J Neurol (2009) 256:320–332

DOI 10.1007/s00415-009-0144-7 REVIEW

Joseph Ferrara Acquired hepatocerebral degeneration

Joseph Jankovic

Received: 31 August 2008
Accepted: 20 October 2008
Published online: 17 February 2009
J. Ferrara, MD · J. Jankovic, MD (쾷)
Dept. of Neurology
Baylor College of Medicine
6550 Fannin, Suite 1801
Houston, Texas 77030, USA
Tel.: 713/798-5998
Fax: 713/798-6808
E-Mail: josephj@bcm.tmc.edu
Web: www.jankovic.org
■ Abstract Cirrhosis and its
co-morbidities may cause a variety
of neurological complications, the
most common being bouts of toxic
metabolic encephalopathy. A pro-
portion of patients with chronic
liver disease develop acquired
hepatocerebral degeneration
(AHD), a chronic progressive
neurological syndrome character-
ized by parkinsonism, ataxia and
other movement disorders. This
article reviews the clinical spec-
trum, pathophysiology, neuroimag-
ing features and differential diag-
nosis of AHD along with emerging
treatment options.
■ Key words acquired hepatocere-
bral degeneration · portosystemic
shunt · cirrhosis · movement
disorder

lowing evidence that, as with Wilson disease, metal in-

Introduction
Acquired hepatocerebral degeneration (AHD) is an of-
ten debilitating neurological disorder characterized by
parkinsonism, ataxia and other movement disorders,
which may accompany various forms of advanced liver
disease, especially those characterized by portosystemic
shunting.
AHD was first reported by W. van Woerkem in 1914
[153], two years following S. A. Kinnear Wilson’s seminal
manuscript on the hereditary form of hepatolenticular
degeneration that now bears his name [159]. Over the
past century, progress in understanding and treating
Wilson disease has been considerable. We now recognize
that Wilson disease is a hereditary disorder of biliary
copper excretion and insights into its etiopathogenesis
have yielded effective treatments for this once devastat-
ing neurological condition, although failure to diagnose
the disease is still the principal cause of death [155].
AHD, by contrast, lacks proven medical therapy and has
received relatively little attention despite its greater
prevalence. Indeed, AHD went virtually unrecognized
until Victor, Adams and Cole’s landmark review in 1965
JON 3144
toxication may contribute to its pathogenesis [25, 29, 41,
68, 69, 109, 115].
The exact prevalence of AHD is not known, but cir-
rhosis affects approximately 5.5 million Americans [4],
and a broad spectrum of movement disorders occur in
20 to 90 % (8, 56, 70, 121, 138, 139) of the nearly 17,000
[152] patients who are currently awaiting liver trans-
plantation. Including patients with less severe degrees of
cirrhosis, the prevalence of AHD may be more in the
range of 2 % [114].
Symptoms of AHD usually begin in adulthood, often
in the fifth to sixth decade of life [8, 67, 114, 154]; how-
ever, AHD occasionally affects children [51, 108], so the
age at onset alone cannot distinguish AHD from Wilson
disease (Table 1).
AHD arises insidiously or subacutely after several
weeks [2] to decades [67] of hepatic dysfunction. While
generally progressive, its course is highly variable: grad-
ual deterioration may be punctuated by years of clinical
stability [8, 30, 154], and symptoms may not parallel
other features of liver disease including hepatic enceph-
alopathy [8, 55]. Survival following the onset of AHD
ranges from several weeks [154] to an excess of 30 years

[154], and even today the disorder remains under-diag- [52]. Most patients eventually die from the systemic
nosed. Recently, however, interest in AHD has grown fol- complications of cirrhotic liver failure including infec-

