Secondary Schizophrenia (135 page)

are known
[4],
some associated with ethnicity, severity, age of onset, or presentation
[5, 10].
Highly dysfunctional mutations lead to early-onset severe hep-Diagnosis and clinical features
atic WD, whereas milder mutations lead to late-onset
Clinical suspicion is imperative in diagnosing WD.

neurological WD
[11].
A cytosine-adenine transver-Initial presentation with hepatic, neurological, or psy-sion may be responsible for 30% of North American
chiatric symptoms, particularly when accompanied by
WD cases
[12].
Animal models include the Bedlington
a family history of WD or the presence of Kayser-terrier, Long Evans Cinnamon rat, toxic milk mouse,
Fleischer rings (KFRs) on slit lamp exam, warrants a
and the murine ATP7B gene deletion model
[4].

diagnostic workup to exclude WD. KFRs result from
corneal-copper deposition, but they may often be
Pathophysiology and pathology

absent in WD associated with psychiatric manifesta-The physiological importance of copper is critical.

tions
[17].
WD is diagnosed by determining low blood
338

Copper is integral to cytochrome c oxidase in the mito-ceruloplasmin (< 20 mg/dl) and high 24-hour urinary
Chapter 27 – Wilson’s Disease

copper levels (> 50
µ
g/dl) and is confirmed by elevated
within 6 months if treatment is not initiated. With-copper levels on liver biopsy (> 150
µ
g/g)
[3].
In cases
out treatment, patients with WD progress to become
involving ambiguous results, the presence of KFRs and
dysarthric, bedridden, and unable to function.

low serum copper can add diagnostic confidence.

Psychiatric symptoms occur in isolation in approx-Putaminal increased signal on MRI T2 images is
imately 20%, are the predominant presenting manifes-supportive of the diagnosis, although increased sig-tation in 33%, and are present at initial presentation in
nal is also often seen in the pons
[18, 19]
and some-67%
[2, 27, 28, 29].
The predominant psychiatric fea-times in the thalamus, globus pallidus, caudate, cere-tures evident across the WD literature include person-bellum, subcortical white matter, and midbrain. T1

ality changes, cognitive disturbances, and mood disor-signal is often reduced in affected structures, but can
ders
[3, 30,
31].
Half of patients undergo psychiatric
be increased in the globus pallidus in liver disease
hospitalization before WD is first diagnosed
[32, 33].

with portocaval shunting
[20].
Common CT find-Tragically, the diagnosis of WD is often missed
[34,

ings are ventricular dilatation, basal ganglia hyper-

35].
Psychiatrists are not alone in missing the diagno-densities, and atrophy of the cerebral cortex, brain-sis. A retrospective Chinese study of 1,011 cases of WD

stem, or cerebellum. Basal ganglia MRI hypointensity
found that 516 cases had been originally misdiagnosed
and CT hypodensity are consistent with cavitation in
as more than 100 different systemic diseases as well as
more aggressive WD. On positron emission tomog-primary psychosis
[36].

raphy (PET), glucose metabolism may be reduced in
the cerebellum and striatum, as well as cortical and
thalamic regions
[21].
Neurological severity correlates
Treatment

with reduced striatal glucose metabolism
[22]
and
A full explication of treatment is beyond the scope
dopamine D2 receptor binding on SPECT imaging
[22,

of this chapter and is elaborated elsewhere
[3].
Gene
23].

therapies are currently under development
[37, 38].

