Handbook of Clinical Neurology, Vol. 121 (3rd series)Neurologic Aspects of Systemic Disease Part IIIJose Biller and Jose M. Ferro, Editors© 2014 Elsevier B.V. All rights reserved

Chapter 84

Neurologic complications in renal transplantation

KAVITHA POTLURI1*, DAVID HOLT2, AND SUSAN HOU1

1Department of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL, USA2Department of Surgery, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION

Kidney transplantation is the preferred choice of treat-ment for end-stage renal disease (ERSD) and in 2008,a total of 17 413 patients received a kidney transplant(USRDS, 2010). Neurologic complications followingkidney transplant are more common than in the generalpopulation and the incidence of neurologic alterations isreported to be around 10–21% (Senzolo et al., 2009).The percentage of kidney transplants done in olderpatients (kidney transplant rate among those 65 yearsof age and older increased by 49% from 2000 to 2008)and patients with diabetes mellitus is increasing, contrib-uting to increased susceptibility to neurologic problems.Moreover, all are treated with immunosuppressive med-ications which either have direct neurotoxicity orincrease the risk of central nervous system (CNS) infec-tions and tumors. Early diagnosis of neurologic prob-lems is important for prompt management as empirictreatment would require use of wide variety of poten-tially toxic drugs in patients who are already burdenedby multiple comorbidities.

The aim of this chapter is to describe the most impor-tant neurologic complications among kidney transplantrecipients and discuss diagnostic and treatment optionsfor effective management.

DRUG-RELATEDNEUROTOXICITY

Calcineurin inhibitors

Tacrolimus is themost commonly used immunosuppres-sivemedicationwith 87%of kidney transplant patients in2008 receiving it as their initial calcineurin inhibitor(CNI) (USRDS, 2010). Ciclosporin is still widely used,especially in patients with poorly controlled diabetesmellitus. Both of these drugs are associated with

*Correspondence to: Kavitha Potluri,M.D., Department ofMedicin

Medical Center, 2160 S. 1st Avenue, Maywood, Illinois 60153, US

neurotoxicity with a higher incidence reported withtacrolimus (Margreiter, 2002), particularly in children(Flynn et al., 2001). The cellular basis for the neurotox-icity associated with either ciclosporin or tacrolimushas not been conclusively identified. Since both drugsmediate their immunosuppressive effects via inhibitionof calcineurin, it is possible that some of the neurotoxiceffects, along with nephrotoxicity and hypertension,are also mediated via the same pathway (Bechstein,2000). Central and peripheral nervous systems areboth enriched with the intracellular binding proteinsfor ciclosporin and tacrolimus (immunophilins cyclophi-lin and FKBP-12, respectively) (Lyson et al., 1993). Thereis striking colocalization of FKBP-12 and calcineurin aswell as cyclophilin and calcineurin (Dawson et al., 1994),suggesting that, within the brain, the function of theimmunophilins and calcineurin are related.

Clinical symptoms range from mild tremors to para-plegia (Table 84.1) and are often similar to symptomscaused by other etiologies. A high degree of vigilanceis necessary for diagnosis of drug-related toxicity asserum drug levels may not correlate with symptoms. For-tunately, most of the neurologic side-effects are revers-ible by lowering the dose or complete discontinuation ofthe drug when possible (Hauben, 1996).

Posterior reversible encephalopathy syndrome(PRES), also known as reversible posterior leukoence-phalopathy syndrome (RPLS), is a rare but importantneurologic complication seen in kidney transplant recip-ients who often have all three risk factors for the syn-drome, namely, hypertension, renal disease, andimmunosuppressive therapies (Hinchey et al., 1996;Parvex et al., 2001). The reported incidence after solidorgan transplant (SOT) is around 0.5% (Besenskiet al., 2005) and appears to be similar among otherSOT subtypes, although there is some difference in

e, Division of Nephrology andHypertension, Loyola University

A. E-mail: kpotluri@lumc.edu

Table 84.1

Neurologic side-effects of calcineurin inhibitors

Tremors

Sleep disturbancesParesthesiasMood disturbancesLeukoencephalopathy

SeizuresMental status changes: confusion, disorientation, lethargy,irritability, hallucinations

