eMedicine Specialties > Neurology > Critical Care Neurology
Neurologic Complications of Organ Transplantation: Treatment & Medication
Updated: Jan 25, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Once the diagnosis is made, medical treatment of neurologic complications in transplant recipients is not significantly different from that in nontransplant patients. Nevertheless, complex drug interactions that may potentially compromise immunosuppression and allograft function must be considered.
- Encephalopathy: Impairments of consciousness of variable etiology and severity, from mild confusion to coma, are not uncommon in transplant recipients. Establishing the cause determines further treatment, and delirious patients may also need symptomatic treatment (neuroleptics). In patients with toxic-metabolic encephalopathies, treatment is directed towards correcting the underlying cause while providing medical support (eg, respiratory support, parenteral feeding). In patients with hyponatremia, gradual correction is recommended.
- Seizure
- The underlying etiology of seizures and overall medical condition (including type of allograft and comorbidities) determine which antiepileptic drugs (AEDs) are used for treatment. Symptomatic seizures resulting from transient toxic and metabolic disturbances are treated by correcting the metabolic disturbance.
- The most commonly used AED in transplant recipients is phenytoin because it is effective and simple to administer. Benzodiazepines (eg, lorazepam, diazepam) are useful in the acute management of seizures, whereas propofol is a third-line agent used for treatment of refractory status epilepticus. Phenobarbital is rarely used because of activation of liver enzymes, sedation, and long half-life, but it may be helpful in individual patients. Other medications used for treatment of refractory status epilepticus include midazolam and pentobarbital.
- Valproic acid may be helpful in patients allergic to phenytoin or if phenytoin cannot be used because of drug interactions. Its use is avoided in liver transplant recipients because of potential hepatotoxicity and also in children younger than 2 years. Use of carbamazepine and oxcarbazepine is limited by the lack of parenteral form.
- Newer AEDs are mostly used as adjunctive agents, and the lack of significant drug interactions of levetiracetam, topiramate, and gabapentin makes them very attractive in transplant patients.
- CNS infections: CNS infections carry high risk of morbidity and mortality. Because presenting signs and symptoms may be quite subtle in transplant recipients who are immunosuppressed, CNS infection should almost always be considered in the differential diagnosis. Depending on the clinical setting, therapy may be initiated with broad coverage (ie, antibiotic, antifungal, antiviral) or may be more focused. Delaying treatment may have catastrophic consequences.
- Stroke and intracranial hemorrhage
- The treatment of ischemic stroke in transplant recipients depends on the etiology and type of stroke (eg, cardioembolic, thrombotic, CNS infection, hypercoagulable state) as in nontransplant patients. Long-term control of cerebrovascular risk factors (eg, cholesterol, glucose control, hypertension, tobacco use) is needed as in nontransplant patients, particularly as improved protocols enable long-term survival. Some immunosuppressive medications (ie, sirolimus, cyclosporin) may worsen or trigger hyperlipidemia and hypertension.
- Intracranial hemorrhage may be difficult to treat in transplant recipients, particularly if it is associated with coagulopathy, thrombocytopenia, or CNS infection.
- Replacement of platelets and clotting factors (fresh frozen plasma) is needed in patients with thrombocytopenia and coagulopathy.
- Neuromuscular disorders: Treatment of neuromuscular complications of transplantation is identical to that in nontransplant patients. Most common neuromuscular disorders in transplant recipients are perioperative neuropathies and critical illness myopathy/polyneuropathy (CIM/CIP). Treatment of patients with perioperative neuropathies and CIM/CIP is supportive with early initiation of physical therapy. Cautious use of paralytic agents and steroids in intensive care settings may decrease the occurrence of CIM. Patients with refractory myasthenia associated with chronic GVHD may benefit from rituximab.
Surgical Care
- Surgical removal of a cerebral hematoma in the acute stage, either by evacuation or aspiration, may be lifesaving.
- Brain biopsy obtained by open or stereotactic technique is helpful in the evaluation of cranial masses of unknown origin, particularly if PTLD or brain tumors are suspected.
