INTRODUCTION

Hematopoietic cell transplantation (HCT) involves the intravenous infusion of hematopoietic progenitor cells from the patient (autologous) or a human leukocyte antigen-matched donor (allogeneic). Before transplantation, the recipient undergoes a conditioning regimen with high-dose chemotherapy or radiotherapy (or both) to destroy a defective bone marrow or residual cancer cells. After allogenic HCT chronic immunosuppression is needed to prevent graft rejection and graft-versus-host disease. The frequency and type of neurological complication depends on the type of HCT, the underlying disease, and the case ascertainment. In this review the neurological complications are presented according to the stage of HCT that they are most likely to occur: (1) conditioning: drug-related encephalopathies and seizures or complications secondary to medical procedures; (2) bone marrow depletion: metabolic and drug-related encephalopathies and seizures, septic cerebral infarctions, and hemorrhages; (3) chronic immunosuppression: infections by viruses and opportunistic organisms; and (4) late events: central nervous system relapses of the original disease, neurological complications of graft versus host disease,

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INTRODUCTION

and second neoplasms.

Hematopoietic cell transplantation has become the standard treatment of several oncological and non-malignant disorders and is under active evaluation for an increased number of diseases.[1] The rationale of the procedure is the intravenous infusion of hematopoietic progenitor cells to reestablish the marrow function destroyed by the chemotherapy given to eradicate neo-plastic cells. The hematopoietic progenitor cells can be obtained from a closely human leukocyte antigen (HLA)-matched sibling or unrelated donor (allogeneic transplantation) or obtained from the patient prior to the administration of the chemotherapy (autologous transplantation) (Table 1). The hematopoietic progenitor cells can be directly harvested from the bone marrow or collected from peripheral blood after the administration of hematopoietic growth factors. The term "hematopoietic cell transplantation" (HCT) is used as it includes both sources of hematopoietic progenitor cells.

Table 1. Comparison of Allogeneic and Autologous Bone Marrow Transplantation

Allogeneic HCT differs from autologous HCT in the need for chronic immunosuppression to prevent graft rejection and graft-versus-host disease (GVHD). It is also associated with much higher mortality rates that may reach 40% if the donor is not a sibling. The frequency and type of neurological complications in HCT varies depending on several factors. The most important are: the type of HCT, the underlying disease, and the case ascertainment.[2-12] Patients with allogeneic HCT and those with leukemia are more likely to have neurological complications. As expected, series based on autopsy studies[6,7,10] find more neurological abnormalities than those that review clinical cases.[5,8,9]

Recommended Checklist for the Management of Neurological Complications of HCT

1. There are several important issues that the neurologist has to bear in mind when evaluating a patient with HCT and a neurological problem:

2. Until proven otherwise, the neurological problem is related to the HCT or the underlying disease.

3. Do not focus only on the neurological problem. Obtain a detailed history of the primary disease, status of the disease when the HCT was done, the risk of central nervous system (CNS) relapse, the use of potentially neurotoxic drugs, and procedures done before or during the HCT.

4. The neurological complications vary depending on when they occur during the course of the HCT. This is particularly true for the infectious complications but also for drug-related neurotoxicities.

5. Unexpected systemic complications may favor the development of neurological dysfunction. Special attention should be given to systemic problems, procedures, and drugs taken by the patient in the days before the onset of the neurological problem.

6. The clinical and radiological presentation of the neurological complication may be atypical. In case of discordance (clinical presentation and magnetic resonance imaging [MRI] scan suggest ischemic stroke but the clinical setting suggests infection) favor the most probable cause for the neurological complication based on information obtained from numbers 1 to 4 above.

7. Patients may have more than one neurological problem at the same time or more than one cause that justifies the neurological syndrome.

This presentation will review the neurological complications of HCT according to when during HCT they are most likely to occur. This classification offers a practical clinical approach to these patients.

