Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 34

Nervous system viral infections in immunocompromised hosts AMY A. PRUITT* Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

INTRODUCTION While other chapters in this volume discuss many viral pathogens covered in this chapter, here the focus is on specific populations with clinical immune deficiencies, organizing the material by likely central nervous system (CNS) viral infections in vulnerable groups and providing a diagnostic and therapeutic timeline of the spectrum of viral infections in these patients. Table 34.1 summarizes the patient conditions and viral infections discussed. These include: (1) patients treated for neoplastic conditions with hematopoietic stem cell transplantation (HCT); (2) solid-organ transplant (SOT) recipients; (3) cancer patients, primarily with hematologic malignancies, treated with immunosuppressive chemotherapy regimens whose degree of immunosuppression may nearly equal that of transplant recipients; (4) the growing population of patients with neurologic, rheumatologic, and autoimmune conditions modified with monoclonal antibodies and other targeted therapies. The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic and antiretroviral therapy complications are covered elsewhere in this volume. The incidence and scope of CNS viral infectious complications in immunocompromised hosts depends on the population studied and the local protocols for transplant conditioning, antirejection regimens, chemotherapy, and infection prophylaxis. Thus, reviews from different hospitals and countries give disparate pictures of the overall problem. What all investigators emphasize, however, is the difficulty of rapid diagnosis and effective treatment and the increased mortality associated with CNS infections (Denier et al., 2006; Fishman, 2007; Schmutzhard and Pfausler, 2008; Barba et al., 2009; Schmidt-Hieber et al., 2009). Ten general factors contribute to the difficulty of prompt and effective clinical diagnosis and therapy of

viral infections in immunocompromised hosts. These include: 1. The wide spectrum of potential pathogens that are normally of low virulence in normal hosts 2. The paucity of signs of inflammation in heavily immunosuppressed patients 3. Concurrent infections with more than one virus or other pathogen and the indirect effects of one virus promoting reactivation of another pathogen 4. Changing patterns of nosocomial infections and emerging viruses (Tyler, 2009a, b), almost 40% of which affect the nervous system, and outbreaks of different types of “old” viral infections (Pe´rezVe´lez et al., 2007); globalization of infection and lack of uniform instructions for travel among patients with transplants complicated by local infection trends (Kotton et al., 2005; Uslan et al., 2008), such as neurocysticercosis in South America (Teive et al., 2008), toxoplasmosis in France (Denier et al., 2006), and dengue fever (Ullah et al., 2007) 5. Trouble establishing diagnosis with extensive differential diagnosis possibilities, including recently recognized conditions such as posterior reversible encephalopathy syndrome (PRES), autoimmune vasculitis, drug adverse effects, secondary malignancy (lymphoma, melanoma), and recurrence of the original illness 6. Lack of effective monitoring, prophylaxis, and therapy for some of the relevant infections, notably JCV-induced progressive multifocal leukoencephalopathy (PML) 7. Variability of antirejection regimens and associated infection trends 8. Growing recognition of the consequences of treatment on vaccination efficacy 9. Questionable relationships between positive viral identification and pathogenesis of syndrome

*Correspondence to: Amy A. Pruitt, M.D., Associate Professor of Neurology, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104, USA. Tel: þ1-215-662-2796, Fax: þ1-215-349-5579, E-mail: [email protected]

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Table 34.1 Patient groups susceptible to central nervous system viral infections Malignancies not treated by transplantation

Hematopoietic cell transplantation

Solid-organ transplantation

Multiple sclerosis

Risk factors

Donor cells Calcineurin inhibitors Corticosteroids Mycophenolate

Donor organ Calcineurin inhibitors Corticosteroids Mycophenolate

Corticosteroids Rituximab Ameltuzumab

Natalizumab Rituximab Corticosteroids Fingolimod

Major immune deficiency mechanism Common viral pathogens

T lymphocyte

T lymphocyte

T and B lymphocyte

T lymphocyte

HHV6, 7 CMV HSV VZV EBV JCV

Rabies Arenavirus LCMV WNV VZV EBV JCV

VZV Enterovirus JCV

VZV JCV

Rheumatologic/ autoimmune disorders Corticosteroids Rituximab Etanercept Mycophenolate Infliximab Methotrexate Adalimumab Ameltuzumab Anakinra T and B lymphocyte VZV EBV JCV

Bold ¼ early ( 6 months of immunosuppression; standard type denotes viruses that can occur at any time after immunosuppressed state begins. HHV, human herpesvirus; CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella-zoster virus; EBV, Epstein–Barr virus; JCV, John Cunningham virus associated with progressive multifocal leukoencephalopathy; LCMV, lymphocytic choriomeningitis virus; WNV, West Nile virus.

(examples include the possibility of paraneoplastic encephalitic syndromes and the diagnostic pitfall produced by the phenomenon of human herpesvirus-6 (HHV-6) chromosomal integration) 10. Diverse consequences of immune reconstitution as immunosuppressive regimens are discontinued or reduced (example: withdrawal of natalizumab for multiple sclerosis)

DIAGNOSTIC APPROACH A general neurologically efficient approach to suspected viral infection of the nervous system in immunocompromised hosts includes consideration of three general themes: 1.

Who is the patient? The patient’s underlying illness and treatment delineate the specific type of immune deficit (T- or B-cell deficiency, gamma globulin deficiency, neutropenia, chronic corticosteroid use), though it must be admitted that there is no straightforward clinically useful way to quantify what has been called the net state of

2.

immunosuppression for any given individual or group (Fishman, 2007). What is the presenting neurologic syndrome? Some viruses are likely to produce focal deficits, including JCV/PML, varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), HHV-6, HHV-7, and Epstein–Barr virus (EBV), while others are more likely to produce a diffuse, non-focal meningoencephalitis (cytomegalovirus (CMV), adenoviruses, enteroviruses). Some viruses produce both types of syndrome (EBV, VZV). Several specific neurotropisms of diagnostic relevance include: (a) West Nile Virus (WNV), which involves preferentially the basal ganglia and anterior horn cells with paralytic syndromes and movement disorders, including stiff-person syndrome. (b) HSV-1, HHV-6, and some of the antibodymediated paraneoplastic syndromes such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis produce limbic symptoms with memory loss, confusion, and possible seizures or autonomic features. Indeed, the California Encephalitis Project identified several patients

