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Neuropsychiatric Complications
Neuropsychiatric complications after liver transplantation are common, with the incidence ranging from 10% to 70% and neuropathological findings common at autopsy. In one of the earliest papers discussing outcomes in liver transplantation, Starzl et al noted a high incidence of acute neuropsychiatric complications including altered mental status, seizure, and central pontine myelinolysis.
Several risk factors for neuropsychiatric complications after liver transplantation have been identified, including advanced age of the recipient, retransplantation, severity of liver disease, pretransplant encephalopathy, ∗
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calcineurin inhibitor toxicity, metabolic derangement, cerebrovascular events and lesions, and infection. Some studies report higher rates of neuropsychiatric complications in patients transplanted for primary biliary cirrhosis and alcoholic liver disease. †
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Others report no association between liver diagnosis and neuropsychiatric complications after transplantation. Generally neurological complications after liver transplantation are associated with significant morbidity, including prolonged hospitalization, ‡
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increased rates of retransplantation, infectious complications, increased disability, and reduced health-related quality of life. Although some studies report comparable survival rates in those with and without neurological complications, §
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others report increased mortality in patients with neurological complications following liver transplantation. ∥
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Classification of Neuropsychiatric Complications
Neuropsychiatric complications generally occur early after transplantation ¶
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and have been classified based on the severity of symptoms. Minor complications include headache, tremor, and insomnia. Major complications include seizures; central pontine myelinolysis; posterior reversible leukoencephalopathy; and altered mental status, ranging from an acute confusional state representing delirium to a persistent encephalopathic state progressing to coma. #
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Psychiatric symptoms, including depression, anxiety, mania, and psychosis, have also been reported. Speech and movement disorders, ∗a
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cortical blindness, and catatonia have also been reported. Memory deficits and residual cognitive impairment are well documented.
Minor Neuropsychiatric Complications: Sleep Disturbance, Tremor, Headache
Minor neuropsychiatric complications are typically transient and self-limited, and symptoms generally resolve with standard treatments. Sleep disturbance is a common side effect of immunosuppressants but may also be a symptom of depression, anxiety, delirium, or mania because of corticosteroid administration.
Tremor of the upper extremities is a frequent complication of liver transplantation. As with headache, it can occur within days of transplantation and in the setting of calcineurin inhibitor (CNI) use. †a
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Higher doses and intravenous administration of CNIs may be contributing factors to this phenomenon. Generally a fine tremor is observed, with a frequency of approximately 10 Hz. However, cases of severe tremor with coarse oscillations exceeding 2.5 cm have been reported. It has been described as intentional and postural. It is generally self-limiting ; however, it may respond to immunosuppression modification such as dose reduction or switching to an alternative agent or treatment with β-blockers. Fasciculations and myoclonus are also prevalent. As with the extremities, the tongue can exhibit a tremor.
Headache is a common complaint in liver transplant recipients and is associated with CNI administration. Calcineurin inhibitors are associated with de novo headaches but can also exacerbate migraines in patients with a history. Headaches generally occur early in the posttransplant period. The features have been characterized as vascular-like, with the potential to worsen with prolonged exposure to CNIs. The quality of the pain is varied and has been characterized as frontal, chronic, or throbbing. CNI headaches have also been characterized as severe and bilateral and presenting like classic migraine. Although most presentations of headache are mild to moderate, there have been case reports of refractory and debilitating pain. Severe headache has been found to be a complication primarily during intravenous administration of the CNIs. Switching to another immunosuppressive agent can result in relief. Although headache in the posttransplant setting may be attributed to CNIs, it may also herald a more sinister cause such as hemorrhage, stroke, or infection. Headache in this setting can be associated with focal neurological findings, which warrant further investigation.
Major Neuropsychiatric Complications
Speech Disorders
Abnormalities of speech have been characterized by tremulousness, stuttering, and a dysarthria with imprecise articulation and distortion of vowels. Speech disorders seen after liver transplantation have also been characterized by slow, hesitant, or halting speech; dysrhythmic or uncoordinated speech; and disarticulate and awkward speech. A more severe form has been described as spastic or hypokinetic. In some cases the patient may be able to produce sounds but no words. Others have exhibited pseudobulbar symptoms of tongue weakness, dysphagia, and dysarthria.
Speech apraxia, or “mutism,” has also been observed after liver transplantation. Mutism is associated with several neuropsychiatric disorders and is known to involve the basal ganglia, frontal lobes, and limbic system. This phenomenon occurs in 1% of liver transplant recipients. Mutism in liver transplantation has been associated with other facial motor apraxias such as the inability to whistle, blow a kiss, or extrude the tongue. It has also been associated with neurological phenomena such as seizures and motor akinesis.
A state of mutism occurring with motor akinesis, or akinetic mutism, has been observed after liver transplantation. It presents with combined speech loss and motor impairment. The patient is awake but unable to speak or move. Eye contact may be absent. Descriptions of the patient appearing trancelike, lacking spontaneous movement, and unresponsive to social cues have been reported. Catalepsy, or waxy flexibility, has also been described. Mutism in liver transplant patients has also been associated with muscle rigidity and orobuccofacial dyskinesia, consisting of grimacing and tongue extrusion.
