NEUROLOGY OF LIVER CIRRHOSIS
NEUROIMAGING CHANGES IN CHRONIC LIVER DISEASE
- Cirrhotic patients frequently display changes on neuroimaging studies; although,
these patients may or may not develop neurological symptoms [1-7].
- The most striking neuroimaging manifestation includes high symmetrical and bilateral signal intensities of various extents involving the basal ganglia and the hypothalamus on T1WI [1,
7,
8].
- Hyperintense signals in the basal ganglia,
namely the globus pallidus,
can be seen in as many as 70-100% of patients with liver cirrhosis (Fig 2) [1,
7].
Fig. 2: Symmetrical T1-hyperintensity involving the bilateral globus pallidus (arrows) in an asymptomatic 54-year old male with hepatitis-B related liver cirrhosis.
- Other sites of involvement include the pituitary gland,
contiguous internal capsule of the hypothalamus, putamen,
caudate,
substantia nigra,
and mesencephalic tegmentum (Fig 3) [8].
Fig. 3: Axial T1-weighted MR images showing hyperintense signal of the caudate nucleus (black arrows) in addition to the involvement of the globos pallidi (white arrows).
- The exact causes and mechanisms of the increased signal intensity remain indefinite,
however several hypotheses have been proposed.
Deposition of paramagnetic substances,
particularly manganese (Mn),
is speculated to be responsible for the signal alteration [1,
7,
8].
- Manganese (Mn) deposition has been attributed to liver dysfunction (hepatocellular failure) and/or portosystemic shunting [7-9].
In addition,
pallidal deposition of manganese also reflects the presence of an adaptive process designed to improve the efficacy of ammonia detoxification by astrocytes [10,
11].
- Although the mechanisms of manganese neurotoxicity are poorly understood,
there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction [12,
13].
- The pituitary gland is another commonly affected site shown on the MR images; and when involved appears homogeneously bright on spin echo T1-weighted images.
The hyperintense signal of the pituitary gland makes it impossible to distinguish between the normal isointense anterior pituitary signal and the posterior pituitary hyperintensity [8].
- Abnormalities on T2-WI within the globi pallidi have been reported to accompany the T1-WI findings,
but these findings may be masked by T1 shortening (Fig 4) [7].
Fig. 4: (A) Axial T2-WI and (B) FLAIR sequence delineating subtle symmetrical hyperintensity involving the bilateral lentiform nuclei in a young 26-year old lady with liver cirrhosis.
- Asymptomatic symmetric high-signal intensity in the hemispheric white matter on fast-FLAIR MR images is present in cirrhosis.
Normalization of this finding after successful liver transplantation and its correlation with MTR values suggest that this signal abnormality reflects mild edema (Fig 5) [8].
Fig. 5: A 40-year old male with alcoholic liver cirrhosis and grade-I hepatic encephalopathy. Fast-FLAIR MR images reveal diffuse high-signal intensity in the hemispheric white matter on either sides.
- DWI (and ADC maps) has also identified abnormalities within the periventricular white,
thalami,
and basal ganglia in studies of patients with cirrhosis with hepatic encephalopathy [9,
10].
- Although no significant relationship has been demonstrated between the presence of these signal intensity changes and the patients' neuropsychiatric status,
nevertheless,
their presence has been shown to relate to both the severity of the liver disease and the presence and degree of portal-systemic shunting of blood [10].
- Another common neuroimaging manifestation in cirrhotic patients is the presence of cerebral atrophy.
Zeneroli et al reported brain atrophy in 87.5% of alcoholic and in 50% of nonalcoholic liver cirrhosis patients (Fig 6) [14].
Fig. 6: Cerebral atrophy accompanying typical intracranial signal intensity changes in a 36-year old patient with long standing cryptogenic cirrhosis. Axial T1-WI shows symmetrical T1-prolongation of the basal ganglia (asterisk) representing manganese deposition. Attendant widening of the sylvian fissures (thick arrows) and ventricular enlargement (thin arrows) suggest cerebral parenchymal atrophy.
- Computerized (CT or MR) morphometric studies of liver-disease brains have revealed ventricular enlargement,
cisternal and sulcal prominence,
selective loss of subcortical white matter,
and prominent subarachnoid CSF spaces.
- Brain atrophy in alcoholic patients can be attributed at least in part to the toxic effect of alcohol,
whereas,
brain atrophy in nonalcoholic liver cirrhosis seems to indicate that the chronic exposure to toxins leads to neuronal alterations and cortical loss (Fig 7) [14-16].
Fig. 7: Ventricular enlargement (white arrow) and subarachnoid CSF-space (sylvian fissure) widening represent cerebral involutional changes in a 30-year old male with alcohol induced liver cirrhosis.
- Amodio et al has shown that brain atrophy in liver cirrhosis is associated with a poor psychometric performance and both brain atrophy and EEG alterations independently predict cognitive dysfunction in cirrhotic patients [16].
- Classical,
MR spectroscopy (MRS) findings include elevated glutamine/glutamate peak coupled with decreased myo-inositol and choline signals on proton MRS [17].
HEPATIC ENCEPHALOPATHY
- Hepatic encephalopathy (HE) is the most frequent cause of altered mental status and coma in cirrhotic patients.
- Patients suspected of acute HE are typically subjected to CT or MR imaging to exclude emergent phenomena such as intracranial hemorrhage or infarction [18].
- Classically,
the most accepted MR imaging finding in patients with chronic hepatic failure has been hyperintensity on T1-WI in the globi pallidi related to manganese,
but this only variably correlates with the plasma ammonia levels and acute HE symptoms.
- Acute HE has an acute phase followed by a chronic one.
Pathologically,
during the acute phase,
there is acute brain edema,
and in the chronic phase,
there is a thin cortex and cortical laminar necrosis [18].
- The proposed cytotoxic edema mechanism in HE is hyperammonia inducing intracerebral accumulation of glutamine,
resulting in astrocyte swelling and brain edema [18].
- On MR imaging,
presence of extensive cortical edema including the deep gray matter,
with symmetric involvement of the cingulate gyrus and insular cortex on DWI or FLAIR imaging,
associated with sparing of the perirolandic and occipital cortex,
appears to be a unique imaging feature of acute HE (Fig 8) [19,
20].
Fig. 8: Typical imaging manifestations of HE. Fast FLAIR images exhibit symmetrical cortical edema involving the insular cortex (arrow) and cingulate gyrus (arrowhead). Note that the occipital cortex (asterisk) is characteristically spared.
- Thus,
the cingulate gyrus and insular cortex appear to be particularly vulnerable to hyperammonemic-hyperglutaminergic encephalopathy,
while the perirolandic and occipital cortex seem relatively resistant.
These MR manifestations therefore should alert the radiologist to the possibility of acute hyperammonemic encephalopathy in appropriate clinical settings (Fig 9) [19,
20].
Fig. 9: Acute HE. DWI displaying extensive symmetrical gyral edema which characteristically involves the insular cortex (arrow) and cingulate gyrus (arrowhead); and, typically spares the perirolandic and occipital cortex (dotted arrow).
