Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose 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 Department of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL, USA

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Department of Surgery, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION Kidney transplantation is the preferred choice of treatment for end-stage renal disease (ERSD) and in 2008, a total of 17 413 patients received a kidney transplant (USRDS, 2010). Neurologic complications following kidney transplant are more common than in the general population and the incidence of neurologic alterations is reported to be around 10–21% (Senzolo et al., 2009). The percentage of kidney transplants done in older patients (kidney transplant rate among those 65 years of age and older increased by 49% from 2000 to 2008) and patients with diabetes mellitus is increasing, contributing to increased susceptibility to neurologic problems. Moreover, all are treated with immunosuppressive medications which either have direct neurotoxicity or increase the risk of central nervous system (CNS) infections and tumors. Early diagnosis of neurologic problems is important for prompt management as empiric treatment would require use of wide variety of potentially toxic drugs in patients who are already burdened by multiple comorbidities. The aim of this chapter is to describe the most important neurologic complications among kidney transplant recipients and discuss diagnostic and treatment options for effective management.

DRUG-RELATED NEUROTOXICITY Calcineurin inhibitors Tacrolimus is the most commonly used immunosuppressive medication with 87% of kidney transplant patients in 2008 receiving it as their initial calcineurin inhibitor (CNI) (USRDS, 2010). Ciclosporin is still widely used, especially in patients with poorly controlled diabetes mellitus. Both of these drugs are associated with

neurotoxicity with a higher incidence reported with tacrolimus (Margreiter, 2002), particularly in children (Flynn et al., 2001). The cellular basis for the neurotoxicity associated with either ciclosporin or tacrolimus has not been conclusively identified. Since both drugs mediate their immunosuppressive effects via inhibition of calcineurin, it is possible that some of the neurotoxic effects, along with nephrotoxicity and hypertension, are also mediated via the same pathway (Bechstein, 2000). Central and peripheral nervous systems are both enriched with the intracellular binding proteins for ciclosporin and tacrolimus (immunophilins cyclophilin and FKBP-12, respectively) (Lyson et al., 1993). There is striking colocalization of FKBP-12 and calcineurin as well as cyclophilin and calcineurin (Dawson et al., 1994), suggesting that, within the brain, the function of the immunophilins and calcineurin are related. Clinical symptoms range from mild tremors to paraplegia (Table 84.1) and are often similar to symptoms caused by other etiologies. A high degree of vigilance is necessary for diagnosis of drug-related toxicity as serum drug levels may not correlate with symptoms. Fortunately, most of the neurologic side-effects are reversible by lowering the dose or complete discontinuation of the drug when possible (Hauben, 1996). Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), is a rare but important neurologic complication seen in kidney transplant recipients who often have all three risk factors for the syndrome, namely, hypertension, renal disease, and immunosuppressive therapies (Hinchey et al., 1996; Parvex et al., 2001). The reported incidence after solid organ transplant (SOT) is around 0.5% (Besenski et al., 2005) and appears to be similar among other SOT subtypes, although there is some difference in

*Correspondence to: Kavitha Potluri, M.D., Department of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, 2160 S. 1st Avenue, Maywood, Illinois 60153, USA. E-mail: [email protected]

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Table 84.1 Neurologic side-effects of calcineurin inhibitors Tremors Sleep disturbances Paresthesias Mood disturbances Leukoencephalopathy Seizures Mental 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

era with low-dose or steroid-free regimens being the norm. It can still be seen when acute kidney rejection is treated with high-dose steroids.

Other immunosuppressive medications Neurotoxicity with Rapamune (sirolimus) is relatively low but PRES associated with Rapamune has been reported (Moskowitz et al., 2007; Qin et al., 2011). OKT3 (muromonab-CD3), rarely used nowadays, has been associated with aseptic meningitis (Martin et al., 1988) within 72 hours of its administration. Its use is contraindicated in patients with underlying neurologic problems such as seizures.