NERVOUS SYSTEM VIRAL INFECTIONS IN IMMUNOCOMPROMISED HOSTS with NMDAR antibodies as the likely cause of their encephalitis. Compared with enteroviral, rabies, and HSV-1 encephalitides, NMDAR encephalitis patients were younger, more often non-Caucasian, and had lower white blood cell median cerebrospinal fluid (CSF) cell counts (Gable et al., 2009). Similarly, several autoimmune encephalitis patients have been recognized among patients previously classified as encephalitis of unknown origin (Pr€ uss et al., 2010). (c) Focal or multifocal ischemic lesions involving both large- and small-vessel territories suggest VZV as the infectious agent. (d) Brainstem lesions give clues to a special set of differential diagnostic possibilities, including infections such as Listeria monocytogenes and PML, though many non-infectious entities produce brainstem pathology, including PRES and the syndromes that are sometimes paraneoplastic, such as chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) (Pittock et al., 2010), anti-Ma2 diencephalic syndrome with vertical gaze paresis, and anti-Hu lowerbrainstem syndrome. Various non-infectious entities preferentially affect the brainstem, such as Wernicke’s encephalopathy, Whipple’s, and osmotic demyelination. Spinal cord tropisms include anterior horn cell destruction by WNV or VZV, whose pathology can be a Brown-Se´quard syndrome, as shown in Figure 34.1 (Hosaka et al., 2010). Other

3.

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distinctive spinal cord syndromes include HHV-7 with a transverse myelitis picture and CMV with a distinctive cauda equinitis. (e) Though not addressed in detail in this chapter, peripheral nervous system syndromes suggest a different set of diagnostic possibilities, including EBV-associated neurolymphomatosis, the graft-versus-host disease (GvHD)-associated pathology of polymyositis or myasthenic syndromes, and acquired inflammatory demyelinating polyneuropathies (chronic inflammatory demyelinating polyneuropathy or Guillain– Barre´ syndrome (GBS)) due to calcineurin inhibitor (tacrolimus/cyclosporine) toxicity. The differential diagnosis of focal lesions in all the above areas should include possible secondary malignancies, as many immunocompromising diseases and their therapies place the patient at risk for additional neoplasms, including primary brain tumors and secondary malignancies with a risk for CNS metastases, exemplified by the association between melanoma and kidney transplantation (Hollenbeak et al., 2005). What do the laboratory data suggest? CSF studies often provide the definitive diagnosis and are discussed in sections about specific organisms. However, they may be difficult to interpret at times as a heavily immunocompromised host may not mount a significant inflammatory response. Therefore, absolute cell counts and differentials must be interpreted in the context of host immune capacity.

Fig. 34.1. Sagittal (A) and axial (B) T2-weighted magnetic resonance images of patient with acute-onset high cervical BrownSe´quard syndrome. Cerebrospinal fluid had over 1000 polymorphonuclear leukocytes and polymerase chain reaction was positive for varicella-zoster virus.

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Differential diagnosis is greatly helped by magnetic resonance imaging (MRI), though it is important to note that the degree of contrast enhancement with gadolinium may be influenced by corticosteroid use and by the degree of immunosuppression and that there is no single definitive picture for many of the infections discussed below (Jagannathan et al., 2008). For example, though HHV-6 is said to involve hippocampal structures, one study found that additional extrahippocampal involvement in other limbic innervated areas was a more specific finding in HHV-6 patients (Noguchi et al., 2006; Provenzale et al., 2008). Similarly, Figure 34.2 shows the wide variety of enhancement patterns of PML depending on host immune defense and shows the distinctive feature of very rapid progression of a non-enhancing lesion in a severely immunocompromised patient. It is appropriate to discuss a frequent syndrome whose diagnosis is best suggested by MRI in this section. Previously referred to as the reversible posterior leukoencephalopathy syndrome and now more frequently called posterior reversible encephalopathy syndrome,

orPRES, this entity is frequently encountered in transplant patients on calcineurin inhibitors and in patients on a wide variety of chemotherapeutic agents. The cardinal features of PRES include subacute headache, confusion, and seizures, often with cortical visual loss (Feske, 2011). Many patients are hypertensive on presentation and the MRI in its most typical form usually poses little diagnostic difficulty, with vasogenic edema, usually symmetric primarily in the occipital and posterior lobes. However, as reviewed in a number of recent publications, there is growing recognition of the variety of radiographic and clinical presentations that can lead to diagnostic uncertainty (McKinney et al., 2007; Fugate et al., 2010). The clinical presentations can include status epilepticus, hemorrhagic lesions, and spinal cord involvement that easily could be confused with other entities. For example, Figure 34.3 shows a rather typical appearance of PRES in a patient after HCT, but the patient then developed fulminant multifocal lesions due to EBV posttransplant lymphoproliferative disorder (PTLD).

Fig. 34.2. Progressive multifocal leukoencepalopathy (PML) in hosts with different levels of immune competence. (A, B) Fluidattenuated inversion recovery (FLAIR) shows rapid 5-week progression of posterior fossa PML in a patient with long-standing chronic myelogenous leukemia who died within 2 months of symptom onset. (C) FLAIR and (D) T1-weighted with gadolinium images show a very different picture in a patient with low CD4 count as her only apparent immunocompromising condition. There is vivid contrast enhancement, suggestive of a vigorous host immune response. This patient survived.

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A

B

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C

Fig. 34.3. (A) This figure shows what appears to be a typical fluid-attenuated inversion recovery (FLAIR) image of posterior reversible encephalopathy syndrome in a patient shortly after hematopoietic stem cell transplantation for acute myelogenous leukemia. Seven weeks later, however, the patient developed fulminant multifocal abnormalities. (B) FLAIR abnormalities in splenium as well as juxtacortically. These enhance with gadolinium (C). Patient had Epstein–Barr virus-associated lymphoproliferative disorder.

Drugs commonly associated with PRES include the calcineurin inhibitors tacrolimus and cyclosporine, sirolimus, vascular endothelial growth factor inhibitors such as bevacizumab, and chemotherapeutic agents such as oxaliplatin and gemcitabine. The importance of recognizing this syndrome radiographically is underscored by data showing the impressive 7–9% incidence of PRES in allogeneic bone marrow transplant patients on cyclosporine with myeloablative conditioning regimens (Bartynski, 2007). There is a lower incidence in SOT than in HCT (Bartynski et al., 2008).

reduction in relapse rate is evident (Gooley et al., 2010). In diseases like diffuse large B-cell lymphoma treated with HCT, non-relapse mortality exceeds relapse mortality in survivors after 8 years and one of the most common causes of late death is infection (Hill et al., 2011). Peripheral blood cell source increases the risk of chronic GvHD and delays immune reconstitution. The range of diseases now treated with HCT has expanded greatly and includes many of concern to neurologists, including myasthenia gravis, inborn errors of metabolism, and multiple sclerosis (Copelan, 2006).