Table 1 Features distinguishing AHD from Wilson disease
Acquired hepatocerebral degeneration
Typical age at onset Middle age and beyond
Family history Typically unrevealing
Kayser-Fleisher rings Not present on slit-lamp examination
Urinary copper excretion Normal except in cases of severe cholestasis
Serum ceruloplasmin Normal or reduced in proportion to albumin
Typical MRI findings Increased T1 signal in the pallidum and nigra
Response to copper-lowering therapies Not formally studied but theoretically poor
tion, coagulopathy, hepatorenal syndrome, hepatocellu-
lar carcinoma, and hepatic coma [114, 154]. In one study
of 16 patients with AHD, after a median follow-up of 29
months, 75 % of patients had died prior to liver trans-
plantation, 12.5 % underwent liver transplantation, and
12.5 % were awaiting surgery [114].
Illustrative case
A 65-year-old woman presented with a six-month his-
tory of subacute-onset, severe, limb-flinging movements
accompanied by instability, slurred speech and difficulty
swallowing. The patient’s medical history was notable
for cryptogenic cirrhosis, Child-Pugh Score 6 (Class A),
with portal hypertension, esophageal varices, and a prior
bout of mild hepatic encephalopathy.
Her neurological examination revealed impaired ori-
entation and concentration. She had generalized chorea,
limb and gait ataxia, cerebellar dysarthria, and asterixis.
Magnetic resonance imaging (MRI) showed homoge-
nously increased T1 signal within the globus pallidus
and subthalamic region, while T2-weighted and gado-
linium enhanced sequences were normal. The patient
had no relevant family history, had not used medications
known to precipitate dyskinesias, and laboratory testing
excluded Wilson disease, Huntington disease, dentato-
rubropallidoluysian atrophy, neuroacanthocytosis, an-
tiphospholipid antibody syndrome, systemic lupus ery-
thematosus and endocrinopathies.
Treatment with lactulose and metronidozole yielded
no benefit. Tetrabenazine lessened the patient’s chorea
but dose titration was limited by sedation.
Clinical manifestations
AHD causes a variety of cognitive and behavioral
changes including prominent apathy, bradyphrenia, and
deficits in attention, although language function, mem-
ory and praxis are usually well preserved [30, 67, 71, 114,
154]. Overt cognitive dysfunction is a frequent but not
321
Wilson disease
Childhood, adolescence or young adulthood
Consistent with autosomal recessive inheritance
Almost always accompany neurological disease
Elevated in symptomatic patients
Usually reduced, rarely in excess of 30 mg/dL
Increased T2 signal in the basal ganglia, white matter, thalamus or
brainstem
Often excellent but not universally successful
universal feature of AHD, even in patients with promi-
nent motor difficulties [30, 154]. A recent study, which
utilized formal psychometric testing, showed that im-
pairments in visuo-spatial attention best separate pa-
tients with AHD from normal controls; however, the
authors found little difference in cognitive parameters
between patients with AHD versus those with cirrhosis
without a movement disorder [143]. Accordingly, in pa-
tients with cirrhosis, movement and cognitive dysfunc-
tion may have distinct causes. In contrast to hepatic en-
cephalopathy, however, movement disorders associated
with AHD are generally not accompanied by a reduced
level of consciousness, nor responsive to ammonia-low-
ering therapies AHD may give rise to various types of
abnormal movement including parkinsonism, ataxia,
dystonia, chorea and orobuccolingual stereotypy, phe-
nomenologically similar to tardive dyskinesias. In pro-
spective studies of patients attending liver clinics, par-
kinsonism and action tremor are most prevalent [8, 56,
121, 138, 139], and about one-fifth of patients hospital-
ized as potential candidates for liver transplant have
definite parkinsonism (mean United Parkinson Disease
Rating Scale Part 3 score of 38) [8]. In case series derived
from neurology clinics, patients with ataxia, chorea and
orobuccolingual dyskinesias are as commonly reported,
likely reflecting referral patterns among hepatologists
[30, 55, 67, 122, 148, 154].
AHD-related parkinsonism, like idiopathic Parkin-
son disease, is characterized by tremor, rigidity, bradyki-
nesia, postural instability and shuffling gait [8]; however,
in most cases other clinical features readily distinguish
the two disorders. In contrast to idiopathic Parkinson
disease, AHD-related parkinsonism is often [8], though
not always [55, 134], bilateral and symmetrical at disease
onset. Compared to Parkinson disease, AHD progresses
more rapidly, with peak severity occurring on average
within 7 months of symptom onset [8] and postural in-
stability or cognitive impairment, early in the course of
disease [8, 67, 134]. Some patients with AHD may have
resting tremor [55, 71], but action tremor is far more
common [8, 30, 41, 154]. The diagnosis of AHD is also
suggested by the presence of additional neurological ab-
322
normalities not seen in Parkinson disease, such as cho-
rea and orobuccolingual dyskinesias, ataxia or myelopa-
thy [41, 118, 122, 142]. Finally,AHD-related parkinsonism
and Parkinson disease differ in their response to ther-
