Clinical manifestations

Presentation and course

The duration of hepatic disease prior to the onset of neurologic symptoms is highly variable—ranging between nine weeks (01) and 38 years (48). One study found a mean delay of 7.4 years between the diagnosis of hepatic disease and the appearance of the neurologic disorder (30), whereas another reports a median interval of only 14.5 months (106). Acquired hepatocerebral degeneration may begin insidiously or subacutely, and in some patients its onset coincides with a decline in hepatic function (59). Thereafter, progression is gradual, sometimes with periods of stability lasting for years (147; 33; 08). Although the typical onset is subacute, a case series featured three cases presenting with acute onset of dysarthria as the sole neurologic manifestation of acquired hepatocerebral degeneration in individuals with no prior diagnosis of liver disease (127). In these individuals, abnormal T1 signal in the globus pallidus and substantia nigra helped make a retrospective diagnosis of liver disease.

Although many patients who develop acquired hepatocerebral degeneration have experienced prior episodes of hepatic encephalopathy, the onset of the disorder may precede both bouts of encephalopathy and systemic signs of liver dysfunction (147; 53; 120; 106). In some case series, the risk of acquired hepatocerebral degeneration increases with repeated or prolonged bouts of hepatic encephalopathy (147). A case report demonstrates a clinical picture in which both occur concurrently in the same patient (45). In other reports the course of the disorder seems unrelated to either the frequency or severity of hepatic encephalopathy (53; 08).

The core features of acquired hepatocerebral degeneration include extrapyramidal signs, ataxia, and cognitive decline (147). Orobuccolingual dyskinesias are the most characteristic—though not the most common—manifestations, present in 15 out of 27 patients in Victor’s case series (147). These movements resemble those seen in medication-induced tardive dyskinesia and are sometimes, but not invariably, accompanied by appendicular chorea (147; 143; 33; 53; 101). When severe, orobuccolingual dyskinesias disrupt speech and swallowing. Some patients also have patterned, longer-duration cranial muscle spasms typical of dystonia; the spasms give rise to forced grimacing, jaw opening, or blepharospasm (33; 08; 51). Dystonia of extraocular muscles resulting in sustained oculogyric deviations may also occur (31). Limb dystonia is not a common feature of acquired hepatocerebral degeneration (53), but it does affect a minority of patients, generally in combination with cranial dystonia (147; 151; 59). In a large population of patients in Thailand with liver disease, the most common movement disorder in patients with acquired hepatocerebral degeneration was intention tremor (85).

Parkinsonism was the first recognized manifestation of acquired hepatocerebral degeneration (146), but its frequency in cirrhotic patients was underestimated until recently. It is now thought to occur in up to 21% of cirrhotic patients (10). Like patients with idiopathic Parkinson disease, those with acquired hepatocerebral degeneration-related parkinsonism exhibit rigidity, bradykinesia, shuffling gait, reduced arm swing, postural instability, hypomimia, micrographia, and tremor (147; 08). However, several features distinguish these populations. On average, acquired hepatocerebral degeneration-related parkinsonism has the following characteristics in contrast to idiopathic Parkinson disease (32):

	• More precipitous onset and more rapidly progressive initial course; in one series the mean duration until maximal symptom severity was seven months (08).
	• Bilateral and often symmetrical motor symptoms at disease onset (08).
	• Earlier onset of postural instability (08; 125) or cognitive impairment (59).
	• Postural or kinetic tremor that has larger amplitude than associated rest tremor (147; 33; 41; 08).
	• Poor response to levodopa and other dopaminergic drugs (125; 154; 01; 60).
	• Remission of symptoms following restoration of hepatic function, usually via liver transplantation (130; 135; 69; 125; 86).
	• Accompanying neurologic abnormalities suggestive of acquired hepatocerebral degeneration such as chorea, ataxia, or myelopathy (112; 108; 41; 135).

None of the preceding features, however, is a requisite to the diagnosis of acquired hepatocerebral degeneration-related parkinsonism. Asymmetrical symptoms (53; 125; 86), predominant rest tremor (53; 62), lack of postural instability (59), and even responsiveness to levodopa (112; 75; 53; 08; 59; 113; 86) all have been noted in patients with otherwise typical acquired hepatocerebral degeneration.

