Curr Neurol Neurosci Rep (2014) 14:487 DOI 10.1007/s11910-014-0487-z
NEUROLOGY OF SYSTEMIC DISEASE (J BILLER, SECTION EDITOR)
Neurologic Manifestations of Gastrointestinal and Liver Diseases José M. Ferro & Sofia Oliveira
# Springer Science+Business Media New York 2014
Abstract Hepatic and gastrointestinal disorders can produce a wide spectrum of neurologic complications both affecting the central nervous system (CNS) and the peripheral nervous system. These manifestations range in severity from coma in acute liver failure and acute pancreatitis, to minor cognitive changes in chronic portosystemic encephalopathy and hepatitis C. Cerebrovascular diseases can complicate hepatitis C infection and inflammatory bowel disease. Demyelinating disorders may co-exist with inflammatory bowel disease. Anti-tumor necrosis factor alpha drugs may induce demyelination. Ataxia may occur in malabsorption syndromes and in gluten related disorders. Characteristic movement disorders are key features of acquired hepatocerebral degeneration and of Whipple disease. Multiple types of neuropathy can be found in association with hepatitis, inflammatory bowel disease and gluten related disorders.
Keywords Hepatic failure . Hepatitis . Pancreatitis . Inflammatory bowel disease . Celiac disease . Whipple disease . Gluten ataxia . Central nervous system . Peripheral nervous system
Introduction Neurologists are often called to Internal Medicine or Gastroenterology and Hepatology wards or to Intensive care Units, to advise on the diagnosis and management of acute neurologic complications on patients suffering from acute or chronic liver failure, inflammatory bowel disease, malabsorption syndromes, and other gastrointestinal (GI) and hepatic diseases. GI disorders should be considered in the differential diagnosis of acute and chronic polyneuropathies and in the work-up of cerebral vasculitis and cerebral venous thrombosis. Several drugs used in the treatment of hepatic and GI diseases can have neurologic side effects. Conversely, drugs used in the treatment of neurologic disorders can cause hepatic dysfunction, thus, they may not be used or their dosage should be reduced in patients with hepatic failure. Patients with hepatic and chronic GI disease may also be afflicted by nonrelated neurologic conditions. Important advances made in the diagnosis and treatment of hepatic failure, hepatitis, inflammatory bowel disease, and other GI disorders and its associated neurologic manifestations, will be briefly updated in this review.
Hepatic Diseases Liver Failure This article is part of the Topical Collection on Neurology of Systemic Disease J. M. Ferro (*) Department of Neurosciences, Service of Neurology, Hospital de Santa Maria, University of Lisbon, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal e-mail: [email protected] S. Oliveira Department of Neurology, Hospital da Luz, Lisbon, Portugal
Besides the encephalopathy of acute liver failure (type A), there are 2 other types of hepatic encephalopathy: type B, encephalopathy associated with portal-systemic bypass and no intrinsic hepatocellular disease; and type C, encephalopathy associated with liver cirrhosis and portal hypertension. They share common pathophysiologic mechanisms, but in acute liver failure, the sequence of damaging events is more rapid, leading to not enough time for compensatory
487, Page 2 of 12
mechanisms to work. Although astrocyte swelling occurs both in acute and chronic encephalopathies, brain edema plays a major role in severe acute liver failure but not in chronic hepatic encephalopathy. Acute Liver Failure Acute liver failure is a rare but very severe disease, producing hepatic dysfunction, abnormal liver function tests, coagulopathy, and eventually encephalopathy, in a patient without previous hepatic disease. The time-course of the development of encephalopathy is less than 8 weeks from symptom onset, but may be as short as 1 week, in fulminant cases. Although survival has improved with modern critical intensive care and with liver transplantation, mortality still remains high (40 %). Many of the victims are young adults [1, 2]. The main causes of acute hepatic failure are dose dependent acetaminophen hepatic toxicity, other idiosyncratic druginduced liver injury, mushroom intoxication, and viral infections. Neurologic symptoms are those of encephalopathy, and due to high ammonia levels and brain edema [1, 2, 3•]. In hepatic failure, the normal detoxification of ammonia to urea is impaired. There is a good correlation between ammonia levels and the degree of encephalopathy. Ammonia is metabolized to glutamine, which increases cellular osmolality and deregulates normal cerebral mitochondrial function and neurotransmitter synthesis, in particular GABA. In acute liver failure, the rise of ammonemia is very rapid, causing astrocytic swelling. In contrast to what happens in chronic liver failure, there is no time for compensatory osmotic mechanisms. Encephalopathy is rare with ammonia levels below 75 μ/L. With ammonia levels of 150–200 μmol/L (255– 340 μg/dL); there is an increased risk of brain edema and increased intracranial pressure (ICP). There is also impaired cerebral vascular autoregulation with increase in cerebral blood flow. In younger patients with brain edema, who have no or minimal brain atrophy, intracranial hypertension rises exponentially. Bilateral diffuse brain edema eventually causes central brain herniation and brain death. Clinical Aspects Patients have jaundice, liver tenderness, and sometimes ascites, but no signs of chronic liver failure. Spontaneous hemorrhages are uncommon. Early neurologic symptoms are related to attention deficits. These can be followed by apathy or excitement, somnolence, altered judgment, and content of speech, temporal and spatial disorientation, slow responses and reasoning, and impairment in short-term memory. More severe cases are characterized by agitation, stupor or even coma. Seizures are uncommon, but either generalized focal, convulsive or nonconvulsive and