Nonimmunosuppressive medications the clinical presentation. When compared to liver transplant recipients, kidney transplant recipients tend to develop PRES later after transplantation (mean duration 14–120 months post-transplant), are severely hypertensive, and have less brain edema (Bartynski et al., 2008). The exact pathophysiology is yet to be understood. It is a clinical radiographic syndrome characterized by headaches, altered consciousness, visual disturbances, moderate to severe hypertension, and seizures with white mater edema in the posterior regions of the cerebral hemispheres, a finding which can also be seen in malignant hypertension. Neuroimaging is essential for diagnosis. Computed tomography (CT) and magnetic resonance imaging (MRI) typically demonstrate focal regions of symmetric, bilateral hemispheric edema with parietal and occipital lobes being most commonly affected, followed by the frontal lobes, the inferior temporal-occipital junction, and the cerebellum (Schwartz et al., 1995; Bartynski et al., 2001). Prompt recognition of PRES is important as symptoms can be reversed by decreasing the drug dose or by discontinuation of the drug when possible, even though the syndrome can present even after several months of exposure to the drug and even when drug levels are therapeutic. Generally, clinical symptoms resolve after a mean of 5–7 days (Lee et al., 2008; Roth and Febert, 2010) with radiologic improvement lagging behind. Late recognition, poor control of hypertension, prolonged seizures, 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 in transplant recipients in the past, is rare in the current

The neurologic side-effects of drugs other than immunosuppressive medications are similar to those seen in the general population with kidney disease and discussed elsewhere in this series. Only a few of the drugs that are frequently used in transplant recipients are briefly discussed.

ACICLOVIR Transplant recipients are at increased risk of herpetic infections and treatment with aciclovir and valaciclovir is common. Renal failure is one of the common sideeffects of aciclovir due to precipitation of aciclovir crystals in the renal tubules (Mason and Nickols, 2008) and as a result, serum levels of the drug rise significantly leading to neurologic side-effects ranging from confusion and hallucinations to coma (Cohen et al., 1984; Bataille et al., 1985). A high degree of vigilance is necessary 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 aciclovirassociated neuropsychiatric symptoms (Hellden et al., 2003).

TRIMETHOPRIM-SULFAMETHOXAZOLE Trimethoprim-sulfamethoxazole (TMP-SMZ, Cotrimoxazole, Bactrim®) is one of the most common causes of drug-induced aseptic meningitis and most renal transplant recipients are placed on Bactrim in the first 12 months post-transplant for Pneumocystis carinii pneumonia prophylaxis. The exact incidence of aseptic meningitis in renal transplant recipients is unknown except for few published case reports (Muller et al., 2001).

NEUROLOGIC COMPLICATIONS IN RENAL TRANSPLANTATION

b-LACTAM ANTIBIOTICS Both penicillins and cephalosporins have a high toxic therapeutic ratio such that no hesitation should exist with regard 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 permeability can lead to mental status changes ranging from confusion to seizures.

INFECTIOUS CAUSES Infections of the central nervous system are estimated to occur in 5–10% of patients after solid organ transplantation. The presentation of CNS infection in transplant recipients can be very different from that in normal population as the anti-inflammatory effects of immunosuppressive therapy may obscure signs of meningeal inflammation associated with meningitis and changes in the level of consciousness may be subtle (Fishman and Rubin, 1998). Also, mental status changes can occur as a result of CNS infection or as a response to bacteremia without meningitis or encephalitis, or even due to a urinary tract infection (UTI), especially in the elderly, and so blood and urine cultures should be part of the workup of any transplant recipient with mental status changes, irrespective of whether the patient is febrile or not. CNS infections in renal transplant recipients are associated with significant mortality and morbidity and so understanding when special methods are needed for detection and isolation of pathogens is extremely important. Bacterial infections remain the most common infections, but unusual pathogens figure prominently in the differential diagnosis of CNS infections in transplant recipients. In the early post-transplant period, transmission of infection from the donor is a problem, particularly when the kidneys are purchased in countries with a thriving black market for organs (Salahudeen et al., 1990). Reactivation of a latent infection in the recipient, due to high-dose immunosuppression in the immediate post transplant period, should be considered.