Other manifestations include ataxia, cognitive decline, and myelopathy. Ataxia is a common feature, present in nearly all patients in the landmark study (147). In patients with alcoholic cirrhosis, the diagnosis of acquired hepatocerebral degeneration-related ataxia is potentially challenging because symptoms can be confused with alcoholic cerebellar degeneration. Prominent limb rather than truncal ataxia and a prolonged interval between alcohol cessation and symptom onset favor the diagnosis of acquired hepatocerebral degeneration. Apathy, psychomotor retardation, memory failure, and deficits in attention and concentration, suggestive of a subcortical dementia, frequently accompany acquired hepatocerebral degeneration (147; 33; 62; 59). Cognitive and psychiatric disease may, however, be subtle or absent despite profound motor disability (147; 33). One study, which compared patients with acquired hepatocerebral degeneration to neurologically unaffected cirrhotics, showed significant impairments in visuospatial attention and sequencing in those with acquired hepatocerebral degeneration (136).

Acquired hepatocerebral degeneration causes various speech abnormalities. Patients may have hypokinetic, high-pitched speech from dystonia (33), hypophonia from parkinsonism, or a scanning pattern from cerebellar involvement (147).

Acquired hepatocerebral degeneration tends not to produce aphasia, apraxia, agnosia, and psychiatric symptoms apart from depression (147; 08), though psychosis rarely occurs (112). Corticospinal tract signs are not a typical manifestation (147; 33; 08; 59), except in those patients who develop myelopathy with spastic paraplegia. Acquired hepatocerebral degeneration-related myelopathy may arise either in conjunction with ataxia and extrapyramidal signs (157; 112; 72; 132) or in isolation (18). Most patients with myelopathy have predominantly pyramidal tract dysfunction with only modest sensory deficits related to dorsal column dysfunction (106). Individuals with acquired hepatocerebral degeneration occasionally develop myoclonus and asterixis (147; 33; 59), but these features may be due to a concomitant hepatic encephalopathy. Other neurologic deficits that have been described in patients with acquired hepatocerebral degeneration, such as cranial neuropathies or hyperventilation syndrome, are either rare or coincidental (112; 120; 12).

There have been some reported cases of acquired hepatocerebral degeneration with atypical presenting features. A case of ballismus in all four limbs was the sole presenting symptom without any other core characteristic (155). Another case also showed the absence of any classic symptoms, with only diplopia and ptosis (36). These cases lack sufficient data on long-term follow-up to determine if more typical features developed later; thus, their significance is uncertain without corroboration with similar cases.

Prognosis and complications

The symptoms of acquired hepatocerebral degeneration may fluctuate (143; 53), but durable spontaneous remissions rarely, if ever, occur (30). Survival following the onset of acquired hepatocerebral degeneration varies considerably, ranging from several weeks (147) to 28 years (48). Patients eventually succumb to systemic complications of advanced liver disease rather than to acquired hepatocerebral degeneration itself.

Biological basis

Etiology and pathogenesis

Acquired hepatocerebral degeneration develops independent of the etiology of hepatic dysfunction. Alcoholic cirrhosis, viral hepatitis, alpha-1 antitrypsin deficiency, nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cirrhosis (59), biliary atresia (47), schistosomiasis (76), and cryptogenic forms of cirrhosis (08) all may cause the disorder. There is a single case report of acquired hepatocerebral degeneration following an episode of fulminant hepatic failure (01), but the great majority of patients have natural or surgical portosystemic vascular shunts from chronic liver disease. Indeed, portosystemic shunting without hepatocellular disease (ie, from portal vein thrombosis, hereditary hemorrhagic telangiectasias, or surgical shunt placement) is sufficient to cause the clinical features, neuroimaging findings, and the neuropathological changes of acquired hepatocerebral degeneration (147; 11; 138; 33; 96; 87; 154; 120).

It is unclear why patients with portosystemic shunting develop acquired hepatocerebral degeneration. Presumably, a neurotoxic substance contained within the portal circulation circumvents first-pass hepatic metabolism (or biliary elimination), enters into the systemic circulation, and transverses the blood-brain barrier. Potential substances include ammonia, which is a known contributor to hepatic encephalopathy, and aromatic amino acids, which theoretically could disrupt the dopaminergic pathways that modulate movement (53). Clinicians have also hypothesized that acquired hepatocerebral degeneration, like Wilson disease, is a form of metal intoxication; but case manganese, not copper, has been suggested as the causative agent. Normally, enteric manganese absorption greatly exceeds physiological demand and excess dietary manganese—over 95% of that absorbed—is rapidly cleared from the portal blood by the liver before it reaches the systemic circulation (20; 25; 52).