Visual disturbances: hemianopsia, cortical blindness,blurred vision

Motor symptoms: paraplegia, quadriplegia, paresis, dystonia

Speech or language disturbances: akinetic mutism, aphasia,slurred speech

Other movement disorders: asterixis

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the clinical presentation. When compared to liver trans-plant recipients, kidney transplant recipients tend todevelop PRES later after transplantation (mean duration14–120 months post-transplant), are severely hyperten-sive, and have less brain edema (Bartynski et al.,2008). The exact pathophysiology is yet to be under-stood. It is a clinical radiographic syndrome charac-terized by headaches, altered consciousness, visualdisturbances, moderate to severe hypertension, and sei-zures with white mater edema in the posterior regions ofthe cerebral hemispheres, a finding which can also beseen in malignant hypertension. Neuroimaging is essen-tial for diagnosis. Computed tomography (CT) andmag-netic resonance imaging (MRI) typically demonstratefocal regions of symmetric, bilateral hemispheric edemawith parietal and occipital lobes being most commonlyaffected, followed by the frontal lobes, the inferiortemporal-occipital junction, and the cerebellum(Schwartz et al., 1995; Bartynski et al., 2001). Prompt rec-ognition of PRES is important as symptoms can bereversed by decreasing the drug dose or by discontinua-tion of the drug when possible, even though the syn-drome can present even after several months ofexposure to the drug and even when drug levels are ther-apeutic. Generally, clinical symptoms resolve after amean of 5–7 days (Lee et al., 2008; Roth and Febert,2010) with radiologic improvement lagging behind. Laterecognition, poor control of hypertension, prolonged sei-zures, or persistence in the use of the culprit drugs may,potentially, result in permanent neurologic deficit(Benziada-Boudour et al., 2010).

Steroids

Steroid psychosis, a relatively common occurrence intransplant recipients in the past, is rare in the current

era with low-dose or steroid-free regimens being thenorm. It can still be seen when acute kidney rejectionis treated with high-dose steroids.

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Other immunosuppressive medications

Neurotoxicity with Rapamune (sirolimus) is relativelylow but PRES associated with Rapamune has beenreported (Moskowitz et al., 2007; Qin et al., 2011).

OKT3 (muromonab-CD3), rarely used nowadays, hasbeen associated with aseptic meningitis (Martin et al.,1988) within 72 hours of its administration. Its use is con-traindicated in patients with underlying neurologic prob-lems such as seizures.

Nonimmunosuppressive medications

The neurologic side-effects of drugs other than immuno-suppressive medications are similar to those seen in thegeneral population with kidney disease and discussedelsewhere in this series. Only a few of the drugs thatare frequently used in transplant recipients are brieflydiscussed.

ACICLOVIR

Transplant recipients are at increased risk of herpeticinfections and treatment with aciclovir and valacicloviris common. Renal failure is one of the common side-effects of aciclovir due to precipitation of aciclovircrystals in the renal tubules (Mason and Nickols, 2008)and as a result, serum levels of the drug rise significantlyleading to neurologic side-effects ranging from con-fusion and hallucinations to coma (Cohen et al., 1984;Bataille et al., 1985). A high degree of vigilance is neces-sary to stop the drug when neurotoxicty is suspected.One study suggested measuring levels of serum CMMG(9-carboxymethoxymethylguanine, the main metabolite)when in doubt to confirm the diagnosis of aciclovir-associated neuropsychiatric symptoms (Hellden et al.,2003).

TRIMETHOPRIM-SULFAMETHOXAZOLE

Trimethoprim-sulfamethoxazole (TMP-SMZ, Co-trimoxazole, Bactrim®) is one of the most commoncauses of drug-induced aseptic meningitis and mostrenal transplant recipients are placed on Bactrim inthe first 12 months post-transplant for Pneumocystiscarinii pneumonia prophylaxis. The exact incidence ofaseptic meningitis in renal transplant recipients isunknown except for few published case reports(Muller et al., 2001).

NEUROLOGIC COMPLICATIONS I

b-LACTAM ANTIBIOTICS

Both penicillins and cephalosporins have a high toxictherapeutic ratio such that no hesitation should exist withregard to their use in patients with renal insufficiency,but when high doses are used as in treating meningitis,a decline in renal function combined with increased per-meability can lead to mental status changes rangingfrom confusion to seizures.

INFECTIOUS CAUSES

Infections of the central nervous system are estimated tooccur in 5–10% of patients after solid organ transplanta-tion. The presentation of CNS infection in transplantrecipients can be very different from that in normalpopulation as the anti-inflammatory effects of immuno-suppressive therapy may obscure signs of meningealinflammation associated with meningitis and changesin the level of consciousness may be subtle (Fishmanand Rubin, 1998). Also, mental status changes can occuras a result ofCNS infection or as a response to bacteremiawithoutmeningitis or encephalitis, or evendue toaurinarytract infection (UTI), especially in the elderly, and sobloodand urine cultures should be part of the workup of anytransplant recipient with mental status changes, irrespec-tive ofwhether the patient is febrile or not. CNS infectionsin renal transplant recipients are associated with signifi-cant mortality and morbidity and so understanding whenspecial methods are needed for detection and isolation ofpathogens is extremely important.