HEMATOPOIETIC CELL TRANSPLANTATION

TERMINOLOGY

In recent years the HCT population has changed significantly, with fewer patients undergoing allogeneic transplantation for chronic myelogenous leukemia since BCR-ABL tyrosine kinase inhibitors such as imatinib have become primary therapy. Concomitantly, increased numbers of acute myelogenous leukemia patients and those with myelodysplastic syndromes receive HCT. The demographic shift also to older patients and more unrelated donors is significant. Additional transplant changes include reduced-intensity conditioning regimens, improved supportive care, use of peripheral blood as the cell source, and combination of calcineurin inhibitor or mammalian target of rapamycin inhibitors with mycophenolate mofetil (MMF) for GvHD prophylaxis (Kersey, 2010). The resulting benefits are reduced overall mortality and mortality not preceded by relapse through better infection prophylaxis and decreased toxicity from myeloablative regimens, though no significant

HCT involves infusion of hematopoietic cells from a human leukocyte antigen (HLA)-matched donor (allogeneic) or from the patient (autologous). Conditioning prior to HCT may be with high- or reduced-intensity chemotherapy or radiotherapy. Chronic immunosuppression after allogeneic HCT is required to prevent rejection and GvHD. Sources of hematopoietic cells may be bone marrow or peripheral blood from a related or unrelated donor or matched cord blood. We will discuss largely allogeneic transplant recipients whose most serious neurologic complications include opportunistic infections, drug toxicity, coagulopathy, and tumor recurrence, and have been the subject of numerous excellent reviews (Denier et al., 2006; Siegal et al., 2007; Craddock, 2008; Barba et al., 2009; Saiz and Graus, 2010). The neurologic consultant needs to review the conditioning regimens to help weigh risks of specific infections. A major example is the increased risk of viral

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infections with alemtuzumab, a humanized monoclonal antibody against CD52 that depletes both T and B lymphocytes. It is used both as part of the initial induction therapy where its use does not greatly increase infectious risk and as part of treatment for rejection which, in the HCT population, has led to an increased rate of many infections, including cryptococcal meningitis, PML, tuberculous meningitis, toxoplasmosis, and VZV and CMV retinitis (Peleg et al., 2007; Cesaro et al., 2008; Safdar et al., 2010). In another study almost 9% of patients receiving reduced-intensity conditioning with alemtuzumab developed GBS or myelitis due to VZV or HSV-7 (Avivi et al., 2004). Median time to neurologic complication was 151 days with progressive peripheral radiculoneuropathy or myelitis associated with EBV, CMV, or HHV-7. Four patients died from respiratory failure due to peripheral weakness. For diagnostic purposes, it is useful to divide the period posttransplant into three timeframes. We will focus on the major viral infections of the period less than 1 month post-HCT, the “middle” period from 1 month to 6 months post-HCT and the late period thereafter.

COMPLICATIONS Early period (1 month to 6 months posttransplant) Throughout the period from the end of the first month to many years posttransplantation, VZV infection remains a significant risk. CMV prophylaxis with ganciclovir has moved the period of risk for VZV to a later time

NERVOUS SYSTEM VIRAL INFECTIONS IN IMMUNOCOMPROMISED HOSTS posttransplant. The type of conditioning regimen does not seem to affect the overall incidence of herpes zoster, which can have a cumulative incidence of 44% at 3 years in patients with reduced-intensity conditioning. Authors of this study (Su et al., 2011) suggest 1 year of antiviral prophylaxis. In a randomized placebo-controlled trial of valacyclovir, chosen for greater ease of administration over acyclovir, giving 1000 mg twice daily from 4 to 24 months post-HCT reduced the incidence of VZV (Klein et al., 2011). Dermatomal or disseminated skin lesions are the most common manifestation whose long-term morbidity is postherpetic neuralgia. Other less recognized VZV syndromes include vascular events with a combination of large- and small-vessel strokes, segmental pontine myelitis, outer retinal necrosis, and spinal cord infarction, often in a Brown-Se´quard pattern (Mathews et al., 2009) (Fig. 34.1). The diagnosis of VZV is not always straightforward. Not all patients have rash before stroke or other complication. Detection of anti-VZV immunoglobulin G (IgG) antibody in CSF is a more sensitive indicator of VZVrelated vasculopathy than is PCR (Nagel et al., 2008). VZV-related vasculopathy has been reported in many types of immunocompromised situations, including AIDS patients, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and

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telangiectasia) syndrome, leukemia and lymphoma, low CD4 counts and immunosuppressive treatment for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In the Nagel et al. (2008) series, 11/30 patients were immunocompromsed and fewer had rash compared with immunocompetent patients. When rash did occur, the average interval to stroke symptoms was 4.1 months (Nagel et al., 2008). CSF-positive VZV PCR, however, was seen in 54% of immunocompromised patients and in only 16% of immune-competent patients. All immunocompromised patients had positive anti-VZV IgG (Nagel et al., 2008). A negative angiogram does not exclude the diagnosis of VZV vasculopathy, as the disease may occur in small vessels. Normal brain imaging studies strongly suggest a diagnosis other than VZV vasculopathy. See Table 34.2 for treatment regimens: optimal treatment with acyclovir, corticosteroids, or both has not been determined. Other VZV syndromes include zoster sine herpete with dermatomal pain or meningoencephalitis. Involvement of cranial nerves IX, X, and XI or upper cervical roots with pain of variable duration may prove difficult to recognize as causally related to VZV. Chronic active VZV radiculopathy can occur and spread to adjacent dermatomes over a period of months. The VZV may reactivate from some dermatomes with rash and from others

Table 34.2 Treatment recommendations for viral infections in immunocompromised patients Organism

Treatment

Reference

Herpes simplex HHV-6 HHV-7 HHV-8 Varicella-zoster virus Acute retinal necrosis

Acyclovir 10–12 mg/kg q8h Ganciclovir 5 mg/kg q12h or foscarnet Foscarnet Cytotoxic therapy Acyclovir 10–12 mg/kg q8h or ganciclovir 5 mg/kg q12h Acyclovir 1012 mg/kg q8h, corticosteroids, aspirin, or valganciclovir Ganciclovir 5 mg/kg q12h and foscarnet Repair of retinal detachment Ganciclovir (5 mg//kg q12h) and/or foscarnet 60 mg/kg q8h Possible alternative: leflunomide

Styczynski et al. (2009) Razonable et al. (2009) Razonable et al. (2009) Razonable et al. (2009)

Progressive outer retinal necrosis Cytomegalovirus{ Epstein–Barr virus Meningoencephalitis PCNSL JC virus (PML)

Ganciclovir 5 mg/kg q12h Rituximab/methotrexate q14 days  8 cycles methotrexate 8 g/m2 Reduce immunosuppression Mefloquine Cidofovir* Mirtazapine Risperidone

Nagel and Gilden (2007) Nakamoto et al. (2004) Avery et al. (2010)

Kleinschmidt-Demasters et al. (2008) Nabors et al. (2009) Brickelmaier et al. (2009) DeRaedt et al. (2008), Weber et al. (2011) Verma et al. (2007) Fugate et al. (2010)

*May be more effective in non-acquired immunodeficiency syndrome (AIDS)-associated PML. { Depends on type of transplant (Kotton et al., 2010). HHV, human herpesvirus; PCNSL, primary central nervous system lymphoma; PML, progressive multifocal leukocencephalopathy.