Bacterial infections LISTERIA MENINGITIS Transplant recipients can develop any type of bacterial meningitis but 69% of listeria infection in nonpregnant adults occurs among immunocompromised patients (Schuchat et al., 1992). Most listeria infections in adults are as a result from oral ingestion of contaminated food. Direct transmission from infected livestock is rare. Clinical presentation and CSF findings are similar to other cases of bacterial meningitis and Gram stain is generally negative and when positive, the Gram-positive rods can

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be confused with pneumococci or diptheroids. Treatment is with ampicillin or TMP-SMZ. It is not sensitive to cephalosporins.

NOCARDIA Nocardial infection has been reported in fewer than 5% of renal transplant recipients (Burke and Cunha, 2001) but CNS involvement in systemic nocardiosis is about 50% with brain abscess being the hallmark of CNS nocardiosis (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 without an accompanying abscess. Diagnosis is facilitated by the common involvement of lung and skin. A presumptive diagnosis can be made by direct visualization of filamentous gram positive rods that are partially acid fast but since the organism is slow growing in cultures, specimens should be held for at least 3 weeks before being discarded. Although TMP-SMZ is the drug of choice, when there is CNS involvement two drug regimens are used with the second drug being third generation cephalosporins or imipenem for 6–12 months with frequent imaging as surgical intervention may be needed if no response to medical treatment (Ozt€ urk et al., 2006).

TUBERCULOSIS Tuberculosis is the major source of morbidity and mortality worldwide in solid organ transplantation. Although infrequently reported in the US, it is 20% more common in transplant recipients when compared to the general population (Riska et al., 1987). This complication can be minimized by treating transplant recipients with positive purified protein derivative (PPD) with isoniazid before 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 and presents as meningitis, CNS tuberculomas, or arachnoiditis. The presentation of TB meningitis can vary from an acute to a very indolent course, and frequently occurs without any active pulmonary lesions. Examination of acid-fast bacilli (AFB) in the CSF remains the most rapid and effective means of reaching an early diagnosis and repeated lumbar punctures (LPs) are frequently needed to achieve this. CSF analysis typically shows low glucose (80% of the cases), high protein, and mononuclear pleocytosis. Rapid detection can be aided by polymerase chain reaction (PCR) for Mycobacterium tuberculosis DNA but sensitivity is low when compared to AFB staining or CSF cultures. Treatment requires a four drug regimen and in severe cases, corticosteroids are helpful (Thwaites et al., 2004). Rifampicin increases the metabolism of ciclosporin and complicates drug dosing in

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

Parasites TOXOPLASMOSIS Toxoplasmosis is caused by a protozoan parasite, Toxoplasma gondii, with immunocompromised and pregnant patients being at the highest risk for severe infection, but the widespread use of TMP-SMZ for Pneumocystis carinii pneumonia has lowered the risk of toxoplasmosis in transplant recipients. The mode of transmission in these patients is mainly due to reactivation of latent disease (reactivation occurring preferentially in the CNS) but contaminated food and transmission through an infected donor can also occur (Rogers et al., 2008). Imaging of the brain shows ring enhancing lesions but CSF findings are nonspecific. Histopathology with demonstration of Toxoplasma cysts or tachyzoites or immunohistochemical staining for specific antigen remains the most reliable method of diagnosis but this is only used in patients who do not respond to empiric treatment in the appropriate clinical setting, given the morbidity associated with brain biopsy (Fig. 84.1). Pyrimethamine-sulfadiazine is the standard therapy although studies in HIV patients have shown that TMP-SMZ is as effective with a better side-effect profile (Torre et al., 1998).

