Secondary Schizophrenia (88 page)

microtubular

neurosteroids

of
tau

A

& remyelination

proteins

β42 formation

Ectopic

Axonal

Neuronal

Neuronal

dendritogenesis,

dystrophy and

amyloid

neurofibrillary

reduced dendritic

eventual loss

deposition

tangle formation

arborization

NEURONAL

NEURONAL DYSFUNCTION

DISCONNECTION

AND LOSS

PSYCHOSIS

DEMENTIA,

+/- MANIA

MOVEMENT DISORDER

Early

Late

Figure 16.3
A model for the development of secondary schizophrenia based on the neuropathological findings in Niemann-Pick Disease
type C. Initial impairment of connectivity through altered dendritic function and myelination results in functional disconnectivity and may lead
to major mental illness prior to frank neuronal loss, whereby the clinical picture then shifts to one of frank motor and cognitive impairment.

where disruptions to myelination predominantly affect
drome, resulting from dysfunction in axonal struc-posterior zones, mania, or affective psychosis occurs
tures prior to degeneration, which is then followed
more commonly than schizophrenia-like psychosis
by frank axonal loss and neurodegeneration in corti-

[152].
The reduced dendritic arborization that occurs
cal and subcortical structures. This model, illustrated
in NPC also bears some homology to that seen in
in
Figure 16.3,
may be applicable to storage disorders
schizophrenia
[142, 143]
and may be an additional
that affect axonal structures early before frank neu-psychotogenic factor through its contribution to cor-ronal loss ensues.

tical disconnectivity at a “microconnectivity” level
In other disorders where predominantly grey-

[153].
The progression of the clinical picture from
matter structures are affected, such as NCL, it may
psychosis to dementia and movement disorder in
be that the connectivity impairments occur at a
221

most cases may reflect an initial disconnectivity syn-

“microconnectivity” level (locally between proximally
Organic Syndromes of Schizophrenia – Section 3

located neurons via synaptic connections) rather than
the latter often increased 30-fold
[103,
155],
although
through “macroconnectivity” (more distally located,
urinary excretion of bile alcohols may be more sen-but functionally interdependent, neural assemblies
sitive
[155];
molecular diagnosis of mutations in the
via axonal connections). Additionally, where neuronal
CYP27A1 gene confirms diagnosis
[156].
With AM,
pathology affects grey-matter regions known to be
diagnosis can be made by a combination of an abnor-disproportionately affected in schizophrenia (frontal-mal pattern of oligosaccharides in the urine
[107],
fol-and temporal-cortical regions, basal ganglia, and tha-lowed by testing for MANB levels in either peripheral
lamus), this regional selectivity of pathology may be
leukocytes from venepuncture or skin fibroblasts from
responsible for the psychotogenic effects of adult-onset
a punch biopsy, and analysis for mis-sense or nonsense
disease. This model can be expanded to encompass
mutations in the MANB gene
[108].

other disorders, such as the mitochondrial disorders
In ACNL, because of the lack of a characteristic
(Chapter 17). Here the regional effect on some regions
biochemical deficiency and molecular model, diagno-of the brain (such as the basal ganglia), interact with
sis rests on tissue diagnosis with microscopic iden-the underlying state of the CNS at the time of max-tification of characteristic fingerprint inclusions and
imal impact of the insult – where lower level neu-granular osmiophilic deposits (GRODs) at the ultra-rodevelopmental systems are predominantly mature,
structural level
[118],
using either cerebral or extrac-but higher level systems are still undergoing significant
erebral (usually rectal mucosal) tissues
[157].
Clin-plastic change. This results in a psychotic syndrome
icians will rarely be at the point of tissue biopsy
before the onset of more “frank” CNS impairment such
without having previously undertaken exhaustive bio-as dementia or motor disturbance.

chemical and enzymatic analyses of blood and cere-brospinal fluid to exclude other, more readily identifi-

Laboratory diagnosis of

able causes of psychosis and neurological disturbance
[136].

storage disorders

The laboratory diagnosis for most storage disorders
The treatment of psychosis in

requires the alert clinician to think specifically about
how the patient’s clinical picture may be indicative of
storage disorders

a storage disorder, as the confirmatory or exclusion-Some storage disorders show improvement in neu-ary biochemical tests may be expensive and/or limited
rological symptoms when given definitive treatment,
in accessibility (e.g. presence of a cherry red spot and
and given the neurobiological basis of psychotic symp-VSO accompanying psychosis in GM2 gangliosidosis,
toms, it seems likely that this would also result in a
or a history of neonatal jaundice and VSO accompany-reduction in psychotic or other psychiatric symptoma-ing psychosis in NPC).

tology. Improvement in neurological symptoms has
GM2 gangliosidosis is generally diagnosed by the
been reported with chenodeoxycholic acid treatment
analysis of hexosaminadase A levels in peripheral
of CTX
[158],
and miglustat treatment of NPC
[159,

blood
[11]
and referencing analysis against mutations
160]
but not yet Tay-Sachs Disease
[161].
The mainstay
to determine carrier or affected status, in addition
of treatment for most psychotic disorders secondary
to the detection of nonsignificant “pseudomutations”

to storage disorders remains antipsychotic medication,
[154].
In particular, at-risk populations such as Ashke-where a number of patients have been reported to
nazi Jewish individuals often are linked into screen-respond to both typical and atypical antipsychotics
ing programs during family planning or even rabbini-

[85, 86,
98].
Given that a number of patients with stor-cal approval of union
s[154].
In adult-onset patients,
age disorder-related psychosis are likely to have neu-genetic analysis is often necessary due to residual
rological and/or cognitive impairment, this is likely
enzyme levels and frequent heterozygosi
ty[19].

to render them vulnerable to the centrally mediated
With NPC, as a serum test is not currently avail-side effects of neuroleptic medication – including
able, skin fibroblasts from a punch biopsy are assessed
extrapyramidal motor side effects, sedation, cognitive
for their rate of esterification, combined with filipin
dulling, and autonomic symptoms. In circumstances
staining for lysosomal accumulation of free choles-where treatment is limited by extrapyramidal or other
terol
[67].
In CTX, elevated plasma cholestanol and
side effects, ECT appears to be a safe and effective treat-

222

cholestanol:cholesterol ratio, is usually present, with
ment in this group of patients.

Chapter 16 – Storage disorders and psychosis

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