apy; although levodopa benefits some patients with
AHD [8, 55, 67, 83, 122], the response is far less consistent
than in Parkinson disease [2, 68, 134, 164]. AHD-related
parkinsonism, however, may improve following liver
transplantation [77, 134, 139, 142].
Ataxia is a ubiquitous feature of AHD in most series,
but alcoholic cerebellar degeneration is a potential con-
founder for patients with a history of alcohol-related
cirrhosis. In this population, features supporting the di-
agnosis of AHD include: appendicular as opposed to
truncal ataxia, a long latency between alcohol cessation
and symptom onset, and imaging findings or other neu-
rological deficits suggestive of AHD.
AHD rarely causes a metabolic myelopathy resem-
bling subacute combined degeneration [14, 114], but
otherwise does not produce pyramidal tract signs or
sensory loss [8, 30, 67]. Other neurological deficits, such
as myoclonus and asterixis, have been tentatively as-
cribed to AHD but may be attributable to co-morbid
hepatic encephalopathy.
The most characteristic motor phenotype of AHD is
cranial dyskinesia, which resembles a medication-in-
duced tardive stereotypy and is often intermixed with
dystonic spasms that produce forced grimacing, jaw
opening, blepharospasm and ocular deviations [8, 29,
30]. Dysarthria is a common feature of AHD and may
reflect combinations of slow, high-pitched speech asso-
ciated with cranial dystonia [30], scanning speech repre-
senting cerebellar dysfunction, and hypophonia from
parkinsonism. Cranial dyskinesias may be part of more
generalized hyperkinetic movement disorder, particu-
larly chorea [30, 55, 107, 148] or dystonia [67, 158].
Pathogenesis
AHD may accompany any form of chronic liver disease
associated with portosystemic shunting and has been
described in the setting of viral hepatitis, alcoholic cir-
rhosis, alpha-1 antitrypsin deficiency, nonalcoholic ste-
atohepatitis, autoimmune hepatitis, primary and sec-
ondary biliary cirrhosis [67, 114], biliary atresia [51],
Byler’s disease [108] and cryptogenic forms of cirrhosis
[8]. Occasionally, AHD occurs in patients who have por-
tosystemic shunts without underlying hepatocellular
disease, such as those with hereditary hemorrhagic te-
langiectasias, surgeries or portal vein thrombosis [9, 30,
93, 100, 127, 144, 164]. The report of a patient who devel-
oped reversible levodopa-unresponsive parkinsonism
several weeks following an episode of fulminant hepati-
tis-E infection suggests that the disorder may arise as a
consequence of acute liver diseases [2]. While hepatocel-
lular failure alone may contribute to AHD [124], AHD in
the absence of portosystemic shunting is unusual.
Portosystemic shunting may predispose patients to
AHD by allowing neuroactive substances contained
within the portal circulation to circumvent hepatic me-
tabolism or biliary elimination through a portacaval
anastomosis, and then enter the brain via the systemic
circulation. While a specific neurotoxin has not been
identified, ammonia, which plays a role in hepatic en-
cephalopathy, and aromatic amino acids, which may dis-
rupt dopaminergic pathways, are candidates [55]. Over
the past two decades, research into the pathogenesis of
AHD has increasingly focused on the role of heavy met-
als, particularly manganese.
Couper first described the neurotoxic properties of
manganese in 1837, and subsequent studies of manga-
nese ore-workers in Africa [123], Asia [45–48] and the
Americas [15, 91] have defined the clinical features of
intoxication, now termed “manganism” [106]. Improved
environmental health regulations have reduced the inci-
dence of manganism in miners, but historically 1 to 4
(and perhaps as much as 25) % of that population devel-
oped symptoms [106]. Recently, manganism unexpect-
edly re-emerged as an important medical topic because
of scientific and legal debate surrounding a potential
connection between welding, manganese, and neuro-
logical disease [54]. Also, recent reports of outbreaks of
manganism in persons exposed to recreational drugs
tainted with manganese have drawn more attention to
the role of this metal in neurological disorders [21,
141].
When reviewing evidence that links manganese to
AHD, it is important to note the similarities and differ-
ences in clinical phenotype between AHD and occupa-
tional manganism. Both disorders may cause cranial
dystonia and a form of atypical parkinsonism that is
subacute in onset, symmetrical, poorly responsive to do-
pamine replacement therapy and characterized by ac-
tion tremor, and an early impairment in postural reflexes
[54]. When compared to occupational manganism, AHD
is much 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 AHD. The speech difficulties and tremor of
occupational manganism may lessen with time, but gait
dysfunction rarely improves, and neurological deficits
do not wax and wane [15]. In contrast, AHD may be in-
terrupted by spontaneous remissions and sudden re-
lapses [55, 148].
A relationship between liver disease and manganese
became apparent when, in 1989, two research groups re-
ported that cirrhotic patients have unusual findings on
brain MRI – specifically, homogenous pallidal hyperin-
tensities on T1-weighted sequences with normal T2-