- Diffuse cortical involvement although can be reversible; often has a higher potential for neurologic sequelae [21].
Concomitant subcortical white matter,
basal ganglia,
thalami,
and brain stem involvement suggests more severe injury [19].
- The MRI extent of cortical involvement on FLAIR and DWI has been shown to strongly correlate with the maximal plasma ammonia level,
and plasma ammonia level correlates well with the clinical outcome. However MRI severity correlates only moderately with the clinical outcome [21,
22].
- On proton MR spectroscopy: an elevated glutamine/glutamate peak coupled with decreased myo-inositol and choline signals,
representing disturbances in cell-volume homeostasis secondary to brain hyperammonemia,
constitute the characteristic imaging manifestations of HE.
- Follow-up MR imaging may show diffuse cortical atrophy with T1 high signals,
involving both basal ganglia and temporal lobe cortex,
representing cortical laminar necrosis (chronic stage of HE) (Fig 10) [19].
Fig. 10: Chronic HE. Axial T1-WI showing cortical atrophy with gyriform T1-hyperintensity representing cortical laminar necrosis in a follow-up case of liver cirrhosis with recurrent episodes of grade-3 HE in the past.
- As opposed to cortical laminar necrosis of chronic HE,
cortical laminar necrosis of hypoxic brain damage preferentially involves the watershed zones or the parieto-occipital regions (as opposed to the temporal lobe cortices) [19].
- It is important to note that although pallidal (T1-WI) hyperintensities are found in approximately 90% of patients with cirrhosis,
these signal-intensity alterations are not closely linked to the presence of HE.
- Patients with cirrhosis and no clinical,
neuropsychological,
or neurophysiologic signs of HE can also show severe signal-intensity alterations,
whereas others with manifest HE may present only slight signal-intensity alterations.
ACQUIRED HEPATOCEREBRAL DEGENERATION
- Acquired (non-Wilsonian) hepatocerebral degeneration (AHD) is a rare chronic progressive debilitating neurologic syndrome that occurs in patients with chronic liver disease associated with multiple metabolic insults [23,
24].
- The pathophysiology and the locations of the cerebral injuries are incompletely understood and are not necessarily related to hyperammonaemia. However,
cerebral deposition of manganese may have a pathogenetic role [25,
26].
- AHD occurs in approximately 1% of patients with liver cirrhosis and seems related to portosystemic shunts [23].
- Clinically,
it is characterized by a combination of parkinsonism and cerebellar signs,
with neuropsychiatric changes and movement disorders usually being prominent clinical manifestations [23-26].
- The syndrome is poorly responsive to medical (antiparkinsonism drugs) therapy,
thus being considered largely irreversible [25].
- MR imaging reveals pallidal and extrapallidal lesions in most patients,
probably reflecting intracerebral deposits of manganese [23,
24].
- In addition to T1-weighted hyperintensities in the globus pallidus,
up to 75% patients also exhibit extrapallidal involvement in the form of T2-weighted hyperintensities involving the brachium pontis (middle cerebellar peduncles) and subcortical white matter (Fig 11) [23,
24].
Fig. 11: A 50-year old liver cirrhosis patient developed cognitive deficits, ataxia, dysarthria, movement disorders, and features of parkinsonism. MR images reveal symmetrical T1-hyperintensity of the basal ganglia (A) with attendant T2-hyperintense changes involving the bilateral middle cerebellar peduncles (B). Imaging findings in the light of the clinical details are in keeping with acquired hepatocerebral degeneration.
- The increased signal intensity in the middle cerebellar peduncles or dentate nuclei bilaterally on T2-weighted images is often indistinguishable from Wilson disease [23-27].
- Since the clinical symptoms,
neuropathological features and MR imaging appearances of AHD are almost similar to those seen in Wilson disease,
so it is also named pseudo-Wilson disease [27].
- The discrimination depends on the following aspects: (1) Age: Wilson disease is a genetic disease that rarely starts after the third decade,
whereas AHD occurs in those with severe liver disease of many causes at different ages.
(2) Copper metabolism: copper metabolism in Wilson's disease is out of balance so that overload copper deposits in the liver,
brain,
kidney,
cornea,
etc,
while the copper metabolizes normally in patients with AHD.
(3) Wilson disease is characterized by Kayser-Fleischer ring of the cornea which is typically absent in AHD [27].
CIRRHOSIS-RELATED PARKINSONISM
- Rapidly progressing parkinsonian symptoms,
which are unresponsive to treatment of hepatic encephalopathy,
indicate cirrhosis-related Parkinsonism [28].
- Cirrhosis-related Parkinsonism was diagnosed in 9 of 214 patients (4.2%) in a recent study by Tryc et al.
In 2 patients,
cirrhosis-related Parkinsonism was associated with hepatic myelopathy [28].
- The presence of significant porto-systemic shunts is considered a precondition for the development of Parkinsonism in patients with cirrhosis.
Moreover,
the observation of an increased manganese deposition in the basal ganglia of patients with liver cirrhosis and its relationship to the degree of porto-systemic shunting has pointed to a possible role of manganese neurotoxicity [28-32].
- The aforementioned hypothesis is supported by the observation that cirrhosis-related Parkinsonism and dystonia could be effectively treated with chelating agents,
and by reports which have shown an improvement of extrapyramidal symptoms after successful liver transplantation in parallel to the disappearance of cerebral MRI signal alterations ascribed to manganese deposition [28-32].
- MR T1-weighted images show characteristic hyperintensity of the basal ganglia including the globus pallidus,
putamen,
and caudate,
subthalamic,
and dentate nuclei with sparing of the thalamus and ventral pons (Fig 12).
When the disease is extensive,
white matter and anterior pituitary involvement can be present [32].
Fig. 12: Symmetrical T1-hyperintensity can be seen involving the basal ganglia (A, B), cerebral peduncles (C), and the dorsal aspect of pons (D) in a patient of liver cirrhosis presenting with features of parkinsonism.
- On T2-weighted images the changes may be appreciated,
however,
to a much lesser extent.
More often than not they are reported as normal on T2-WI [32].
- It has been shown that normalization of manganese blood levels improves the findings on brain MRI [33].
CIRRHOTIC or HEPATIC MYELOPATHY
- Hepatic or cirrhotic myelopathy is a rare complication of chronic liver disease that is associated with extensive portosystemic shunts [34,
35].
- The main clinical feature of hepatic myelopathy is progressive spastic paraparesis in the absence of sensory or sphincter impairment.
Typically,
a patient with underlying chronic liver disease,
develops progressive pure motor spastic paraparesis with minimal or no sensory deficit and without bowel and bladder involvement [34].
- The exact pathogenesis of HM is still unclear. However,
it has been hypothesized that the hepatocerebral dysfunction secondary to recurrent episodes of hepatic encephalopathy,
and prolonged exposure to bypassed nitrogenous waste (ammonia,
fatty acids,
indoles,
and mercaptans) cause myelin damage resulting in the pathological white matter demyelination in the brain and the spinal cord (Fig 13) [35].