The hypothesis that manganism is responsible for the extrapyramidal signs of acquired hepatocerebral degeneration followed the advent of MR imaging. A majority of patients with advanced cirrhosis have homogenous pallidal hyperintensities on T1-weighted sequences with normal T2-weighted imaging. This finding is uncommon in settings other than manganese toxicity (27; 49; 41; 89; 52). Subsequent work has confirmed that serum (08), cerebrospinal fluid (55; 08), and cerebral (tissue) manganese levels are indeed elevated in cirrhotic patients. Pallidal manganese concentrations in persons who expire from hepatic coma are approximately 3- to 9-fold higher than in control patients (107; 77; 46; 116; 60). Manganese levels are also elevated in other brain regions, including the striatum, but usually to a lesser degree (61; 116; 60). A much smaller increase in basal ganglia copper is also present in some cirrhotic patients, but the brain concentrations of other common metals are normal (68; 77; 60).

Manganese is a well-documented neurotoxin. Between 1% and 4% (and perhaps as much as 25%) of miners who were exposed to large quantities manganese-laden dust developed a constellation of neurologic symptoms termed “manganism” (100). Historically, manganism affected ore-workers worldwide, including those in Europe (23), Asia (42), Africa (114), and the Americas (84; 19). Whether welding is an occupational risk factor for manganese-induced parkinsonism is a matter of scientific and legal debate (52). Improved workplace monitoring has greatly reduced the incidence of occupational intoxication. However, an atypical parkinsonian syndrome associated with elevated blood manganese levels and symmetric T1 hyperintensity in the globus pallidus on MRI has been observed in intravenous drug users residing in Eastern Europe. These individuals were found to have injected a home-manufactured formulation of methcathinone (ephedrone) synthesized by potassium permanganate oxidation (133; 126). Accordingly, manganism may still be encountered in selected populations through nontraditional routes of exposure.

Signs of manganese intoxication develop insidiously, usually following exposure to high manganese concentrations for several months to years, though rarely symptoms begin within weeks of exposure or are delayed beyond a decade (114). Occupational manganism begins with psychosis and compulsive behaviors, which are typically superseded by parkinsonism and dystonia. Like acquired hepatocerebral degeneration, the parkinsonism of manganism is of subacute onset, initially symmetrical, marked by early postural instability, accompanied by action tremor, and poorly responsive to dopamine replacement therapy (52). The dystonia of occupational manganism may involve cranial, axial, and appendicular muscles, giving rise to blepharospasm, orospasm, grimacing, torticollis, oculogyric crisis, and a characteristic cock-like gait (100).

Although similarities in clinical phenotype between acquired hepatocerebral degeneration and occupational manganism are apparent (for example, both cause cranial dystonia and parkinsonism), there are noteworthy clinical differences, and these disparities have led some to question whether manganese deposition underlies the neurologic symptoms of acquired hepatocerebral degeneration (32). When compared to occupational manganism, acquired hepatocerebral degeneration is more likely to cause ataxia and chorea but less likely to produce limb dystonia, psychosis, or compulsive behaviors. So-called “manganese madness,” the initial period of psychomotor excitement that often precedes motor symptoms in miners, has not been observed in patients with acquired hepatocerebral degeneration. The speech difficulties and tremor of occupational manganism may lessen with time, but gait dysfunction rarely improves, and neurologic deficits do not wax and wane (19). In contrast, acquired hepatocerebral degeneration may be interrupted by spontaneous remissions and sudden relapses (53; 143). Also, recovery from acquired hepatocerebral degeneration has been reported to follow liver transplantation in multiple patients within hours of surgery (see the “Management” section below). It is questionable whether the effects of chronic manganese accumulation could improve so rapidly after transplant, and this observation provides support for the role of reversible metabolic factors distinct from manganese in acquired hepatocerebral degeneration (32).

How manganese causes neurotoxicity is not known. The metal collects in glial cells at a concentration of approximately 200 times that of the extracellular compartment. Within glia, the majority of manganese resides inside mitochondria where it may disrupt energy metabolism (97). Positron emission tomography studies of patients with occupational manganism have shown reduced pallidal fluorodeoxyglucose uptake (implying decreased pallidal metabolism) (124), normal striatal fluorodopa uptake (indicating intact presynaptic nigrostriatal dopaminergic terminals) (153; 124; 43), and variably reduced D2 receptor levels (suggesting damage to postsynaptic nigrostriatal pathways) (124; 56). The functional neuroimaging characteristics of patients with acquired hepatocerebral degeneration are not known, but an autopsy study of cirrhotic patients without the disorder revealed diminished D2 receptor levels within the basal ganglia (90). Several molecular mechanisms of neurotoxicity may occur in patients with liver failure, including oxidative/nitrosative stress, glutamate NMDA-receptor-mediated excitotoxicity, and neuroinflammatory mechanisms (09).