- The decision to proceed with aspiration or open removal of a brain (or spinal cord) abscess is guided by the location, clinical course, and the degree of mass effect exerted by the abscess to the surrounding tissue. Stereotactic aspiration can be performed with deep abscesses.
- Decompressive surgery is an emergency treatment of rapidly evolving hydrocephalus that is not responding to medical measures (ie, hyperventilation, mannitol).
- Intraventricular placement of an Ommaya reservoir permits intrathecal treatment of fungal CNS infection.
Consultations
A multidisciplinary approach is essential to the effective care of a transplant recipient. The transplant team has a central role in determining the level of immunosuppression. Various consultants play active roles in the care of these patients.
- A neurologist is primarily a consultant in the management of transplant patients but may serve as a primary team member if the patient is stable enough.
- Transplant team members have a central role in the treatment of transplant recipients. They coordinate with other teams and determine the required level of immunosuppression.
- A critical care medicine specialist is particularly important in the early postoperative course.
- An infectious disease specialist is invaluable in helping to evaluate possible opportunistic systemic and CNS infections.
- Consulting a physical therapist is important because early initiation of physical therapy may accelerate recovery of transplant recipients.
- Other medical and surgical specialists (including nephrologists, pulmonologists, cardiologists, neurosurgeons, and others) are also actively involved in the care of transplant recipients, depending on the type of allograft, comorbidities, and ongoing medical problems.
Diet
Following transplantation, various dietary products may interfere with pharmacokinetics of immunosuppressive and other medications (eg, grapefruit juice).
- Certain foods may increase risk of infection such as raw milk, soft cheeses, and hot dogs (Listeria monocytogenes).
- Sodium restriction (2 g/d) may be helpful in management of cyclosporine-related hypertension.
- Rapamycin and, to a lesser extent, cyclosporine are associated with hypercholesterolemia. Conversion from cyclosporine to tacrolimus may be helpful.
- Use of statins in combination with cyclosporine may lead to rhabdomyolysis.
Activity
No specific activity restrictions are necessary for patients with neurologic complications of transplantation.
Medication
Principles of medical therapy of neurologic complications in transplant patients are not altered by their transplant status. Nevertheless, additional attention must be paid to complex drug interactions and possible neurotoxicity so that the immunosuppression regimen and allograft function are not compromised.
Antibiotics
Bacterial CNS infections are relatively uncommon in transplant recipients and are usually caused by opportunistic pathogens rare in immunocompetent individuals.
Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin)
Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication PO.
Used in treatment of listeriosis.
Adult
250-500 mg PO q6h
500 mg to 1.5 g IM q4-6h
500 mg to 3 g IV q4-6h; not to exceed 12 g/d
Pediatric
50-100 mg/kg/d PO divided q4-6h
100-400 mg/kg/d IV/IM divided q4-6h
Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of PO contraceptives
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction
Gentamicin (Garamycin, I-Gent, Jenamicin)
Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.
Not the DOC. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.
Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be administered IV/IM.
Adult
Serious infections and normal renal function: 3 mg/kg/dose IV q8h
Loading dose and maintenance dose: 1-2.5 mg/kg IV and 1-1.5 mg/kg IV, respectively, q8h
Extended dosing regimen for life-threatening infections: 5 mg/kg/d IV/IM q6-8h
Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion
Pediatric
<5 years: 2.5 mg/kg/dose IV/IM q8h
>5 years: 1.5-2.5 mg/kg/dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d; monitor as in adults
Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking agents, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (patient not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment
Antifungals
Fungal CNS infections are frequently fatal in transplant recipients, and early diagnosis and initiation of treatment are of uttermost importance.
Amphotericin (Amphocin, Fungizone)
Polyene antibiotic produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death.
Liposomal preparation is more expensive but is associated with less nephrotoxicity.