weighted sequences [25, 79]. This abnormal MRI signal,
suggestive of deposition of a paramagnetic substance
within brain tissue, is identical to MRI changes seen in
nonhuman primates intoxicated with manganese [99,
133], patients with occupational manganism [41], and
persons exposed to total parenteral nutrition [97] or in-
travenous drugs contaminated with manganese [21,
141]. Subsequent studies have confirmed that patients
with advanced liver disease have excessive amounts of
manganese in their blood [8] and have shown that blood
levels correlated with imaging abnormalities [11, 69, 100,
138]. Cerebrospinal fluid [8, 59] and brain tissue manga-
nese concentrations [49, 68, 84, 115, 124] have been found
to be elevated, demonstrating that the metal can traverse
the blood-brain barrier of patients with chronic liver
disease. Indeed, patients who expire from liver failure
have pallidal manganese levels that are between 3- and
9-fold higher than in controls [49, 68, 84, 115, 124], while
the brain concentrations of other common metals are
normal or only modestly elevated [68, 84, 116].
Most [33, 53, 70, 73, 121, 156], though not all [138,
146], studies indicate that increased pallidal signal, and
thus brain manganese levels, parallel portosystemic
shunting. Such a correlation is not surprising consider-
ing the liver’s role in the metabolism of manganese and
other metals. In healthy persons, the gastrointestinal
tract provides the most important means of manganese
uptake and elimination. Typically, dietary manganese
intake exceeds physiological requirements in excess of
95 %, and most manganese that enters the portal blood
is promptly excreted into bile before reaching the sys-
temic circulation [17, 24, 54]. In patients with liver dis-
ease, however, normal manganese excretion is impaired
and the metal enters the systemic circulation and brain.
The transfer of manganese from the portal to systemic
circulation appears to be the critical pathogenic event,
as patients who have obstructive jaundice without por-
tosystemic shunts are less prone to increased pallidal
signal [6]. Despite strong evidence that portosystemic
shunting results in brain manganese accumulation, evi-
dence directly linking manganism with neurological
symptoms in this population is scarce. Furthermore,
manganese blood levels, correlate only with pallidal sig-
nal and do not predict the presence of neurological dis-
ease [138].
In contrast to patients with idiopathic Parkinson dis-
ease, those with occupational manganism have normal
fluorodopa positron emission tomography (PET) imag-
ing, suggesting that the metal does not cause loss of pre-
synaptic nigrostriatal dopaminergic nerve terminals
[45, 132, 161]. However, recent work using 11-C-raclo-
pride/amphetamine PET in a non-human primate model
of manganism showed impaired striatal dopamine re-
lease in the absence of dopaminergic nerve terminal
loss, leaving open the possibility of more subtle presyn-
aptic dysfunction [38]. PET using dopamine receptor
323
ligands reveals a variable reduction of D2 receptor den-
sity, which indicates that manganese disturbs postsyn-
aptic nigrostriatal pathways [62, 132]. Fluorodeoxyglu-
cose PET, a technique that measures regional metabolic
activity, shows reduced uptake in the globus pallidum
[132], as one might expect considering the pallidal le-
sions on MRI. Likewise, autopsy studies of patients with
occupational manganism confirm that neurodegenera-
tion occurs predominantly in the globus pallidum – es-
pecially the medial segment – followed by the striatum
and substantia nigra par reticularis [163]. In two pa-
tients with action tremor and parkinsonism from AHD,
functional neuroimaging using dopamine transporter
ligands revealed normal uptake in the striatum, indicat-
ing integrity of the presynaptic dopaminergic pathway
similar to manganism [64, 109].
In patients with AHD, neuropathological examina-
tion often shows diffuse brain atrophy and regions of
translucent discoloration within the cortex and basal
ganglia [30, 154]. On light microscopy, small vacuoles
are present (polymicrocavitation) corresponding to the
translucent lesions seen on gross inspection. Vacuolar
change originates in the deep cortical layers and basal
ganglia. Within the cortex, polymicrocavitation is often
most severe in the posterior frontal, parietal and occipi-
tal areas [30], but the temporal lobes may also be affected
[66, 137]. In some patients, polymicrocavitation is great-
est adjacent to sulci [148, 154], while in others, it is more
prominent at the gyral summits [30, 66, 137, 144]. Within
the basal ganglia, the superior pole of the putamen, cau-
date heads, pallidum and subthalamic nuclei are most
involved [36, 66, 154]. Characteristically, polymicrocavi-
tation extends into adjacent white matter tracts where it
appears to displace rather than destroy surrounding
neurons. In some cases, however, white matter vacu-
olization is accompanied by myelinolysis [66, 78, 137].
Polymicrocavitation does not involve the cerebellum,
and ataxia in patients with AHD may be related to de-
generation of the dentate nuclei, Purkinje cell loss, and
Bergmann’s gliosis. Though pathologically striking, the
relevance of polymicrocavitation is unsettled because of
questions regarding clinicopathological correlation. For
example, most patients with AHD lack weakness and
sensory loss despite profound vacuolization of the fron-
toparietal cortices, while some patients with clinically
typical AHD lack polymicrocavitation entirely [154]. In-
deed, the only consistent neuropathological feature of
AHD is the presence Alzheimer type II glia, reactive as-
trocytes exhibiting large pale nuclei with one or more
small basophilic nucleoli (Fig. 1). Alzheimer type II glia
are abundant in, but not restricted to, regions of vacu-
olization [68, 154], and although universally present in
patients with AHD, they are not pathognomonic for this
disorder. Alzheimer type II glia also arise in patients
with uncomplicated cirrhosis, various metabolic en-
cephalopathies, Wilson disease, and curiously, in both a
324