Our knowledge of acquired hepatocerebral degeneration’s neuropathology is derived from small case series, but available data are reasonably consistent. On gross examination, cortical atrophy may be present, and some patients have visible regions of glassy discoloration within the cortex and basal ganglia (147; 33). Microscopic analysis reveals polymicrocavitation (vacuolation) corresponding to the lesions found on gross inspection. In the cortex, vacuolar change is most pronounced in the posterior frontal, parietal, and occipital cortices (33) but may be present in the temporal lobes as well (128; 58). The brunt of spongy degeneration is in the deep cortical layers with extension into the immediate subcortical white matter. Some authors have found cortical polymicrocavitation to be most pronounced at the depths of sulci (147; 143), whereas others noted more prominent changes at the gyral summits (138; 33; 128; 58). Polymicrocavitation is also commonly present in the putamen (especially the superior poles), caudate heads, pallidum, and subthalami (147; 38; 58). As with cortical lesions, vacuolation is typically extended to neighboring white matter tracts--in this case the internal capsules. The polymicrocavitation seen in acquired hepatocerebral degeneration is characteristic amongst neurodegenerative disorders insofar as vacuoles seem to displace rather than destroy surrounding neurons. Prominent myelin loss, however, may accompany vacuolar change in some cases, and the pathological distinction between polymicrocavitation and extrapontine myelinolysis is at times difficult (128; 70; 58). Within the cerebellum, acquired hepatocerebral degeneration is characterized by loss of dentate neurons, Purkinje cell loss, and Bergmann gliosis (147). Some degree of cerebellar degeneration is present in the majority of individuals succumbing to end-stage liver disease, irrespective of alcohol consumption (64).

Alzheimer type II glia is the only constant neuropathological finding of acquired hepatocerebral degeneration. They are abundant in, but not restricted to, regions of microcavitation and are sufficient to produce fixed neurologic deficits without coexistent vacuolar change (147; 60). On hematoxylin and eosin staining, these astrocytes are characterized by large, lobulated, hypochromatic nuclei, frequently containing basophilic nucleoli. Although universally present in patients with acquired hepatocerebral degeneration, Alzheimer Type II astrocytes are not pathognomonic for this disorder (09); they are also found in patients with uncomplicated cirrhosis, in patients with Wilson disease, and most provocatively, in a primate model of manganism (99).

Clinicopathological correlation of acquired hepatocerebral degeneration is problematic in regards to both the severity and location of brain lesions: extrapyramidal signs may be severe despite only modest changes in the basal ganglia, whereas spasticity or sensory loss are usually absent despite prominent lesions in the frontoparietal cortex and internal capsule (147). Furthermore, the fact that longstanding neurologic deficits and imaging findings may remit following liver transplantation suggests that the physiological or anatomical defects that underlie the acquired hepatocerebral degeneration’s phenotype are reversible (78).

Epidemiology

The prevalence of acquired hepatocerebral degeneration is not known. Extrapyramidal signs are apparent in between 20% and 90% of patients with advanced cirrhosis who are awaiting liver transplantation (110; 129; 63; 130; 08; 54). In patients with more modest liver disease, the prevalence is considerably less (65). Two database reviews of cirrhotic patients seen by gastroenterology/hepatology clinicians report a prevalence of 0.8 and 2% (106; 30). Chronic liver disease and cirrhosis affect approximately 5.5 million persons in the United States (02) and are the twelfth leading cause of death, claiming over 30,000 lives each year (13). At present, over 17,000 patients with advanced liver disease are awaiting organ transplantation (03). Accordingly, a large population is at risk for acquired hepatocerebral degeneration.

On average, acquired hepatocerebral degeneration affects persons in their fifth to sixth decade of life, but variability is considerable (147; 08; 59; 106; 30). Patients with childhood-onset liver disease may develop the disorder when much younger, at an age more typical of Wilson disease (47; 102), though only two pediatric cases have been reported, and imaging was atypical for acquired hepatocerebral degeneration in one (102). Cirrhosis affects men in excess of women, but in most case series acquired hepatocerebral degeneration has no additional gender predilection. One group found a statistically significant male predominance (106).