Fungi ASPERGILLUS Aspergillosis is by far the most common etiology of brain abscesses in organ transplant recipients and typically 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 reported to be around 24 days post-transplant. Invasive aspergillosis in renal transplant recipients has been reported in 0.4–7% with high dose and prolonged duration of corticosteroids, graft failure requiring dialysis, and potent immunosuppressive therapy known to be the risk factors. CNS involvement frequently presents with altered mental status and is often rapidly progressive. The most common location for brain abscess is the frontoparietal region of the cerebral hemispheres but the cerebellum and brainstem may also be involved. Radiologically, the lesions are frequently multifocal with a predilection to the gray and white matter junction. Diagnosis is made by identifying branching septate hyphae on sputum or CSF specimens or by positive culture (Fig. 84.2). A combination of voriconazole and caspofungin is generally recommended and although successfully treated cases have been rarely reported, the mortality rate associated with CNS aspergillosis remains 100%.

CRYPTOCOCCAL MENINGITIS Cryptococcal meningitis is the most common subacute meningitis seen in renal transplant recipients, especially in patients who are exposed to birds, and is universally fatal without treatment. Like all other fungi, cryptococci enter the body through the respiratory tract but CNS is the primary target (Vilchez et al., 2002). Presenting symptoms may wax and wane over time and include headaches, fever, lethargy, personality changes, memory loss, and coma. CSF analysis is needed for diagnosis and opening pressures are high with increased number of white cells, predominantly mononuclear, and minimal change in protein and glucose content. Imaging of the brain should be done before LP as 10% of patients have mass lesions. Encapsulated yeast forms are seen in 50% of the cases with Indian ink staining with cryptococcal

Fig. 84.2. A microscopic view of Aspergillus fumigatus.

NEUROLOGIC COMPLICATIONS IN RENAL TRANSPLANTATION antigen and cultures being positive in 90% of the cases. Treatment is with amphotericin B and flucytosine. Maintenance therapy with oral fluconazole for 6–12 months is continued in transplant patients to prevent relapse. Longer duration of maintenance therapy may be warranted in 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 herpes virus 6 and 8 (HHV-6 and HHV-8). Herpes virus infections are extremely common in renal transplant recipients but meningoencephalitis is a rare and potentially life-threatening complication mostly caused by HSV-1. HSV-1 The frequency of HSV-1 encephalitis is not increased significantly in renal transplant recipients when compared to the general population (Gomez et al., 1997; Amenabar et al., 2006). Clinical symptoms include fever, change in level of consciousness, and focal neurologic deficits. CSF examination typically shows a lymphocytic pleocytosis, an increased number of erythrocytes, and elevated protein. Low glucose in CSF is uncommon and when present, may suggest an alternate diagnosis (Nahmias et al., 1982). Detection of the virus by PCR in CSF is the gold standard with sensitivity as high as 98%. The test can be positive up to 1 month after the onset of clinical disease (Biovin, 2004). Temporal lobe involvement, often unilateral, would support the diagnosis but when absent, does not exclude the diagnosis. Electroencephalogram (EEG) typically shows focal sharp and slow wave complexes and periodic lateralized epileptiform discharges. Mortality and long-term disability are high even after treatment with aciclovir and it is important to remember that the drug itself can cause mental status changes, as mentioned above. VZV In addition to causing chickenpox and shingles, VZV infection can lead to various CNS manifestations, including post-varicella cerebellitis, aseptic meningitis, and meningoencephalitis, which are less commonly seen in renal transplant recipients (Kashtan et al., 1997). Nevertheless, kidney transplant patients with cutaneous zoster manifestations are treated with higher doses of aciclovir to prevent systemic dissemination (Ketteler et al., 2003). Immunosuppression should be reduced temporarily.

