Incidence of seizures (%)
Bone marrow transplant
Seizures may be focal or generalized in onset. They are essentially a non-specific symptom of cerebral dysfunction. In the setting of organ transplantation, they may result from drug-induced neurotoxicity, metabolic/electrolyte disturbances, central nervous system (CNS) infections, malignant hypertension, ischemic or hemorrhage stroke, or CNS malignancy.
The general approach to the evaluation of seizures in this population differs little from the general population. The priorities are: (1) to abort the seizure in order to minimize neurologic and systemic morbidity, (2) to minimize seizure recurrence by identifying and treating the etiology when possible, and (3) to determine if there is need for long-term antiepileptic drugs (AEDs) . A few additional considerations specific to this patient population also apply and are outlined in this chapter.
Initial Patient Evaluation and Treatment
In the acute setting, the primary goal is to abort the seizure. Because most seizures are self-limited, there is a tendency to think that most patients will not require emergent treatment and can be observed, however, seizures in these fragile postoperative patients may lead to major systemic complications (aspiration, myocardial demand ischemia, rhabdomyolysis). We opt for a short two week course with an antiepileptic with a good safety profile such as levetiracetam. Obviously in the case of recurrent seizures or status epilepticus, emergent pharmacologic treatment with intravenous AEDs is recommended.
Most post-transplant seizures respond to first line treatment with benzodiazepines with preferred agents being lorazepam or midazolam . When seizures continue despite benzodiazepine administration efforts should be made to rapidly identify and correct any readily reversible precipitating factors (i.e., severe hyponatremia) and a second line intravenous AED should be administered. Options include phenytoin, fosphenytoin, valproic acid, phenobarbital, or levetiracetam .
The next step is to find a possible cause of the seizure (Table 15.2). This is especially pertinent in transplant patients who are immunosuppressed with antirejection medications and therefore at higher risk for infections and neurotoxicity related to the antirejection drugs. Investigation of serum electrolyte levels including magnesium, sodium, calcium, and glucose as well as a complete blood count with differential, ammonia, blood cultures, and antirejection medication levels should be performed.
Possible causes of seizures in transplant recipients
• Arterial ischemic infarcts
• Intracranial hemorrhage
• Cerebral venous thrombosis
• B-cell lymphoma
• Post-transplant lymphoproliferative disorder
• JC virus
• Herpes Viruses (HSV, CMV, VZV, EBV, HHV-6 )
Medication induced neurotoxicity
• CNIs: Tacrolimus, cyclosporin A
• OKT3 (muronmonab-CD3)
• Chemotherapy: busulfan and carmustine
• Quinolone Class
• Carbapenem class
Because seizures are comparatively more common in CNS infections associated with transplantations an infectious evaluation should be initiated if seizures occur one month after transplantation (CNS infections are exceedingly rare in the postoperative period). A history of preceding headache , confusion, signs of increased intracranial pressure including transient visual obscurations, morning headaches, or signs of meningismus on examination justifies a lumbar puncture but immunosuppressed post-transplant patients should undergo neuroimaging prior to lumbar puncture. Empiric antimicrobial therapy should be started while neuroimaging and lumbar puncture are performed.
Because of their immunosuppressed status, imaging is strongly considered in these patients, even when a clear trigger (i.e., severe hypocalcemia) is present. A non-contrast CT is the first investigational step to rule out the presence of a lesion that may require emergent intervention. Non-contrast CT can also be useful in detecting the typical vasogenic edema of posterior reversible encephalopathy syndrome (PRES) (Fig. 15.1), a mass-like lesion such as brain abscess, intracerebral hemorrhage, or diffuse cerebral edema.
(a, b) Computed tomography and (c, d) magnetic resonance imaging fluid attenuated inversion recovery (FLAIR/T2 weighted sequences demonstrating a typical pattern of vasogenic edema associated with PRES). The edema is bilateral, asymmetric, predominantly subcortical, and preferentially affecting the posterior regions and frontal lobes
If initial investigations are unrevealing, MRI with contrast can be considered. Smaller brain abscesses, empyema, septic emboli, pachymeningeal or leptomeningeal enhancement, brainstem infarctions, radiologic signs of PRES , and central pontine myelinolysis are more readily identified on MRI compared with CT .