Prevention

Evidence-based prevention strategies for acquired hepatocerebral degeneration are lacking. Available data associate portosystemic shunting with the development of acquired hepatocerebral degeneration (147; 33; 08; 154; 120; 18); therefore, when feasible, avoidance of portosystemic shunts (endovascular or surgical) may reduce risk.

If manganese toxicity underlies acquired hepatocerebral degeneration, then iron deficiency anemia may contribute to its development. The proportion of manganese absorbed and retained in tissue varies inversely with iron stores (83; 34; 57), likely because manganese and iron share membrane transport and serum binding proteins, specifically divalent metal transporter-1 and transferrin (28). Common transport systems may also explain why various metals (including iron, copper, and manganese) all preferentially accumulate within the basal ganglia.

Differential diagnosis

The differential diagnosis of acquired hepatocerebral degeneration encompasses neurologic diseases with a similar clinical phenotype, neurologic conditions with a similar appearance on neuroimaging, and neurologic diseases encountered in the setting of hepatic failure.

The differential diagnosis of acquired hepatocerebral degeneration-related orobuccolingual dyskinesias and parkinsonism are shown in Tables 1 and 2 respectively (66; 37). For patients who present with ataxia, cognitive impairment, or myelopathy, the differential diagnosis is extensive; clinicians might suspect acquired hepatocerebral degeneration only in those individuals with clinical evidence of cirrhosis or findings suggestive of the disorder on neuroimaging.

Table 3 lists the differential diagnosis of pallidal hyperintensities on T1-weighted MR imaging—the radiological hallmark of acquired hepatocerebral degeneration (39; 32). Most of these disorders are easily differentiated from acquired hepatocerebral degeneration based on their clinical phenotype as well as their appearance on other MR imaging sequences.

In patients with known hepatic dysfunction, other neurologic diseases to consider include Wilson disease, central pontine or extrapontine forms of myelinolysis, alcoholic cerebellar degeneration, and hepatic (toxic-metabolic) encephalopathy. The distinction between acquired hepatocerebral degeneration and hepatic encephalopathy may be particularly challenging. In general, hepatic encephalopathy is reversible, responsive to ammonia-lowering therapies, and accompanied by a reduced level of consciousness, whereas the cognitive manifestations of acquired hepatocerebral degeneration are not (147). However, the two conditions may coexist; the symptoms may fluctuate (143; 53), and even longstanding acquired hepatocerebral degeneration may abate following liver transplantation (108). A firm separation of acquired hepatocerebral degeneration from hepatic encephalopathy is not possible without a better understanding of pathophysiological mechanisms underlying motor and cognitive symptoms. Hemochromatosis is a hereditary disorder characterized by increased duodenal iron absorption resulting in liver dysfunction. Case reports implicate hemochromatosis as a cause of neurologic diseases including movement disorders; however, the association in some cases may be merely coincidental (118).

Table 1. Differential Diagnosis of Orobuccolingual Dyskinesias

Tardive drug-induced stereotypy
	• Dopamine receptor-blocking drugs
Acute drug-induced chorea
	• Levodopa, dopamine receptor agonists, cocaine, amphetamines, oral contraceptives, anabolic steroids, antimalarials, anticholinergics
Hereditary chorea
	• Huntington disease, neuroacanthocytosis, Lesch-Nyhan disease
Toxin-induced chorea
	• Carbon monoxide, mercury, thallium, toluene
Metabolic chorea
	• Hyperthyroidism, hyperparathyroidism, hypoparathyroidism, chorea gravidarum, hyperglycemia, nutritional deficiencies, various electrolyte imbalances
Immune-mediated chorea
	• Sydenham chorea, antiphospholipid antibody syndrome, systemic lupus erythematosus, various vasculitides, postvaccinal chorea
Cerebrovascular and hematological disease
	• Basal ganglia stroke or hemorrhage, anoxia, polycythemia vera, arteriovenous malformation
Other causes
	• Spontaneous buccolingual dyskinesias of the elderly, edentulous dyskinesias, stereotyped movements in schizophrenia, acquired hepatocerebral degeneration