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CMV CMV infections are the most prevalent viral infection in renal transplant patients (Brennan, 2001) but encephalitis was rarely seen even in the preganciclovir era (Bamborschke et al., 1992). HHV-6 The novel herpes virus HHV-6 has been proposed to be the most neuroinvasive of the herpes viruses. Emerging data from solid organ transplant recipients suggest meningoencephalitis as a significant complication of HHV-6 infection, although data on CNS manifestations in renal transplant recipients is sparse and limited to case reports (Koukourgianni et al., 2009). Primary infection with HHV-6 after renal transplantation is extremely rare. Demonstration of previous exposure to HHV-6 before transplantation is common in both donors and recipients (Yoshikawa et al., 1992), suggesting reactivation after transplant as the primary cause of infection. One report of donor-derived HHV-6 infection to two renal transplant recipients has been published so far suggesting transmission from donor is possible (Pilmore et al., 2009). Clinical manifestations include headache, fever, speech disturbances, seizures, confusion, and coma. HHV-6 viremia is seen in a majority of the patients. CSF findings are nonspecific with pleocytosis generally lacking in 50% of the cases. Definitive diagnosis is by detection of HHV-6 DNA by PCR in CSF which is virtually never detectable in immunocompromised patients without CNS symptoms (Wang et al., 1999). Treatment is with ganciclovir or foscarnet in resistant cases. Mortality is reported to be as high as 58% in HHV-6 encephalitis.

WEST NILE VIRUS The first two deaths from West Nile virus were described in transplant recipients from a single infected donor (Iwamoto et al., 2003). Deceased donors are not routinely tested for West Nile virus as testing has a high false-positive rate which would lead to failure to use good organs and net loss of life (Kiberd and Forward, 2004). This practice may change if more accurate tests for West Nile virus are developed. Living donors who reside in endemic areas can be questioned about exposure to mosquitoes in the immediate predonation period if West Nile virus is occurring in the area and the donor can be tested when suspicion is high since the disease is seasonal and the period of infectivity is short. Transplant recipients present with symptoms similar to the general population but the risk of neuroinvasive disease is 40 times higher (Kumar et al., 2004) after West Nile virus infection, generally manifesting as encephalitis, flaccid

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paralysis, and movement disorders. CSF examination shows atypical lymphocytes and hyperintense lesions usually involving the white matter noted on MRI. No proven effective treatment or prophylaxis exists and most patients survive, but permanent sequelae are common.

JC VIRUS JC polyomavirus is one of the viral infections that can cause neurologic symptoms in transplant recipients. The virus is ubiquitous in the normal population and causes disease only in the setting of impaired cellular immunity. Virulence depends on rearrangements in the regulator region of the virus. The most common manifestation is infection of oligodendrocites causing demyelination of white matter. Presenting symptoms depend on the location of the lesions and include limb weakness, sensory deficits, cranial nerve abnormalities, hemianopsia, aphasia, gait disturbances, and impairment of cognitive function (Tan and Koralnik, 2010). The disease is usually progressive and fatal within 6 months. The affected areas appear as hypodense areas on CT and T1-weighted MRI images and hyperintensity on T2weighted images. More definitive diagnosis is made by positive PCR in the CSF or brain biopsy. The mainstay of treatment is reduction in immunosuppressive therapy. Cidofovir, cytarabine, mirtaziine and mefloquine have been used to treat JC virus infections without convincing evidence for efficacy. The prognosis of the disease is so dire that most recommend complete cessation of immunosuppressive therapy with the attendant risk of losing the kidney. Some authors have suggested a connection between JC virus infections and specific immunosuppressive agents but it is more likely a result of total immunosuppression. The one specific drug group that may cause increased risk is monoclonal antibodies, of which rituximab is sometimes used in renal transplants.

RABIES Rabies is an acute encephalitis caused by a rhabdovirus and is uniformly fatal in unvaccinated hosts. Human infection is extremely rare in the Western world, with no more than six cases reported in any year in the past decade in the US. In the US, the primary mode of transmission is through a bite from an infected animal, most commonly a bat. Transmission of rabies virus from the donor through transplantation of solid organs has been reported and all four patients (including two kidney transplant recipients) had rapid neurologic deterioration and died within 50 days of transplant (Srinivasan et al., 2005). Such a scenario would be extremely important to consider when patients buy kidneys from countries where rabies is more prevalent and where there is no implementation of universal vaccination of pet animals. Patients who insist on going abroad

for kidney transplant should be advised to get rabies vaccine prior to transplant.