Bacterial infections remain the most common infec-tions, but unusual pathogens figure prominently in thedifferential diagnosis of CNS infections in transplantrecipients. In the early post-transplant period, transmis-sion of infection from the donor is a problem, particu-larly when the kidneys are purchased in countries witha thriving black market for organs (Salahudeen et al.,1990). Reactivation of a latent infection in the recipient,due to high-dose immunosuppression in the immediatepost transplant period, should be considered.

Bacterial infections

LISTERIA MENINGITIS

Transplant recipients can develop any type of bacterialmeningitis but 69% of listeria infection in nonpregnantadults occurs among immunocompromised patients(Schuchat et al., 1992). Most listeria infections in adultsare as a result from oral ingestion of contaminated food.Direct transmission from infected livestock is rare. Clin-ical presentation and CSF findings are similar to othercases of bacterial meningitis and Gram stain is generallynegative and when positive, the Gram-positive rods can

be confused with pneumococci or diptheroids. Treat-ment is with ampicillin or TMP-SMZ. It is not sensitiveto cephalosporins.

NOCARDIA

Nocardial infection has been reported in fewer than 5%ofrenal transplant recipients (Burke and Cunha, 2001) butCNS involvement in systemic nocardiosis is about 50%with brain abscess being the hallmark of CNSnocardiosis (Wilson et al., 1989; Beaman and Beaman,1994). Presenting symptoms are diverse and include fever,meningismus, seizures, and focal neurologic deficits.Meningitis is uncommon and can occur with or withoutan accompanying abscess. Diagnosis is facilitated by thecommon involvement of lung and skin. A presumptivediagnosis can be made by direct visualization of filamen-tous gram positive rods that are partially acid fast butsince the organism is slow growing in cultures, specimensshould be held for at least 3 weeks before being discarded.Although TMP-SMZ is the drug of choice, when there isCNS involvement two drug regimens are used with thesecond drug being third generation cephalosporins or imi-penem for 6–12months with frequent imaging as surgicalintervention may be needed if no response to medicaltreatment (Ozt€urk et al., 2006).

TUBERCULOSIS

Tuberculosis is the major source of morbidity and mor-tality worldwide in solid organ transplantation. Althoughinfrequently reported in the US, it is 20% more commonin transplant recipients when compared to the generalpopulation (Riska et al., 1987). This complication canbe minimized by treating transplant recipients with pos-itive purified protein derivative (PPD) with isoniazidbefore or at the time of transplant (Currie et al., 2010).CNS tuberculosis (TB) is uncommon and when it occurs,it is generally due to reactivation of dormant disease andpresents as meningitis, CNS tuberculomas, or arachnoi-ditis. The presentation of TB meningitis can vary froman acute to a very indolent course, and frequently occurswithout any active pulmonary lesions. Examination ofacid-fast bacilli (AFB) in the CSF remains the most rapidand effective means of reaching an early diagnosis andrepeated lumbar punctures (LPs) are frequently neededto achieve this. CSF analysis typically shows low glucose(80% of the cases), high protein, and mononuclear pleo-cytosis. Rapid detection can be aided by polymerasechain reaction (PCR) for Mycobacterium tuberculosisDNA but sensitivity is low when compared to AFB stain-ing or CSF cultures. Treatment requires a four drug reg-imen and in severe cases, corticosteroids are helpful(Thwaites et al., 2004). Rifampicin increases the metab-olism of ciclosporin and complicates drug dosing in

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transplant patients. One center attributed a high rateof graft loss to such interaction (El-Agroudy et al.,2003). Rifabutin could be used an alternative as itis a weaker inducer of cytochrome P450 compared torifampicin (Lopez-Montes et al., 2004).