An electroencephalogram (EEG) is not performed in most settings due to the fact that the majority of seizures last less than 1 min and patients recover quickly from these seizures. However, patients who remain persistently encephalopathic following a seizure will need an urgent EEG in order to determine if the patient is in nonconvulsive status epilepticus. Because undefined rhythmic movements are so common in the postoperative period an EEG can also be useful to characterize the nature of uncertain “spells” of unresponsiveness or abnormal movements. For example, to differentiate multifocal myoclonus (seen in metabolic encephalopathy) or tremors from seizures in unresponsive patients or in patients awakening from anesthesia .
Seizures in Transplant Patients: Specific Causes
Immunosuppressant agents such as cyclosporine, tacrolimus, mycophenolate mofetil, and corticosteroids are universally administered following organ transplantation to reduce the risk of rejection and improve graft survival. In the acute post-transplant period, induction agents can be used including thymoglobulin, OKT3, and basiliximab. These are followed with maintenance steroids, mycophenolate mofetil, or calcineurin inhibitors such as cyclosporine or tacrolimus. Most transplant patients are then continued on a long-term regimen consisting of a calcineurin inhibitor or mycophenolate mofetil .
Because of the narrow therapeutic windows of antirejection drugs and the higher propensity for metabolic derangements in the post-transplant period, drug toxicity from calcineurin inhibitors or mycophenolate mofetil can be considered as a potential cause for seizures. Post-transplant drug-induced encephalopathy affects up to 40% of patients with the incidence peaking within the early postoperative period due to high loading doses [7, 8]. Drug toxicity from antirejection agents is the most common cause of seizures and is the cause in about 25% of cases . The calcineurin inhibitors have been mostly responsible for most drug-induced seizures due to their mechanism of action. They inhibit calcium signaling pathways that are essential to T-cell activations. However, calcineurin also plays an essential role in regulating neuron excitability, blood–brain barrier permeability, and sympathetic activation . The neurotoxic effects of calcineurin inhibitors may be potentiated by pre-existing disruption of the blood–brain barrier in the perioperative period due to hepatic encephalopathy or perioperative hypotension . Ultimately, these disruptions can lead to vasogenic edema, posterior reversible encephalopathy syndrome (PRES) , and seizures.
The diagnostic criteria for CNI induced toxicity include development of seizures or encephalopathy in patients receiving CNIs who have high serum trough levels of the drug at the time of symptoms onset and rapid increase in drug levels prior to symptomatic presentation. Neurotoxicity from CNIs is more commonly seen in the first month of post-transplant care due to the higher intravenous dosing . Postural tremors and headaches are the most common symptoms encountered and can be seen with tacrolimus neurotoxicity. However, both tacrolimus and cyclosporine neurotoxicity can manifest with focal or generalized tonic-clonic seizures that can be seen with or without the presence of posterior reversible encephalopathy syndrome (PRES) . Risk factors for CNI toxicity include hepatic dysfunction, hypertension, low magnesium levels, and administration of medications such as corticosteroids, amphotericin, and ganciclovir which inhibit drug metabolism . While it is important to monitor drug levels during the early phase of maintenance immunosuppression while on these therapies, it has been demonstrated that no correlation exists between seizures and drug levels themselves . Rather, it is the rapid increase in drug levels that is thought to be a provoking cause. In addition, levels of metabolites, rather than the drug itself, can be associated with seizures .
Over the past several years, there has been a switch from cyclosporine to tacrolimus as the antirejection agent of choice in organ transplant patients. Tacrolimus is associated with lower rates of hypertension, acute rejection, and possibly a better neurotoxicity profile as compared to cyclosporine. The incidence of seizures is similar when comparing the two drugs .
Newer agents such as sirolimus and everolimus have been introduced to be used as either first line agents or calcineurin inhibitor (CNI) sparing agents in cases of neurotoxicity. Despite their similar appearing names, these medications are mammalian target of rapamycin (mTOR) inhibitors , not CNIs. There has not been any compelling evidence to suggest that sirolimus itself potentiates seizures. However, there have been few case reports of PRES associated with sirolimus, predominantly in association with hypertensive crises [15, 16].