within the basal ganglia. Areas of manganese accumula-

tion, however, do not reflect the brain concentration of
transferrin receptors [27] and neuronal [5] as well as as-
trocytic [26] transport may facilitate redistribution. It is
also unclear how the manganese causes neural damage.
Some studies have found that the metal accumulates in
high concentrations within the mitochondria of glial
cells and that symptoms may be the result of disrupted
energy metabolism [101], but data in this arena remain
discordant [39, 57].

Fig. 1 Photomicrograph (hematoxylin and eosin staining) of the cerebral hemi-
sphere, centrum semiovale from a patient with liver failure showing numerous
Alzheimer type 2 astrocytes (arrows). Image is courtesy of Dr. Adekunle Adesina
primate and rodent model of manganism [42, 103, 113].
Alzheimer type II glia, however, have not yet been re-
ported in humans with occupational manganism, and
brain polymicrocavitation also has not been observed in
manganese ore workers [113].
Although autopsy and PET studies of individuals
with manganism have localized the predominant sites of
neurotoxicity to the globus pallidum, it is not clear why
manganese preferentially accumulates in this brain re-
gion. Like iron, manganese appears to transverse the
blood-brain barrier through receptor-mediated endo-
cytosis in complex with transferrin and via the divalent
metal transporter 1, though other mechanisms likely
contribute [32]. One might speculate that shared metal
transport systems explain why various metals, including
iron, copper and manganese, accumulate predominantly
Diagnosis
AHD has protean manifestations and may mimic a broad
range of diseases. Even AHD’s most characteristic pre-
sentation, craniofacial dyskinesias, has an extensive dif-
ferential diagnosis (Table 2) [28, 35, 76]. In patients who
present with cognitive impairment, parkinsonism or
ataxia, clinicians might suspect AHD only when there is
clinical evidence of liver disease or signs of AHD on
brain MRI. Even in patients with established liver dis-
ease, the diagnosis of AHD remains challenging because
there are multiple potential associations between he-
patic and neurological disease. Apart from AHD, other
neurological diseases to consider in persons with cir-
rhosis include hepatic (toxic-metabolic) encephalopa-
thy, central pontine myelinolysis [74], alcoholic cerebel-
lar degeneration [10] and Wernicke’s encephalopathy
[72].
Sporadic case reports suggest that hereditary hemo-
chromatosis, which is known to cause cirrhosis, may
also precipitate various movement disorders [23]; how-
ever, the connection remains unproven [126]. An asso-
ciation between hereditary hemochromatosis and
movement disorders seems plausible given the fact that
abnormal regulation of brain iron homeostasis is an es-

Table 2 Differential diagnosis of orobuccolingual dyskinesias

Drug-induced 1. Acute forms due to dopaminergic drugs, stimulants, oral contraceptives, anabolic steroids, anticholingerics, anticonvulsants
and antimalarials
2. Tardive forms due to dopamine receptor-blocking drugs
Hereditary Huntington disease, neuroacanthocytosis, Lesch-Nyhan disease, Wilson disease, neurodegeneration with brain iron accumula-
tion, dentatorubropallidoluysian atrophy, Machado-Joseph disease, benign familial chorea, porphyria, various inborn errors of
metabolism including mitochondrial disorders, GM1 gangliosidosis, neuronal ceroid lipofuscinoses and others
Toxin-induced Carbon monoxide, manganese, mercury, thallium, toluene, kernicterus
Metabolic Hyperthyroidism, hyper- or hypoparathyroidism, striopallidodentate calcinosis, hyperglycemia, nutritional deficiencies,
electrolyte imbalances, chorea gravidarum, acquired hepatocerebral degeneration
Immune-mediated Sydenham disease, antiphospholipid antibody syndrome, systemic lupus erythematosus, post-vaccinal chorea, paraneoplastic
disorders such as anti-NMDA receptor encephalitis [50]
Cerebrovascular or hematological Basal ganglia or brainstem stroke or hemorrhage, anoxia, polycythemia vera, arteriovenous malformation, vasculitides, cerebral
palsy
Other Idiopathic and secondary craniocervical dystonias, tic disorders (Gilles de la Tourette syndrome or secondary tourettism), spon-
taneous buccolingual dyskinesias of the elderly, edentulous dyskinesias, stereotyped movements in schizophrenia, encephalitis
lethargica, oculomasticatory myorhythmia from Whipple’s disease, facial myoclonus of central origin, and other orolingual
rhythmical movements [135]