Initial neurological signs are subtle and include
Treatment considerations include selection of anti-mild tremor, speech difficulties, or micrographia. In
copper therapies and the treatment of specific mana study of 19 patients with a duration of WD of
ifestations
[3, 8,
39].
Early recognition and treat-at least a decade, 17 (89%) had basal ganglia signs,
ment of WD are imperative because improvement
whereas 2 (11%) had oculomotor or cerebellar signs
with treatment is limited to the first 5 years of symp-

[24].
In a Chinese study of 71 patients with WD hos-tomatic illness and the first 2 years of treatment
[27,

pitalized over an 11-year period, 52 patients (73.2%)
40].
Copper-chelating agents (penicillamine and tri-had neurologic symptoms at the time of diagnosis,
entine) increase urinary copper excretion. Trientine is
including tremors (66.2%), dysarthria (56.3%), gait
also known as triethylene tetramine dihydrochloride.

disturbances (46.5%), generalized or multifocal dys-Copper-depleting agents (zinc and tetrathiomolyb-tonia (42.3%), decreased facial expression (40.8%),
date) reduce copper absorption and induce copper
and rigidity (33.8%)
[25].
Akinetic-rigid syndrome
sequestration into a hepatic nontoxic pool. Consider-was seen in nine patients. Personality changes (38%)
ation must be given to the various indications, dosing,
were not uncommon. Other less-frequent presenta-side effects, and other factors in administering these
tions were increased deep-tendon reflexes (23.9%),
agents, discussed elsewhere
[3, 8,
39].
Copper chela-epileptic seizures (5.6%), and hypokalemic periodic
tors have been recommended for hepatic WD, whereas
paralysis (1.4%); tremor was mainly kinetic and pos-copper depletors have been recommended for neuro-tural and 32 (45%) of the 71 patients had the clas-logical WD
[3, 8,
39].
Improvement with anticopper
sic wing beating tremor
[25].
As neurological fea-agents often occurs only after 6 months of treatment.

tures progress, however, common findings in order
Exacerbations of neurological and psychiatric symp-of decreasing frequency include dysdiadochokinesia,
toms sometimes occur during the first several months
dysarthria, bradykinesia, postural tremor, parkinson-of therapy due to rapid copper mobilization. A vari-ism, hyperkinesia, and ataxia
[26].
Although rela-ety of treatment techniques have been advocated in the
tively rare in adults
[26]
, dystonia and chorea are
context of such exacerbations
[3,
35, 41, 42],
but the
particularly common in children
[24].
Seizures occur
basic concept is to switch to a less aggressive agent.

in a minority of patients, often remitting with WD

Liver transplantation is curative and has its own spe-

339

treatment. Patients with neurological WD can die
cial indications
[3, 10, 16,
43].
Patient survival after
Organic Syndromes of Schizophrenia – Section 3

transplant exceeds 80%
[3,
44].
Plasma exchange and
normative prevalence of 0.2%–0.5% based on contem-peritoneal dialysis have been used in fulminant WD

porary nosology
[48]
, but reporting biases are possi-and WD hemolytic anemia, but are rarely necessary.

ble. Dening and Berrios retrospectively studied a series
Good results have been reported with tetra-

of 195 WD patients undergoing an initial neurological
thiomolybdate in patients with psychiatric WD
[45].

hospital admission. Two raters reviewed charts. Def-Incongruous behavior and cognitive impairment have
inite delusions occurred in two (1%), possible delu-been found to improve more than irritability and
sions in one (0.5%), definite hallucinations in one
depression after WD treatment
[40]
. Other con-

(0.5%), and possible hallucinations in one (0.5%), and
ditions reported to improve with WD treatment
the prevalence of schizophreniform psychosis was not
include amnestic disorder, dementia, hypersexuality,
increased above normative rates
[28].

aggression, hyperactivity, and disinhibition. Psychi-Other studies, however, suggest higher preva-

atric symptoms may resolve more often in patients
lences. In a series of 34 consecutive patients with con-lacking dysarthria, incongruous behavior, and hepatic
firmed diagnoses of WD, one patient (2.9%) had been
symptoms.

previously diagnosed with schizophrenia
[33].
In a
Against this backdrop of understanding WD in

Chinese study of 71 patients with WD (45 male and 26

general, we first consider psychosis within the context
female) hospitalized over an 11-year period, 8 (11.3%)
of WD, then review other WD psychiatric features that
were found to have hallucinations
[25].
In patients
have been documented in schizophrenia, and finally
with neurological WD, psychosis and catatonia each
discuss critical issues in treating WD psychosis.

occurred in 8% of the patients
[35].