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Parasites

TOXOPLASMOSIS

Toxoplasmosis is caused by a protozoan parasite, Toxo-plasma gondii, with immunocompromised and pregnantpatients being at the highest risk for severe infection, butthe widespread use of TMP-SMZ for Pneumocystiscarinii pneumonia has lowered the risk of toxoplasmosisin transplant recipients. Themode of transmission in thesepatients is mainly due to reactivation of latent disease(reactivation occurring preferentially in the CNS) but con-taminated food and transmission through an infecteddonor can also occur (Rogers et al., 2008). Imaging ofthe brain shows ring enhancing lesions but CSF findingsare nonspecific. Histopathology with demonstration ofToxoplasma cysts or tachyzoites or immunohistochemicalstaining for specific antigen remains the most reliablemethod of diagnosis but this is only used in patientswho do not respond to empiric treatment in the appropri-ate clinical setting, given the morbidity associated withbrain biopsy (Fig. 84.1). Pyrimethamine-sulfadiazine isthe standard therapy although studies in HIV patientshave shown that TMP-SMZ is as effective with a betterside-effect profile (Torre et al., 1998).

Fungi

ASPERGILLUS

Aspergillosis is by far the most common etiology ofbrain abscesses in organ transplant recipients and typ-ically occurs in the early post-transplant period, withy

Fig. 84.1. A Toxoplasma-positive reaction, stained by

immunofluroescence (IFA). (CDC Photo.)

the median onset of CNS aspergillosis in SOT reportedto be around 24 days post-transplant. Invasive aspergil-losis in renal transplant recipients has been reported in0.4–7% with high dose and prolonged duration of cor-ticosteroids, graft failure requiring dialysis, and potentimmunosuppressive therapy known to be the risk fac-tors. CNS involvement frequently presents with alteredmental status and is often rapidly progressive. Themost common location for brain abscess is the fronto-parietal region of the cerebral hemispheres but the cer-ebellum and brainstem may also be involved.Radiologically, the lesions are frequently multifocalwith a predilection to the gray and white matter junc-tion. Diagnosis is made by identifying branching sep-tate hyphae on sputum or CSF specimens or bypositive culture (Fig. 84.2). A combination of voricona-zole and caspofungin is generally recommended andalthough successfully treated cases have been rarelyreported, the mortality rate associated with CNS asper-gillosis remains 100%.

CRYPTOCOCCAL MENINGITIS

Cryptococcal meningitis is the most common subacutemeningitis seen in renal transplant recipients, especiallyin patients who are exposed to birds, and is universallyfatal without treatment. Like all other fungi, cryptococcienter the body through the respiratory tract but CNS isthe primary target (Vilchez et al., 2002). Presentingsymptoms may wax and wane over time and includeheadaches, fever, lethargy, personality changes, mem-ory loss, and coma. CSF analysis is needed for diagnosisand opening pressures are highwith increased number ofwhite cells, predominantly mononuclear, and minimalchange in protein and glucose content. Imaging of thebrain should be done before LP as 10% of patients havemass lesions. Encapsulated yeast forms are seen in 50%of the cases with Indian ink staining with cryptococcal

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Fig. 84.2. A microscopic view of Aspergillus fumigatus.

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antigen and cultures being positive in 90% of the cases.Treatment is with amphotericin B and flucytosine.Main-tenance therapy with oral fluconazole for 6–12months iscontinued in transplant patients to prevent relapse. Lon-ger duration of maintenance therapy may be warrantedin patients on high-dose immunosuppression.

Viral

HERPES VIRUS

The human herpes viruses include herpes simplex 1 and 2(HSV-1 and HSV-2), cytomegalovirus (CMV), Epstein–Barr virus (EBV), varicella zoster (VZV), human herpesvirus 6 and 8 (HHV-6 and HHV-8). Herpes virus infec-tions are extremely common in renal transplant recipi-ents but meningoencephalitis is a rare and potentiallylife-threatening complication mostly caused by HSV-1.

HSV-1

The frequency ofHSV-1 encephalitis is not increased sig-nificantly in renal transplant recipients when comparedto the general population (Gomez et al., 1997; Amenabaret al., 2006). Clinical symptoms include fever, change inlevel of consciousness, and focal neurologic deficits.CSF examination typically shows a lymphocytic pleocy-tosis, an increased number of erythrocytes, and elevatedprotein. Low glucose in CSF is uncommon and when pre-sent, may suggest an alternate diagnosis (Nahmias et al.,1982). Detection of the virus by PCR in CSF is thegold standard with sensitivity as high as 98%. The testcan be positive up to 1 month after the onset of clinicaldisease (Biovin, 2004). Temporal lobe involvement,often unilateral, would support the diagnosis but whenabsent, does not exclude the diagnosis. Electroencepha-logram (EEG) typically shows focal sharp and slowwave complexes and periodic lateralized epileptiformdischarges. Mortality and long-term disability are higheven after treatment with aciclovir and it is importantto remember that the drug itself can cause mental statuschanges, as mentioned above.