692 A.A. PRUITT without rash. Thus, this ganglionitis may be the cause of purview it can be seen with cryptococcal meningitis, prolonged pain without rash in individuals with no histuberculous meningitis, or JCV, to be discussed next. tory of VZV (Wolf et al., 2012). A recent case report of VZV mimicking giant cell arteritis underscores the Late period (more than 6 months diversity of VZV manifestations and the need to pursue posttransplant) the diagnosis aggressively (Nagel et al., 2013). PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Antibodies to VZV in CSF are essential for diagnosis of The human polyoma disease-causing viruses, especially VZV-related neurologic syndromes (Nagel and Gilden, BK and JC, have been the subject of several recent excel2007). Diagnosis is made by anti-VZV IgG antibody in the CSF with reduced serum to CSF ratio of anti-VZV lent reviews (Aksamit, 2008; Boothpur and Brennan, IgG compared with albumin or total IgG. Alternative tests 2010; Focosi et al., 2010; Tan and Koralnik, 2010). About include measurement of anti-VZV IgM in serum or CSF 50–80% of humans are seropositive to BK virus and VZV PCR. One-third of patients may have no CSF pleocyJCV. Clinical disease in immunocompetent hosts is tosis and, since many may also have no rash, who should extremely rare, but the viruses remain latent in lymphoid be tested? Any immunocompromised patient with multitissue, neuronal tissue, and the kidneys, and may reactivate. Neurotropic disease is essentially due to JCV, while focal vasculopathy for the purposes of this discussion BK virus is nephrotropic, causing interstitial nephritis should undergo VZV evaluation. Anti-VZV IgG in the serum alone is not useful, as most adults have positive associated with high graft loss rates. Aksamit (2008) results (Gilden et al., 2009). See Table 34.2 for treatment reported a large series of 58 HIV-negative patients at recommendations (Styczynski et al., 2009). the Mayo Clinic through the year 2005. Of these, 55% had lymphoreticular malignancies, 15% had connective EPSTEIN–BARR VIRUS tissue disease, 5% had RA, 7% had SLE, and 9% had sarcoidosis, 7% were SOT, others included cirrhosis and EBV presents a host of diagnostic difficulties in HCT diabetes, and 7% had no clearcut immune deficit. In patients (Kutok and Wang, 2006). In the SOT transplant theHCT population rituximab and fludarabine have been population (see below), EBV is associated with clonal the best-substantiated associations. Cyclosporine, tacroexpansion near the grafted organ with rare CNS involvelimus, sirolimus, and MMF all likely are associated. Sevment. In the HCT group PTLD is a spectrum of disorders eral lines of evidence suggest that MMF confers a ranging from a mononucleosis-like picture to fulminant special risk of PML and PML has been reported in lymphoma with multiple contrast-enhancing mass patients who are receiving MMF as their sole therapy. lesions (Fig. 34.3). A case with fulminant EBV encephaThere are five syndromes (classic PML, PML-IRIS, litis and a tumor-like lesion responded to reduction in granule cell neuronopathy, encephalopathy, and meninimmunosuppression and ganciclovir (Khalil et al., gitis) (Tan and Koralnik, 2010). The disease may occur at 2008). Though EBV infection usually occurs within any time after HCT; it usually begins more than 1 month weeks of transplantation, as did that of the patient picafter transplant with a median of about 5 months, but the tured in Figure 34.3, Khalil’s case was 8 years after kidrisk is related to the duration of immunosuppression and ney and pancreas transplantation. A mainstay of therapy extends many years after HCT or SOT at a time when may be cytotoxic chemotherapy and rituximab. Under immunosuppression may appear quite minimal. Spinal development are approaches that involve pre-emptive cord and optic nerves are usually not involved, a distincmanagement of EBV reactivation with donor-derived tion that may be important in evaluating the possibility of EBV-specific T cells or repetitive treatment with rituxicalcineurin inhibitor toxicity. MRI can evolve very mab (Ahmad et al., 2009). quickly and may affect infratentorial structures frequently (Fig. 34.2) (Bag et al., 2010). In such cases, craIMMUNE RECONSITITUTION INFLAMMATORY SYNDROME nial nerve involvement is possible (Hodel et al., 2012). Immune reconsititution inflammatory syndrome (IRIS) Less commonly, JCV affects cerebellar granule cells denotes the dramatic and frequently dysfunctional or cortical pyramidal neurons (Koralnik et al., 2005; inflammatory response to recent infections after a rapid W€ utrich et al., 2009). Several cytotoxic agents increase rise in CD4þ count, usually in the AIDS population but the risk of PML. The degree of gadolinium enhancement increasingly in the posttransplant period or even several on MRI depends on the extent of immunosuppression months after discontinuation of immunosuppression. and complicates the differential, which can include There is elevation of CSF pressure, pleocytosis, and PTLD or lymphoma, fungal infection, or even PRES. enhancement of meninges or at times a tumefactive-type PML/IRIS is a recognized phenomenon (Fig. 34.4). Surbrain parenchymal appearance (Airas et al., 2009). The vival in PML correlates with detectable CD8 þ cytotoxic syndrome is important to recognize as in the neurologist’s T lymphocytes in blood (Marzocchetti et al., 2009). One-

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Fig. 34.4. Patient who had recently been started on antiretroviral therapy and developed seizures, left homonymous heminaopia, and hemineglect. Cerebrospinal fluid JC virus polymerase chain reaction was negative. He underwent biopsy for enhancing mass lesion involving right posterior hemisphere and splenium. He was found to have progressive multifocal leukocencephalopathy.

year survival is about the same for HIV þ/PML and HIV–/PML (52% and 58% respectively (Marzocchetti et al., 2009). Patients with cytotoxic T lymphocyte response have an increased likelihood of contrast enhancement of PML lesions and immune reconstitution (Fig. 34.2). Other causes of mass lesions in the CNS in transplant circumstances include the rare involvement of the brain with GvHD and multiple sclerosis-like inflammatory demyelinating syndromes (Shortt et al., 2006; Kamble et al., 2007; Matsuo et al., 2009).