Table 2. Differential Diagnosis of Parkinsonism

Idiopathic Parkinson disease Vascular parkinsonism Drug-induced parkinsonism
	• Dopamine receptor-blocking drugs, dopamine-depleting medications
Neurotoxins
	• 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, carbon monoxide, cyanide, methanol, manganese
Diffuse Lewy body disease Normal pressure hydrocephalus Fahr disease Postencephalitic parkinsonism Parkinson-plus diseases
	• Multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration
Other rare neurodegenerative disorders
	• Frontotemporal dementia with parkinsonism-17, pantothenate kinase-associated neurodegeneration, acquired hepatocerebral degeneration

Table 3. Differential Diagnosis of Increased T1 Signal in the Basal Ganglia on MR Imaging

Acquired hepatocerebral degeneration Manganese intoxication
	• Exposure to manganese ore • Manganese-tainted total parenteral nutrition or intravenous drugs • Iron deficiency
Microhemorrhage of the basal ganglia
	• Hypoxia • Infections including Japanese encephalitis and HIV • Microangiopathies including hemolytic-uremic syndrome
Calcification Neurodegeneration with brain iron accumulation Hyperglycemic hyperosmolar state Hypoxic-ischemic injury Carbon monoxide poisoning Neurofibromatosis type I Wilson disease Kernicterus Fucosidosis Langerhans cell histiocytosis Mitochondrial encephalomyopathy

Diagnostic workup

No diagnostic studies are specific for acquired hepatocerebral degeneration. Laboratory investigations may reveal abnormalities reflecting cirrhosis, such as hyponatremia, thrombocytopenia, coagulopathy, hypoalbumenia, elevated serum aminotransferases, and hyperammonemia. In one report, serum albumin and gamma-glutamyl transpeptidase levels were significantly lower in patients with acquired hepatocerebral degeneration than in other cirrhotics, but overlap is considerable (106). Abdominal CT with intravenous contrast may reveal portosystemic shunts, which, in one cohort, were visible in all patients in whom scans were performed (30). Serum and whole-blood manganese levels are elevated in most patients with advanced liver disease, but they are of limited clinical utility because levels do not correlate with the presence of acquired hepatocerebral degeneration (129; 78). Blood manganese levels do, however, correlate with increased pallidal T1 signal on MR imaging, a surrogate of manganese deposition (61; 129; 96; 104; 15). Cerebrospinal fluid manganese levels may likewise be elevated (55; 08), but spinal fluid is otherwise normal, except occasionally for a modest elevation in protein (147; 112). Unlike Wilson disease, slit lamp examination and studies of copper metabolism (serum copper, serum ceruloplasmin, and urinary copper excretion) are normal. Cobalamin deficiency should be excluded in patients with acquired hepatocerebral degeneration-related myelopathy.

The majority of patients with advanced cirrhosis have characteristic MR imaging findings, ie, homogenous T1 hyperintensities affecting both globus pallidi (89). Increased T1 signal may also extend to adjacent basal ganglia structures, hemispheric white matter, cerebellum, internal capsule, and the mesencephalon (30; 26). T2-weighted and contrast-enhanced sequences usually are normal but occasionally show corresponding pallidal changes (149; 130; 141; 145; 59) or lesions in other structures such as the brachium pontis (40; 70). A published review of the literature suggests that those patients presenting with primarily ataxia-plus symptoms are more likely to exhibit T2 hyperintensities on MRI, particularly in the cerebellum and middle cerebellar peduncles, whereas those who demonstrate parkinsonism are more inclined to show the conventional T1 hyperintensities of the globus palladi (122). The authors suggest that this difference may be related to a difference in pathomechanism; however, details remain to be established. One prospective observational study of 120 patients failed to show a statistically significant correlation between degree of T1 pallidal hyperintensity and UPDRS score (04). Pallidal T1 hyperintensities correlate with blood manganese levels, and identical MRI findings are present in persons with occupational manganism (41), nonhuman primate models of manganism (95; 123), and parkinsonian patients exposed manganese-rich total parenteral nutrition (92) or manganese-tainted intravenous drugs (24; 133; 126). These associations suggest that the MRI changes are related to manganese deposition; however, this is not fully established, as there are other known causes of increased T1 signal in the basal ganglia (see Table 3). In a report, a patient with acquired hepatocerebral degeneration (levodopa-unresponsive parkinsonism) had typical pallidal hyperintensities on T1 imaging, but susceptibility-weighted imaging was normal in the pallidum. Because susceptibility-weighted imaging is a sensitive modality for detecting ferromagnetic and paramagnetic substances, this raises questions whether other factors, apart from manganese, may account for the increased T1 signal (07). In addition, the relationship between MRI findings and clinical symptoms remains unclear: some studies show a correlation between neurologic dysfunction and pallidal signal (156; 65; 110; 140; 130; 131), whereas others do not (49; 142; 149; 62; 63; 96). Most studies (49; 65; 110; 149; 63; 35) but not all reports (140; 129) show a correlation between pallidal signal and the presence of portosystemic shunting. One group found that the presence of extrapallidal T1 hyperintensities was associated with cognitive impairment in patients with acquired hepatocerebral degeneration (30). One publication featured a patient with acquired hepatocerebral degeneration whose MRI 1 year after symptom onset was negative for T1 hyperintensities, but did show basal ganglia hyperintensities on proton density-weighted images only. Seven months later, the characteristic T1 pallidal hyperintensities did appear on MR imaging. This may have significant implications for early diagnosis and treatment of acquired hepatocerebral degeneration (29). Clinicoradiographic correlations require further study.