Fig. 13: A 50-year old male patient with hepatic myelopathy. MR spine failed to depict any overt intramedullary signal alteration; however, screening of brain revealed symmetrical hyperintensity along the bilateral corticospinal tracts.
- Neuropathological studies show demyelination in the corticospinal tracts with varying degrees of axonal loss.
The selective predisposition for the motor system has been demonstrated by involvement of the lateral corticospinal tracts in autopsy studies [35].
- Motor-evoked potential studies may be suitable for the early diagnosis of hepatic myelopathy,
even in patients with preclinical stages of the disease [34-37].
- Early and accurate diagnosis of hepatic myelopathy is important because patients with early stages of the disease can fully recover following liver transplantation [34-36].
- Hepatic myelopathy remains a default diagnosis assigned only after the exclusion of other causes of spastic paraparesis and partial transverse myelopathy. Accordingly,
a detailed and accurate history along with appropriate imaging and laboratory findings remain crucial for establishing the diagnosis [37].
- Imaging features include increased signal intensity in lateral pyramidal tracts in the cervical cord and caudally,
on T2-weighted MRI.
However,
many a times MR may not reveal any abnormality yet the motor-evoked potential studies may indicate corticospinal electrophysiologic abnormalities [34-38].
- Motor-evoked potential studies thus play a pivotal role for diagnosing and monitoring disease progression and response to treatment [38].
- In contrast to hepatic encephalopathy,
hepatic myelopathy does not respond to blood ammonia lowering therapies but must be considered as an indication for urgent liver transplantation [6].
CIRRHOSIS-RELATED INTRACEREBRAL HEMORRHAGE
- Spontaneous intracerebral hemorrhage (ICH) accounts for 10–15% of all cases of stroke and systemic hypertension,
elderly age group and alcohol consumption constitute the most important risk factors [39,
40,
44].
- The risk for development of ICH in patients with liver cirrhosis is debatable; nonetheless,
various studies have proposed that liver cirrhosis is a risk factor for ICH [39-44].
- Chronic liver disease is a risk factor for ICH primarily due to impaired coagulation.
Coagulopathy in patients with liver disease results from impairments in the clotting and fibrinolytic systems,
as well as from reduced number and function of platelets (Fig 14,
15) [41].
Fig. 14: Unenhanced CT in a liver disease patient with deranged coagulation profile shows a large intraparenchymal hematoma (thick white arrow) in right frontal lobe with contiguous extension into the ipsialteral ventricle (dotted arrow). In addition, there is synchronous contralateral intracerebral bleed seen in the left frontal region (thick black arrow). Furthermore, there is evidence of extra-axial bleed that can be seen along the interhemispheric fissure (thin black arrow).
Fig. 15: Infratentorial bleed in a delirious patient with decompensated liver cirrhosis. Axial CT sections reveal a large hematoma involving the cerebellar vermis (arrow) causing compression and effacement of the fourth ventricle with upstream obstructive ventriculomegaly (arrowhead). The cerebral sulci are effaced and the cortico-medullary junction indistinct (asterisk) suggesting raised intracranial pressure.
- Huang et al recently reported an overall incidence of 0.8% in a retrospective study of 4515 patients with liver cirrhosis.
The incidence in the alcohol-related group was 1.9% whereas the virus-related group had an incidence of 0.3%.
A combined group (patients with both virus- and alcohol-related cirrhosis) had an incidence of 3% [39].
- The relation between high alcohol intake and ICH may involve several mechanisms among which alcohol-induced hypertension and coagulation disorders are speculated to be the most likely etiological factors [41].
INFECTIVE COMPLICATIONS OF CIRRHOSIS
- Cirrhosis has been characterized as the commonest acquired immunodeficiency syndrome worldwide (exceeding even AIDS) and infectious complications in cirrhotic patients can cause severe morbidity and mortality [45,
46].
- Bacterial infections have been acknowledged as an important factor in disease mortality and are estimated to cause up to 25% of deaths in cirrhotic patients [45,
46].
- The specific risk factors for infection in cirrhotic patients are low serum albumin,
gastrointestinal bleeding,
repeated intensive care unit admissions for any cause,
and therapeutic endoscopy [45].
- Certain infectious agents that are more virulent and more common in patients with liver disease include Vibrio,
Campylobacter,
Yersinia,
Plesiomonas,
Enterococcus,
Aeromonas,
Capnocytophaga,
and Listeria species,
as well as organisms from other species [45].
- Changes in gut motility,
mucosal defense and microflora allow for translocation of enteric bacteria into the blood stream (bacteremia).
Additionally,
the cirrhotic liver is ineffective at clearing bacteria and associated endotoxins from the blood thus allowing for seeding of the sterile peritoneal fluid [47].
- Compared to the general population,
the mortality of infections is more than 20 times increased in cirrhosis.
The incidence of bacteremia,
peritonitis,
urinary tract infection,
pneumonia, meningitis,
and tuberculosis is increased more than tenfold,
and the mortality of each episode 3-10 times higher [48].
- Liver cirrhosis patients are at increased risk of bacterial meningitis and often have a poor prognosis (Fig 16) [49,
50].
- Molle et al in a nation-wide cohort of 22,743 patients (with liver cirrhosis in Denmark) reported an incidence rate of bacterial meningitis of 54.4 per 100,000.
The highest incidence rate was found in patients with alcoholic cirrhosis,
65.3 per 100,000 person-years.
The 30-day case fatality rate was 53.1% (95% CI 38.3-67.5),
and high age and alcoholic cirrhosis were associated with the highest case fatality rates [50].
Fig. 16: Pyogenic meningitis and ventriculitis in a 42-year old patient with NASH related liver cirrhosis. Post gadolinium T1-WI reveals inflammation, thickening and abnormal enhancement of the right lateral ventricle ependyma (A, B) and choroid plexus (C) in keeping with ventriculitis and choroid plexitis. In addition, abnormal leptomeningeal enhancement can be seen along the right mesial temporal lobe (D) in keeping with leptomeningitis.
- The main bacterial pathogens include Streptococcus pneumoniae,
Escherichia coli,
Listeria,
and unspecified bacteria [49-51].
- Often,
nuchal rigidity may be a delayed or even absent clinical sign.
Also,
the initial presentation of brain abscess may not be fever or leukocytosis,
but focal neurologic deficits [49-51].
- Mortality may reach 80% in patients with Child-Pugh stage C cirrhosis [49,
50].
Fig. 17: Miliary tuberculosis in a middle aged liver cirrhosis patient with history of longstanding alcohol abuse. Contrast enhanced T1-WI shows multiple pinhead sized enhancing granulomas randomly scattered in the bilateral cerebral hemispheres.
- Lastly,
intracranial tuberculosis should also be kept in mind when confronted with brain space-occupying lesions in the immunocompromised or malnutritional hosts such as liver cirrhosis (Fig 17) [52].
DIFFUSE CEREBRAL EDEMA IN ACUTE or ACUTE-ON-CHRONIC LIVER FAILURE
- Cerebral edema is very common in patients with fulminant or acute liver failure.