Adult
25-300 mcg IT q48-72h and increase to 500 mcg as tolerated
Alternatively, 0.25-1.5 mg/kg/d IV
Liposomal: 3-5 mg/kg/d IV over approximately 120 min
Pediatric
25-100 mcg IT q48-72h and increase to 500 mcg as tolerated
Alternatively, 0.5-0.7 mg/kg/d IV
Liposomal: Administer as in adults
Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine
Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor renal function, serum electrolytes such as magnesium and potassium, liver function, CBC, and hemoglobin concentrations; resume the therapy at the lowest level (eg, 0.25 mg/kg) when the therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock
Voriconazole (VFEND)
Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Also may be used in the treatment of coccidiosis and blastomycosis.
Adult
Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 4 mg/kg IV q12h infused over 2 h; switch to 200 mg PO q12h when able to tolerate; may increase to 300 mg PO q12h if inadequate response
<40 kg: Average maintenance dose is 100 mg PO q12h (may increase to 150 mg PO q12h)
Pediatric
Not established
CYP450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP450 inducers (eg, rifampin) have shown to decrease steady state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or 2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids), others may need more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG CoA inhibitors, benzodiazepines, calcium channel blockers)
Documented hypersensitivity; CrCl <50 mL/min (decreased excretion of IV vehicle) if administering IV
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Decrease maintenance dose in hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (including Stevens-Johnson syndrome and phototoxicity), and respiratory disorder; rare cases of severe hepatotoxicity reported; administer PO dosage form 1 h ac or pc
Antiviral agents
Viral CNS infections in immunosuppressed transplant recipients are caused by a variety of pathogens, and early treatment is essential.
Acyclovir (Zovirax)
Has affinity for viral thymidine kinase and once phosphorylated causes DNA chain termination when acted on by DNA polymerase.
Has demonstrated inhibitory activity against both HSV-1 and HSV-2. Selectively incorporated into infected cells.
Adult
Encephalitis: 1500 mg/m2/d IV q8h or 10 mg/kg/dose for 10 d
Pediatric
Administer as in adults
Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity of acyclovir
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal failure or when using nephrotoxic drugs
Ganciclovir (Cytovene, Vitrasert)
Used in the treatment of viral infections with limited response to acyclovir, particularly with CMV infections.
Synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells.
Adult
Induction: 5 mg/kg IV over 1 h q12h for 14-21 d (do not use PO ganciclovir for induction treatment)
Maintenance PO: 500 mg q4h or 1 g tid
Maintenance IV: 5 mg/kg qd for 5-7 d/wk
Pediatric
<3 months: Not established
>3 months: Administer as in adults
Concomitant administration with cytotoxic drugs such as dapsone, vinblastine, Adriamycin, pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim/sulfamethoxazole combinations, or other nucleoside analogs may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks); coadministration with imipenem-cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); serum creatinine may increase following concurrent use of ganciclovir with either cyclosporine or amphotericin B; in presence of probenecid, ganciclovir renal clearance is reduced; bioavailability may increase when didanosine is administered either 2 h prior to or simultaneously with ganciclovir; bioavailability of ganciclovir may decrease in presence of zidovudine, while bioavailability of zidovudine is increased in presence of ganciclovir
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Clinical toxicity of ganciclovir includes granulocytopenia, anemia, and thrombocytopenia; because PO ganciclovir is associated with higher rate of CMV retinitis progression compared to IV formulation, use only when benefits outweigh risks (advanced HIV disease); half-life and plasma/serum concentrations of ganciclovir may be increased as a result of reduced renal clearance; dosages > 6 mg/kg IV may result in increased toxicity; rapid infusions may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (11); phlebitis or pain may occur at site of IV infusion despite further dilution in IV fluids; administration of ganciclovir should be accompanied by adequate hydration; photosensitization (photoallergy or phototoxicity) may occur
Immunomodulatory agents
Agents with targeted immunotherapy are emerging treatment options that may find wider use in the near future.
Rituximab (Rituxan)
Rituximab has been used in the treatment of PTLD and refractory myasthenia in transplant recipients and in the treatment of paraproteinemic neuropathies in nontransplant patients.
Antibody genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Antibody is an IgG1 kappa immunoglobulin containing murine light and heavy chain variable region sequences and human constant region sequences.