VZV

In addition to causing chickenpox and shingles, VZVinfection can lead to various CNS manifestations,including post-varicella cerebellitis, aseptic meningitis,and meningoencephalitis, which are less commonly seenin renal transplant recipients (Kashtan et al., 1997). Nev-ertheless, kidney transplant patients with cutaneous zos-ter manifestations are treated with higher doses ofaciclovir to prevent systemic dissemination (Ketteleret al., 2003). Immunosuppression should be reducedtemporarily.

NEUROLOGIC COMPLICATION

CMV

CMV infections are the most prevalent viral infection inrenal transplant patients (Brennan, 2001) but encephali-tis was rarely seen even in the preganciclovir era(Bamborschke et al., 1992).

HHV-6

The novel herpes virus HHV-6 has been proposed to bethe most neuroinvasive of the herpes viruses. Emergingdata from solid organ transplant recipients suggestmeningoencephalitis as a significant complication ofHHV-6 infection, although data on CNS manifestationsin renal transplant recipients is sparse and limited to casereports (Koukourgianni et al., 2009). Primary infectionwith HHV-6 after renal transplantation is extremelyrare. Demonstration of previous exposure to HHV-6before transplantation is common in both donors andrecipients (Yoshikawa et al., 1992), suggesting reactiva-tion after transplant as the primary cause of infection.One report of donor-derived HHV-6 infection to tworenal transplant recipients has been published so far sug-gesting transmission from donor is possible (Pilmoreet al., 2009). Clinical manifestations include headache,fever, speech disturbances, seizures, confusion, andcoma. HHV-6 viremia is seen in a majority of thepatients. CSF findings are nonspecific with pleocytosisgenerally lacking in 50% of the cases. Definitive diagno-sis is by detection of HHV-6 DNA by PCR in CSF whichis virtually never detectable in immunocompromisedpatients without CNS symptoms (Wang et al., 1999).Treatment is with ganciclovir or foscarnet in resistantcases. Mortality is reported to be as high as 58% inHHV-6 encephalitis.

WEST NILE VIRUS

The first two deaths fromWest Nile virus were describedin transplant recipients from a single infected donor(Iwamoto et al., 2003). Deceased donors are not rou-tinely tested for West Nile virus as testing has a highfalse-positive rate which would lead to failure to usegood organs and net loss of life (Kiberd and Forward,2004). This practice may change if more accurate testsfor West Nile virus are developed. Living donors whoreside in endemic areas can be questioned about expo-sure to mosquitoes in the immediate predonation periodif West Nile virus is occurring in the area and the donorcan be tested when suspicion is high since the disease isseasonal and the period of infectivity is short. Transplantrecipients present with symptoms similar to the generalpopulation but the risk of neuroinvasive disease is 40times higher (Kumar et al., 2004) after West Nile virusinfection, generally manifesting as encephalitis, flaccid

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paralysis, and movement disorders. CSF examinationshows atypical lymphocytes and hyperintense lesionsusually involving the white matter noted on MRI. Noproven effective treatment or prophylaxis exists andmost patients survive, but permanent sequelae arecommon.

JC VIRUS

JC polyomavirus is one of the viral infections that cancause neurologic symptoms in transplant recipients.The virus is ubiquitous in the normal population andcauses disease only in the setting of impaired cellularimmunity. Virulence depends on rearrangements in theregulator region of the virus. The most common mani-festation is infection of oligodendrocites causing demy-elination of white matter. Presenting symptoms dependon the location of the lesions and include limb weakness,sensory deficits, cranial nerve abnormalities, hemianop-sia, aphasia, gait disturbances, and impairment of cogni-tive function (Tan and Koralnik, 2010). The disease isusually progressive and fatal within 6 months. Theaffected areas appear as hypodense areas on CT andT1-weighted MRI images and hyperintensity on T2-weighted images. More definitive diagnosis is made bypositive PCR in the CSF or brain biopsy. The mainstayof treatment is reduction in immunosuppressive therapy.Cidofovir, cytarabine, mirtaziine and mefloquine havebeen used to treat JC virus infections without convincingevidence for efficacy. The prognosis of the disease is sodire that most recommend complete cessation of immu-nosuppressive therapy with the attendant risk of losingthe kidney. Some authors have suggested a connectionbetween JC virus infections and specific immunosup-pressive agents but it is more likely a result of totalimmunosuppression. The one specific drug group thatmay cause increased risk is monoclonal antibodies, ofwhich rituximab is sometimes used in renal transplants.