In severe cases,
this can lead to potentially fatal herniation [53].
- Whilst the primary cause of death in patients with acute liver failure (ALF) is multi-organ failure; cerebral edema and ensuing brain herniation constitute a major cause of mortality [54].
- Brain swelling in acute liver failure is produced by a combination of cytotoxic (cellular) and vasogenic edema [53-55].
Although cytotoxic edema appears predominant event leading to cerebral edema,
vasogenic edema presumably represents secondary event causing intracranial hypertension [56].
- Cytotoxic brain edema is presumably secondary to astrocytic accumulation of glutamine,
whilst vasogenic edema represents an increase in cerebral blood volume and cerebral blood flow,
in part due to inflammation to glutamine and to toxic products of the diseased liver [54-56].
- Astrocyte swelling has been demonstrated to be the commonest histological feature in patients with ALF [56].
- Ranjan et al have demonstrated significantly lower apparent diffusion coefficient in cortical and deep white and gray matter regions of interest (on MRI performed in patients with ALF) compared to controls (p < 0.001),
suggesting cytotoxic cell swelling as the primary cause of cerebral edema [57].
- The most accurate method of diagnosing cerebral edema is intracranial pressure monitoring [54].
- CT & MR imaging is valuable not only to visualize signs of cerebral edema which include sulcal and cisternal effacement,
loss of distinction between the grey and white matter and indistinct boundaries of the lenticular nucleus,
but,
also for excluding hemorrhagic complications as most of these patients are coagulopathic (Fig 18,
19) [53].
Fig. 18: Diffuse cerebral edema in a patient with acute on chronic (Hepatitis-B and C related)liver failure. Noncontrast CT shows effaced sulci with loss of cortico-medullary differentiation and indistinct margins of the lenticular nuclei suggesting diffuse cerebral edema and raised intracranial tension.
Fig. 19: Fulminant hepatic failure. T2W MR imaging reveals effaced cerebral sulci with slit-like ventricles (A, B) and diffuse gyral swelling (C, D) in keeping with diffuse ceerbral edema. The cisternal spaces are also effaced suggesting impending herniation (C, D).
- Although CT and MR imaging have been traditionally considered unreliable for the diagnosis of intracranial hypertension (owing to their poor correlation with intracranial pressure); nonetheless,
if interpreted carefully they can provide pivotal information [53,
58,
59].
- Also,
cross sectional imaging is effective at establishing the diagnosis of cerebral herniation,
which will guide important decisions regarding therapeutic options and prognosis (Fig 20).
Fig. 20: (A, B) Sagittal and axial T2-WI show bilateral medial part of the temporal lobes protruding over the tentorial edge in keeping with uncal herniation (black arrows). In addition, there is downward cerebellar herniation (tonsillar herniation or coning) seen in this patient of fulminant hepatic failure. The patient was subsequently declared brain dead and succumbed to the disease.
- Therapeutic measures proposed to control intracranial hypertension in liver failure patients mainly include administration of mannitol,
hypertonic saline,
indomethacin,
thiopental,
and hyperventilation [53-56].
ALCOHOL-RELATED NEUROLOGICAL DISORDRES
- The pathogenesis of alcohol‐related neurological damage has been considered to be multifactorial and attributed to genetic predisposition,
nutritional factors,
and the neurotoxic effects of ethanol or its metabolites [60,
61].
- Alcohol related neurological disorders that may complicate alcohol related liver disease may range from Wernicke's encephalopathy,
hepatocerebral degeneration,
head trauma,
central pontine myelinolysis,
Marchiafava-Bignami syndrome to ethanol neurotoxicity [61,
62].
OSMOTIC DEMYELINATION SYNDROMES
- Adams and colleagues in 1959 described central pontine myelinolysis (CPM) as a disease affecting alcoholics and the malnourished [63].
- The concept was extended from 1962 with the recognition that lesions can occur outside the pons,
so-called extrapontine myelinolysis (EPM).
In 1976 a link between these disorders and the rapid correction of sodium in hyponatraemic patients was suggested,
and by 1982 substantially established [64].
- The association with alcoholism was the first to be noted and continues to be particularly frequent (in up to 40% of cases). It has been suggested that alcohol itself interferes with sodium/water regulation by suppression of antidiuretic hormone,
and inadequate nutrition of alcoholics is an obvious accompaniment [64-66].
- CPM is also a recognized complication of liver transplantation.
In a 10 year retrospective series of 627 transplants it occurred in 2% of cases (and contributed to the overall neurological complication rate of 26%) [64,
65].
- Clinically,
whenever a patient who is gravely ill with alcoholism and malnutrition or a systemic medical disease develops confusion,
quadriplegia,
pseudobulbar palsy,
and pseudo coma (‘locked-in syndrome’) over a period of several days,
a diagnosis of osmotic demyelination (CPM) should be considered [64].
- Radiological confirmation is necessary to exclude other diagnosis and to determine the exact extension of the demyelination.
Since CT can underestimate the real extension MRI plays a pivotal role in the determination of the presence,
number and extension of the lesions [65].
- In acute CPM,
MRI shows signal alteration in the central pons with sparing of the tegmentum,
ventrolateral pons and corticospinal tracts (Fig 21,
22).
Fig. 21: Central pontine myelinolysis. Sagittal T2-WI shows relatively bulky appearing pons with attendant signal intensity changes (black arrow) in a 48-year old patient with alcoholic liver cirrhosis.
Fig. 22: (A, B) Axial Fast FLAIR and T2-WI of the aforementioned patient shows hyperintensity involving the central pons with characteristic sparing of the periphery. Careful evaluation suggests that there is predominant involvement of the transverse pontine fibres - finding which is quite characteristic of CPM.
- In EPM,
symmetric signal alterations can be seen in the basal ganglia,
thalami,
lateral geniculate body,
cerebellum,
and cerebral cortex (Fig 23) [66].
Fig. 23: Extra-pontine myelinolysis. Axial FLAIR images showing extra-pontine areas of signal alteration (demyelination) involving the left thalamus (white arrow) and the right cerebellar hemisphere (black arrow) in a malnourished chronic alcoholic male patient with decompensated liver cirrhosis.
- About 25–50% of patients with CPM also have EPM; this usually affects the cerebellum but may also affect parts of the cerebrum.
In up to 25% of patients the demyelination is exclusively extrapontine [67].
WERNICKE ENCEPHALOPATHY
- Wernicke encephalopathy (WE) is a neurologic emergency caused by a thiamine deficiency.
It is commonly seen in the alcoholic population but can also be seen with malignancy,
total parenteral nutrition,
abdominal surgery,
hyperemesis gravidarum,
hemodialysis,
or any situation that predisposes an individual to a chronically malnourished state [66].
- If untreated,
irreversible brain damage may ensue and could even lead to coma,
death,
or Korsakoff syndrome,
a permanent brain injury that results in antegrade amnesia and confabulation.
The classic triad of WE includes ataxia,
global confusion,
and opthalmoplegia.
