vancomycin |
Isoniazid |
Metronidazole |
Trimethoprim/sulfamethoxazole (TMP-SMX) |
Antiviral agents |
Acyclovir |
Ganciclovir |
Foscarnet |
Antifungal agents |
Amphotericin B |
Encephalopathy Related to Organ Failure
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].
Calcineurin Inhibitor Neurotoxicity and Posterior Reversible Encephalopathy Syndrome
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.
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Fig. 18.1
PRES. A 69-year-old woman with a history of CNS lymphoma who presented 4 months after autologous HSCT with seizures, confusion, and acute renal failure from thrombotic thrombocytopenic purpura–hemolytic uremic syndrome. MRI shows increased T2 signal in the subcortical white matter throughout the brain consistent with PRES (a). Imaging findings resolved on repeat imaging 6 months later (b)
Seizures
The incidence of seizures (generalized, partial, or status epilepticus) in HSCT patients ranges from 2 to 15% depending on the clinical series [26]. Potential causes of seizures are numerous. CNS imaging may be normal or abnormal depending on the underlying etiology. CNS infections, strokes, hemorrhages, and leukoencephalopathies often produce imaging findings, whereas electrolyte disturbances and acid–base abnormalities are typically associated with normal CNS imaging.
Busulfan , an agent used in preparative regimens, is associated with generalized seizures in up to 10% in adults treated with this agent [27]. Seizures typically occur on the third or fourth day of busulfan administration. The mechanism of toxicity is unknown but may relate to busulfan kinetics in the cerebrospinal fluid [28]. Several agents have been used for seizure prophylaxis. Phenytoin can be easily loaded intravenously but does induce cytochrome P450 enzymes and increases clearance of oral busulfan. Benzodiazepines, such as clonazepam and lorazepam, do not induce cytochrome P450 enzymes but can be sedating. Although case series suggest that newer nonenzyme-inducing antiepileptics such as levetiracetam can be used for seizure prophylaxis with busulfan administration [29], this has not been well studied. With the use of seizure prophylaxis, the incidence of seizures in children receiving a busulfan-containing regimen is low (1.3%) [30].
CNS Infections
CNS Infections occur in 3–8% of patients after allogeneic, syngeneic, or autologous HSCT [31]. Even though they are less common than systemic infections, CNS infections are potentially fatal [32]. A discussion of atypical/opportunistic pathogens seen in the HSCT population is as follows.
The post-transplantation risk of infection is based on the status of immune recovery [33]. Prior to engraftment (0–30 days post-transplantation), patients are neutropenic with weakened mucosal barriers. The most common pathogens are bacteria, Candida, and herpes simplex virus (HSV) reactivation. If the neutropenic period is prolonged, the risk of Aspergillus increases. Patients undergoing autologous transplantation are primarily at risk during this phase. In the early post-engraftment period (30–100 days post-transplantation), allogeneic HSCT patients have deficient cellular immunity caused by acute GVHD and immunosuppressant medications. In this setting, fungal (Aspergillus and Pneumocystis jirovecii), cytomegalovirus (CMV), and gram-positive bacterial infections are seen. In the late post-engraftment period (>100 post-transplantation), autologous transplant patients recover immune function more rapidly and have a lower risk of opportunistic infections than allogeneic transplant patients. Because of cell-mediated and humoral immunity defects and impaired functioning of the reticuloendothelial system, allogeneic transplant patients with chronic GVHD and recipients of allogeneic transplant with matched unrelated, cord blood, or mismatched family-related donors are at risk of infections with CMV, VZV, EBV-related post-transplantation lymphoproliferative disease, community-acquired respiratory virus infection, and infections with encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae [34].
Aspergillus
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.
Candida
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].
Toxoplasma
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.
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