In addition to abnormal T1 signal, MRI may also show atrophy (04; 26). In some cases, the pattern of atrophy corresponds to the clinical presentation (for example, pontocerebellar atrophy in cases of ataxia) (81); however, this is not universally the case.

Magnetic resonance spectroscopy in patients with cirrhosis shows reduced choline and myoinositol resonance present in both gray and white matter structures (130), sometimes accompanied by increased glutamate/glutamine resonance (91). MRS abnormalities correlate with extrapyramidal signs and normalize following liver transplantation in parallel with neurologic improvement and in advance of MR imaging abnormalities (69). A case study of acquired hepatocerebral degeneration secondary to primary biliary cholangitis showed unique changes on nuclear medicine scans including increased globus pallidus melanin intensity by neuromelanin sensitive imaging, decreased frontal and parieto-occipital lobe blood flow by IMP-SPECT, and decreased striatal uptake by DAT-SPECT (98).

Though electrodiagnostic studies are not routinely needed in patients with acquired hepatocerebral degeneration, they are occasionally informative. In patients with clinical evidence of myelopathy, spine MR imaging is unrevealing, and motor evoked potentials can confirm localization, which is usually to the thoracic spinal cord (72; 18; 94). In individuals with acquired hepatocerebral degeneration, electroencephalography can show diffuse slowing yet may be abnormal only with concurrent encephalopathy (147).

Management

Presently there are no FDA-approved therapies or published management guidelines for acquired hepatocerebral degeneration and no prospective studies on which to base treatment decisions. However, observational evidence regarding both symptomatic and disease-modifying treatments offers some clinical guidance as well as a direction for future research.

Ammonia-lowering therapies (such as dietary protein restriction, lactulose, neomycin, metronidazole, and colonic exclusion) may benefit individual patients with acquired hepatocerebral degeneration (147; 67), but the preponderance of data suggests that, in contrast to hepatic encephalopathy, these approaches are ineffective (112; 143; 105; 75; 53; 121; 30; 148).

Reports regarding the utility of dopamine replacement therapy in patients with acquired hepatocerebral degeneration-related parkinsonism are conflicting. Patient responsiveness to levodopa and dopamine agonists ranges from poor (125; 154; 01; 60; 30) to robust (75; 88; 08; 59). A randomized, double-blind control trial of 50 patients with cirrhosis and parkinsonism showed a statistically significant improvement in UPDRS score after a 12-week treatment with bromocriptine (119). Variable dopa response may be due to heterogeneous pathology of the caudate. A review of 10 case studies showed levodopa response in all 6 patients with preserved dopamine uptake in the caudate on DAT-SPECT, with no levodopa response in 2 of the 4 patients with decreased caudate uptake (98). Although acquired hepatocerebral degeneration has not been conclusively linked to manganese toxicity, it is noteworthy that levodopa is ineffective for parkinsonism related to occupational manganism (19; 44; 74), despite initial reports to the contrary (21; 82; 117). For patients with acquired hepatocerebral degeneration-related chorea, dopamine receptor antagonists can be effective (115), but drugs in this class may cause parkinsonism or a tardive drug syndrome. Accordingly, some clinicians recommend tetrabenazine for such patients, which is not associated with tardive dyskinesia (101).