RABIES

Rabies is an acute encephalitis caused by a rhabdovirusand is uniformly fatal in unvaccinated hosts.Human infec-tion is extremely rare in the Western world, with no morethan six cases reported in any year in the past decade in theUS. In the US, the primary mode of transmission isthrough a bite from an infected animal, most commonlya bat. Transmission of rabies virus from the donor throughtransplantation of solid organs has been reported and allfour patients (including two kidney transplant recipients)had rapid neurologic deterioration and diedwithin 50 daysof transplant (Srinivasan et al., 2005). Such a scenariowould be extremely important to consider when patientsbuy kidneys from countrieswhere rabies ismore prevalentand where there is no implementation of universal vacci-nation of pet animals. Patients who insist on going abroad

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for kidney transplant should be advised to get rabies vac-cine prior to transplant.

NEOPLASTIC DISEASES

The most frequent malignancies of the brain in renaltransplant recipients are lymphomas and metastatictumors which are, for the most part, de novo malignan-cies from immunosuppression. There are several casereports of CNS tumor being transmitted from donorswho had primary CNS tumor with no recognized extra-cranial spread, but this is rare, as donors with primaryCNS tumors are not routinely used nowadays unless theyare completely benign in nature (Detry et al., 2000).

Lymphomas

The risk of malignant lymphoma in transplant recipientsis significantly higher than age-matched nontransplantindividuals; one study reported an 11.8-fold increasedrisk over a 10 year period (Opelz and Dohler, 2004).A predilection exists for extranodal disease with theCNS being the primary site in 24% of the cases(Snanoudj et al., 2003). B cell lymphomas are the mostcommon primary CNS tumors diagnosed in renal trans-plant recipients and EBV (Epstein–Barr virus) can beidentified in most tumors. Patients with negative EBVserology prior to the transplant are at increased riskfor lymphoma, particularly if they receive a kidney froman EBV-positive donor. As patients who are EBV sero-negative are rare, most patients with CNS lymphomasare seropositive before transplant.Most donors are sero-positive as well and requiring an EBV-negative donor fora seronegative recipient would often preclude trans-plant. Although ciclosporin and antithymocyte globulinhave been associated with increased frequencies of lym-phoma, the risk is more likely related to the total amountof immunosuppression rather than a specific drug. Themost common presentation for CNS lymphomasincludes focal neurologic deficits, seizures, or symp-toms of raised intracranial pressure. Diagnosis is usuallymade by the discovery of enhancing lesions on CT scanor MRI. Biopsy is needed for a definitive diagnosis asintracerebral abscess or toxoplasmosis can have similarradiologic appearance. Reduction in immunosuppres-sion alone is rarely sufficient and a combination of radi-ation and chemotherapy is often required for the bestoutcomes.

Other CNS tumors

The risk of Kaposi sarcoma is increased among trans-plant recipients but CNS involvement is rare. Theincreased risk of lymphoma and Kaposi sarcoma intransplant recipients has been explained on the basisof decreased immune surveillance resulting in cancers

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associated with identified viruses, either latent in therecipient or introduced from the donor. Glioblastomashave also been described in transplant recipients andgenerally appear years after the transplant; prognosisis poor. Cadaveric donors with glioblastomas confinedto the brain have been accepted in the past because oflow rates of extracranial spread. In rare cases of tumortransmission, it has been reported in the transplantedkidney and other sites outside the CNS.

CEREBROVASCULAR DISEASE

The incidence of atherosclerotic disease, either cardio-vascular or cerebrovascular, is higher in renal transplantrecipients than in the general population. The prevalenceof stroke is reported to be around 8% in renal transplantrecipients with diabetic nephropathy as the underlyingcause of end-stage kidney disease, age>40 years andperipheral vascular disease being the strongest predic-tors for stroke in this population (Oliveras et al.,2003). There are conflicting data regarding the risk ofstroke and intracranial hemorrhage in renal transplantrecipients with autosomal dominant polycystic kidneydisease (ADPKD). While a few reports suggested anincreased risk of stroke (Pirson et al., 1996) and intracra-nial bleed in this patient group (Wijdicks et al., 1999;Oliveras et al., 2003), others did not find any such asso-ciation and reported ADPKD renal transplant patients tobe more susceptible to ischemic than hemorrhagicstrokes (Adams et al., 1986; Watschinger et al., 2008).Regardless of the risk, as in the general population, renaltransplant recipients with ADPKD should have brainimaging done when there is a family history of intracra-nial hemorrhage. Mortality has been reported to be highin transplant patients with stroke, with one US studyattributing 8% of deaths in kidney transplant recipientsto stroke (Howard et al., 2002). Efforts to prevent strokeinclude aggressive control of hypertension, diabetes, andhyperlipidemia. There is no contraindication to the use oflow-dose aspirin, even in transplant recipients with renalinsufficiency.