Neurological Complications During Hematopoietic Cell Harvesting and Conditioning Regimens

In this stage, neurological complications are usually caused by toxicity from the chemotherapy regimen used to destroy the bone marrow or from medical procedures such as insertion of jugular catheters and lumbar puncture (LP) (Table 2).[13,14] There are several antineoplastic drugs commonly used in the conditioning regimens of HCT that may cause neurological complications. Ifosfamide and busulfan may cause reversible encephalopathy, myoclonus, seizures, and hallucinations.[15,16] Patients on busulfan are routinely treated with antiepileptics to prevent seizures. Rarely, treatment with intrathecal methotrexate may be followed by pain and a myeloradicular syndrome that is usually reversible.[16] A delayed (1 to 2 months), reversible encephalopathy with MRI evidence of white matter disease was reported by Tahsildar and colleagues[17] but not described in other series. Lastly, transient global amnesia and cerebral infarction have rarely been described at the time of infusion of the cryopreserved bone marrow or peripheral blood progenitor cells.[18]

Table 2. Neurological Complications during Hematopoietic Progenitor Harvest and Conditioning Regimens

Neurological Complications During the Period of Bone Marrow Depletion

Reconstitution of the bone marrow takes at least 2 weeks after the transplantation. Recovery is usually faster in autologous than in allogeneic HCT. In a few patients (up to 10% in allogeneic transplantation from an unrelated donor), the engraftment is delayed or fails with the subsequent prolongation of the aplasia, increasing the risk of neurological complications. During the period of aplasia, patients are at risk of neurological complications from several sources: systemic organ failure, drug toxicity, infections, coagulation disorders, and, in allogeneic HCT, the effects of the sustained immunosuppression caused by the drugs used to prevent graft rejection and GVHD.

The most common reasons for neurological consultation in this period are confusion or delirium and

seizures. In both situations, and in addition to the general guidelines described above, it is crucial to clarify: (1) when the neurological symptoms started (the neurologist may be called when the patient has a seizure, but review of the chart including nursing comments and interviews of the relatives may prove that the patient had been encephalopathic for several days); (2) whether the patient is in nonconvulsive status epilepticus;[19] (3) whether the patient is at risk for a vitamin deficiency;[20] and (4) whether the neurological examination suggests focal brain damage. Because neurological examination is often not sensitive enough to rule out focal, structural brain damage, the majority of patients will require neuroimaging, preferably with MRI.

The subsequent approach to the patient will depend on the MRI findings. If the MRI is normal and there are no focal signs on neurological examination, the most probable cause of the encephalopathy or seizures are systemic metabolic abnormalities or drug toxicity. Even if there is a clear metabolic abnormality that justifies the encephalopathy, it is important to analyze all potentially neurotoxic drugs that the patient is taking and adjust levels accordingly.[19,21] In patients with seizures, the role of those antibiotics frequently associated with seizures or nonconvulsive status epilepticus, such as cefepime or imipenem, must be strongly considered and discontinued whenever possible.[19] In encephalopathic patients and allogeneic HCT with normal MRI, two other diagnoses should be considered: drug toxicity, related to cyclosporine or amphotericin-B and cytomegalovirus (CMV) infection. Both will be described in the next section. In some patients with encephalopathy, the cause will remain unclear after the initial evaluation and may be the first manifestation of impending multiple organ failure.[22]

The neurological complications that usually cause focal neurological syndromes during the period of bone marrow depletion are hemorrhages and, in allogeneic HCT recipients, infections and drug toxicity. The most common hemorrhagic complication is subdural hematoma (Fig. 1). This complication is strongly associated with an underlying myeloblastic leukemia and persistently low platelet counts. In one study, subdural hematomas were more frequent in autologous (8%) than in allogeneic (0.6%) HCT, but this has not been observed in other series.[8,23,24] In some patients, there is a clear association between the development of post-LP headache and the subdural hematoma.[24] In these cases, the MRI discloses other signs of intracranial hypotension. Recommended initial treatment is conservative, including maintenance of platelet count > 50 × 109/L and dexamethasone. Intraparenchymal brain hemorrhages are less frequent (< 2%) than subdural hematomas and are almost always observed in patients with myeloblastic leukemia and allogeneic HCT.[8,23,25]

Septic embolism from Aspergillus species is the most common infectious complication during this period

Figure 1. Subdural hematoma. MRI scan (coronal T1-weighted) showing subdural effusions on the left convexity with hemorrhage at different stages consistent with an acute and subacute evolution.

and accounts for 15% of the neurological complications in autopsy series.[10] Cerebral infarctions from fungal emboli are more common in allogeneic HCT but may occur in autologous HCT with prolonged periods of neutropenia and the prophylactic use of antibiotics that favor the occurrence of fungal infections. MRI discloses multiple non- or subtle contrast-enhancing lesions with preferential involvement of the basal ganglia, cerebral hemispheres, and corpus callosum (Fig. 2).[26] Identification of the organism is difficult[27] and treatment should be started on the basis of the clinical and MRI information. The prognosis, even in promptly treated patients, is dismal.[28,29]