Curr Neurol Neurosci Rep (2014) 14:487
subtle seizures can occurs. Seizures aggravate brain edema and cerebral damage. Myoclonus may be present but asterixis is rare. Paratonia is common and abnormal flexor or extensor posturing may be seen, even in reversible cases. Pupils are initially unaltered but can change to bilateral fixed dilatation, if central herniation occurs. Oculocephalic reflexes are often preserved, but periodic alternating gaze deviation and dysconjugate gaze may be seen. Ancillary Procedures Laboratory findings include elevated transaminases and bilirubin levels, very high ammonia levels, hypoglycemia, hyponatremia, and other electrolyte abnormalities. Brian CT shows effacement of cortical sulci and other signs of diffuse brain edema. Besides brain edema, MR may show periventricular, thalamic and brainstem abnormalities in FLAIR, and DWI sequences, the latter related to cytotoxic edema. EEG and continuous EEG monitoring may be helpful in detecting nonconvulsive and electrographic seizures. Treatment Comprehensive intensive care, use of antidotes in cases due to acetaminophen (N-acetylcysteine) or mushroom poisoning (activated charcoal and penicillin), treatment of brain edema and early hepatic transplant, if indicated, remain the crucial aspects of acute hepatic failure [1]. Treatments used in chronic liver failure, such as neomycin and lactulose may be inappropriate in acute liver failure. Patients with encephalopathy who are agitated or have depressed levels of vigilance (grades II and IV) need to be intubated, sedated, and mechanically ventilated. Treatment of brain edema follows the general pattern of management of this condition and includes: (1) avoiding Valsalva’s maneuvers due to agitation, cough, suctioning, and motor agitation, (2) facilitating venous return by correct positioning of the head (30° elevation) and neck (straight), in neutral position, (3) detecting and treating aggravating conditions such as seizures, fever, hypertension, hypovolemia, hypoglycemia, and electrolyte disturbances, (4) osmotic therapy either with mannitol or hypertonic saline (target osmolarity
NEUROLOGY OF SYSTEMIC DISEASE (J BILLER, SECTION EDITOR)
Neurologic Manifestations of Gastrointestinal and Liver Diseases José M. Ferro & Sofia Oliveira
# Springer Science+Business Media New York 2014
Abstract Hepatic and gastrointestinal disorders can produce a wide spectrum of neurologic complications both affecting the central nervous system (CNS) and the peripheral nervous system. These manifestations range in severity from coma in acute liver failure and acute pancreatitis, to minor cognitive changes in chronic portosystemic encephalopathy and hepatitis C. Cerebrovascular diseases can complicate hepatitis C infection and inflammatory bowel disease. Demyelinating disorders may co-exist with inflammatory bowel disease. Anti-tumor necrosis factor alpha drugs may induce demyelination. Ataxia may occur in malabsorption syndromes and in gluten related disorders. Characteristic movement disorders are key features of acquired hepatocerebral degeneration and of Whipple disease. Multiple types of neuropathy can be found in association with hepatitis, inflammatory bowel disease and gluten related disorders.
Keywords Hepatic failure . Hepatitis . Pancreatitis . Inflammatory bowel disease . Celiac disease . Whipple disease . Gluten ataxia . Central nervous system . Peripheral nervous system
Introduction Neurologists are often called to Internal Medicine or Gastroenterology and Hepatology wards or to Intensive care Units, to advise on the diagnosis and management of acute neurologic complications on patients suffering from acute or chronic liver failure, inflammatory bowel disease, malabsorption syndromes, and other gastrointestinal (GI) and hepatic diseases. GI disorders should be considered in the differential diagnosis of acute and chronic polyneuropathies and in the work-up of cerebral vasculitis and cerebral venous thrombosis. Several drugs used in the treatment of hepatic and GI diseases can have neurologic side effects. Conversely, drugs used in the treatment of neurologic disorders can cause hepatic dysfunction, thus, they may not be used or their dosage should be reduced in patients with hepatic failure. Patients with hepatic and chronic GI disease may also be afflicted by nonrelated neurologic conditions. Important advances made in the diagnosis and treatment of hepatic failure, hepatitis, inflammatory bowel disease, and other GI disorders and its associated neurologic manifestations, will be briefly updated in this review.