Adult
375 mg/m2 IV qwk for 4 doses (days 1, 8, 15, and 22)
Pediatric
Not established
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypotension, bronchospasm, and angioedema may occur; discontinue treatment if life-threatening cardiac arrhythmias occur
Anticonvulsant
Seizures in transplant recipients can be attributable to transient metabolic disturbances, drug neurotoxicity, focal CNS lesions, to the activation of a low seizure threshold, or to the exacerbation of a preexisting seizure disorder.
Long-term treatment with antiepileptic drugs (AEDs) may significantly complicate maintenance of immunosuppression because some AEDs (particularly phenytoin) may interfere with metabolism of cyclosporine and tacrolimus. Newer AEDs including topiramate, levetiracetam, and gabapentin seem to have a better adverse effect profile and may be better tolerated by transplant recipients.
Phenytoin (Dilantin)
First-line agent in the treatment of seizures and status epilepticus.
In transplant recipients, phenytoin may interfere with tacrolimus and cyclosporine metabolism.
Individualize dose. Administer larger dose before retiring if dose cannot be divided equally.
Adult
Loading: 15-20 mg/kg PO/IV; not to exceed 50 mg/min to avoid hypotension and arrhythmias
Alternatively, loading can be performed in divided doses of 100-150 mg at 30-min intervals
Initial: 100 mg (125 mg susp) IV/PO tid
Maintenance: 300-400 mg/d PO/IV divided tid or qd/bid if using ER; increase to 600 mg/d (625 mg/d susp) may be necessary; not to exceed 1500 mg/d
Pediatric
<6 years: 15-20 mg/kg PO/IV loading dose once or in divided doses; follow by initial 5-mg/kg/d maintenance dose (range 4-8 mg/kg) PO/IV divided bid/tid
>6 years: May require minimum adult dose (300 mg/d PO/IV); not to exceed 300 mg/d
Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity
Phenytoin effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate
Phenytoin may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, PO contraceptives, and valproic acid
Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if a skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes mellitus (may elevate blood sugars); discontinue use if hepatic dysfunction occurs
Fosphenytoin (Cerebyx)
Phenytoin derivative with better adverse effect profile.
Diphosphate ester salt of phenytoin, which acts as water-soluble prodrug of phenytoin. Following administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin. Phenytoin in turn stabilizes neuronal membranes and decreases seizure activity. To avoid need to perform molecular weight–based adjustments when converting between fosphenytoin and phenytoin sodium doses, express dose as phenytoin sodium equivalents (PE). Although can be administered IV and IM, IV route is route of choice and should be used in emergency situations.
Concomitant administration of an IV benzodiazepine is usually necessary to control status epilepticus. The antiepileptic effect of phenytoin, whether administered as fosphenytoin or parenteral phenytoin, is not immediate.
Adult
Loading: 15-20 mg PE/kg IV/IM at 100-150 mg PE/min
Maintenance: 4-6 mg PE/kg/d IV/IM at 150 mg PE/min to minimize risk of hypotension
Pediatric
Loading: 15-20 mg PE/kg IV/IM
Initial: 5 mg PE/kg/d IV/IM
Maintenance: 4-8 mg PE/kg IV/IM
<6 years: Not established
>6 years: May require minimum adult dose (300 mg PE/d IV/IM); not to exceed 300 mg PE/d
Amiodarone, benzodiazepines, chloramphenicol, cimetidine, disulfiram, ethanol (acute ingestion), omeprazole, phenacemide, phenylbutazone, succinimides, fluconazole, isoniazid, metronidazole, miconazole, sulfonamides, trimethoprim, and valproic acid may increase phenytoin toxicity
Phenytoin effects may decrease when taken concurrently with barbiturates, carbamazepine, theophylline, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, and sucralfate. Phenytoin may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, methadone, metyrapone, mexiletine, PO contraceptives, quinidine, theophylline, and valproic acid
Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; Adams-Stokes syndrome
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Blood dyscrasias have occurred, perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter; discontinue use if skin rash appears; if rash is exfoliative, bullous, or purpuric do not resume use; death from cardiac arrest has occurred after too-rapid IV administration preceded sometimes by marked QRS widening; administer cautiously to patients with acute intermittent porphyria; exercise caution when administering to patients with diabetes mellitus; may raise blood sugar levels; discontinue drug if hepatic dysfunction occurs
Midazolam (Versed)
Short-acting benzodiazepine used for sedation and treatment of refractory status epilepticus.
