Neurological Complications

Rapid Assessment Before Calling the Neurologist

The neurological complications of liver transplant can be acute or chronic. The first task of physicians is to determine whether the patient is stable medically; if this is the case, then the next question is what part of the nervous system is being affected. This question may seem irritating on the surface, but in reality it is far from an academic exercise, because most of the time physicians face a global dysfunction of the brain due to systemic illness (e.g., a toxic-metabolic encephalopathy). Thus the recognition of a diffuse neurological dysfunction is relevant because almost always the treatment is medical and should target the underlying systemic problems leading to multiorgan failure. The finding of focal neurological signs, on the other hand, may indicate a primary neurological problem, such as stroke. Focal neurological signs, however, can merely indicate that an old neurological problem has been exacerbated by acute illness, which frequently happens when a person with an old stroke becomes encephalopathic, “reexpressing” the stroke. Neuroimaging is fundamental in this particular scenario to understand what is happening to the patient.

A fast neurological assessment can be done in 5 minutes and consists of the following four steps:

• 1.

  Observe the state of consciousness: Note whether the patient is spontaneously awake or able to stay awake for a few seconds after calling the person’s name or shaking the shoulder. If no response is elicited, it is relevant to know whether the alteration in the state of consciousness is due to diffuse brain dysfunction or a brainstem problem. At this point a crucial issue is whether the patient is receiving medications with sedation potential. If so, all sedatives can be tapered or stopped, and the examination can be repeated later.

• 2.

  Examine the cranial nerves: To determine whether the brainstem has been compromised, one simply needs to examine the cranial nerves. If the pupils react equally to light, the corneal reflex is present bilaterally, and if the oculocephalic reflex (doll’s eyes) is elicited, then the brainstem is probably intact. If these reflexes are absent, then the patient may have a catastrophic problem involving the brainstem, such as stroke or hypoxic-ischemic encephalopathy. One important caveat is that a person who is sufficiently awake will suppress the oculocephalic reflex. Of note also is that the gag reflex is not very useful, because it is absent in many patients (older adults in particular).

• 3.

  Perform speech testing: A seemingly alert person who is unable to speak and expresses frustration because of the difficulty is aphasic and needs prompt neuroimaging (unless there is documented history of such deficit). Difficulty articulating words is not necessarily a focal sign, because many encephalopathic patients are dysarthric.

• 4.

  Observe spontaneous movements: The close observation of spontaneous motor behavior can help localize a lesion, even if the patient cannot cooperate with the examination. A patient may not be able to move one side, as if anchored to the bed. Subtler degrees of weakness can become clear when the examiner raises the patient’s arms passively (a drift will occur on the weak side) or flexes the legs at the knees with the feet held together (one side will slip back into the bed faster). These postures can also reveal the presence of asterixis, an intermittent interruption of posture resulting in flapping of the affected limbs. Scratching the plantar aspect of the foot usually results in immediate withdrawal of a limb (and can help unveil an extensor plantar response or Babinski’s sign, which is always pathological in adults). Symmetrical rhythmical jerking, however subtle, should raise concern about status epilepticus. On the other hand, asymmetrical arrhythmic jerking suggests myoclonus, which is a nonspecific and more mundane accompaniment of metabolic encephalopathies.