- CT has been shown to have a low sensitivity for the detection of WE,
and when findings are present,
they are often nonspecific areas of low density [66].
Fig. 24: Wernicke encephalopathy. Axial T2-WI showing confluent areas of increased intensity surrounding the aqueduct and the third ventricle in a debilitated and malnourished patient of alcohol induced liver cirrhosis complaining of ataxia and opthalmoplegia.
Fig. 25: Coronal T2-WI showing bilateral areas of increased intensity surrounding the aqueduct and the third ventricle contiguously extending into the mamillary bodies.
Fig. 26: Fast FLAIR images of the same patient showing symmetrical signal alterations at characteristic sites including periventricular region of the third ventricle, periaqueductal area, thalamus, and mamillary bodies.
- On MRI,
typical manifestations include symmetrical areas of increased T2- and FLAIR signal intensity surrounding the aqueduct and the third ventricle,
at the floor of fourth ventricle,
in the medial thalami,
and in the capita of caudate nuclei (Fig 24-26) [66].
- MR spectroscopy (MRS) may depict lactate peak and low levels of N-acetylaspartate (N-NAA)/creatine (Cr) in the affected areas but does not have a clinical prognostic impact [66].
MARCHIAFAVA-BIGNAMI DISEASE (MBD)
- MBD is a rare disorder that results in progressive demyelination and necrosis of the corpus collosum.
MBD is generally associated with chronic alcohol abuse but is occasionally seen in nonalcoholic patients.
MBD is most prevalent in men between 40 and 60 years of age [66].
- The main pathologic change associated with MBD is degeneration of the corpus callosum,
which may vary from demyelination to frank necrosis.
- The disease may present in two major clinical forms: acute and chronic.
In the acute form,
which often results in death,
patients present with severe impairment of consciousness,
seizures,
and muscle rigidity.
The chronic form of the disease may last for several months or years and is characterized by variable degrees of mental confusion,
dementia,
and impairment of gait.
- CT shows diffuse periventricular low density and focal areas of low density in the genu and splenium of the corpus callosum.
On MRI,
there is high T2-and FLAIR signal intensity changes involving the body of the corpus callosum,
genu,
splenium,
and adjacent white matter.
These appear hypointense on T1-WI and during the acute phase,
may show peripheral contrast enhancement [66].
Fig. 27: Sagittal T2-WI in a chronic alcoholic male showing relatively atrophic posterior body of the corpus callosum (white arrow) with focal area of signal alteration within the splenium (black arrow). In addition, note is made of disproportionate cerebellar atrophy (arrowhead) - likely representing alcoholic cerebellar degeneration.
- As the disease progresses,
signal alterations become less evident,
but residual atrophy of the corpus callosum is usually observed (Fig 27).
MBD may be found in association with other alcohol-related diseases,
including WE,
Korsakoff syndrome,
and central pontine myelinolysis [66].
ALCOHOL WITHDRAWAL SYNDROME (AWS)
- Alcohol withdrawal syndrome (AWS) is a constellation of symptoms observed in a person who stops drinking alcohol after a period of continuous and heavy alcohol consumption [66].
- In AWS,
disturbances in cognition,
perception hallucinations,
visual impairment,
nausea,
and tinnitus are thought to relate to cortical dysfunction.
Tremor,
sweating,
depression,
and anxiety are related to effects on the limbic system.
Changes in consciousness and gait disorders are associated with brainstem involvement.
Fig. 28: Axial FAST FLAIR image in a liver cirrhosis patient with auditory hallucinations following alcohol withdrawal showing subtle symmetrical bi-temporal hyperintensity (arrows).
- In alcoholics with withdrawal seizures,
MRI depicts cytotoxic edema in temporal regions during the acute and subacute phases and significant volume loss (Fig 28).
It could therefore be deduced that epileptic seizures affect alcoholic subjects similarly to temporal epilepsy,
in which reversible edema with some volume loss and consequent hippocampus atrophy is observed [66].
- Reversible vasogenic edema in the cerebellum; thalami; and cortical,
subcortical,
and deep parietal white matter has also been described in the clinical setting of posterior reversible encephalopathy syndrome complicating alcohol withdrawal [66].
ALCOHOLIC COGNITIVE DECLINE AND CEREBRAL ATROPHY
- Approximately 50 - 70 % of alcohol abusers have cognitive deficits on neuropsychological testing.
Imaging tests,
neuropathological observations,
and animal studies suggest that ethanol neurotoxicity may contribute to this cognitive dysfunction [68-70].
- Nevertheless,
there is no unequivocal evidence for a brain lesion in humans that is caused solely by chronic ethanol ingestion and that is unrelated to coexisting nutritional deficiency,
liver disease,
or trauma.
- CT and MRI show enlargement of the cerebral ventricles and sulci in the majority of alcohol abusers.
There is evidence for regional vulnerability in the brains of alcohol abusers with frontal lobe changes being the most pronounced (Fig 29).
- Neuronal density in the superior frontal cortex was reduced by 22 percent in alcohol abusers compared with nonalcoholic controls in one report.
Selective loss of neurons in frontal brain regions is mirrored by regional hypometabolism on PET studies,
and might correlate with deficits in working memory observed in alcohol abusers [68-69].
Fig. 29: Axial FLAIR and T2WI showing selective bi-frontal cerebral atrophy in a 36-year old chronic alcoholic male patient with underlying liver cirrhosis.
- Quantitative morphometry suggests that alcohol abusers,
including those with liver disease and Wernicke encephalopathy (WE),
lose a disproportionate amount of subcortical white matter compared with cortical gray matter [68,
69].
- The loss of cerebral white matter is evident across a wide range of ages,
and is of sufficient magnitude to account for the associated ventricular enlargement.
Diffusion-tensor imaging detects microstructural abnormalities in the white matter tracts of alcohol abusers even in the absence of macroscopic lesions.
- MRI imaging of alcohol abusers shows an increase in white matter volume following three months of abstinence,
suggesting that a component of the white matter injury is reversible.
ALCOHOLIC CEREBELLAR DEGENERATION
- Besides the frequently reported effects of ethanol on supratentorial brain,
cerebellar involvement is also commonly observed in chronic alcoholics [71,
72].
- Alcoholic cerebellar degeneration typically occurs after 10 or more years of alcohol abuse.
These chronic ethanol abusers develop a chronic cerebellar syndrome related to the degeneration of Purkinje cells in the cerebellar cortex.
- Midline cerebellar structures,
especially the anterior and superior vermis are predominantly affected [71,
72].
- Symptoms,
primarily related to gait disturbance,
usually develop gradually over weeks to months,
but it may also evolve over years or commence abruptly.
Fig. 30: Alcoholic cerebellar degeneration. DIffuse cerebellar atrophy is seen in the form of cerebellar foliar prominence, ventricular enlargement and prominence of the infratentorial subarachnoid CSF spaces in a 44-year old male cirrhotic with history of chronic alcohol abuse.
- CT or MRI scans typically show cerebellar cortical atrophy,
however,
one-half of alcoholic patients with this finding may not be ataxic on examination.