SOLID-ORGAN TRANSPLANTATION Neurologic complicationsoccur inapproximately one-third ofSOT recipients, some being commonto all types of transplant and others specific to certain transplanted organs (Rosenfeld and Pruitt, 2006; Marco et al., 2009; Pruitt et al., 2013). Early problems during the first month include complications of the surgical procedure itself, hospitalacquired infections, and donor-acquired infections.

Early period (1 month after SOT) VARICELLA-ZOSTER VIRUS In one series, herpes zoster occurred in 12% of 209 liver transplant recipients, nearly one-third of whom went on to have postherpetic neuralgia. The use of MMF and azathioprine appeared to be risk factors (Herrero et al., 2004). Among lung and heart transplantation patients, the incidence of VZV infection is around 15%, with a median time to symptomatic infection of 9 months. The risk appears lower in liver transplant patients (8.6%) (Gourishankar et al., 2004). In another series of kidney transplant recipients the cumulative risk of VZV reactivation was 11.2%, with a constant rate of new cases between 6 months and 4 years. Risk factors were increasing age at transplantation and seronegative recipient status (Arness

et al., 2008). Among lung transplant patients, the cumulative probability of VZV infection was 20.2% at 5 years. Antiviral prophylaxis in this series (primarily for CMV) as in others was protective against VZV (Manuel et al., 2008).

HHV-6, HHV-7, AND HHV-8 The manifestations of HHV-6 and HHV-7 are discussed in the relevant section on HCT complications. HHV-8 is the etiologic agent of Kaposi’s sarcoma, a multicentric neoplasm of lymphatic endothelium-derived cells, usually presenting with mucocutaneous lesions with dissemination to viscera (Castleman’s primary effusion lymphoma). Geographic location of transplantation is important in overall risk as there is a greater seroprevalence in Mediterranean and Middle Eastern countries, with an even higher prevalence in Africa. CNS disease is rare. Median time to development of HHV-8-related symptoms is 30 months posttransplant with a range of 3–124 months (Razonable et al., 2009).

EBV PTLD, LYMPHOMA, AND OTHER SECONDARY NEOPLASMS

Organ transplant recipients have a three- to fourfold increased risk of malignant disease compared with the general population due to reduced immune surveillance and oncogenic viruses (Marco et al., 2009). Malignant clonal expansion of EBV-positive B cells is favored by an imbalance between EBV-infected B cells and EBVspecific T cells. The most common CNS neoplasms are lymphoma and glioma, though melanoma, with its high rate of CNS metastasis, is a clinically important entity as well. The risk of EBV-induced lymphoma is strongly influenced by the type of organ transplanted. In the first year, there is a 20-fold higher risk in kidney transplants and a 120-fold higher risk in heart transplant recipients than in the general population, but the risk is highest in small-bowel or heart–lung transplants. In pancreas transplantation recipients, PTLD has been reported to be unusually aggressive, with greater CNS involvement and a tendency toward association with recent CMV infection (Paraskevas et al., 2005). More kidney transplant lymphoma patients had CNS involvement than did heart transplant patients (Gottschalk et al., 2005).

Late events after SOT PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Although HIV patients account for over 82% of all PML cases, SOT are at risk for this often fatal infection by virtue of their immunosuppressive regimens with a variety of drugs, including azathioprine, cyclosporine, tacrolimus, and sirolimus. Furthermore, these patients remain

NERVOUS SYSTEM VIRAL INFECTIONS IN IMMUNOCOMPROMISED HOSTS at risk for opportunistic infections for many years, as exemplified by a case of PML developing 10 years post liver transplantation (Yehia et al., 2009). Recently recognized is the special risk conferred by conversion from cyclosporine or tacrolimus to MMF after two decades after kidney transplant (Manfro et al., 2009). Similarly, a flare of another polyomavirus (BK) in kidney transplant recipients seems to be associated with more effective immunosuppression provided by MMF (Mueller, 2008). A Food and Drug Administration (FDA) safety report in April 2008 noted the association between MMF, now used in more than 75% of renal transplants, and PML, with median of 37 months post renal transplantation to PML (Boren et al., 2008). While the incidence of PML is low in kidney transplant recipients, the trend toward increased cases in recent years during which there is increased utilization of MMF is notable (Neff et al., 2008). Withdrawal of MMF is associated with regression of PML lesions, though one pediatric patient also received cidofovir which, although it does not seem to help AIDS patients with PML and is potentially nephrotoxic, is used to treat transplant nephropathy caused by the BK polyomavirus (Weber et al., 2011). The evolving antirejection regimens in SOT will likely bring different ranges of neurologic complications. Malignancies are an increasing cause of mortality, overtaking cardiovascular diseases in some renal series. Calcineurin inhibitors are closely linked with posttransplant malignancy, but MMF and rapamycin are not. MMF increases the risk of CMV reactivation (Marce´n, 2009), as does low-dose rituximab induction therapy (Nishida et al., 2009; Kamar et al., 2010).

HEMATOLOGIC MALIGNANCIES TREATED WITHOUT TRANSPLANTATION The increasing intensity of immunosuppression, particularly of leukemias and lymphomas without HCT, has led to a range of viral complications similar to those seen in the transplant population. Support of chemotherapyinduced cytopenias with blood products carries the risk of transfusion-transmitted disease caused by many viruses, including hepatitis, HIV (in circumstances where screening is deficient), CMV, EBV, and HHV-8 (Shaz, 2009). Alemtuzumab has been discussed previously, but the therapy most closely associated with a change in the distribution of opportunistic infections arguably is rituximab, which therefore deserves specific discussion.