In cases of neurotoxicity, the primary treatment strategy is reducing the dose or changing the offending agent [17, 13, 18]. This decision should not be taken lightly as it puts the transplanted organ at potential risk for rejection. Various strategies exist for restarting the antirejection transplant regimen including transitioning one CNI to another or an alternative agent such as an mTOR inhibitor or muromonab-CD3 (OKT3) . OKT3 is a murine immunoglobulin monoclonal antibody that is rarely used today for very limited indications such as acute steroid-resistant rejection of allogenic renal, cardiac and liver transplant patients. Neurotoxicity is uncommon with the most commonly reported manifestation being the development of an aseptic meningitis within 72 h of administration . It is in this context that seizures have, rarely, been reported.
Busulfan is commonly used to condition patients in preparation of hematopoietic stem cell transplantation . This agent has been frequently reported to cause seizures in HSCT patients. This complication typically occurs in the 3rd or 4th day of administration and appears to be dose dependent [21, 22]. Although hard evidence is lacking regarding seizure prophylaxis, it has become a generally accepted practice when initiating high-dose busulfan. This is complicated by the fact that the seizure prophylaxis must not have any interaction or toxicity with the conditioning regimen, interfere with the donor cells, or interact with other medications that the patient is receiving. Phenytoin is not an ideal agent for prevention of seizures in this setting due to the risk of toxicity and its ability to induce busulfan metabolism. Current data support the use of benzodiazepines such as clonazepam or lorazepam as seizure prophylaxis. Levetiracetam is another promising agent due to its limited drug–drug interactions and adverse effects.
A number of other agents, both chemotherapeutic and immunosuppressive, have been associated with seizures in transplant patients. Carmustine is a chemotherapeutic agent used in preparation of HSCT. This agent has been associated with seizures in a number of studies [23, 24]. Azathioprine and mycophenolate mofetil have also been associated with seizures in the post-transplant setting .
Many antibiotics used to treat infections in immunosuppressed patients are associated with reductions in seizure threshold. Quinolone antibiotics have a variable effect on the seizure threshold. Trovafloxacin has the greatest potential for seizure induction and levofloxacin has the lowest rate of seizure induction. Imipenem and meropenem have also been associated with seizures in prior studies [26, 27]. While the overall risk of seizures in these patients is low, close monitoring of transplant patients on these drugs is recommended  and they should probably be avoided entirely in patients with pre-existing epilepsy .
Post-transplant pain is often managed with opioid medications such as meperidine . Meperidine has a high central nervous system depressant effect, however, its metabolite is normeperidine, which has twice the CNS neurotoxic effect of meperidine and is a CNS excitatory agent. Accumulation of normeperidine in the CNS can result in generalized seizures, myoclonus, tremors, and hyperreflexia. These effects cannot be reversed by opioid antagonists. Risk factors for meperidine related seizures include hepatic or renal dysfunction .
Management in the setting of drug-induced seizures is primarily cessation of the drug after which recurrent seizures are not expected. If seizures recur after the suspected causal drug has been discontinued and sufficient time to allow five half-lives of the drug has passed, an alternative cause for the seizures should be sought.
Acute Metabolic Change
An acute metabolic change should be considered in all patients with post-transplant seizures as in many cases, these disturbances are easily reversible. Metabolic disturbances can result from acute electrolyte imbalances in the early postoperative period. Delayed onset idiopathic hyperammonemia has also been reported and can result in refractory seizures, however, this rare complication is not easily reversible .
Hyponatremia and hypo-osmolality can contribute to seizures in the early postoperative period . In one study of seizures in children who seized within 24 h following a kidney transplant, the patients with seizures had more pronounced shifts in sodium levels and serum osmolality that those without seizures . Renal transplant patients are particularly prone to hyponatremia and shifts in serum osmolality due to their high rates of postoperative polyuria. This is due to renal tubular dysfunction and can be exacerbated by aggressive fluid resuscitation. Severe hyponatremia as a result of post-transplant polyuria can result in generalized tonic-clonic seizures . Low sodium levels have also been associated with seizure events in cystic fibrosis patients following lung transplant  and rapid changes in sodium levels have been associated with seizures in liver transplant patients . Treatment is often correction with hypertonic saline, however, care must be taken to not reverse the hyponatremia too quickly otherwise the patient will be at risk for the development of central pontine myelinolysis (CPM) [36, 37].