Hepatic Diseases Liver Failure This article is part of the Topical Collection on Neurology of Systemic Disease J. M. Ferro (*) Department of Neurosciences, Service of Neurology, Hospital de Santa Maria, University of Lisbon, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal e-mail: [email protected] S. Oliveira Department of Neurology, Hospital da Luz, Lisbon, Portugal
Besides the encephalopathy of acute liver failure (type A), there are 2 other types of hepatic encephalopathy: type B, encephalopathy associated with portal-systemic bypass and no intrinsic hepatocellular disease; and type C, encephalopathy associated with liver cirrhosis and portal hypertension. They share common pathophysiologic mechanisms, but in acute liver failure, the sequence of damaging events is more rapid, leading to not enough time for compensatory
487, Page 2 of 12
mechanisms to work. Although astrocyte swelling occurs both in acute and chronic encephalopathies, brain edema plays a major role in severe acute liver failure but not in chronic hepatic encephalopathy. Acute Liver Failure Acute liver failure is a rare but very severe disease, producing hepatic dysfunction, abnormal liver function tests, coagulopathy, and eventually encephalopathy, in a patient without previous hepatic disease. The time-course of the development of encephalopathy is less than 8 weeks from symptom onset, but may be as short as 1 week, in fulminant cases. Although survival has improved with modern critical intensive care and with liver transplantation, mortality still remains high (40 %). Many of the victims are young adults [1, 2]. The main causes of acute hepatic failure are dose dependent acetaminophen hepatic toxicity, other idiosyncratic druginduced liver injury, mushroom intoxication, and viral infections. Neurologic symptoms are those of encephalopathy, and due to high ammonia levels and brain edema [1, 2, 3•]. In hepatic failure, the normal detoxification of ammonia to urea is impaired. There is a good correlation between ammonia levels and the degree of encephalopathy. Ammonia is metabolized to glutamine, which increases cellular osmolality and deregulates normal cerebral mitochondrial function and neurotransmitter synthesis, in particular GABA. In acute liver failure, the rise of ammonemia is very rapid, causing astrocytic swelling. In contrast to what happens in chronic liver failure, there is no time for compensatory osmotic mechanisms. Encephalopathy is rare with ammonia levels below 75 μ/L. With ammonia levels of 150–200 μmol/L (255– 340 μg/dL); there is an increased risk of brain edema and increased intracranial pressure (ICP). There is also impaired cerebral vascular autoregulation with increase in cerebral blood flow. In younger patients with brain edema, who have no or minimal brain atrophy, intracranial hypertension rises exponentially. Bilateral diffuse brain edema eventually causes central brain herniation and brain death. Clinical Aspects Patients have jaundice, liver tenderness, and sometimes ascites, but no signs of chronic liver failure. Spontaneous hemorrhages are uncommon. Early neurologic symptoms are related to attention deficits. These can be followed by apathy or excitement, somnolence, altered judgment, and content of speech, temporal and spatial disorientation, slow responses and reasoning, and impairment in short-term memory. More severe cases are characterized by agitation, stupor or even coma. Seizures are uncommon, but either generalized focal, convulsive or nonconvulsive and
Curr Neurol Neurosci Rep (2014) 14:487
subtle seizures can occurs. Seizures aggravate brain edema and cerebral damage. Myoclonus may be present but asterixis is rare. Paratonia is common and abnormal flexor or extensor posturing may be seen, even in reversible cases. Pupils are initially unaltered but can change to bilateral fixed dilatation, if central herniation occurs. Oculocephalic reflexes are often preserved, but periodic alternating gaze deviation and dysconjugate gaze may be seen. Ancillary Procedures Laboratory findings include elevated transaminases and bilirubin levels, very high ammonia levels, hypoglycemia, hyponatremia, and other electrolyte abnormalities. Brian CT shows effacement of cortical sulci and other signs of diffuse brain edema. Besides brain edema, MR may show periventricular, thalamic and brainstem abnormalities in FLAIR, and DWI sequences, the latter related to cytotoxic edema. EEG and continuous EEG monitoring may be helpful in detecting nonconvulsive and electrographic seizures. Treatment Comprehensive intensive care, use of antidotes in cases due to acetaminophen (N-acetylcysteine) or mushroom poisoning (activated charcoal and penicillin), treatment of brain edema and early hepatic transplant, if indicated, remain the crucial aspects of acute hepatic failure [1]. Treatments used in chronic liver failure, such as neomycin and lactulose may be inappropriate in acute liver failure. Patients with encephalopathy who are agitated or have depressed levels of vigilance (grades II and IV) need to be intubated, sedated, and mechanically ventilated. Treatment of brain edema follows the general pattern of management of this condition and includes: (1) avoiding Valsalva’s maneuvers due to agitation, cough, suctioning, and motor agitation, (2) facilitating venous return by correct positioning of the head (30° elevation) and neck (straight), in neutral position, (3) detecting and treating aggravating conditions such as seizures, fever, hypertension, hypovolemia, hypoglycemia, and electrolyte disturbances, (4) osmotic therapy either with mannitol or hypertonic saline (target osmolarity