Encephalopathy

Encephalopathy is an instance of acute organ failure, an alteration of brain function characterized by fluctuation in the state of consciousness and sleep-wake cycle, accompanied by behavioral, cognitive, and sensory disturbances. Most patients with delirium have lethargy and excess daytime sleep, although about a third may experience bouts of psychomotor agitation. Examples of these behavioral problems include restlessness and pacing, whereas typical cognitive changes include disorientation, apathy, distractibility, and losing train of thought; sensory disturbances include illusions and hallucinations. Such a picture of neurological dysfunction is often called delirium . The word delirium derives from the Latin roots de (“out of”) and lira (“furrow”), which conveys the idea that affected individuals are “deranged” or “out of track.” Delirium is an exceedingly common problem faced by all medical specialties, including surgeons. Nonspecific encephalopathies complicate about 1 out of 10 of all hospital admissions, and liver patients are particularly prone to this complication. Encephalopathy affects about 20% to 50% of patients with end-stage liver disease and may complicate almost one third of liver transplants. Regardless of the underlying cause, delirium is associated with increased morbidity and mortality, longer hospital stays, and higher medical costs. Moreover, the incidence of delirium will probably increase with the aging of the population and as sicker individuals receive liver transplantation. The risk for encephalopathy is also increased by a history of encephalopathy before surgery or preexisting neurological problems. It is very important to keep in mind that delirium is almost always a manifestation of systemic disease; Figure 82-1 presents a flow chart depicting a proposed diagnostic workup.

In spite of delirium’s frequency, there is a deficient understanding of its pathophysiological characteristics. Apart from descriptions of slowing of the electroencephalographic (EEG) background and studies of the forebrain cholinergic pathways, limited literature tackles the problem. EEG has a restricted role in the assessment of delirium and assigning specific causes to it, but it may detect nonconvulsive status epilepticus and occasionally offer other relevant diagnostic clues. Based on historical clinicopathological observations, it is adduced that alterations in the state of consciousness occur with dysfunction of two broad neuroanatomical structures: the reticular activating system and the cortical forebrain. However, most neuroimaging studies of delirious patients are uninformative, showing unremarkable pathological characteristics on computed tomography (CT) or magnetic resonance imaging (MRI). On the other hand, it is often speculated that some patients with delirium probably have an underlying dementing syndrome that has gone undiagnosed, in other words, that delirium can potentially represent the first symptom of dementia. Recent studies confirm the old suspicion that delirium is associated with long-term, unremitting cognitive problems : it is not uncommon to hear families complain that a patient “was never the same” after a prolonged hospital stay. This is a common consideration in older individuals and those with a history of alcoholic liver disease. Making the distinction between dementia and delirium is difficult and may be impossible using standard diagnostic technology. Although the most common form of dementia, Alzheimer’s disease, has promising biomarkers, including amyloid imaging with positron emission tomography (PET) and cerebrospinal fluid (CSF) profile of tau and amyloid proteins, it is not known whether patients with delirium have dissimilar PET or CSF profiles.

Some simple strategies (listed in Table 82-1 ) are effective at preventing delirium, at least in elderly patients. These measures have been shown to decrease the incidence of delirium by about 5% as compared to usual care; in contrast, the treatment of delirium has limited success, which makes prevention particularly relevant. Because encephalopathies are usually a consequence of a systemic process, therapy should naturally target the underlying problem. The first step in the treatment of delirium is to stabilize medically: physicians must ensure that the airway is protected and expediently address any hemodynamic derangements. Once this is appropriately covered, broad-spectrum antibiotics should be considered if the patient is hyperthermic or presents unexplained leukocytosis or leukopenia. Treatment of delirium warrants a conservative outlook: pharmacological interventions for delirium are not desirable, because psychomodulating pharmaceuticals frequently cause sedation and may potentially deteriorate a patient’s condition. In fact, many cases of delirium quickly improve after a few medications are discontinued. Polypharmacy is one of the most important factors contributing to delirium that can be modified. Pharmacological interactions may lead to unusual neuropsychiatric reactions, particularly when patients have hepatorenal dysfunction. Numerous medications are administered with little prudence to fragile patients, with the potential of worsening or inducing delirium. These medications include analgesics (opiates), antiemetics (e.g., dopamine antagonists such as metoclopramide and prochlorperazine), antihistamines (notoriously, diphenhydramine), and anticholinergics (e.g., glycopyrrolate and scopolamine). Hence a judicious management of delirium always begins with a careful look at the medication list. Physicians must consider discontinuing all drugs that are not critically needed and carefully balance the merits and disadvantages of each individual drug being used: for instance, is improving gastric emptying, preventing gastrointestinal bleeding, or controlling excess bronchial secretions more important than improving delirium? Such an exercise should be repeated on a regular basis, particularly in the face of unremitting delirium.