In addition,
a structural imaging study is also required to exclude mass lesions or other diagnoses (Fig 30) [71,
72].
- The absence of cranial nerve abnormalities differentiates alcoholic cerebellar degeneration from vascular disorders of the posterior circulation,
mass lesions,
and demyelinative disease.
The age of onset and clinical course sets this disorder apart from some of the spinocerebellar ataxias.
Multiple systems atrophy,
including olivopontocerebellar degeneration,
may be difficult to distinguish on clinical grounds alone and require corroboratory imaging studies.
WILSON DISEASE-RELATED NEUROIMAGING MANIFESTATIONS
- Wilson disease is an uncommon,
autosomal recessive,
inborn defect in copper metabolism characterized by abnormal accumulation of copper in various tissues,
particularly in the liver and the brain [73].
- In Wilson disease,
ceruloplasmin,
the serum transport protein for copper,
is deficient.
Copper accumulates in the tissues of patients primarily in the liver and later in the brain.
- Despite the ubiquitous presence of toxic copper within the brain,
pathologic findings are limited primarily to the basal ganglia,
thalamus,
and brain stem.
The initial neurological presentations frequently include dysarthria and tremors,
with later manifestations of neuropsychiatric problems,
and Parkinsonian tremors,
ataxia,
dystonia,
and chorea.
- The most frequently identified abnormality on MR imaging was bilateral symmetric high signal intensity in the putamen on T2-weighted images,
followed by the caudate nucleus,
globus pallidus,
thalamus,
midbrain (Fig 31) [73,
74].
Fig. 31: Axial T2-WI in a patient with Wilson disease depicting symmetrical increased signal intensity of the bilateral lentiform nuclei (ahite arrow), thalami (black arrow) and caudate nuclei (arrowhead).
References: Image reproduced from: Arora A et al. Intracranial MR manifestations of Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518
- Diffusion-weighted images can show areas of restricted diffusion early in the disease process due to cytotoxic edema or inflammation due to excessive copper deposition (Fig 32).
However,
this restricted diffusion is not seen in chronic cases [73].
Fig. 32: DWI in a patient with Wilson disease depicting diffusion restriction involving the lentiform and caudate nuclei (hepatolenticular degeneration) during the acute phase of the disease.
References: Image reproduced from: Arora A et al. Intracranial MR manifestations of Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518
- Hypointensity on T2-weighted images can be seen sometimes,
secondary to copper deposition or iron deposition (Fig 33) [73].
Fig. 33: Axial T2WI (A) and T2*GRE (B) showing hypointense signal and blooming reflecting heavy metal deposition in the lentiform nuclei in a patient of Wilson disease.
- High-signal-intensity lesions in the basal ganglia on T1-weighted images reflects hepatic involvement of Wilson disease—namely,
chronic liver disease or liver cirrhosis; and,
is often the most common initial abnormality detected (Fig 34).
Fig. 34: Symmetrical increased T1-signal intensity involving the lentiform nuclei in a patient of Wilson disease.
References: Image reproduced from: Arora A et al. Intracranial MR manifestations of Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518
- Diffuse brain atrophy suggests a generalized susceptibility and longstanding effect of the central nervous system to copper intoxication.
- ‘Face of the Giant Panda’ is an uncommon intracranial manifestation of Wilson’s disease which was first described by Hitoshi et al in 1991.
This appearance is caused by a combination of signal intensity changes at the level of midbrain on T2-WI.
These include: high signal intensity in the tegmentum,
normal signals in the red nuclei and lateral portion of the pars reticulata of the substantia nigra,
and hypointensity of the superior colliculus (Fig 35) [73,
74].
Fig. 35: (A, B) Giant panda sign in a young patient of Wilson disease. (C) The sign is due to a combination of high signal intensity in the tegmentum (black arrow) with sparing of the red nuclei (dotted arrow), pars reticulate (white arrow) and the superior colliculi (arrowhead).
References: Image reproduced from: Arora A et al. Intracranial MR manifestations of Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518
Fig. 36: Giant panda cub. Axial T2WI in a patient of Wilson disease depicting signal alteration in the dorsal pons simulating the face of a giant panda - popularly referred to as 'giant panda cub' sign.
References: Image reproduced from: Arora A et al. Intracranial MR manifestations of Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518
- The exact pathogenesis of this SIGN is not known,
but it is postulated that the paramagnetic effects of the deposition of heavy metals,
such as iron and copper,
may be responsible.
It is believed that iron is assumed to play a more important role than copper in reducing the signal intensity of the superior colliculi on the T2-weighted scan.
At times,
signal alteration may also be encountered within the dorsal pons which has been popularly called as ‘Giant Panda Cubs’ (Fig 36) [74].
HCV-RELATED CNS COMPLICATIONS
- Chronic infection with hepatitis C virus (HCV),
a hepatotropic and lymphotropic agent,
is a growing global health issue affecting an estimated 170 million people [75].
- Neurological complications occur in a large number of patients and the speculative pathogenetic mechanisms responsible for nervous system dysfunction are mainly related to the upregulation of the host immune response with production of autoantibodies,
immune complexes,
and cryoglobulins [75].
- HCV-related CNS complications encompass a wide spectrum of disorders ranging from cerebrovascular events to autoimmune syndromes [75-79].
- ACUTE CEREBROVASCULAR EVENTS: including ischemic stroke,
transient ischemic attacks,
lacunar syndromes (Fig 37),
or rarely hemorrhages (secondary to occlusive vasculopathy and vasculitis),
have been reported,
being the initial manifestation of HCV infection in some cases [75,
76].
Fig. 37: Transient ischemic attacks in a 39-year old patient with chronic (hepatitis-C related) liver disease. DWI reveals multiple acute lacunar infarcts involving the left pareito-temporal and right cerebellar hemisphere - possibly secondary to occlusive vasculopathy or vasculitis.
- ACUTE OR SUBACUTE ENCEPHALOPATHIC SYNDROMES: clinically characterized by cognitive impairment,
confusion,
altered consciousness,
dysarthria,
dysphagia,
and incontinence,
have been associated with diffuse involvement of the white matter in HCV chronically infected patients.
An ischemic pathogenesis of these rapidly evolving syndromes is supported by MRI findings showing small lesions in subcortical regions and periventricular white matter (Fig 38).
Moreover,
severe and diffuse infra- and supratentorial white matter alterations,
highly suggestive of vasculitis,
are observed in subjects with coincidental systemic vasculitis [75].
Fig. 38: A young 36-year old patient of hepatitis-C related liver cirrhosis and progressive neurocognitive decline. Axial FAST FLAIR imaging reveals bilateral multifocal patchy and confluent areas of subcortical white matter hyperintensities.
- COGNITIVE DECLINE: slowly evolving cognitive decline,
clinically characterized by impairment of attention,
executive,
visual constructive,
and spatial functions,
has been correlated to an increased occurrence of periventricular white matter high intensity signals on T2-weighted MRI (Fig 39).