Because midazolam is water soluble, reaching peak EEG effects takes approximately 3 times longer than diazepam. Thus, the clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose.
Adult
Loading: 0.2 mg/kg IV
Continuous infusion: 0.1-0.4 mg/kg/h IV
Intubation and pressor support may be necessary
Alternatively: 10-15 mg IM; when other access impossible
Pediatric
Loading: 0.15 mg/kg IV
Maintenance: 1 mcg/kg/min IV
Titrate dose upward q5min until clinical seizure activity is controlled
Sedative effects of midazolam may be antagonized by theophyllines; narcotics and erythromycin may accentuate sedative effects of midazolam because of decreased clearance
Documented hypersensitivity; preexisting hypotension; narrow-angle glaucoma
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in congestive heart failure, pulmonary disease, renal impairment, and hepatic failure
Lorazepam (Ativan)
First-line medication for immediate treatment of seizures and status epilepticus.
By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation. Important to monitor patient's blood pressure after administering dose. Adjust as necessary.
Adult
0.1 mg/kg for treatment of status epilepticus
4 mg/dose IV slowly over 2-5 min and repeat in 10-15 min prn; cumulative dose of 8 mg/d typically considered maximum
1-10 mg/d PO/IV/IM divided bid/tid
Pediatric
Infants and children: 0.1 mg/kg IV slowly over 2-5 min; repeat prn in 10-15 min at 0.05 mg/kg IV; not to exceed 4 mg/dose
Adolescents: 0.07 mg/kg IV slowly over 2-5 min and repeat in 10-15 min prn; not to exceed 4 mg/dose
Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs
Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in elderly patients and patients with renal or hepatic impairment or organic brain syndrome
Propofol (Diprivan)
Used in treatment of refractory status epilepticus.
Phenolic compound unrelated to other types of anticonvulsants. Has general anesthetic properties when administered IV.
Adult
Loading: 0.2 mg/kg IV
Maintenance: 0.1-0.2 mg/kg/min (6-12 mg/kg/h) IV
Pediatric
Not established; recommended dose is 2-2.8 mg/kg IV
Reduce propofol dose when administered concomitantly with benzodiazepines, opiates, phenothiazines, ethanol, and narcotics; propofol may potentiate neuromuscular blockade of vecuronium; theophylline may weaken effects of propofol, and dose increase may be needed
Documented hypersensitivity; no mechanical ventilation
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Do not administer with blood or blood products using the same IV catheter; patients may develop apnea; may experience a decrease in systemic vascular resistance leading to hypotension
Propofol infusion has high content of lipids, and patients may receive very high amount of calories
Levetiracetam (Keppra)
Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for primary generalized tonic-clonic seizures. Mechanism of action is unknown. Useful in transplant patients as it has minimal drug-drug interactions.
Adult
1000 mg/d PO divided bid (500 mg bid); may increase by 1000 mg/d increments q2wk; not to exceed 3000 mg/d; long-term experience at doses >3000 mg/d is relatively minimal, and there is no evidence that doses >3000 mg/d offer additional benefit
Pediatric
Partial onset seizures:
<4 years: Not established
4-15 years: 20 mg/kg/d PO divided bid; may increase by 20 mg/kg/d increments q2wk; not to exceed 60 mg/kg/d; use oral solution if weight <20 kg
>16 years: Administer as in adults
Myoclonic seizures:
<12 years: Not established
>12 years: Administer as in adults
Tonic-clonic seizures:
<6 years: Not established
6-15 years: 10 mg/kg PO bid; may increase daily dose by 20-mg/kg increments q2wk, not to exceed 30 mg/kg bid
>16 years: Administer as in adults
None reported; does not inhibit CYP450 isoenzymes, epoxide hydrolase, or UDP-glucuronidation; probenecid inhibits renal clearance of ucb L057 (inactive levetiracetam metabolite)
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal impairment (reduce dose); major side effects include somnolence, asthenia, incoordination, mild leukopenia (3%) and behavioral changes such as anxiety, hostility, emotional lability, depression and psychosis (1-2%), and depersonalization; seizure frequency may increase following discontinuing drug (discontinue gradually); statistically significant decreases in RBCs and WBCs have been observed
Topiramate (Topamax)
Used as add-on therapy for partial seizures.