NEOPLASTIC DISEASES The most frequent malignancies of the brain in renal transplant recipients are lymphomas and metastatic tumors which are, for the most part, de novo malignancies from immunosuppression. There are several case reports of CNS tumor being transmitted from donors who had primary CNS tumor with no recognized extracranial spread, but this is rare, as donors with primary CNS tumors are not routinely used nowadays unless they are completely benign in nature (Detry et al., 2000).

Lymphomas The risk of malignant lymphoma in transplant recipients is significantly higher than age-matched nontransplant individuals; one study reported an 11.8-fold increased risk over a 10 year period (Opelz and Dohler, 2004). A predilection exists for extranodal disease with the CNS being the primary site in 24% of the cases (Snanoudj et al., 2003). B cell lymphomas are the most common primary CNS tumors diagnosed in renal transplant recipients and EBV (Epstein–Barr virus) can be identified in most tumors. Patients with negative EBV serology prior to the transplant are at increased risk for lymphoma, particularly if they receive a kidney from an EBV-positive donor. As patients who are EBV seronegative are rare, most patients with CNS lymphomas are seropositive before transplant. Most donors are seropositive as well and requiring an EBV-negative donor for a seronegative recipient would often preclude transplant. Although ciclosporin and antithymocyte globulin have been associated with increased frequencies of lymphoma, the risk is more likely related to the total amount of immunosuppression rather than a specific drug. The most common presentation for CNS lymphomas includes focal neurologic deficits, seizures, or symptoms of raised intracranial pressure. Diagnosis is usually made by the discovery of enhancing lesions on CT scan or MRI. Biopsy is needed for a definitive diagnosis as intracerebral abscess or toxoplasmosis can have similar radiologic appearance. Reduction in immunosuppression alone is rarely sufficient and a combination of radiation and chemotherapy is often required for the best outcomes.

Other CNS tumors The risk of Kaposi sarcoma is increased among transplant recipients but CNS involvement is rare. The increased risk of lymphoma and Kaposi sarcoma in transplant recipients has been explained on the basis of decreased immune surveillance resulting in cancers