Speech disorders are associated with calcineurin toxicity. ‡a
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In several series, speech disorders improved or resolved with dose reduction or withdrawal and substitution of the CNI. §a
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However, residual impairments can persist for weeks to years after insult. Several papers describe residual persistent dysarthria ranging from mild or moderate to disabling. ∥a
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Catatonia is a neuropsychiatric syndrome that consists of speech and motor abnormalities. Mutism, reduced speech, and echolalia have been observed in catatonia, as well as verbigeration. Stupor and unresponsiveness with lack of response to painful stimuli can occur. Repetitive motor behaviors and catalepsy have also been observed. Agitation, delusional thinking, paranoia, and hallucinations have also been described.
Seizures
Seizure has been one of the most frequently reported neuropsychiatric complications after liver transplantation. ¶a
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Earlier studies reported rates ranging from 25% to 45%, though it has been suggested that rates are declining, possibly because of improvements in medical management of predisposing factors. #a
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Generally seizures occur early in the posttransplant period. ∗b
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Partial seizures have been observed, though generalized tonic-clonic seizure is most commonly reported. †b
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Cases of nonconvulsive status epilepticus have also been reported. Seizures may be an isolated event and self-limited ‡b
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and without long-term neurological consequences. However, they may be severe in presentation or refractory, with serious complications. Tonic-clonic seizures can result in self-injury, aspiration, hemodynamic compromise, and displacement of lines. In the case of status epilepticus, seizures may present with a relatively subtle change in mental status, and it may be clinically underrecognized, because it is difficult to diagnose or distinguish from a toxic metabolic state without electroencephalography.
The cause of seizures after liver transplantation is multifactorial and includes preexisting seizure disorder ; metabolic derangement §b
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; central nervous system infection ∥b
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; structural lesions ; cerebrovascular events such as stroke, hemorrhage, or hypoxic-ischemic injury ¶b
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; and drug neurotoxicity. #b
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Immunosuppressants are frequently cited as a cause of seizure after liver transplantation. ∗c
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Toxicity has been ascribed to intravenous loading in the immediate posttransplant period and elevated cyclosporine levels. Hypomagnesemia, hypocholesterolemia, and corticosteroid use have also been associated with seizure in the context of cyclosporine administration.
Similar neurotoxicity has been reported with tacrolimus. †c
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Early studies showed increased rates of neurological complications with tacrolimus compared to cyclosporine. However, other studies report similar rates of neurological complications with tacrolimus and cyclosporine. Immunosuppressant neurotoxicity can occur even in the context of normal plasma drug levels. ‡c
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Several papers report improvement and resolution of severe symptoms with dose reduction, discontinuation, §c
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or conversion to a different immunosuppressant. However, residual neurological sequelae are sometimes seen despite medication adjustments. Seizure may be the only manifestation of CNI toxicity. However, seizure may occur in the context of other neurological entities, including the posterior reversible encephalopathy syndrome (PRES) or central pontine myelinolysis.
Posterior Reversible Encephalopathy Syndrome
PRES is a clinical, neurological, and radiological entity associated with immunosuppression neurotoxicity after transplantation. Hinchey first used the term reversible posterior leukoencephalopathy syndrome to describe a unique cluster of symptoms comprising headache, altered mental status, vision changes, and seizures. This symptom cluster was correlated with bilateral, symmetrical white matter lesions of the parietal and occipital areas of the brain. The clinical symptoms and radiological changes were found to be reversible with dose reduction or discontinuation of immunosuppression.
Clinical Symptoms
In the original paper by Hinchey, altered mental status ranged from decreased alertness and confusion alternating with agitation, to stupor and coma. Headache was also a prominent feature. Visual abnormalities included blurred vision, hemianopsia, neglect, and cortical blindness. Seizures were reported to occur at both the early and later stages of the evolution of the syndrome, were usually generalized, and were often recurrent.
These hallmark symptoms originally described by Hinchey have been subsequently reported in the vast PRES literature. Other symptoms, including nausea and vomiting, visual hallucinations, and focal neurological signs, including hemiparesis, have also been described in the setting of PRES. Some studies have reported concomitant hypertension, but others have reported PRES in the absence of hypertension. Intracerebral hemorrhage has also been reported and occurs in up to 15% of cases. Hemorrhage is a potentially catastrophic complication of PRES, associated with risk for irreversible damage and death.
Seizures
Seizures may often be the initial presenting symptom or the only clinical manifestation of PRES. Multiple and recurrent seizures have been reported. Status epilepticus has also been reported as a relatively rare complication of PRES. In cases of nonconvulsive status epilepticus the diagnosis may be delayed, because mental status changes may be subtle. Uninterrupted seizure activity can be associated with poor outcomes, including progression to a focal epilepsy. Cases of persistent seizure activity after radiographic normalization of PRES have been reported. The elderly patient may be at increased risk for morbidity and mortality in cases of nonconvulsive status epilepticus.
Cortical Blindness and Visual Hallucinations
Seizures in PRES frequently originate in the occipital lobe. They can manifest as visual hallucinations, homonymous hemianopsia, or visual loss. Visual disturbances may be the sole presenting symptom of PRES. Occipital lobe seizures consist of multicolored spots or achromatic flashes of light. More complex visual hallucinations, characteristic of parietooccipital seizures, have also been described. Immunosuppressant-associated cortical blindness is characterized by acute bilateral loss of visual sensation with preservation of papillary reflexes and without afferent defect. Some reports describe reversal of cortical blindness in liver transplant recipients with immunosuppression adjustment. Resolution of magnetic resonance imaging (MRI) findings can occur in parallel with sight restoration. However, there have been case reports of persistent cortical blindness after liver transplantation, correlated with severe unresolved occipital lesions.
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