PERIPHERALNEUROPATHY

Uremic polyneuropathy seen in patients with advancedrenal failure generally improves after transplantationbut may persist in patients who have been on dialysisfor years prior to the transplant.

The incidence of Guillain–Barre syndrome (GBS) insolid organ transplant is unknown although commonlyreported in bone marrow transplant patients. Publishedcases in such a setting suggest a higher incidence inmales and association with CMV infection at or beforethe onset of GBS (El-Sabrout et al., 2001).

Acute femoral neuropathy in the immediate post-transplant period may occur in 2% of renal transplant

NEUROLOGIC COMPLICATION

patients as a result of perioperative nerve compressionand ischemia. Clinical features include knee buckling,absent patellar reflex, and weak anterior thigh muscles,and generally develop within 1–2 days after surgery.Complete recovery of motor function may take up to4–9 months (Sharma et al., 2002).

Lumbosacral plexopathy characterized by pain in thehip with asymmetric weakness of the proximal legmuscles has been described after dual kidney transplan-tation (Dhillon and Sarac, 2002). The lumbosacralplexus with its rich anastomostic blood supply can bepredisposed to ischemic injury during dual kidney trans-plant as it involves larger and more time-consumingdissection.

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METABOLIC CAUSES

Despite the long list of esoteric neurologic problems seenamong transplant recipients, many of the most commonproblems, specifically the metabolic causes, are similarto those seen in the general population. Patients withrenal disease, with or without a renal transplant, havea more profound response to metabolic events thanthose without renal disease with the sole exception ofsevere hyperglycemia in dialysis patients, who are sparedvolume contraction from osmotic diuresis. Transplantrecipients are frequently monitored for such changesand so many of the metabolic problems do not pose adiagnostic dilemma.

Although uremia certainly causes neurologic symp-toms, the elevated blood urea nitrogen (BUN) and creat-inine levels are rarely the cause of lethargy and mentalstatus changes. Myoclonus, tremors, and asterixis arecommonly seen with high BUN and creatinine levels.There is no definite cut-off value for BUN as symptomsof uremia have appreciable interpatient variation anddepend on the rapidity of renal failure, the age of thepatient, and any underlying CNS disease (Bleck et al.,1993). Since metabolism of most drugs is affected inrenal failure, it might be difficult to distinguish uremiafrom effects induced by medications. Acute uremicencephalopathy generally reverses with dialysis (withan occasional lag period of 1–2 days) and other etiologiesneed to be pursued when this does not happen.

Hyperglycemia is common as many patients developpost-transplant diabetes mellitus, for which they are rou-tinely monitored. This is more common in the immediatepost-transplant period as a result of medication side-effects and restoration of normal kidney function whichshortens the half-life of insulin. Accordingly, diabeticrenal transplant recipients are instructed tomonitor theirblood sugar at home even if they did not require anymedicines while on dialysis.

Hypercalcemia can occur when hypertrophied para-thyroid glands continue to secrete the parathyroid

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hormone (PTH) even in the setting of near normalrenal function. PTH levels generally drop in fewweeks but some patients may have tertiaryhyperparathyroidism leading to symptomatic hypercal-cemia (anxiety, confusion, and in severe cases, stuporand coma as well).

Hypomagnesemia due to calcineurin inhibitors fre-quently coexists leading to muscle weakness, behavioralchanges, and seizures.

Profound muscle weakness leading to paralysis dueto hypo- or hyperkalemia can occur, although rarely,because these conditions are generally detected andtreated before potassium levels are so profoundlyabnormal.

Hyponatremia and hypernatremia are rare with nor-mal renal function but should always be considered inpatients with mental status changes, especially in theelderly. In either case, restoring normal serum sodiumlevels at no more change than 10–12 mEq per day shouldbe aimed for, to prevent central pontinemyelinolysis andcerebral edema respectively.

Renal transplant recipients are more prone to devel-oping rhabdomyolysis leading to profound muscleweakness from the combination of calcineurin inhibitorsand statins. The muscle weakness may take longer toresolve than the renal function abnormalities.

Although liver failure can occur when hepatotoxicdrugs are used in patients with underlying liver disease,it rarely occurs, as liver function tests are closely moni-tored in transplant patients.