NEUROLOGIC COMPLICATIONS IN RENAL TRANSPLANTATION 1251 associated with identified viruses, either latent in the patients as a result of perioperative nerve compression recipient or introduced from the donor. Glioblastomas and ischemia. Clinical features include knee buckling, have also been described in transplant recipients and absent patellar reflex, and weak anterior thigh muscles, generally appear years after the transplant; prognosis and generally develop within 1–2 days after surgery. is poor. Cadaveric donors with glioblastomas confined Complete recovery of motor function may take up to to the brain have been accepted in the past because of 4–9 months (Sharma et al., 2002). low rates of extracranial spread. In rare cases of tumor Lumbosacral plexopathy characterized by pain in the transmission, it has been reported in the transplanted hip with asymmetric weakness of the proximal leg kidney and other sites outside the CNS. muscles has been described after dual kidney transplantation (Dhillon and Sarac, 2002). The lumbosacral plexus with its rich anastomostic blood supply can be CEREBROVASCULAR DISEASE predisposed to ischemic injury during dual kidney transThe incidence of atherosclerotic disease, either cardioplant as it involves larger and more time-consuming vascular or cerebrovascular, is higher in renal transplant dissection. recipients than in the general population. The prevalence of stroke is reported to be around 8% in renal transplant recipients with diabetic nephropathy as the underlying METABOLIC CAUSES cause of end-stage kidney disease, age > 40 years and Despite the long list of esoteric neurologic problems seen peripheral vascular disease being the strongest predicamong transplant recipients, many of the most common tors for stroke in this population (Oliveras et al., problems, specifically the metabolic causes, are similar 2003). There are conflicting data regarding the risk of to those seen in the general population. Patients with stroke and intracranial hemorrhage in renal transplant renal disease, with or without a renal transplant, have recipients with autosomal dominant polycystic kidney a more profound response to metabolic events than disease (ADPKD). While a few reports suggested an those without renal disease with the sole exception of increased risk of stroke (Pirson et al., 1996) and intracrasevere hyperglycemia in dialysis patients, who are spared nial bleed in this patient group (Wijdicks et al., 1999; volume contraction from osmotic diuresis. Transplant Oliveras et al., 2003), others did not find any such assorecipients are frequently monitored for such changes ciation and reported ADPKD renal transplant patients to and so many of the metabolic problems do not pose a be more susceptible to ischemic than hemorrhagic diagnostic dilemma. strokes (Adams et al., 1986; Watschinger et al., 2008). Although uremia certainly causes neurologic sympRegardless of the risk, as in the general population, renal toms, the elevated blood urea nitrogen (BUN) and creattransplant recipients with ADPKD should have brain inine levels are rarely the cause of lethargy and mental imaging done when there is a family history of intracrastatus changes. Myoclonus, tremors, and asterixis are nial hemorrhage. Mortality has been reported to be high commonly seen with high BUN and creatinine levels. in transplant patients with stroke, with one US study There is no definite cut-off value for BUN as symptoms attributing 8% of deaths in kidney transplant recipients of uremia have appreciable interpatient variation and to stroke (Howard et al., 2002). Efforts to prevent stroke depend on the rapidity of renal failure, the age of the include aggressive control of hypertension, diabetes, and patient, and any underlying CNS disease (Bleck et al., hyperlipidemia. There is no contraindication to the use of 1993). Since metabolism of most drugs is affected in low-dose aspirin, even in transplant recipients with renal renal failure, it might be difficult to distinguish uremia insufficiency. from effects induced by medications. Acute uremic encephalopathy generally reverses with dialysis (with PERIPHERAL NEUROPATHY an occasional lag period of 1–2 days) and other etiologies Uremic polyneuropathy seen in patients with advanced need to be pursued when this does not happen. renal failure generally improves after transplantation Hyperglycemia is common as many patients develop but may persist in patients who have been on dialysis post-transplant diabetes mellitus, for which they are roufor years prior to the transplant. tinely monitored. This is more common in the immediate The incidence of Guillain–Barre´ syndrome (GBS) in post-transplant period as a result of medication sidesolid organ transplant is unknown although commonly effects and restoration of normal kidney function which reported in bone marrow transplant patients. Published shortens the half-life of insulin. Accordingly, diabetic cases in such a setting suggest a higher incidence in renal transplant recipients are instructed to monitor their males and association with CMV infection at or before blood sugar at home even if they did not require any the onset of GBS (El-Sabrout et al., 2001). medicines while on dialysis. Acute femoral neuropathy in the immediate postHypercalcemia can occur when hypertrophied paratransplant period may occur in 2% of renal transplant thyroid glands continue to secrete the parathyroid

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hormone (PTH) even in the setting of near normal renal function. PTH levels generally drop in few weeks but some patients may have tertiary hyperparathyroidism leading to symptomatic hypercalcemia (anxiety, confusion, and in severe cases, stupor and coma as well). Hypomagnesemia due to calcineurin inhibitors frequently coexists leading to muscle weakness, behavioral changes, and seizures. Profound muscle weakness leading to paralysis due to hypo- or hyperkalemia can occur, although rarely, because these conditions are generally detected and treated before potassium levels are so profoundly abnormal. Hyponatremia and hypernatremia are rare with normal renal function but should always be considered in patients with mental status changes, especially in the elderly. In either case, restoring normal serum sodium levels at no more change than 10–12 mEq per day should be aimed for, to prevent central pontine myelinolysis and cerebral edema respectively. Renal transplant recipients are more prone to developing rhabdomyolysis leading to profound muscle weakness from the combination of calcineurin inhibitors and statins. The muscle weakness may take longer to resolve than the renal function abnormalities. Although liver failure can occur when hepatotoxic drugs are used in patients with underlying liver disease, it rarely occurs, as liver function tests are closely monitored in transplant patients.