Knowledge of previous medications is also important, because delirium can occur as consequence of drug withdrawal. Medications that can cause a withdrawal syndrome include benzodiazepines, opiates, amphetamines, anticonvulsants (particularly phenobarbital and carbamazepine), recreational drugs (cocaine, marijuana), baclofen, and clonidine. Sudden cessation of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors may cause symptoms called discontinuation syndrome . In particular, venlafaxine (Effexor) and paroxetine (Paxil) are notorious culprits because of their relatively short half-lives.

Psychomodulating drugs should be used only when patients are in severe distress to the point that physical injury to themselves or others is imminent, or when treatment is being gravely disrupted. When the decision is made that psychoactive drugs are needed, the choice of a specific agent is based on the desired effect: decreasing psychomotor agitation, combating hallucinations, improving anxiety, or ameliorating insomnia. If a patient has hallucinations, then the drug of choice is haloperidol. If the patient has agitation or anxiety, and a withdrawal syndrome is suspected, then the drug of choice is a benzodiazepine. Haloperidol is used at a dose of 0.5 to 1 mg PO twice daily, with additional doses every 4 hours as needed. Although the recommended pathway is intramuscularly, the additional doses can be administered intravenously (IV) if patients are coagulopathic. The effects of haloperidol should be verified after 20 to 30 minutes. Other dopamine antagonists can be used, although contrary to the usual advertisement, their side-effect profile is not particularly different from haloperidol. Moreover, low-dose haloperidol has the rare advantage of having been tested in controlled randomized trials for delirium prophylaxis, where it was well tolerated. A reasonable option is quetiapine, which may also induce mild sedation to agitated patients at a dose of 12.5 to 25 mg orally every 8 to 12 hours. The major problem with dopamine antagonists, besides sedation, is the potential for extrapyramidal side effects (including tremor, bradykinesis, rigidity, tardive dyskinesis) and prolonged corrected QT interval on electrocardiogram. This class of medications should be avoided, if possible, in patients with Parkinson’s disease and neuroleptic malignant syndrome. When a benzodiazepine is used, the typical choices are lorazepam (0.5 to 1 mg IV every 2 to 4 hours as needed), diazepam, clonazepam, and midazolam. The problems with these medications are sedation and the potential for respiratory insufficiency. Their liver metabolism may also translate into a longer-than-expected half-life.

It is unclear whether pharmacological arousal makes a difference for lethargic patients. The use of amphetamines is not considered useful, and the merits of caffeine and modafinil are unclear. The recent publication of a negative study evaluating the cholinesterase inhibitor rivastigmine as adjunct to standard therapy with haloperidol illustrates the ongoing interest in the therapy of delirium and the challenges faced by this type of research.

Hemodiabsorption with activated charcoal whole-blood exchange, charcoal hemoperfusion, and plasma exchange with hemoperfusion are promising therapeutic strategies that are being tested to support liver patients. A meta-analysis of 12 randomized studies compared the efficacy of these artificial and bioartificial support systems with standard medical therapy for severe liver failure. These technologies reduced mortality in acute-on-chronic liver failure compared with standard medical therapy and decreased the risk for liver encephalopathy by about 33%. However, the significance of such findings is at this point unclear, because the various studies included in the review were heterogeneous and no effect was noted on the bridging to liver transplantation.