Rituximab Rituximab has been in clinical use for more than 12 years and its range of indications has expanded. The absolute infection risk due to rituximab is difficult to quantify

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because of concurrent use of other immunosuppressive or chemotherapeutic agents and effects of the underlying illness. The drug causes B-cell death by targeting the surface protein CD20. B-cell depletion is profound and lasts several months, though immunoglobulin levels remain normal in most patients (Gea-Banacloche, 2010). The best-established risks are hepatitis B reactivation and enteroviral meningitis (Quartier et al., 2003; Padate and Keidan, 2006; Cooper et al., 2009; Ganjoo et al., 2009; Kiani-Alikhan et al., 2009; Gea-Banacloche, 2010). Hepatitis B patients may need to be treated with lamivudine (Liang, 2009; Yeo et al., 2009). In an overview of infections during maintenance treatment of lymphoma it is noted that rituximab-treated patients have more episodes of infection, including JCV, enteroviruses, VZV, and CMV, than those without rituximiab (Aksoy et al., 2009). Many low-grade lymphoma patients are also T-cell-impaired due to powerful agents like fludarabine. The most important epidemiologic shift after widespread use of rituximab in non-transplanted hematologic malignancy patients is the increasing variety of settings of PML, often with negative CSF PCR for JCV (Mawhorter et al., 2005; Carson et al., 2009; Hanbali and Khaled, 2009; Pei et al., 2010). The addition of rituximab to CHOP chemotherapy (RCHOP) for lymphoma has been associated with PML after just a few cycles of treatment (Kranick et al., 2007). Rituximab increased complications of post-HCT complicated CMV in non-Hodgkin’s lymphoma patients (Lee et al., 2008). Finally, the effect of rituximab on the humoral response to vaccinations, particularly influenza, in patients with systemic disease that require frequent use of rituximab infusions should be borne in mind and revaccination advice should be sought from infectious disease consultants (Oren et al., 2008).

VZV IN NON-TRANSPLANT CANCER PATIENTS An emerging risk group for VZV is patients with multiple myeloma treated with bortezomib in whom the incidence of dermatomal zoster within the first few cycles is around 20% without acyclovir or valacyclovir prophylaxis (Chanan-Khan et al., 2008; Vickrey et al., 2009). The true incidence of VZV in this group is probably underestimated, as noted by reports of patients with meningoradiculitis or persistent radiculopathy without skin lesions (zoster sine herpete), in whom the diagnosis is made by anti-VZV IgG in CSF (Blumenthal et al., 2011; Kennedy, 2011).

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A.A. PRUITT cases of dermatomal VZV reactivation are recorded. Primary brain tumor With the latest figures, the PML risk can be quoted to Most CNS infectious issues in this patient population are patients as 1/100 000 in the first year, 127/100 000 in bacterial or fungal due to barrier disruption, but now an the second year, and 171/100 000 in the third year, with increasing number of patients on long-term temozoloan average risk of 1/1000 in exposed individuals mide live with chronically low CD4 counts and may be (Rudick et al., 2010). Because of the PML risk, natalizuat risk for opportunistic infections (Pruitt, 2010). One mab is available only through a restricted distribution viral syndrome is unique to this group: HSV encephalitis program, called the TOUCH prescribing program. can develop during radiation therapy for primary brain A study looking at discontinuation of the drug for a holtumor and may be easily missed as it may be ascribed iday described relapse in 28% with median time to to radiation-related early edema or seizures. HSV and relapse of 3 months. About a third of these were particsubsequent CMV have been described in a patient with ularly severe relapses, reminiscent of an IRIS phenomCNS lymphoma as well as systemic lymphoma on enon (West and Cree, 2010; Ortega et al., 2012). Very RCHOP. The authors review the literature that contains similar figures in a smaller number of patients are seven other cases of HSV encephalitis after radiation for reported from The Netherlands (Killestein et al., 2010). CNS malignancies, both primary and secondary (Suzuki Up to 40% of patients in other series, again at median et al., 2008). Mortality from HSV encephalitis in immuinterval of 3 months from end of therapy, experienced nocompromised hosts is six times higher than in immusignificant relapses (Wenning et al., 2009; Lenhard nocompetent patients (Tan et al., 2012). et al., 2010). These observations have led to concern about discontinuation of therapy (Killestein et al., Multiple sclerosis 2010; West and Cree, 2010). In one recent series 38% Increasingly, patients with multiple sclerosis are treated of patients experienced unusually widespread inflamwith intensive immunosuppressive regimens that involve matory activity on MRI exceeding that of their preboth B- and T-cell alterations. Not surprisingly, some of natalizumab therapy and CSF findings were suggestive these regimens have led to infectious complications not of IRIS (Miravalle et al., 2011). Other infections may previously seen in this population group. Of these, the occur with increased frequency in Tysabri-treated one that has occasioned the greatest concern is PML in patients, including herpes infections, Pneumocystis jiropatients on natalizumab (Tysabri), a humanized monovecii, and Mycobacterium avium intracellulare. clonal antiobdy against the very late activating For the clinician wary of relapse but concerned about antigen-4 that prevents lymphocyte trafficking into the opportunistic infection the question becomes one of how CSF. Initial reports led to the discontinuation of FDA’s to predict who is at risk. Blood and urine analyses are not 2004 approval by early 2005 (Kleinschmidt-DeMasters particularly helpful. Rudick and colleagues (2010) anaand Tyler, 2005; Langer-Gould et al., 2005). As the risk lyzed almost 13 000 blood and urine samples from of PML is related to duration of immunosuppression, almost 1400 patients. JCV was found in plasma in 4 cases have continued to be reported. As of December patients using a commercial test and 2 more using an 2012 over 250 cases of PML had been reported to the ultrasensitive assay (detecting 10 copies per mL comFDA and the European Medicines Agency teams pared to 50 copies per mL). Thus, about 0.5% of the (Biogen Idec, 2012). Data are available to physicians entire study group were JCV-positive. None of the online to assist with explanation of risk to patients (medpatients went on to develop PML and none of the 5 info.biogenidec.com/medinfo). Twenty percent of these patients in the studies who developed PML had detectMS patients have died and the survivors have varying able virus in the blood before developing disease degrees of disability. The lowest number of months on (Rudick et al., 2010). Urine also is unhelpful, but a newer therapy before PML developed is 12. There are approxenzyme-linked immunosorbent assay antibody test may imately 90 000 patients worldwide on the drug, of whom be helpful (Gorelik et al., 2010). These investigators used over 40 000 are in the USA. Prior immunosuppressive urine antibody test as a screen and then tested blood. Of use (azathioprine, mycophenolate, and cyclophosphathese patients, 53.6% were serum antibody-positive and mide most commonly) raises risk of PML by fourfold many urine-negative patients had positive antibody tests. (Linda et al., 2009). Since 2011, a JCV serologic test One hundred percent (17/17) of the patients who went on (JCV Stratify) has been available. Seropositivity for to develop PML tested positive 16–180 months before JCV in the blood increases the incidence of symptoms. Thus, patients without detectable levels of natalizumab-associated PML to as much as one per anti-JCV antibodies are at low risk, but more patients 100 patients after 2 years of treatment (Aksamit, are needed to confirm these findings. After discontinu2012). Other infections are less common. A fatal case ation of the drug, virus may persist (Ryschkewitsch of HSV encephalitis has been reported and numerous et al., 2010). In this study 11 of 13 MS patients had plasma