DIAGNOSTIC APPROACH A detailed history including recent and remote travel as well as exposure to mosquitoes, pets, and bird and rodent droppings should be obtained as atypical infections are common in transplant patients. History should also include a careful review of occupational hazards, gardening, agricultural and home remodeling projects. Medication history should be reviewed for any drugs known to cause neurologic symptoms with the recognition that sedatives and narcotics have an exaggerated and prolonged response in patients with kidney disease despite being metabolized by the liver. Pretransplant workup generally includes serology for EBV, CMV, HSV, varicella, RPR, and PPD status. Donor serologies for EBV and CMV are generally available if evaluated at US transplant centers. Clinical features might be similar in many different illnesses and neurologic examination alone may not clarify the etiology. A careful search for evidence of systemic or focal disease outside the CNS may be helpful for diagnosis or at least providing tissue for diagnosis. CSF examination is essential in determining the nature of infectious processes but may be nonspecific in immunocompromised patients (Table 84.2). CT or MRI of the head is indicated in most patients unless there is a clear-cut metabolic abnormality. Radiologic studies will also be needed in asymptomatic patients with systemic illnesses that have a high propensity for CNS involvement as management or duration

Table 84.2 Diagnostic findings in central nervous system disorders in renal transplant recipients

Tuberculosis

Crypotococcus

Toxoplasmosis Listeria

Cerebrospinal fluid

Radiologic studies

Glucose: 80% þ ve Glucose: mild abnormality Protein: mild abnormality Mononuclear cells: 50–75% Cryptococcal Ag: 90% Culture: 90–100% Protein elevated Mononuclear pleocytosis Protein elevated Glucose: low in 50% PMN predominant

Tuberculomas 5–10% Hydrocephalus Cerebral infarcts Basilar meningeal enhancement

Mass lesion 10%

Ring enhancing lesions

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Table 84.2 Continued Cerebrospinal fluid

Radiologic studies Hyperintense lesions in white matter

Nocardia Lymphoma

Protein 60–140 mg/dL Glucose: normal WBC: mixed differential Protein elevated Glucose: normal Lymphocytic pleocytosis PCR > 95% þve Generally unremarkable Unremarkable

Luekoencephalopathy

Unremarkable

West Nile virus

Herpes simplex virus encephalitis

Temporal lobe lesions

Single or multiple loculated abscesses Enhancing lesions Multifocal 75% Hyperintense lesions in white matter

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

and mode of therapy (intravenous or oral) might change in such a case. Brain biopsy might be necessary to make a diagnosis of malignancy, and less commonly in infection. However, the risk of morbidity and sometimes even mortality associated with brain biopsy is so high that every effort should be made to establish a diagnosis with other tests when possible.

TREATMENT Most of the infectious problems respond to specific antimicrobial therapy but in life-threatening infection, reduction of immunosuppression will be necessary. Drug toxicity can be addressed by reducing the dose or changing to a different class of drugs when possible. If resolution of drug-related symptoms is slow even after adjustments are made, other possibilities need to be explored. Correction of metabolic abnormalities is done along the same lines as in the general population. Decreasing immunosuppression is almost always a part of treating malignancy. Further management (surgery versus chemotherapy versus immunotherapy) is based on the type and aggressiveness of the tumor. Treatment of cerebrovascular disease is similar to that in the general population, with the recognition that aggressive treatment of risk factors is needed.

SUMMARY Renal transplant recipients are at increased risk of a wide range of conditions that can lead to neurologic symptoms. Decreased cellular immunity-accelerated atherosclerotic vascular disease, the need for multiple drugs, and the frequency of metabolic abnormalities are the most common

predisposing factors for neurologic abnormalities in this population. Effective treatment requires early recognition of life-threatening conditions requiring early specific treatment from easily treated or self-limited infections. The time frame for diagnosis and treatment is often hours to a few days except in tumors, but early diagnosis improves prognosis even in such patients. CSF analysis and neuroimaging are key to making a diagnosis and in some cases, repeated CSF examinations will be needed. A clear collaboration between transplant physicians and neurologists is necessary for heightened vigilance, and a thorough familiarity with these problems.

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