Cyclosporine and less frequently tacrolimus are routinely given in allogeneic HCT for prophylaxis of GVHD. Both drugs cause similar neurotoxicity, particularly in the first months of treatment when doses are higher.[30] The most common neurological side effects are tremor (up to 30% of patients) and subjective paresthesias (11%) that usually require no treatment and subside when the dose is decreased. Isolated seizures are reported in up to 5% of patients and are sometimes associated with hypomagnesemia. Although more severe neurological complications are rare, two CNS syndromes have been recognized. The first is a posterior leukoencephalopathy syndrome associated with confusion, cortical blindness, visual hallucinations, seizures, and motor deficits.[31,32] The second is characterized by predominant motor features of parkinsonism, ataxia, or quadriparesis.[33] The MRI in the posterior leukoencephalopathy is usually abnormal with multiple lesions in the white matter, particularly in the occipital lobes, with variable cortical involvement.[34-36] In one study, the MRI pattern was associated with the type of conditioning regimen. Patients conditioned with total-body irradiation presented with isolated white matter lesions, whereas those conditioned with chemotherapy presented with a mixed pattern of cortical and white matter lesions. Occasional cortical enhancement (never with a gyral pattern) was only seen in the latter (Fig. 3).[34] However, fluid-attenuated inversion recovery imaging, which is more sensitive in detecting cortical involvement, was not done in that study.[35,36] The etiology of the cortical lesions is unclear, although it has been suggested that they represent vasogenic edema.[34-36] Diffusion-weighted imaging studies support this hypothesis.[35,36] Patients with seizures or mild degrees of encephalopathy or occipital lobe dysfunction may have a normal MRI.[37] Normal serum levels of cyclosporine or tacrolimus do not rule out drug-related neurotoxicity. Evidence of HCT-related thrombotic microangiopathy is frequently found in these patients.[34] The neurological dysfunction is almost always reversible but may not resolve until several weeks after the drug has been stopped. Valproic acid is recommended for treatment of seizures because it does not induce hepatic metabolism of cyclosporine or tacrolimus and can be given either orally or intravenously. Although cyclosporine and

Figure 2. Cerebral aspergillosis. Axial T1-weighted MRI scan reveals a cortico-subcortical nonenhancing hypointensity in the right frontal lobe.

tacrolimus have a similar neurotoxicity profile, patients who develop severe neurological complications from one drug can be switched to the other without reinduction of the neurological dysfunction. A similar syndrome with confusion, tremor, and parkinsonism may be caused by amphotericin-B.[38]

Neuromuscular complications during this stage are unusual. The most common are steroid myopathy or pressure-related peroneal nerve palsies. Patients with persistent, severe thrombocytopenia may have mono-neuropathies due to intraneural hemorrhage[8,39] or spinal subdural hematomas after lumbar puncture.[40] A few patients have developed acute neuropathies resembling Guillain-Barré syndrome, mostly in the setting of autologous HCT.[41]

Neurological Complications After Bone Marrow Reconstitution

Secondary to Chronic Immunosuppression

Patients with allogeneic HCT are at increased risk of infection by viruses and opportunistic organisms due to the immunosuppression necessary to prevent rejection of the graft and GVHD. The frequency of these infections is highest between the second and sixth months after HCT. In the first month, the frequency is lower and the differential diagnosis must include common bacterial infections, toxoplasmosis, and Aspergillus. After the sixth month, the risk of infections persists in those patients who need elevated doses of immunosuppressants.

Toxoplasma gondii is the most frequent parasitic CNS infection in transplant patients. The frequency of this infection ranges from 0% in centers with low seroprevalence (< 30%) to 1.4% in centers with intermediate or high (> 60%) seroprevalence.[42,43] Patients present with focal symptoms and varying degrees of encephalopathy. MRI shows multiple mass lesions, mainly involving the basal ganglia, that unlike those seen in AIDS patients may be non-contrast-enhancing and rarely hemorrhagic (Fig. 4).[44] Patients with CNS toxoplasmosis and non-contrast-enhancing MRI lesions are more leukopenic and received higher doses of corticosteroids. The infection usually occurs in the first month post-HCT compared with those patients with typical contrast-enhancing toxoplasma lesions.[44] Polymerase chain reaction techniques may be useful to identify T. gondii DNA in the cerebrospinal fluid (CSF), but the technique is currently not well standardized. Prophylaxis with trimethoprim/sulfamethoxazole probably decreases but does not completely eliminate the risk of CNS toxoplasmosis.