Hypomagnesemia is another well-established risk factor for seizures in the post-transplant population . This is especially true in the liver transplant population where hypomagnesemia is an independent risk factor of seizures as well as in patients receiving small bowel transplants and HSCT [35, 38, 39]. Hypomagnesemia can potentiate the effects of drug-induced neurotoxicity  and can also result from cyclosporine induced renal wasting [41, 42]. Hypomagnesemia frequently presents with muscle weakness prior to its more serious manifestations such as behavioral changes and seizures. Reversal of the electrolyte deficiency is the only way to prevent further seizures in these patients.
Hypocalcemia is another side effect of CNIs such as cyclosporine. Like hypomagnesemia, it is due to increased excretion of the electrolyte in the urine. Hypocalcemia occurs with a nadir level at about one week post-transplant . Hypocalcemia has been shown to be a predictor of PRES in patients with chronic kidney disease, including transplant patients .
Hypoglycemia induced seizures are also not uncommon and may be most likely to occur in patients receiving combined pancreas-renal transplants.
Idiopathic hyperammonemia is a rare complication in organ transplant recipients but is often devastating [31, 45]. This most commonly occurs while patients are severely neutropenic. Patients present with acute lethargy, confusion, seizures, and then progress to coma. Serologic evaluation demonstrates ammonia levels over 200 μmol/L with mild elevation of liver enzymes . Patients with liver failure or who are receiving valproic acid can also experience high serum ammonia levels. Imaging evaluation of these patients demonstrates diffuse cerebral edema. There are no pharmacologic treatments for idiopathic hyperammonemia although some have reported success with lactulose , nonabsorbable antibiotics, dialysis or sodium benzoate for trapping, and removal of ammonia [31, 46].
Infections most commonly occur one to six months following solid organ transplantation . In the first month following the transplant, patients are at high risk for pneumonia or wound infection. Patients with hematopoietic stem cell transplant are at higher risk of opportunist infections in the first month as they are under maximal immunosuppression during this period. This is in contrast to solid organ transplant patients who are not on maximal therapy until about 1 month following the transplant. Beyond 6 months, patients who have not experienced rejection, poor graft function, or GVHD are generally given a lower dose of immunosuppressants and are thus at a lower risk for infectious complications. However, those who are maintained on high doses of immunosuppressant agent remain susceptible to many typical and opportunistic infections .
A CNS infection should be considered in any patient with headache, mental status changes, or seizure . It is important to keep in mind that initial CSF studies may be underwhelming and even the imaging manifestations of a CNS infection may not be striking. Both the development of an inflammatory response in the CSF and formation of an abscess require a robust immune response; thus many of these patients may have only a mild CSF pleocytosis or a more phlegmon appearing lesion in their brain rather than an organized, diffusion restricting walled off fluid collection .
Bacterial infections account for a substantial proportion of infections in this population. Special consideration should be given to opportunistic infections such as Listeria and Nocardiosis. Nocardiosis presents as a pulmonary infection that is diagnosed with sputum, skin, or brain tissue and can present with a mass lesion. CNS involvement occurs in 50% of the cases and can present with fevers, meningismus, focal deficits, and seizures. It has been reported in <5% of renal transplant patients (1–6% of solid organ transplants [47–49]). Listeria presents with gastrointestinal symptoms, fevers, focal deficits, and seizures. Diagnosis is made by identification of gram positive bacilli in the CSF or blood.
Immunosuppressed patients are at high risk for opportunistic fungal infections such as aspergillosis, candidiasis, and cryptococcosis. All three of these fungal infections can present with disseminated pulmonary infiltrates and nodules while candida and cryptococcosis can also present in the lungs. These infections can manifest clinically as meningitis or with more focal symptoms suggestive of an abscess, both of which can lead to seizures . Aspergillosis is unique in that it can present with septic and hemorrhagic infarctions. Presentation of fungal CNS infections includes encephalopathy (90%), focal neurological deficits (33%), seizures (40%), and meningeal signs (20%) . Diagnosis depends on CSF and blood cultures and rarely, brain histology.