The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C, Good Practice Point [GPP]) are defined at the end of the "Major Recommendations" field.
Immunosuppression Neurotoxicity
Cyclosporine (CS) and Tacrolimus (FK506) Neurotoxicity
Prevention requires minimum efficacious doses, oral administration as soon as possible, strict monitoring of plasma levels (including metabolites), electrolyte imbalance (i.e., hypomagnesemia) and hypertension check and correction, and attention to pharmacological interactions (level C). Brain magnetic resonance imaging (MRI) is the choice diagnostic tool (level B) and should be performed as soon as severe neurotoxicity is suspected (Good practice point [GPP]). In case of major side effects, prompt switching to a non-calcineurin inhibitor (e.g., sirolimus) is indicated (GPP). Secondary options include conversion from cyclosporine to tacrolimus and vice versa (GPP). Minor complications require switching only in case of intractable and invalidating symptoms. Generally, their treatment should follow the guidelines for these disorders, administering drugs lacking both hepatotoxicity and interference with immunosuppressants (e.g., gabapentin for paresthesiae, riboflavin for migraine prophylaxis) (GPP).
OKT3 Neurotoxicity
Prevention consists of administering minimal dosages and premedication with corticosteroids (GPP). Aseptic meningitis does not need treatment, because it is usually self-limiting. Encephalopathy requires antiedema agents and very rarely OKT3 withdrawal (GPP).
Corticosteroid Neurotoxicity
Severe acute behavioural disorders may be treated by a temporary reduction and/or withdrawal of intravenous steroid administration. Brief regimens of low-dose neuroleptics (e.g., haloperidol, olanzapin, quetiapin, risperidon) may be considered (GPP).
Seizures
Seizure prevention requires close monitoring of metabolic parameters (in particular, electrolytes) and immunosuppressant levels, and caution in managing discontinuation or adjustment of epileptogenic drugs (GPP). The diagnostic approach should routinely include laboratory tests, electroencephalogram (EEG) and neuroimaging. Cerebrospinal fluid (CSF) examination is indicated when central nervous system infection is suspected (GPP). Brain MRI is the current standard of reference (level B). When MRI is not available or contraindicated, computerized tomography (CT) can be applied (level C). The first-line intravenous antiepileptic drug is phenytoin, the administration of which in adults should not exceed 50 mg/min to obtain serum levels between 10 and 20 micrograms/mL (GPP). When oral administration is possible, new antiepileptics could be considered, e.g., gabapentin or levetiracetam (GPP). Status epilepticus must be managed in accordance with guidelines for the general population (Treiman et al., 1998) (level A). In most cases, antiepileptic therapy can be suspended after 3 months (level C).
Central Pontine Myelinolysis
Given enough time before orthotopic liver transplantation (OLT), hyponatremia should be corrected slowly. The variations in serum sodium concentration must be carefully monitored and controlled before and during surgery to avoid major fluctuations (GPP). If the patient is hyponatremic when undergoing OLT, a perioperative hourly correction rate at or below 0.5 mM/L/h should be maintained. The correction rate should not exceed 8 mM/L/day (GPP). MRI should be performed early and repeated if negative (GPP).
Neuromuscular Disorders
Perioperative Mononeuropathies
Prevention implies caution during catheterization, avoiding blinded cannulations and external compressions by blood pressure cuff or tourniquet (GPP). To reduce perioperative malpositioning it is indicated to maintain the arms at <90 degrees of abduction, to maintain the arms at <30 degrees of extension when combined with abduction, padding of the exposed nerves (i.e., at the level of fibular head, popliteal space, calcaneus, under forearms, under hands), frequent repositioning during prolonged surgery. Patients should be instructed to avoid postures potentially compressing or stretching the nerves (GPP).
Generalized Weakness
Prevention requires avoiding, when possible, the prolonged use of non-depolarizing neuromuscular blocking agents and minimizing the use of high-dose intravenous corticosteroids (level C). In case of calcineurin inhibitor toxicity, prompt switching to a different agent (e.g., sirolimus) is recommended (GPP). Customary general measures for critical illness, including aggressive insulin therapy, and conventional management of Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy are indicated (level B).
Cerebrovascular Disorders
Prevention includes correction of coagulopathies before surgery (e.g., administration of platelets and blood products but with caution because of the risk of consumptive coagulopathy), avoiding perioperative cerebral hypoperfusion and control of cerebrovascular risk factors after OLT (especially hypertension) (GPP). According to general guidelines, CT scan is the preferred diagnostic test in early phases of acute cerebrovascular disorders, especially to detect haemorrhage (level C). MRI, despite its greater sensitivity, could be not tolerated or not applicable immediately after OLT, but it should be considered to characterize some vascular lesions or to rule out other etiologies (GPP).
A search for bacteremia or fungemia to detect infection should be routinely applied (GPP). General treatment of cerebrovascular disorders in OLT should not differ from that applied in the general population (GPP). Concomitant antifungal treatment should be given in the presence of angiopathy related to central nervous system infections (level C).
Central Nervous System Infections
An early in-depth diagnostic approach is advocated, including brain CT/MRI, lumbar puncture, and possibly brain biopsy, and the search for extracerebral sources of infection (GPP). Cerebrospinal fluid polymerase chain reaction is essential for viral infections (level A). Prompt administration of therapy, upon suspicion of the diagnosis without definitive proof is needed to control infection (GPP). An exhaustive search for latent infection in donor and recipients is required, including close monitoring for intestinal strongyloidiasis in patients who have lived for long periods in tropical or subtropical countries (level C). Exposure to hospital contamination must be avoided (level C). Specific drug protocols to prevent brain infections are not required (GPP). Treatment of neurolisteriosis consists of prolonged administration of ampicillin plus gentamicin; second choice includes trimethoprim-sulfamethoxazole (level C). For brain nocardiosis, prolonged administration of trimethoprim–sulfamethoxazole is suggested (level C). For brain aspergillosis, the first-choice drug is voriconazole: initially, 6 mg/kg intravenously (i.v.) every 12 h in two doses, then 4 mg/kg i.v. every 12 h, switching to oral dosing (same dosage) as tolerated and clinically justified; maintenance regimen consists of 200 to 300 mg orally every 12 h. Duration of intravenous therapy should be between 6 and 27 days, followed by oral administration for 4 to 24 weeks (level A). In case of intolerance, contraindications or therapy failure: liposomal amphotericin B (1 to 5 mg/kg/day) or caspofungin 50 mg/day (loading dose: 70 mg day 1) or itraconazole (except after voriconazole) (level B). Surgical resection may be considered. First-line treatment for cryptococcal meningitis is a combination of liposomal amphotericin B plus 5-flucytosine. Schedule treatment includes: induction with amphotericin B (0.7 mg/kg/day) and flucytosine (150 mg/kg/day) for 2 weeks, followed by consolidation with fluconazole for 8 to 10 weeks (400 to 800 mg/day), followed by 6 to 12 months at lower doses of fluconazole (200 mg/day) (level A). Treatment for herpesvirus-6 and cytomegalovirus encephalitis is ganciclovir and foscarnet, either alone or in combination (level C). For progressive multifocal leukoencephalopathy cidofovir is a possible option (GPP).
Definitions:
Evidence Classification Scheme for a Diagnostic Measure
Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations for a Diagnostic Measure
Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.
Rating of Recommendations for a Therapeutic Intervention
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
Good Practice Point Clinical areas exhibiting class IV scientific evidence, for which recommendations were based on the agreement obtained by the Delphi process, were indicated as good practice points (GPP).