White matter hyperinyensities likely reflect the occurrence of small vessel disease,
which leads to chronic hypoperfusion of the white matter and local alteration of the blood-brain barrier [75].
Fig. 39: A 45-year old male with (hepatitis-C) liver cirrhosis and rapidly progressive dementia and neurocognitive decline. FAST FLAIR images reveal patchy and confluent areas of signal alteration involving the periventricular as well as hemispheric white matter.
- ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM): Sacconi and Sim et al.
have described ADEM,
an autoimmune postinfectious CNS disease,
developing after HCV infection and responsive to steroid therapy,
further supporting the role of cellular immune mediated mechanisms in CNS complications of HCV infection [77,
78].
- MYELITIS: is an infrequent neurological complication in patients chronically infected with HCV.
HCV-related myelitis occurs acutely or subacutely,
the neurological presentation ranging from transverse myelitis to acute partial transverse myelopathy,
or spastic paraplegia; many patients present a recurrent course and have a multisegmental spinal involvement at MRI,
usually at cervical and thoracic levels [75,
79].
LIVER TRANSPLANTATION-RELATED COMPLICATIONS
Neurologic complications are more common after liver transplantation than other solid-organ transplants primarily due to the poorer clinical condition of liver disease patients due to malnutrition,
coagulopathy,
electrolyte imbalance,
and pre-transplant encephalopathy.
In addition,
the highly complex and lengthy surgical procedure with major hemodynamic changes and blood/fluid shifts also predisposes these patients to develop diverse neurological problems [80,
81].
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
- Posterior reversible encephalopathy syndrome (PRES) is an increasingly recognized neurological complication after transplantation with an overall incidence of approximately 1% following liver transplantation [82,
83].
- The syndrome is likely initiated by a leakage of fluid into the interstitium of the brain tissue that is detected as vasogenic edema.
- The exact pathophysiology is poorly understood but the widespread vasoconstriction induced by calcineurin inhibitors (cyclosporine/ tacrolimus) may lead microvascular damage with disruption of the blood–brain barrier,
increasing the risk of neurologic dysfunction posttransplant [82,
83].
- Other vascular phenomena,
such as hypertension with the failure of vascular autoregulation and hyperperfusion,
have also been implicated as the cause of edema development in PRES.
- Patients with a pre-liver transplant history of alcoholic liver disease are more likely to develop PRES.
Chronic alcohol presumably creates alterations in cerebral blood flow and induce morphologic and biomechanical changes in cerebral vessels resulting in more friability and less elasticity of blood vessels which may influence cerebral blood flow distribution possibly contributing to the development of PRES [82,
83].
- Characteristic clinical findings include altered mental status,
seizures,
visual abnormalities,
and/or focal neurological deficits.
- PRES is diagnosed radiologically,
often by a distinguishing imaging pattern involving the cortical or subcortical areas of the parietal or occipital lobes (hence the name ‘posterior’).
- CT or MR imaging typically show reversible vasogenic edema of the white matter commonly in areas of parenchyma supplied by posterior circulation; however,
involvement of other areas such as frontal lobes,
basal ganglia and brain stem are also reported (Fig 40) [82,
83].
Fig. 40: PRES in a post liver-transplant patient. Axial FAST FLAIR sequence exhibiting cortico-subcortical areas of T2-hyperintensity in the parieto-occipital region.
- Additionally concomitant hemorrhage can occur in up to 15% of patients with PRES (Fig 41).
Fig. 41: Axial T2*GRE image of the hitherto discussed patient with PRES showing punctate areas of blooming in keeping with petechial hemorrhages in the left occipital lobe.
- If timely diagnosed,
the patients experience a good recovery without sequelae.
Nevertheless,
when unrecognized,
PRES can progress to ischemia or massive infarction with significant morbidity and mortality [82,
83].
IMMUNOSUPPRESSANT-RELATED LEUKOENCEPHALOPATHY
- A wide variety of neurologic side effects has been described with the use of immunosuppressant drugs – most of them being minor (for e.g.
headache,
tremor,
paresthesia).
However,
immunosuppression-associated major neurotoxicity such as leukoencephalopathy may develop in some post transplant recipients [84-86].
- Leukoencephalopathy syndrome is a neurologic complication caused primarily by the neurotoxic effects of immunosuppressive agents on cerebral white matter [84].
- Tacrolimus and cyclosporine are lipophilic immunosuppressant agents that cross the blood-brain barrier and are speculated to have a direct neurotoxic effect especially on the lipid-rich white matter [85].
- The reported incidence of leukoencephalopathy syndrome in liver transplant recepients is 0.4% to 6% [84].
- Time to onset of leukoencephalopathy syndrome in liver transplantation tends to be shorter than in other organ transplantations,
and in most cases,
it occurs within first three months of the transplantation [84].
- Clinically,
it is characterized by a reversible syndrome of headaches,
sudden onset of seizures,
visual abnormalities,
and hemiparesis [84-87].
- The diagnosis of leukoencephalopathy requires either CT or MR imaging – MR imaging indubitably has a higher sensitivity for delineating the pathology.
T2-WI MRI characteristically shows high-signal intensity involving the occipital,
parietal,
and temporal white matter in a scattered fashion (Fig 42) [84].
Fig. 42: Immunosupressive leukoencephalopathy. A 56-year old post liver transplant patient on tacrolimus complaining of unrelenting headaches and visual disturbances. MR images show multifocal areas of white matter signal alteration involving the parieto-occipital lobes and right fronto-parietal region appearing bright on T2WI (A) and dark on T1WI (B).
- Clinico-radiological differentiation from progressive multifocal leukoencephalopathy (PML) can be challenging [84,
85].
A biopsy procedure is usually not considered to be necessary to differentiate between the two especially when after cessation or dose reduction of tacrolimus the clinical condition improves.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
- Progressive multifocal leukoencephalopathy (PML),
a progressive demyelinating disease of the brain caused by JC virus (JCV),
can be seen following liver transplantation and other conditions associated with immunosuppression [88].
- Clinical course of PML is characterized by a rapid progressive neurological decline (hemiparesis,
visual field deficits,
and cognitive impairment) coinciding with the presence of white matter lesions on cross sectional neuroimaging [89].
- In late stages of disease,
patients can develop cortical blindness,
quadriparesis,
severe dementia and even coma.
Death usually occurs within 6 months of diagnosis [90].
- MRI is undoubtedly more sensitive than CT in depicting the white matter changes [89].
- On MRI,
PML lesions typically appear as hyperintense signal on T2-weighted and FLAIR images (corresponding hypointense signal on T1-WI) involving the subcortical white matter,
devoid of contrast enhancement or mass effect [88].
The lesions are multifocal albeit most commonly involve the parieto-occipital white matter (Fig 43).
Fig. 43: Suspected PML in a 44 year old post liver transplant patient with neurocognitive decline. Axial FLAIR images showing patchy and conflueent scattered hyperintensities in bilateral parieto-temporal and frontal white matter.