Fig. 2 MRI showing increased T1 signal within the pallidal nuclei of a patient with
parkinsonism associated with AHD. Image is courtesy of Dr. Jeffrey Guptill
tablished cause of several movement disorders, now
known collectively as neurodegeneration with brain
iron accumulation (NBIA) [75, 87]. However, unlike pa-
tients with NBIA, those with hereditary hemochromato-
sis have not been shown to have basal ganglia iron
deposition on autopsy. Furthermore, while hereditary
hemochromatosis is a relatively common disorder, very
few patients with movement disorders have been re-
ported, and these patients are heterogeneous in terms of
their clinical, imaging and genetic findings [126].
Although rare, Wilson disease is unquestionably the
most important diagnosis to exclude because it is fatal,
yet is reversible when treated with copper lowering ther-
apies such as zinc, chelating agents and tetrathiomolyb-
date (Table 1).
Patients with AHD develop a variety of laboratory
and neuroimaging abnormalities that are typical of cir-
rhotic liver disease; however, it is unclear which of these,
if any, are related to the neurological phenotype. The
most characteristic finding in this population is in-
creased T1 signal on MRI within the pallidal nuclei,
sometimes extending into adjacent basal ganglia struc-
tures and the thalami [95] (Fig. 2). T2-weighted and
contrast-enhanced MRI sequences are typically normal,
but rarely show abnormalities in the pallidi [67, 139, 147,
151, 156] or lesions in other structures, such as the
brachium pontis [40, 78]. Several other disorders pro-
duce T1 hyperintensities within the basal ganglia; how-
ever, apart from other forms of manganese deposition,
all are easily differentiated from AHD based upon their
appearance on T2-weighted sequences, contrast en-
hancement or clinical features (Table 3). In patients with
evidence of myelopathy, MR imaging of the spine is usu-
ally normal; however, motor evoked potentials demon-
325
strate spinal cord dysfunction, usually at the thoracic
level [14, 80].
Treatment
Little has been published concerning the medical man-
agement of AHD, and available data are derived from
case-reports or small retrospective case series. Accord-
ingly, treatment recommendations for AHD, in terms of
disease prevention, modification, and symptomatic
therapies, are tenuous pending well-designed prospec-
tive studies.
AHD-related chorea and orobuccolingual dyskine-
sias often respond to dopamine receptor antagonist
drugs; however, these medications introduce the risk of
an irreversible tardive drug syndrome, and their long-
term safety in patients with AHD is uncertain. Further-
more, phenotypic similarities between AHD and tardive
stereotypy may encumber monitoring for this complica-
tion. Tetrabenazine, a presynaptic dopamine-depleting
drug [61], is an alternative medication which is preferred
by some clinicians [107] as it poses no risk of a tardive
syndrome and is effective for a broad range of hyperki-
netic movement disorders [60]. Tetrabenazine has only
recently been approved for use in the United States, and
like dopamine receptor antagonists, can cause parkin-
sonism, sedation, mood changes and other abnormali-
ties, but in contrast to the dopamine receptor blocking
drugs (neuroleptics), the adverse effects of tetrabenazine
are usually dose-related and reversible.
For patients with parkinsonism related to AHD, in-
formation regarding the utility of dopamine replace-
ment therapy is conflicting. Some patients exhibit a sub-
stantive response to levodopa and dopamine agonists,
approaching the effect seen in idiopathic Parkinson dis-
ease [8, 67, 83, 94], while in others, symptoms are recal-
citrant to therapy [2, 68, 109, 134, 164]. In view of the
possible relationship between AHD and manganese, it is
notable that, contrary to initial reports [18, 89, 125], do-
pamine replacement therapy is minimally beneficial for
occupational manganism [15, 48, 82]. Beta-blockers and
anticholinergics also have yielded little improvement in
patients with tremor [109].
Thus far, no medications appear to retard the pro-
gression of AHD, and development of future neuropro-
tective therapies is hampered by clinical heterogeneity,
uncertainties regarding the pathogenesis and relative
scarcity of cases thus preventing large clinical trials
powered to show efficacy of active treatment over pla-
cebo. Lactulose, antibiotics and short-term dietary pro-
tein restriction may minimize co-morbid toxic-meta-
bolic encephalopathy and may reduce symptoms of
AHD in some patients [117, 154]; however, AHD-related
movement disorders seldom respond well to ammonia-
reducing therapies [55, 83, 110, 114, 122, 131, 148].
326

Table 3 Differential diagnosis of T1 hyperintensities in the basal ganglia on MRI