Longitudinal studies also observe higher preva-

Psychosis in Wilson’s Disease

lences. In a retrospective longitudinal case history
review of 24 WD patients presenting with psychiatric symptoms at the time of WD diagnosis, psy-Psychotic features
chosis was present in 2 patients (8.3%), including
Wilson reported two cases of psychosis (cases 2 and
1 with catatonia
[32].
Oder and colleagues prospec-3) in his original paper, including auditory halluci-tively studied 45 patients with WD (27 had neu-nations, control delusions of made action, and delu-rological features), finding prominent delusions in
sions of reference
[2].
Psychotic features can be the
3 patients (6.7%)
[26],
whereas the expected com-presenting sign of WD, hence, the clinical admoni-bined age-adjusted life prevalence of schizophrenia
tion to exclude WD in first-onset psychosis. Psychotic
and schizophreniform disorder together would be
features appear to be more prevalent in neurological
≤
2.0%
[49].

WD than in hepatic WD
[28,
31, 32, 35].
Although an
Prevalence studies to date suffer from inconsis-increased prevalence of psychosis in WD is the subject
tent selection factors, referral biases, reporting biases,
of debate, clinical evidence suggests WD as an etiology
are often of limited sample size, and are usually ret-of psychotic manifestations.

rospective in nature. Case reports, however, reveal
Although early studies suggested an association
antipsychotic-refractory
[50, 52, 54, 56],
anticopper
of psychosis and WD related to basal ganglia pathol-therapy-responsive
[26,
41, 50, 51, 52, 53, 54]
psy-ogy
[46]
, Beard maintained that coincidental primary
choses that develop in parallel with the evolution of
schizophrenia and improper diagnosis of schizophre-WD neurological features
[50, 51, 54, 56],
suggesting
nia in cases that later manifested dementia fully
that WD can induce schizophreniform psychoses.

accounted for psychosis in WD
[47].
Davison and
A number of case reports indicate that the

Bagley pointed out, however, that subsequent devel-psychosis of WD is frequently misdiagnosed as
opment of dementia by no means invalidated the ini-schizophrenia or some other primary psychosis
tial diagnosis of schizophrenia but rather strength-despite the presence of WD neurological features
[50,

ened the supposition that the original psychosis was
51, 54].
Sometimes these neurological features have
attributable to underlying WD pathology
[48].

been misinterpreted as antipsychotic side effects
[51].

Prevalence studies have produced mixed findings.

Presenting psychotic features have included audi-Davison and Bagley found 8 (1.5%) “acceptable” cases
tory
[54, 55]
and visual
[56]
hallucinations, delusions
and 11 (2.1%) questionable cases of schizophrenia
[52, 54, 55],
paranoia
[53],
incoherence
[52],
inap-

340

among 520 reported WD cases, exceeding the accepted
propriate and derailing speech
[55],
neologisms
[55],

Chapter 27 – Wilson’s Disease

catatonia
[54, 56],
disinhibited
[55]
and disorganized
been associated with brainstem signs and dystonia but
[56]
behavior, suicide attempts
[55],
mannerisms
[52],

not tremor
[28]
. Personality syndromes also corre-social withdrawal
[53],
and dysphoria
[53].
Delusions
late with dyskinesia, dysarthria, and putaminal and
have involved nihilistic
[54],
persecutory
[54, 55],
and
pallidal lesions
[58].
Psychopathic features are asso-somatic
[55]
themes. Depressive
[53, 54, 56]
and anxi-ciated with dysarthria
[59].
Incongruous, disinhib-ety
[53]
symptoms have sometimes attended these psy-ited, aggressive, hyperactive, and hypersexual behav-choses. At times, psychotic features emerge within sev-iors, but not irritability, have improved with treatment
eral months after commencing anticopper therapy due
of the underlying WD
[27,
40].