May be used in patients with hepatic impairment, but use is limited by lack of IV preparation.
Sulfamate-substituted monosaccharide with broad spectrum of antiepileptic activity that may have a state-dependent sodium channel blocking action. Potentiates the inhibitory activity of GABA. May block glutamate activity. Not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. On occasions, addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome.
Adult
50 mg/d PO and titrate by 50 mg/d at 1-wk intervals to target a dose of 200 mg bid; not to exceed 1600 mg/d
Pediatric
Not established
Phenytoin, carbamazepine, and valproic acid can significantly decrease topiramate levels; topiramate reduces digoxin and norethindrone levels when administered concomitantly; concomitant use with carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; use topiramate with extreme caution when administering concurrently with CNS depressants because it may have an additive effect in CNS depression, as well as other cognitive or neuropsychiatric adverse events
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Risk of developing a kidney stone is increased 2-4 times over that of the untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment; patients taking topiramate should seek immediate medical attention if they experience blurred vision or periorbital pain; continued usage after symptoms develop can lead to glaucoma; primary treatment is discontinuation of topiramate; if left untreated, serious sequelae, including permanent vision loss, may occur
Valproic acid (Depacon, Depakene, Depakote)
Because of potential hepatotoxicity, this drug is avoided in liver transplant recipients.
Chemically unrelated to other drugs that treat seizure disorders. Although the mechanism of action is not established, activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channels, or have a direct membrane-stabilizing effect. For conversion to monotherapy, concomitant AED dosage can ordinarily be reduced by approximately 25% q2wk. This reduction may start at initiation of therapy or be delayed by 1-2 wk if concern exists that seizures may occur with a reduction. Monitor patients closely during this period for increased seizure frequency.
As adjunctive therapy, divalproex sodium may be added to the patient's regimen at 10-15 mg/kg/d. May increase by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses <60 mg/kg/d.
Adult
Monotherapy: 10-15 mg/kg/d PO in 1-3 divided doses, increase by 5-10 mg/kg/wk; not to exceed 60 mg/kg/d until seizures are controlled or adverse effects prevent further increases
If daily dose >250 mg, administer in divided doses IV; divide q6h
Pediatric
Administer as in adults
Coadministration with cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce valproate levels; in pediatric patients, protein binding and metabolism of valproate decrease when taken concomitantly with salicylates; coadministration with carbamazepine may result in variable changes of carbamazepine concentrations with possible loss of seizure control; valproate may increase diazepam and ethosuximide toxicity (monitor closely); valproate may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; valproate may displace warfarin from protein binding sites (monitor coagulation tests); may increase zidovudine levels in HIV seropositive patients
Documented hypersensitivity; hepatic disease or dysfunction
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Thrombocytopenia and abnormal coagulation parameters have occurred; the risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and 135 mcg/mL in males; at periodic intervals and prior to surgery determine platelet counts and bleeding time before initiating therapy; reduce dose or discontinue therapy if hemorrhage, bruising, or a hemostasis/coagulation disorder occur
Hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness
More on Neurologic Complications of Organ Transplantation |
| Overview: Neurologic Complications of Organ Transplantation |
| Differential Diagnoses & Workup: Neurologic Complications of Organ Transplantation |
 Treatment & Medication: Neurologic Complications of Organ Transplantation |
| Follow-up: Neurologic Complications of Organ Transplantation |
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References
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Further Reading
Keywords
opportunistic infection, immunosuppression, central nervous system infection, CNS infection, organ transplant, solid organ transplantation, kidney transplantation, liver transplantation, heart transplantation, lung transplantation, intestinal transplantation, posttransplant immunosuppression, opportunistic infection