Diagnosis Notes Reference

Acquired hepatocerebral T1 hyperintensities are homogenous and symmetrical. Abnormal signal is located predominantly in the pallidum; lesions do [95]
degeneration (AHD) not enhance
T2 sequences and CT are normal
Manganese intoxication MRI findings are identical to AHD [21, 41, 43,
Causes include: (1) exposure to manganese ore, (2) injection of manganese-tainted total parenteral nutrition or intravenous 65, 97, 141]
drugs, and (3) iron deficiency
Hyperglycemic T1 hyperintensities are typically asymmetrical and are located in the striatum more often than the pallidum; lesions do not [12, 102]
hyperosmolar state enhance
T2 sequences may show low, iso-, or high signal intensity lesions with restricted diffusion in the basal ganglia
CT may be normal or show high-attenuation lesions in the striatum
Wilson disease T1 sequences more often show low or iso-, signal intensity lesions in the basal ganglia, but hyperintensities have been [105, 130, 136]
reported; lesions do not enhance
T2 sequences may show low or high signal intensity lesions with restricted diffusion
FLAIR sequences may show the “giant panda face“ sign
CT may show low-attenuation lesions in the basal ganglia and thalamus
Cortical, subcortical white matter, thalamic, cerebellar and brainstem lesions often accompany basal ganglia disease
Neurodegeneration Four NBIA subtypes include: Pantothenate kinase associated neurodegeneration (PKAN), infantile neuroaxonal dystrophy, [75, 87]
with brain iron neuroferritinopathy and aceruloplasminemia
accumulation (NBIA) NBIA may cause increased T1 signal in the basal ganglia, but changes on T2-weighted imaging are the more common and
prominent finding; lesions do not enhance
T2 and fast spin echo sequences distinguish NBIA subtypes. All 4 subtypes cause T2 hypointensities within the globus pallidus
and substantia nigra. Infantile neuroaxonal dystrophy typically results in no additional abnormalities.
PKAN universally causes an area of central T2 hyperintensity within the globus pallidus – so called “eye of the tiger sign.”
Aceruloplasminemia causes T2 hypointensities within the putamen, caudate and thalamus (all three). Like aceruloplas-
minemia, neuroferritinopathy also may causes additional T2 hypointensities within the putamen, caudate, thalamus,
dentate or cerebral cortex. In addition, neuroferritinopathy sometimes results in either eye of the tiger sign or confluent
cavitary lesions involving the putamen or globus pallius.
Basal ganglia Common causes include parathyroid disease and Fahr syndrome [3, 128]
calcification T1 sequences more often show low or iso-, signal intensity lesions in the basal ganglia, but hyperintensities have been
reported; lesions do not enhance
T2 sequences usually show corresponding iso- or hypointense lesions
CT universally shows high-attenuation lesions and is the preferred imaging modality
Hypoxic-ischemic Prominent T1- hyperintensities of the basal ganglia may be seen following hypoxic-ischemic injury, sometimes with [16, 44, 149, 162]
injury gadolinium enhancement, but T2 lesions and restricted diffusion commonly co-occur
Associated imaging abnormalities are commonly found outside the basal ganglia, e.g., cortical laminar necrosis
In neonates with hypoxic ischemic injury, metabolic disorders such as perinatal hypoglycemia, bilirubin encephalopathy, non-
ketotic hyperglycinemia, and urea-cycle disorders also may cause basal ganglia hyperintensities on T1-weighted imaging
CT may show low-attenuation basal ganglia lesions
Carbon monoxide Basal ganglia T1- hyperintensities are possible, but T1 sequences more often show low signal intensity lesions in the medial [81]
poisoning globus pallidus, which may enhance
T2 sequences usually show corresponding hyperintense lesions and apparent diffusion coefficient maps show restricted
diffusion
CT may show low-attenuation basal ganglia lesions
Langerhans cell T1 pallidal hyperintensities are common and gadolinium enhancing lesions may be present T2 sequences may show low, iso-, [22, 119, 160]
histiocytosis or high signal intensity lesions
co-morbid extra-axial (osseous and dura-based) lesions always accompany parenchymal changes and other brain sites such as
the pineal, pituitary, white matter, dentate and brainstem are commonly involved
CT may show lytic lesions in the skull or skull base
Neurofibromatosis Basal ganglia T1- iso- or hyperintensities are possible, but T2 hyperintensities are more common; some lesions may enhance [92]
type I Lesions may be bilateral but are less homogenous than AHD
Other MRI lesions may co-occur including astrocytomas, optic gliomas, sphenoid dysplasia, and plexiform neurofibromas
CT typically shows normal basal ganglia
Fucosidosis T1 sequences may show pallidal hyperintensities similar to AHD but T2 sequences usually show corresponding basal ganglia [34, 104, 120]
hypointensities
T2 sequences may show prominent white matter abnormalities and thalamic lesions
CT may show low-attenuation lesions within the globus pallidus
Microhemorrhage Bilateral basal ganglia microhemorrhage may result from hypoxia, infections such as Japanese encephalitis, or microangiopa- [1, 58, 88, 129,
of the basal ganglia thies such as hemolytic-uremic syndrome or AIDS-related microangiopathy 140]
T1 and T2 sequences show low, iso-, or high signal intensity lesions depending on the oxidation state of degraded
hemoglobin
Apparent diffusion coefficient maps may show restricted diffusion from concurrent infarction
CT may show low-attenuation basal ganglia lesions from ischemia or high-attenuation lesions from hemorrhage