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Table 84.2

Diagnostic findings in central nervous system disorders in ren

Cerebrospinal fluid

Tuberculosis Glucose: <45 mg/dL (Protein: 100–500 mg/dLymphocytes (PMN e

PCR: 30–60%AFB smears:1 smear<40%þve

4 smears>80%þvCrypotococcus Glucose: mild abnorm

Protein: mild abnorma

Mononuclear cells: 50Cryptococcal Ag: 90%Culture: 90–100%

Toxoplasmosis Protein elevated

Mononuclear pleocytoListeria Protein elevated

Glucose: low in 50%

PMN predominant

DIAGNOSTIC APPROACH

A detailed history including recent and remote travel aswell as exposure to mosquitoes, pets, and bird androdent droppings should be obtained as atypical infec-tions are common in transplant patients. Historyshould also include a careful review of occupationalhazards, gardening, agricultural and home remodelingprojects. Medication history should be reviewed forany drugs known to cause neurologic symptoms withthe recognition that sedatives and narcotics have anexaggerated and prolonged response in patientswith kidney disease despite being metabolized by theliver.

Pretransplant workup generally includes serology forEBV, CMV, HSV, varicella, RPR, and PPD status.Donor serologies for EBV and CMV are generally avail-able if evaluated at US transplant centers. Clinical fea-tures might be similar in many different illnesses andneurologic examination alone may not clarify the etiol-ogy. A careful search for evidence of systemic or focaldisease outside the CNS may be helpful for diagnosis orat least providing tissue for diagnosis.

CSF examination is essential in determining thenature of infectious processes but may be nonspecificin immunocompromised patients (Table 84.2). CT orMRI of the head is indicated in most patientsunless there is a clear-cut metabolic abnormality. Radio-logic studies will also be needed in asymptomaticpatients with systemic illnesses that have a high propen-sity for CNS involvement as management or duration

al transplant recipients

Radiologic studies

80%)Larly)

e

Tuberculomas 5–10%HydrocephalusCerebral infarcts

Basilar meningeal enhancement

alitylity

–75%

Mass lesion 10%

sis

Ring enhancing lesions

Table 84.2

Continued

Cerebrospinal fluid Radiologic studies

West Nile virus Protein 60–140 mg/dLGlucose: normalWBC: mixed differential

Hyperintense lesions in white matter

Herpes simplex virus encephalitis Protein elevated

Glucose: normalLymphocytic pleocytosisPCR>95%þve

Temporal lobe lesions

Nocardia Generally unremarkable Single or multiple loculated abscessesLymphoma Unremarkable Enhancing lesions

Multifocal 75%

Luekoencephalopathy Unremarkable Hyperintense lesions in white matter

PMN, polymorphonuclear leukoctes (neutrophils); PCR, polymerase chain reaction; AFB, acid-fast bacilli; Ag, antigen; WBC, white blood

cell count.

NEUROLOGIC COMPLICATIONS IN RENAL TRANSPLANTATION 1253

and mode of therapy (intravenous or oral) might changein such a case.

Brain biopsy might be necessary to make a diagnosisof malignancy, and less commonly in infection. How-ever, the risk of morbidity and sometimes even mortalityassociated with brain biopsy is so high that every effortshould be made to establish a diagnosis with other testswhen possible.

TREATMENT

Most of the infectious problems respond to specific anti-microbial therapy but in life-threatening infection,reduction of immunosuppression will be necessary.Drug toxicity can be addressed by reducing the doseor changing to a different class of drugs when possible.If resolution of drug-related symptoms is slow evenafter adjustments are made, other possibilities need tobe explored. Correction of metabolic abnormalities isdone along the same lines as in the general population.Decreasing immunosuppression is almost always a partof treating malignancy. Further management (surgeryversus chemotherapy versus immunotherapy) is basedon the type and aggressiveness of the tumor. Treatmentof cerebrovascular disease is similar to that in the generalpopulation, with the recognition that aggressive treat-ment of risk factors is needed.

SUMMARY

Renal transplant recipients are at increased risk of a widerange of conditions that can lead to neurologic symptoms.Decreased cellular immunity-accelerated atheroscleroticvascular disease, the need for multiple drugs, and the fre-quency of metabolic abnormalities are the most common

predisposing factors for neurologic abnormalities in thispopulation. Effective treatment requires early recognitionof life-threatening conditions requiring early specifictreatment from easily treated or self-limited infections.The time frame for diagnosis and treatment is often hoursto a few days except in tumors, but early diagnosisimproves prognosis even in such patients. CSF analysisand neuroimaging are key to making a diagnosis and insome cases, repeated CSF examinations will be needed.A clear collaboration between transplant physicians andneurologists is necessary for heightened vigilance, anda thorough familiarity with these problems.

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