Figure 3. Cyclosporine toxicity. (A) Fluid-attenuated inversion recovery MRI scan showing high signal lesions in the frontal lobe (left) and posterior parietal regions bilaterally. (B) T1-weighted image corresponding to A shows superficial enhancement in the regions of signal abnormalities.

The viruses more likely to cause neurological complications are those of the herpes group and more rarely adenovirus.[45] Routine prophylaxis with acyclovir and control of possible CMV reactivation has greatly reduced the incidence of encephalitis due to herpes simplex virus type-I, varicella-zoster virus, and cytomegalovirus.[46-48] Recently, human herpesvirus-6 has been responsible for several posttransplant complications, including limbic encephalitis. These patients present with short-term memory loss, seizures, confusion, and behavioral changes. The MRI shows hyperintense T2 lesions in medial temporal lobes, especially in the hippocampus and amygdala (Fig. 5). Polymerase chain reaction is useful for the detection of herpesvirus-6 variant B in the CSF. It is important to recognize this condition because patients usually respond to ganciclovir or foscarnet.[49,50]

Other CNS infections are rare. Listeria monocytogenes, Mycobacterium tuberculosis, and Cryptococcus neoformans are unusual causes of meningitis whereas Nocardia asteroides, Mucorales, and sporadic cases of other fungi may cause brain abscesses.[51] Candida species had been reported as the second most frequent causative organism of brain abscess in early series of HCT but the frequency has dropped in

Figure 4. Cerebral toxoplasmosis. Axial T1-weighted MRI scan reveals multiple foci of high signal in the basal ganglia consistent with hemorrhage.

Figure 5. Herpesvirus-6 limbic encephalitis. Coronal T2-weighted MRI scan showing increased T2 signal of the head of both hippocampi.

more recent series, probably due to more effective prophylactic strategies.[52] Progressive multifocal leukoencephalopathy has been reported in a few patients after autologous or allogeneic HCT. All patients had profound immunosuppression for several months after HCT and before development of the infection.[53,54]

Neurological Complications Related to GVHD

GVHD occurs in 40 to 75% of patients with allogeneic HCT. The disease is mediated by the donor T cells directed against host antigens. The neurological complications involve the peripheral nervous system and appear several months after the transplantation when the patient develops chronic GVHD. The most frequent complication is polymyositis, which has a clinical presentation similar to that of idiopathic cases.[55] Less frequently, patients may develop myasthenia gravis or peripheral neuropathies with the clinical profile of an acute Guillain-Barré syndrome or a chronic idiopathic demyelinating polyneuropathy.[41,56,57]

CNS involvement in GVHD is controversial. Autopsy series have not demonstrated a consistent neuropathological pattern, and the belief that major histocompatibility complex antigens are not expressed in brain does not support damage by alloreactive T cells. However, a few clinical and pathological cases of possible CNS involvement have been reported. Patients presented with subacute encephalopathy in the setting of other systemic complications. Neuropathological studies revealed widespread T-cell infiltrates without conclusive evidence of viral infection.[58] Padovan and colleagues[59] described five patients with chronic GVHD that presented several years after HCT with clinical and MRI features compatible with cerebral vasculitis that was confirmed by pathology in one patient. Other indirect evidence that GVHD may affect the brain is the frequent observation of MRI abnormalities, mainly atrophy and white matter lesions, in long-term survivors of allogeneic HCT. The MRI changes were associated with the chronic GVHD and treatment (corticosteroids and cyclosporine), so that the independent role of each variable could not be determined.[60-62]

Neurological Complications Due to Cancer and its Treatment

HCT recipients may present with neurological complications due to the original disease or relapse, development of secondary neoplasms, or delayed neurotoxicity from treatment, usually methotrexate and whole-brain radiotherapy, given before or during transplantation. Tumor relapse is more frequent after autologous HCT and usually occurs after the third month. The risk factors for relapse and the possibility of nervous system infiltration by the original tumor have to be considered at the time of neurological evaluation.

Two types of neoplasms that involve the nervous system may arise after HCT. In the first year posttransplant, there are Epstein-Barr virus-induced lymphoproliferative disorders with frequent extranodular involvement, including the nervous system in 10% of the patients.[63]

The disorder almost always appears after allogenic HCT, and the intensity of T-cell depletion is the most important risk factor. Long-term survivors of HCT, however, are at increased risk for solid tumors, including malignant gliomas and primary neuroectodermal tumors. The risk of malignant brain tumors is 4.3 times higher in those patients who received an allogeneic HCT that included total body irradiation as part of the conditioning regimen. The risk tends to be highest for patients with acute leukemia compared with those patients with lymphoma.[64]

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