Several patients with acquired hepatocerebral degeneration have undergone liver transplantation, and in the majority of published cases, surgery has dramatically lessened or fully reversed neurologic disability (32; 14; 134; 50). Cognitive deficits (135; 80; 59; 137), parkinsonism (108; 110; 130; 135; 69; 125), cranial or appendicular chorea (67; 135; 101; 121; 134), ataxia (105; 121; 106), and myelopathy (144; 150; 93; 106) all may remit following restoration of hepatic function, and even patients with neurologic deficits of over 10 years’ duration have responded favorably (108). One study showed complete resolution of neurologic as well as radiological signs in three patients undergoing living donor liver transplant in contrast to 100% mortality in the three who were treated medically (111). The latest published reports include several case reports that clearly demonstrate significant if not complete resolution of clinical neurologic symptomatology and at least partial resolution of radiologic findings (05; 109). A study showed that 18 patients with hepatocerebral degeneration who underwent transplant had a statistically significant improvement in their UPDRS scores at 3 months, with continued improvement at 1 year; basal ganglia T1 hyperintensities were also resolved at 1 year (04). Improvement following liver transplantation usually occurs gradually over the course of 1 to 4 months but may continue beyond 1 year (108; 125) and, on occasion, immediately follow transplant surgery (59; 101; 121). Increased pallidal signal on T1-weighted MRI, abnormalities on MRS, and blood manganese levels also recede to varying degrees following liver transplantation. Of these modalities, MRS correlates closest with improvement in motor function (69). The duration of response following transplantation is not known. Favorable outcomes are now reported to be in excess of six years following transplantation (134).

Liver transplantation is not, however, universally successful in reversing the symptoms of acquired hepatocerebral degeneration. Some patients suffer serious postoperative complications (72; 134), some show no response (22; 30), and some have reemergence of neurologic deficits either in the setting of graft rejection (121; 14) or otherwise (101). In some patients who do not show neurologic improvement following liver transplantation, persistent portosystemic shunts have been identified, and residual shunting may account for variation in neurologic outcomes (30). In such patients, post-transplant MRI abnormalities also fail to improve, which is in contrast to patients who fared better in terms of clinical symptoms (106). Atluri and colleagues review other possible causes of neurologic dysfunction following liver transplantation, which include CNS toxicity of immunosuppressant drugs like calcineurin inhibitors (06).

Other therapies in need of further study are endovascular occlusion of portosystemic shunts (79; 17; 139; 18) and branched-chain amino acids (145). Dietary manganese restriction is theoretically prudent for patients with acquired hepatocerebral degeneration and perhaps all patients with advanced cirrhosis, yet there are no studies addressing dietary modification. Ethylenediamine tetraacetic acid, a chelator of manganese, is untested in acquired hepatocerebral degeneration, ineffective in longstanding occupational manganism (42), and potentially toxic. Two publications explore the use of chelating agents in patients with acquired hepatocerebral degeneration. One report indicates that trientine, an oral chelating agent used to treat Wilson disease, decreased neurologic deficits, MRI abnormalities, and manganese blood levels in a patient with acquired hepatocerebral degeneration-related parkinsonism (103). A second patient, also with parkinsonism, was treated with penicillamine (16). This individual had liver cirrhosis secondary to chronic hepatitis C, but was also a heterozygote carrier of ATP7B mutation, the gene responsible for Wilson disease. Despite the lack of a second ATP7B mutation and normal copper studies, penicillamine provided clinical benefit to this individual. The authors speculate that subtle alterations in copper metabolism may have facilitated the appearance of neurologic symptoms, and they raise the question of whether heterozygote ATP7B mutations are a risk factor for acquired hepatocerebral degeneration. These observations require confirmation, especially as trientine and penicillamine have not been proven to effectively chelate manganese (32).

More research is needed to better understand the pathogenesis of acquired hepatocerebral degeneration, define which patients are at risk, and develop satisfactory treatments.

Outcomes

When medically indicated, liver transplantation is the predominant means of altering prognosis. Causes of death include hepatic decompensation (hepatic coma), hepatorenal syndrome, infection (for example, spontaneous bacterial peritonitis), hemorrhage from coagulopathy or varices, and hepatocellular carcinoma (147; 106; 30). Patients with acquired hepatocerebral degeneration who undergo liver transplantation may enjoy a complete and durable neurologic recovery (134).

Special considerations

Pregnancy

No information is available regarding pregnancy in patients with acquired hepatocerebral degeneration.

Anesthesia

Advanced liver disease results in multiorgan dysfunction and severe metabolic derangements. Anesthesia should be administered to patients with acquired hepatocerebral degeneration by a physician familiar with these challenges.