Ethylenediaminetetraacetic acid (EDTA) is a chelator
of manganese [20], and a proven therapy for some forms
of heavy metal poisoning, but its efficacy in AHD is
uncertain. In one report, EDTA yielded unsatisfactory
results in a series of patients with occupational man-
ganism [47]. Furthermore, intravenous EDTA poses po-
tentially serious risks, including nephrotoxicity, provid-
ing grounds for caution in its off-label use. A recent
report indicates that trientine, an oral chelating agent
used to treat Wilson disease, decreased neurological
deficits, MRI abnormalities and manganese blood levels
in a patient with AHD-related parkinsonism [109]. This
observation requires confirmation, especially since tri-
entine has not been proven to effectively chelate manga-
nese [7].
The effects of dietary manganese restriction has yet
to be studied for patients with AHD or cirrhotic patients
who are at risk; however, low manganese intake is pru-
dent for such patients on theoretical grounds. Major di-
etary sources of manganese include grains, nuts, tea,
fruits, legumes and other vegetables [111, 112]. Since the
proportion of manganese absorbed from the intestine
and retained in tissue varies inversely with iron stores
[31, 65, 90], iron deficiency anemia may contribute to the
progression of AHD and should be corrected when pres-
ent. If symptoms of AHD result from false neurotrans-
mitters derived from aromatic amino acids, supplement-
ing branched-chain amino acids may be useful, as they
compete with aromatic amino acids to cross the blood-
brain barrier [63]. There is scant evidence supporting
this therapy for patients with AHD [151], but further
studies are needed.
Since AHD is related to portosystemic anastomoses
[8, 14, 30, 127, 154, 164], deferring placement of endovas-
cular or surgical shunts (used to minimize variceal hem-
orrhage) may limit risk of disease. In selected patients
who suffer neurological deterioration following shunt
placement, it may be possible to obstruct an existing
shunt [13, 14, 85, 145]; however, shunt occlusion is poten-
tially risky as it could worsen portal hypertension and
precipitate variceal hemorrhage.
Although long assumed to be irreversible, mounting
evidence suggests that even long-standing AHD may im-
prove remarkably following liver transplantation [118,
143], including hyperkinetic movement disorders [107,
117, 131, 142], parkinsonism [77, 118, 121, 134, 139, 142],
ataxia [110, 131], myelopathy [98, 114, 150, 157] and cog-
nitive dysfunction [67, 86, 142]. Blood manganese levels
and MRI changes also improve following restoration of
hepatic function, although normalization of these pa-
rameters is gradual and sometimes incomplete. Mag-
327
netic resonance spectroscopy (MRS) of the brain is an
alternate means of tracking recovery following liver
transplantation, since MRS abnormalities resolve in uni-
son with clinical improvement and in advance of changes
on standard MRI [77]. In this population, the changes on
MRS that correlate with the presence of parkinsonism or
encephalopathy include reduced choline and myoinosi-
tol resonance [139] and increased glutamate/glutamine
resonance [96].
Recovery following liver transplantation is usually
gradual over the course of several months [114, 118, 134],
yet remarkably, some patients improve within hours of
transplant surgery [67, 107, 131]. Such a precipitous re-
covery has potentially important implications regarding
the pathophysiology of AHD, as it provides support for
the role of reversible metabolic factors in AHD. Further-
more, it is unlikely that the effects of chronic manganese
accumulation could improve so rapidly. In patients with
occupational manganism deficits will initially worsen
and then remain static for decades following removal
from the exposure [46]. This observation, in conjunction
with previously noted phenomenological differences
between AHD and occupational manganism have not
been addressed by those who attribute AHD to manga-
nese intoxication.
The durability of clinical benefit in patients who do
respond to transplantation remains unknown. Some pa-
tients eventually develop re-emergent neurological defi-
cits either secondary to graft rejection [131] or for other
reasons [107], some do not respond to transplantation
[19], and some suffer from peri-operative complications
[80]. Nonetheless, it should be stressed that AHD is not
a contraindication to liver transplantation and in some
cases may be the only effective therapy.
Conclusion
AHD remains an underrecognized entity with high
morbidity and no proven pharmacological therapies,
although liver transplantation is remarkably helpful in
some patients. More research is needed to better under-
stand the pathogenesis of AHD, define which patients
are at risk and develop effective strategies to arrest dis-
ease progression and minimize disability.
■ Conflict of interest The authors have no association or vested inter-
est in the subject matter or products mentioned in the manuscript.
■ Acknowledgments The authors would like to thank Drs. Adekunle
Adesina and Jeffrey Guptill for providing neuropathological and ra-
diological images, respectively.
328
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