NERVOUS SYSTEM VIRAL INFECTIONS IN IMMUNOCOMPROMISED HOSTS 697 exchange to remove Tysabri. Even though all 13 develthe drug for Crohn’s disease (Van Assche et al., 2005). oped IRIS, 7 of the patients had persistent JCV DNA The FDA, European Medicines Agency, and World in CSF. Thus, neurologists need to follow patients longiHealth Organization have all issued warnings of PML tudinally because some of ongoing deficits after PML following ritxumab administration. Informed decision may be due to smoldering PML and not to MS. There making and patient informed consent for these theraare no known interventions that can adequately treat pies, ways to detect virus, and attempts to minimize PML (see Table 34.2 and discussion earlier in this chapimmunosuppression must be investigated and emphater, as well as in Chapter 17). Three to five sessions of sized in physician education (Tyler, 2010). Analyzing plasma exchange over 5–12 days accelerate Tysabri the role of specific drug toxicity is difficult in diseases clearance and are favored by many specialists. that themselves produce some immune suppression FDA approval of the first oral disease-modifying drug and that are often treated with multiple types of for multiple sclerosis, fingolimod (Gilenya) occurred in immune-altering drugs. For example, PML has been September 2010. Fingolimod is a sphingosine observed in RA and SLE without rituximab, and in pso1-phosphate receptor modulator. It inhibits egress of naı¨ve riasis patients treated with efalizumab alone or in comand central memory lymphocytes from lymph nodes, but bination with other immune-suppressive regimens does not impede effector memory T cells. In the premar(Korman et al., 2009). Sarcoidosis presenting as PML keting studies an increased risk of dermatomal VZV was has been reported and the authors note that it may be noted (Aktos et al., 2010). Serum VZV titers are obtained responsive to cidofovir, a drug that has not proved helpprior to first drug dose and antibody-negative patients are ful in the AIDS population, raising the question of vaccinated before fingolimod treatment (Novartis, 2010). whether less heavily immunosuppressed patients may Nevertheless, postmarketing experience includes case respond to therapies ineffective in AIDs patients reports of VZV and multiple cranial neuropathies as well (Boren et al., 2008; DeRaedt et al., 2008; Carson et al., as VZV encephalitis and vasculopathy (Gross et al., 2012; 2009). Other monoclonal antibodies such as adalimumb Ratchford et al., 2012). As more oral agents are approved also have been associated with PML and other viral clinicians will need to be alert to similar infectious risks infections, as has the fusion protein efalizumab and abathat perhaps may be specific to the individual agents. tacept and anakinra when used for RA (Smitten et al., 2007; Salliot et al., 2009; Schwab et al., 2009; Tan and Koralnik, 2010). Brentuximab, an antibody–drug conjuOPPORTUNISTIC VIRAL INFECTIONS IN gate linking the antimicrotubule agent monomethyl aurPATIENTS WITH OTHER istatin E to a CD30 monoclonal antibody, has also been RHEUMATOLOGIC/AUTOIMMUNE reported to produce PML as well as PML-IRIS in several DISORDERS patients (von Geldern et al., 2012). MMF also has been The group of diseases loosely grouped here includes associated with diffuse large B-cell EBV-associated lymrheumatologic conditions such as RA and SLE, and phoma in a patient with SLE (Tsang et al., 2010). PML immune thrombocytopenia, as well as diseases of immecan occur in patients with minimal immunosuppression diate relevance to neurologists, including myasthenia and the MRI appearance may differ considerably when gravis. The long-term uses of corticosteroids and the host response produces an exuberant inflammatory more recent introduction of rituximab account for much response (Gheuens et al., 2010) (Fig. 34.3). of this risk. In 2009, in a national estimate of hospitalInhibition of tumor necrosis factor (TNF-a) is an ized patients with PML, 82% were HIV-associated, effective RA treatment for patients resistant to conven8.4% had hematologic cancers and solid cancers tional disease-modifying drugs and this class of drug is (2.8%), and rheumatic diseases, including SLE, RA, used also for ankylosing spondylitis, psoriatic arthritis, and other connective tissue diseases, accounted for inflammatory bowel disease, uveitis, and as an alternaabout 1% (Calabrese and Molloy, 2009; Molloy and tive in steroid-refractory neurosarcoidosis. Strangfeld Calabrese, 2009). Carson and colleagues (2009) reported and colleagues (2009) explored associations between 57 cases of PML occurring after rituximab therapy for anti-TNF therapy and viral disease from the German biorheumatologic disorders and noted that these cases, logics registry. One-half of the cases of VZV they found gleaned from a number of cancer and academic centers, were linked with adalimumab or infliximab and another from the manufacturer, and from FDA reports, proba15% had had the fusion protein etanercept. The VZV rate bly represent an underestimate. Ninety percent of cases in this study was 11.1 per 1000, a risk comparable to were fatal (Carson et al., 2009). The major clinically relpatients over age 80. The risk increased when patients evant demographic point is that the populations at risk were switched to adalimumab or infliximab but not to are expanding (Major, 2010). One of the original three etanercept. One-fifth of infections were severe enough cases of PML associated with natalizumab received to require hospitalization. The increased risk for this

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population therefore was considerably less than that of the transplant patients (Strangfeld et al., 2009; Whitley and Gnann, 2009). Other drugs associated with an increased incidence of VZV when used in the RA population include cyclophosphamide, azathioprine, and prednisone, but not, at least in one survey, methotrexate (Wolfe et al., 2006). On the other hand, polyradiculopathy due to methotrexate-induced EBV-associated lymphoproliferative disorder reminds us that this drug also impairs immunity (Kumar et al., 2008). Live virus herpes zoster vaccine is contraindicated in patients on these drugs. Therefore, administration of the vaccine before anti-TNF-a therapy appears reasonable (Harpaz et al., 2008). As important immunomodulators, TNF-a inhibitors and other biologic therapies have been reported to cause the appearance of systemic autoimmune diseases (SLE, vasculitis, sarcoidosis, and organ-specific illnesses such as optic neuritis and multiple sclerosis) (Ramos-Casals et al., 2010). The unmasking of clinically latent MS is seen most frequently with etanercept. The MRI appearance generates a complicated differential diagnostic list of rapidly evolving, sometimes enhancing, multifocal lesions that can raise concern about PML, PTLD, and other infections. De novo appearance of demyelinating disease and both remission and exacerbation of preexisting MS have been reported in patients receiving this class of drugs, with etanercept the most frequently implicated (Davis et al., 2008; Gomez-Gallago et al., 2008; Pfueller et al., 2008). Diagnosis can be difficult, as is evident in the 21 reported cases of optic neuritis associated with TNF inhibition with adalimumab, many of which were receiving the drug for uveitis, iridocyclitis, and other primarily ocular conditions (Li et al., 2010). In this group of rheumatologic diseases, multiple sclerosis emerging in the context of immune dysregulation is reminiscent of cases described during immune reconstitution following HCT (Armstrong et al., 2010). The MRI differential diagnosis is further complicated by the substantial proportion of patients with PRES who have underlying autoimmune conditions and whose multifocal abnormalities on MRI may cause diagnostic confusion (Fugate et al., 2010).

