Discussion

Organ transplantation has become a practical and effective option for patients with acute and/or chronic irreversible organ disease. Tacrolimus and cyclosporin A are calcineurin inhibitors used to prevent rejection following allogenic solid organ transplantation.

Calcineurin is expressed in several areas of the brain: cerebral cortex, striatum, substantia nigra, cerebellum and hippocampus [4]. Calcineurin is the only calcium-activated phosphatase in the brain and a major regulator of key proteins essential for synaptic transmission and neuronal excitability, involved in memory and synaptic plasticity [5].

Tacrolimus is a macrolide calcineurin inhibitor. It reduces peptidylprolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein), creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin, thus inhibiting calcium-dependent events, such as T-lymphocyte signal transduction, interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation and apoptosis [9].

Neurological complications in transplant patients treated with tacrolimus have been well documented, especially after liver transplantation [6,10]. Early calcineurin inhibitor-induced neurotoxicity is considered when neurological symptoms occur within 4 weeks after transplantation [7]. Neurotoxicity can occur both at therapeutic and at high CsA or Tac levels [8]. Sometimes, neurotoxicity can be only indirectly inferred from the resolution of the clinical symptoms when treatment is discontinued. Neurotoxic effects can manifest either in the central or in the peripheral nervous system.

The major central neurotoxic effect of calcineurin inhibitors is Posterior Reversible Leukoencephalopathy Syndrome (PRES). Other major side effects include akinetic mutism, toxic encephalopathy, seizures. The minor central effects include insomnia, visual symptoms, headache, tremor, paraesthesia and mood changes; they are more frequent than major effects, occurring in almost 40% of transplant patients.

Peripheral toxicity occurs weeks to months after starting immunosuppressive treatment. Both the nerve and the muscle may be involved [9]. Axonal and demyelinating neuropathy has been reported. The more severe forms have been observed during Tac therapy, such as multifocal demyelinating neuropathy resembling Chronic Inflammatory Demyelinating Neuropathy (CIDP).

The physiopathological mechanism causing neurotoxicity of tacrolimus has not been clarified. Certain authors suggested that factors such as hypocholesterolaemia or hypomagnesaemia may predispose, as is well known for cyclosporin A [11]. No such factors were identified in the present case.

In previous reports with histopathologic analysis of tacrolimus leukoencephalopathy: the white matter was described to show small areas of demyelination, which were associated with veins and with sparing of axons in these areas [12,13]. Philippe Grimbert, et al. reported a case of Tacrolimus (FK506)-induced severe and late encephalopathy in a renal transplant recipient and identified significant tac levels in the CSF indicating that the molecule can cross the blood-brain barrier and probably attaches to myelin which is rich in lipids, permitting tac to exert a direct toxic effect [14].

MRI should be performed early in the diagnostic evaluation of patients on calcineurin inhibitors who develop significant neuropsychiatric events [15]. Imaging findings are similar to pattern of PRES with MRI showing typical distribution in the posterior regions of the white matter of the brain. Involvement of periventricular and supraventricular white matter with diffusion restriction is more commonly seen with immunosuppressant induced toxicity as compared to more cortical-subcortical pattern of involvement in PRES with diffusion restriction being less common [16].

A large amount of data has suggested that TAC induced encephalopathy is not a homogenous entity: indeed, is often presented with atypical and potentially misleading imaging characteristics not always corresponding to PRES, and includes reversible deep white matter edema and laminar cortical infarcts with hemorrhagic transformation, associated with distal vasospasms on Magnetic Resonance Angiography (MRA) [17].

Our case presented with atypical PRES like features with involvement of deep white matter and basal ganglia which can be attributed to disruption of blood brain barrier and non-specific demyelination as seen with PRES.

Another unique finding seen in our case was aseptic meningitis. There are 2 major proposed mechanisms for drug induced aseptic meningitis which includes direct irritation of the meninges by the drug and immunological type III/ IV hypersensitivity to the drug [18]. As tacrolimus itself is an immunosuppressant, aseptic meningitis can be attributable to blood-brain barrier disruption and direct meningeal irritation by the drug.

Clinical recovery after stoppage of the culprit drug is usually complete; however MRI signal changes may persist on follow up imaging as was seen in our case [19].