Finally, insomnia is a frequent problem in the hospital, which is known to exacerbate and even induce delirium. The challenge begins with the fact that hospitals are not particularly inviting environments for sleep. Nonpharmacological interventions (inelegantly called sleep hygiene ) include setting a sleep schedule, avoiding waking the patient at night for procedures or testing, reducing background noise, and providing mobilization, sunlight exposure, and physical activity whenever possible during the daytime. Pharmacotherapy with benzodiazepines or non-benzodiazepine drugs such as zolpidem, eszopiclone, and zaleplon should be avoided if possible. However, a useful alternative may be melatonin, the “hormone of darkness.” This medication was shown to be superior to placebo at increasing sleep quality and duration in 24 critically ill patients. The dose of melatonin used in this study was 10 mg PO given at 9:00 pm , but in view of a pharmacokinetics analysis, the authors suggested that 1 to 2 mg may be a more optimal dose. Another randomized, placebo-controlled trial of melatonin showed reduction in the incidence of delirium in elderly patients hospitalized to a general internal medicine service. The addition of magnesium and zinc (at doses of 225 and 12.5 mg, respectively) to melatonin also improved sleep quality in residents of a long-term care facility complaining of insomnia. These intriguing results call for investigating the effects of the tripartite combination in liver patients. Lastly, obstructive sleep apnea is a common factor disrupting the circadian rhythm of acutely ill patients, which can be treated with continuous positive airway pressure.

Specific Encephalopathies

Brain Edema

Diffuse brain edema leading to increased intracranial pressure is often seen with fulminant liver failure. The clinical manifestation is usually lethargic delirium progressing to deep coma. The diagnosis is usually based on neuroimaging. However, evidence of this complication may escape the vigilant eye of radiologists and may become clear only in retrospect. Hence a high degree of suspicion is needed. A spinal tap can be done to support the diagnosis, because brain edema is usually associated with increased opening pressure. Treatment consists of head elevation to 30 degrees, induction of hypocapnia through hyperventilation, IV sedation with propofol and fentanyl, chemical paralysis for ventilator synchrony, and the empiric use of hyperosmolar agents such as 3% saline and mannitol. Intracranial pressure monitoring devices can help guide therapy, but this is frequently hampered by the presence of coagulopathy. In refractory cases, prolonged hypothermia (using ice packs and external cooling devices for up to 5 days) has been effective in at least a handful of published cases.

Withdrawal Syndromes

Alcoholic cirrhosis is one of the major pathological conditions that can be treated with liver transplantation. Unfortunately, alcoholism has chronic neurological consequences that may not necessarily improve with the transplant; in addition, alcohol intake can recur in the posttransplantation period with the risk for toxicity to the new organ. On the other hand, benzodiazepines, opiates, anticonvulsants, and other drugs with withdrawal potential are commonly used on transplant patients, sometimes in combination. As result, withdrawal syndromes occur in transplant patients.

Delirium tremens is the most representative type of withdrawal syndrome. It is manifested by agitated delirium that usually occurs after 48 hours to 1 week of sobriety. Nevertheless, inconsistent alcohol and drug ingestion may distort the temporal association between the time of last alcohol intake and symptom onset. Symptoms of withdrawal include anxiety, insomnia, tremulousness, delusional thinking, muscle jerking, vivid visual and tactile hallucinations, and tonic-clonic generalized seizures. Hyperadrenergic signs are common accompaniments and include skin flushing, diaphoresis, hypertension, and tachycardia. Patients may be febrile, which may be confused with a picture of sepsis. Hallucinations usually consist of frightening animal imagery (particularly reptiles and insects crawling on the walls or bed), whereas tactile hallucinations mainly consist of “formication,” the false feeling of critters crawling on the skin. Wernicke’s encephalopathy may emerge in alcoholics as the agitated delirium phase subsides.

Prevention of withdrawal syndromes is paramount because these can be fatal. An invaluable tool in the prevention of this problem is the careful record of current and recently discontinued medications, as well as alcohol and illicit drug consumption. Treatment consists of rapid titration of benzodiazepines to limit agitation and decrease hyperadrenergic symptoms; subsequently a rapid taper can be attempted over 1 week if possible. It is unwise to adhere to rigid taper schedules; instead, it is recommended to assess how much benzodiazepines are needed based on the requirements of the previous 24 hours. In fact, reducing benzodiazepine dose when the patient has been agitated over the previous 24 hours may only worsen the symptoms of withdrawal. Several medications can be used in lieu of or to supplement benzodiazepines; these include carbamazepine, haloperidol, phenytoin, gabapentin, and clonidine.