- The gold standard for the diagnosis of PML is a brain biopsy,
although the combination of a recent onset of neurological disease with white matter lesions on MRI and a positive PCR for the JC virus in the CSF can confirm the diagnosis in the absence of a brain biopsy [89].
- PML is distinguished from immunosuppressant neurotoxicity by its rapid radiological and clinical progression [91].
- There is no direct antiviral therapy available against the JC polyomavirus.
Restoration of the immune response achieved by tapering or terminating the immunosuppressive regimen is the mainstay of treatment.
However,
the prognosis remains extremely poor regardless of treatment [89].
CEREBROVASCULAR COMPLICATIONS
- Cerebrovascular complications,
including ischemic strokes and intracranial hemorrhage,
have been reported to be prevalent in 2-4% of liver transplant recipients [92].
- An increased risk of intracranial hemorrhage has been demonstrated in patients with thrombocytopenia,
old age,
and overwhelming infections.
That risk is further compounded by coagulopathy associated with hepatic failure (Fig 44) [92].
Fig. 44: Multifocal areas of bilateral intracerebral hemorrhage in a 56-year old post liver-transplant patient.
- Other less common causes of intracranial bleeding in post transplant recipients include Aspergillus angiopathy and mycotic aneurysms.
- In addition,
hypercholesterolaemia,
diabetes,
and hypertension secondary to long term use of immunosuppressive therapy may also compound the risk of cerebral bleeds.
- Ischemic strokes are overall less common than intracranial hemorrhages,
and are often associated with similar risk factors as in general population,
including hypertension. Hepatic encephalopathy is also associated with dysregulation of cerebral blood flow autoregulation (Fig 45) [92].
Fig. 45: Right middle cerebral artery (MCA) infarct. Axial T2WI (A) and DWI (B) showing acute infarct with diffusion restriction involving the right temporal lobe in the MCA territory.
- Perioperative events,
such as cerebral hypoperfusion and massive transfusion,
may also favor cerebrovascular injury.
Fig. 46: Anoxic-hypoxic ischemic encephalopathy following liver transplant (day-3). DWI showing diffusion restriction and extensive gyral swelling involving the bilateral cerebral hemispheres in a contiguous fashion.
- Diffuse cortical (laminar) necrosis in the setting of acute anoxic insult (global hypoperfusion) has a universally poor prognosis with most patients either progressing to brain death or remaining in a persistent vegetative state [92].
POST-TRANSPLANT ENCEPHALOPATHY
- Common causes of post-transplant encephalopathy in liver allograft recipients include hepatic dysfunction,
medication toxicity,
infectious causes (CNS infections or septic encephalopathy),
complex metabolic disturbances (uremia,
CPM),
cerebrovascular events or seizures.
- Higher risk of encephalopathy has been reported in patients with history of severe hepatic encephalopathy,
alcohol-induced hepatic disease,
metabolic liver disease,
greater severity of pre-transplant liver injury [92].
Fig. 47: Severe hyperammonemic encephalopathy in a 35 year old post liver transplant patient (post operative day 6). Axial FLAIR images showing extensive cortical swelling and T2 prolongation especially along the insular cortices and cingulate gyrus.
- Delayed allograft function can precipitate hepatic encephalopathy with clinical manifestations of ranging from subtle cognitive slowing and memory difficulties,
to somnolence,
stupor and coma (Fig 47).
- In addition,
during early post-transplant period,
a delayed arousal can be related to persisting hepatic dysfunction,
immunosuppressant related neurotoxicity or intracerebral hemorrhage [92].
OPPORTUNISTIC INFECTIONS
- Chronic immunosuppression increases the risk of opportunistic infection in liver transplant recipients with an overall reported incidence of 5% [92].
- The highest risk of developing a post transplant CNS infection is seen between 1 – 6 months after transplantation.
- Fungal and viral infections are the most common in post transplant recipients,
while bacterial and protozoic infections are less common.
- Exposure to infectious agents may stem from donor-related infections,
recipient-related infections,
nosocomial infections and community infections.
- Fungal CNS infections are usually associated with systemic fungal infections,
and may also extend locally following fungal sinusitis (Fig 48) [92].
Fig. 48: Post-transplant invasive fungal sinusitis, orbital cellulitis & meningitis in a 26 year old female. Axial CT section showing destruction of the lamina papyracea (white arrow) with extension of the fungal elements into the right orbit with attendant orbital cellulitis (asterisk).
- Candida is the most common fungal infection after liver transplantation,
but CNS infections caused by Candida species are rare.
- Most common fungal CNS infections are caused by Cryptococcus neoformans and Aspergillus species [92].
- Increased risk of CNS aspergillosis has been reported after liver retransplantation.
Vasoinvasive CNS fungal infections (e.g.,
Aspergillus species) are often associated with hemorrhagic strokes.
Fig. 49: Invasive mucormycosis. Post liver-transplant patient with invasive fungal sinusitis (asterisk) invading the left orbit (star) and ipsilateral cavernous sinus (white arrow) with contiguous extension into the left peri-mesencephalic cistern (arrowhead).
References: Dr Rajiv Gupta, Radiology, Medanta, The Medicity, Gurgaon, India
- Opportunistic bacterial CNS infections are relatively less common after liver transplantation but the risk may be increased with environmental exposure.
- Toxoplasmosis is the most common protozoal infection in transplant recipients.
- Neuroimaging,
spinal tap after excluding increased intracranial pressure,
and a search for signs of systemic infection are the core of diagnosis.
Brain biopsy may be warranted in selected cases [92,
93].
OSMOTIC DEMYELINATION
- Up to 1-2% of liver transplant recipients may develop osmotic demyelination (pontine or extrapontine) [66,
92].
- Relatively high prevalence of central pontine (CPM) or extrapontine myelinolysis (EPM) in the early period after liver transplantation is probably attributable to large fluid shifts,
similarly as in rapid correction of hyponatremia [92].
Fig. 50: Central pontine myelinolysis in a post liver transplant patient. Axial FLAIR image showing predominant involvement of the transverse pontine fibres (white arrow) with characteristic sparing of the descending corticospinal tracts (asterisk). Note the peripheral pontine fibers (black arrow) are also spared - hence the term 'central' pontine myelinolysis.
- Due to massive fluid shifts in early posttransplant period,
the risk of CPM/EPM is also higher in first 48 h after transplantation (Fig 49).
- In addition,
higher risk of has been reported in patients with preoperative hyponatremia and worse liver dysfunction [92,
93].
POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER
- Lymphoma is the commonest cerebral brain tumor seen in transplant recipients; and,
the CNS may be the primary site of involvement or associated with systemic posttransplantation lymphoproliferative disorder (PTLD) [94].
- Majority of the PTLD cases are associated with Epstein-Barr virus (EBV) infection and occur a few years following solid organ transplantation.
- Intracranial involvement is more often parenchymal than leptomeningeal [94].
- On imaging,
the lesions tend to be multiple (often periventricular) and often show avid enhancement.
- Differentiation from toxoplasmosis may be challenging.
However,
an increased uptake on single-photon emission CT (SPECT) may be useful to differentiate the two entities [94].