Authors: Perminder S. Sachdev

Secondary Schizophrenia (99 page)

nervous system myelin
[140].
Psychosine is toxic to
PMD generally presents in infancy with intellectual
white matter and causes rapid loss of oligodendro-delay, nystagmus, stridor, cerebellar dysfunction, and
cytes, demyelination, and secondary axonal degen-a progressive upper motor neuron pattern of dis-eration
[141]
. Globoid cells are seen on pathology
ease
[148].
However, it may also present in adulthood
and likely reflect phagocytosis of galactolipids by
with dementia or psychosis
[149].
The prevalence of
macrophages. Findings on MRI include white-matter
psychosis in PMD is unknown. Treatment remains
lesions that may be seen in the periventricular parieto-supportive.

occipital regions and then become more diffuse
[142].

Diagnosis is made by measuring galactocerebrosidase
activity in peripheral leukocytes and by molecular
analysis of the galacto-sylceramidase gene. The inci-

Cerebrotendinous Xanthomatosis

dence of Krabbe’s Disease varies geographically, and is
Cerebrotendinous xanthomatosis is an autosomal
approximately 1 in 100,000 in the United States and
recessive disorder of bile acid synthesis. It is caused
as high as 1 in 6,000 in a Druze kindred in Israel
by deficiency in the mitochondrial enzyme sterol
[143].

27-hydroxylase (CYP27), resulting in an inability to
Krabbe’s Disease most commonly presents before
convert cholesterol to cholic and chenodeoxycholic
6 months of age with irritability, spasticity, blind-acids and the accumulation of bile alcohols in various
ness, hearing loss, seizures, and rapid motor and
organs, including the nervous system and cholesteanol
mental deterioration, culminating in death within a
which can be toxic to oligodendiocytes
[150].
In
few years. Onset after 6 months of age is termed
the brain, cerebral xanthomas can form, and there
248

late-onset Krabbe’s Disease and has a variable but
is loss of myelin, resulting in diffuse white-matter
Chapter 18 – Psychosis associated with leukodystrophies

abnormalities. While previously thought to be a rare
Membranous lipodystrophy

disorder, it is now considered to be one of the main
Membranous lipodystrophy, also known as polycys-causes of leukoencephalopathies in adults. Diagnosis
tic lipomembranous osteodysplasia with sclerosing
is confirmed by measurement of elevated plasma and
leukoencephalopathy or Nasu-Hakola Disease, is a
bile cholestanol and increased urinary excretion of bile
rare, recessive disorder associated with bone cysts and
alcohol glucuronides in association with clinical fea-neuropsychiatric symptoms. Patients generally present
tures of the disorder.

in their second to third decade of life with pain in their
Clinical manifestations include chronic diarrhea,
ankles and wrists and associated pathological frac-bilateral cataracts, Achilles tendon xanthomas, pre-tures
[155].
This is followed by psychosis, progressive
mature atherosclerosis, osteoporosis, and progressive
dementia, myoclonus, seizures, or gait disturbances
neurological symptoms, including ataxia, pyramidal
in the third to fourth decade of life. The true inci-signs, and dementia
[151].
Psychiatric symptoms were
dence of psychosis is unknown. The disease is gen-reported in 4 of 35 patients in a series by Berginer
erally fatal by age 50. The disease has recently been
and colleagues
[152].
Two patients were psychotic with
linked to mutations in the gene encoding a tyrosine
auditory hallucinations and delusions, one patient pre-kinase binding protein
[155]
, although the molecu-sented with catatonia, and one patient developed agita-lar and cellular pathogenesis remains unknown. In the
tion, aggression, and negativistic behavior. All patients
brain, there is loss of myelin particularly in the frontal
in the series had diffuse white-matter abnormalities
lobes, astrocytic gliosis, enlarged ventricles, calcifica-and no focal lesions. Treatment with chenodeoxycholic
tions and atrophy of basal ganglia, and atrophy of the
acid reduces cholestanol levels and generally results in
corpus callosum
[156].
There is no known treatment.

marked clinical improvement, particularly if started
prior to significant neurological deterioration
[150].

Therefore, it is essential that patients with psychosis
Principles of management for patients

and features of cerebrotendinous xanthomatosis be
appropriately investigated for this potentially treatable
with inherited leukodystrophies

disorder.

Monitoring the course of illness

Once the diagnosis of an inherited leukodystrophy
Alexander’s Disease

has been made, it becomes important to monitor the
progress of the underlying pathology. The following
Alexander’s Disease is a sporadic leukodystrophy asso-investigations are useful in this regard:
ciated with the accumulation of glial fibrillary acidic
protein (GFAP) and heat shock proteins in astrocytes,
1. Cranial MRI at regular intervals, every 2–5 years
forming characteristic inclusions termed Rosenthal
or as clinically indicated

fibers
[153, 154].
There is associated diffuse myelin
2. An EEG at baseline and as clinically indicated
loss, with white-matter abnormalities most promi-thereafter, given the common complication of
nent in the frontal lobes. The prevalence is unknown,
seizures and the need to rule out seizure activity
with approximately 450 cases reported in the world
as a cause of psychiatric decompensation
literature. Diagnosis is generally based on MRI find-3. Cognitive testing at baseline and at regular
ings, although genetic testing of the GFAP gene is now
intervals

available. Alexander’s Disease typically presents in
infancy with megalencephaly, seizures, mental retar-4. EMG and nerve conduction studies to assess
dation, spasticity, and rapid death. Rarely, it may
peripheral nerve function

present in adolescence and adulthood with ataxia,
5. Regular neurological examinations
spasticity, bulbar signs, and dementia
[154].
Typically,
there is less myelin loss in adult forms of the disease.