OTHER SYSTEMIC DISEASES AND TREATMENTS: WHAT IS AN IMMUNOCOMPROMISED HOST? The clinician’s definition of an immunocompromised host needs to be quite broad. For example, can one consider patients treated with interferon for chronic hepatitis B and C immune-compromised? The interferons can induce leukopenia, conferring more of a risk for bacterial than for viral infections. However, viral illnesses are

not rare: a patient with longitudinally extensive enterovirus-associated transverse myelitis from C3 to conus had been on interferon-pegylated-a2a for 40 weeks for chronic HBV. His CD4 count was 53 and he had a brisk CSF pleocytosis of 480 cells. Entecavir was started along with steroids (Polidori et al., 2010). Sources of immune compromise can be hard to dissect out and epidemiologic patterns are evolving. For example, careful consideration of complementary medicines is necessary: a patient with chronic renal disease taking traditional Chinese medicine likely supplemented by steroids got the unusual virus, Chikungunya , an emerging Togavirus with new variant, causing epidemic on the island of La Re´union and in India, as well as Italy (Kee et al., 2010). This emerging virus can cause encephalomyelitis as well as GBS-like syndrome and acute flaccid paralysis (Tyler, 2009b). A second example involves the epidemiology of EBV in mildly immunocompromised patients. In general, primary CNS lymphomas (PCNSLs) in the elderly are not thought to be due to EBV and laboratory investigation for EBV is not routinely performed. However, a recent report suggests this stance may require modification: the striking feature of four cases of patients over age 65 who had been treated with a variety of immunosuppressive drugs for autoimmune disorders was multifocal necrotic brain lesions, proven on biopsy to be PCNSL. Withdrawing immunosuppressives led to some PCNSL regression. One patient treated successfully with rituximab and methotrexate died of systemic melanoma, also likely immunosuppression-related. Thus, a defensible suggestion would be to do PCNSL testing by immunohistochemistry or in situ hybridization in any patient on any immunosuppressive medication (Kleinschmidt-DeMasters et al., 2008). Again, Gheuens’ sobering series of 38 PML cases with minimal or occult immunosuppression reminds clinicians that a broad range of diseases not traditionally associated with marked immunosuppression confers infection risk. Her series included idiopathic CD4þ T-cell lymphocytopenia and untreated dermatomyositis, alcoholic cirrhosis, and renal failure, and 22 patients (57.9%) had no specific underlying diagnosis (Gheuens et al., 2010)!

GENERAL MANAGEMENT AND DISEASESPECIFIC TREATMENT GUIDELINES Table 34.2 summarizes disease-specific treatment recommendations. Guidelines for prevention of infectious complications among HCT recipients have been published in detail elsewhere (Tomblyn et al., 2009). In general, for critically ill immunocompromised patients with potential CNS infections, expeditious workup with brain MRI and CSF studies offers the best chance of expeditious diagnosis and treatment. It may be necessary to

NERVOUS SYSTEM VIRAL INFECTIONS IN IMMUNOCOMPROMISED HOSTS cover broadly for bacterial and fungal pathogens while virus-specific etiologies are confirmed. In the author’s opinion, EEG monitoring is underutilized in most centers. A study of continuous EEG monitoring confirmed that electrographic seizures or periodic epileptiform discharges were seen in almost half of patients. More than half of the electrographic seizures had no clinical correlate and both types of EEG abnormality were independently associated with poor outcome. Additional work would be needed to determine the efficacy of prophylactic or postsymptomatic treatment of the EEG findings to improve outcome (Carrera et al., 2008). Defining the causal relationship between a clinical syndrome and a potential pathogen is particularly complex in immunocompromised patients. Evidence that an organism is causal is strengthened by demonstrating a microbe-specific immune response in the CSF. Detailed guidelines for confirmation of encephalitis, etiology and definitions of confirmed, probable and possible encephalitis have been published (Granerod et al., 2010). The causative agent of encephalitis is not identified in up to 75% of cases in encephalitis worldwide and general supportive care as described in detail by the Infectious Diseases Society of America may be the only indicated therapy (Tunkel et al., 2008). Use of unbiased new molecular discovery technologies offers the possibility of identifying novel pathogens without confining the investigation to assays selective for known or expected agents (Palacios et al., 2008; Quan et al., 2010). While effective antiviral therapies as indicated for VZV, HSV, and CMV exist, the controversial treatment of PML requires special attention (see Chapter 17). The mainstay of treatment is restoration of immunocompetence as in the AIDS population by reduction of immunosuppressants and optimization of antiretroviral therapy. For multiple sclerosis patients, the risk of immune reconstitution following cessation of natalizumab appears considerable and recommendations for corticosteroid anti-inflammatory treatment are evolving (Aksamit, 2012). Cidofovir has been the subject of some positive reports in AIDS and RA patients. Combination therapy with cidofovir and cytarabine or interleukin-2 and cytarabine has had mixed results. Inhibition of JCV with nucleoside analogs and inhibitors of topoisomerase has been equivocal (Focosi et al., 2010). The topisomerase inhibitor topetecan is tolerated poorly due to bone marrow toxicity. Ganciclovir, ribavarin, acyclovir, and foscarnet and combinations of these have no effect. While JCV may infect human endothelial cells and glial cells independently of the serotonin 2A receptor (Chapagain et al., 2008), the rationale has led to trials to block at least these receptors with mirtazapine, risperidone, or ziprasidone (Focosi et al., 2010; Verma et al., 2007). On the basis of in vitro data from large-scale drug

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screens for activity against JCV, Biogen Idec and Elan Pharmaceuticals have conducted mefloquine trials (Brickelmaier et al., 2009). However, one recently reported trial of mefloquine for both HIV-negative and positive patients failed to demonstrate improvement in MRI or JC viral DNA load (Clifford et al., 2011).

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