Psychosis has not been reported in Alexander’s Dis-Treatment of psychiatric illness
ease. This may be a result of underrecognition or the
Patients with leukodystrophies frequently prove
relative preservation of myelin in adult forms. There is
refractory to traditional medication regimens. This
249

no effective treatment for the disease.

indeed may be what prompts the initial investigation
Organic Syndromes of Schizophrenia – Section 3

for an underlying metabolic disorder. They may also
without a pre-existing epileptic disorder. One would
be especially vulnerable to developing medication side
imagine the risk to be much higher when used in the
effects
[107],
necessitating regular reassessment of
context of an underlying neurometabolic condition.

the risk:benefit ratio of any treatment regimen. Many
Several of the newer antipsychotic drugs such
psychotropic agents interfere with mitochondrial
as olanzapine and clozapine are associated with a
function. Specifically, many antipsychotic agents,
metabolic syndrome and may compound the risk
both typical and atypical, have been shown to inhibit
of patients with mitochondrial disorders developing
complex 1 of the respiratory chain and, therefore,
diabetes.

may worsen symptoms
[157].
In addition, the inhibition of oxidative phosphorylation and increased
production of free radicals
[157,
158] could worsen
Summary and future directions

the underlying disease process, particularly in those
Patients with adult-onset forms of the inherited
with mitochondrial diseases. Certain psychotropic
leukodystrophies have a very high prevalence of neu-medications known as amphiphilic agents have been
ropsychiatric disturbances, many of which closely
shown, in vitro and in vivo, to accelerate lipid depo-resemble the clinical features of schizophrenia. This
sition and promote lysosomal excretion of certain
is of interest for two reasons. For one, there are
enzymes
[159].
These effects have been implicated in
obvious therapeutic implications. Many medications
a worsening of the underlying pathological process in
used to treat psychiatric symptoms have the poten-certain metabolic disorders, such as the gangliosidoses
tial to exacerbate the clinical consequences of neu-

[160, 161]
and might also be relevant in the treatment
rometabolic disorders and, in some cases, may worsen
of patients with other inherited metabolic diseases.

the underlying disease process. A substantial propor-Extrapyramidal side effects (EPS) can exacerbate
tion of patients with schizophrenia are refractory to
the functional impairment associated with upper
treatment. Might these individuals harbor an unrec-motor neuron pathology and the anticholinergic prop-ognized leukodystrophy or other neurometabolic dis-erties of many psychotropic agents will tend to exac-order?

erbate cognitive impairment. Anticholinergic medica-There is another reason to note the high preva-tions may be particularly problematic in the case of
lence of psychiatric illness in patients with inher-patients with ALD who may also have Addison’s Dis-ited leukodystrophies. At the present time, we do
ease, and prone to develop hypotension.

not understand the pathological processes that give
Benzodiazepines have the potential to exacerbate
rise to the clinical syndrome we call schizophrenia.

problems of dysarthria, gait disturbance, and short-The key feature common to all central leukodys-term memory impairment to which these patients are
trophies is the disconnection of brain regions from
vulnerable.

one another. Careful attention to the precise localiza-Patients with leukodystrophies frequently develop
tion of the white-matter lesions may help us under-seizures, and status epilepticus is a leading cause of
stand the pathobiology of particular psychiatric symp-death in patients with mitochondrial disease. Unfor-toms, and advances in the identification of genotype–
tunately, most psychotropic agents, other than ben-phenotype relationships may illuminate why some
zodiazepines, lower the seizure threshold. For this
patients develop psychiatric illness and others do not.

reason, when mood symptoms are prominent, anti-Finally, as treatments for inherited leukodystro-seizure medications may be preferable to lithium. Val-phies develop, it will be imperative to accurately iden-proic acid, however, can cause a secondary impair-tify affected individuals who may benefit from these
ment of mitochondrial function through the induction
new approaches
[164].

of carnitine deficiency
[162].
The atypical antipsychotic, clozapine, which might otherwise be chosen
to treat refractory psychotic symptoms, is associated
Acknowledgments

with a lifetime cumulative risk of seizures: 10% after
We wish to thank Mary Wilson for her expert and care-3.8 years of treatment
[163],
even among those
ful assistance in preparing this chapter.

250

Chapter 18 – Psychosis associated with leukodystrophies

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Neurology, 1994.
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