Second edition

10.qxd 3/10/08 5:52 PM Page 440
440 Vascular disorders
times may also be due to a progressive leukoencephalopathy,
and in rare instances CADASIL may present with a
dementia secondary to the leukoencephalopathy in the
absence of stroke (Filley et al. 1999; Mellies et al. 1998).
Two unusual manifestations of CADASIL must also be
kept in mind, namely intracerebral hemorrhage and a
reversible delirium. Intracerebral hemorrhage, primarily
of the thalamus or basal ganglia, may occur but is uncommon
(Choi et al. 2006). Delirium has also been reported
but appears rare. Patients present with a subacute delirium,
often accompanied by seizures and fever, which may
progress to coma; recovery is spontaneous and occurs after
1–2 weeks (Schon et al. 2003).
Magnetic resonance scanning will reveal any prior lacunar
infarctions. Furthermore, most patients will also have a
diffuse leukoencephalopathy and, indeed, this may be
present early on, even before the first stroke. The leukoencephalopathy
is evident on either T2-weighted or FLAIR
imaging: patchy, confluent areas of increased signal intensity
are seen in the centrum semiovale and the periventricular
white matter, and also, classically, in the external
capsule and, most notably, in the white matter of the anterior
temporal lobe (O’Sullivan et al. 2001). Recent work
using gradient echo imaging has also identified evidence
for old microhemorrhages in the thalamus and basal ganglia
(Choi et al. 2006; Lesnik Oberstein et al. 2001).
Diagnosis may be made by genetic testing. Skin biopsy
may also be performed, but false negatives are common
(Malandrini et al. 2007).
Course
The overall course is as described above; death occurs in
the seventh through ninth decades, often from pneumonia
(Opherk et al. 2004).
Etiology
As noted, CADASIL is an autosomal dominant disorder:
mutations are found in the Notch3 gene on chromosome
19 (Joutel et al. 1997; Tournier-Lasserve et al. 1993).
Pathologically, there is concentric fibrous thickening of
small penetrating arteries (Sourander and Walinder 1977),
leading to both the subcortical infarcts and the widespread
leukoencephalopathy (Baudrimont et al. 1993). Although
peripheral nerves (Schroder et al. 1995) and skin (Ruchoux
et al. 1994) may also be involved, symptoms referable to
them are generally absent.
Differential diagnosis
Lacunar strokes occurring in CADASIL must be distinguished
from lacunar infarctions occurring on the basis of
lipohyalinosis or atherosclerosis. Similarly, the dementia
occurring in CADASIL must be distinguished from the
dementia occurring in lacunar dementia and in Binswanger’s
disease. In all these instances, a positive family history is most
helpful as it points to CADASIL; however, in some cases such
a history may be unavailable. Other features suggesting
CADASIL are migraine with aura and, most importantly, the
early appearance of leukoencephalopathy in the anterior
portion of the temporal lobe, which, although common in
CADASIL, is most unlikely in other disorders.
Cerebral amyloid angiopathy may cause some diagnostic
difficulty, as it can present with a dementia in the setting
of a diffuse leukoencephalopathy with old microhemorrhages.
Here, MRI evidence of lacunar infarctions or anterior
temporal leukoencephalopathy point to CADASIL,
and the appearance of lobar intracerebral hemorrhages at
any time generally indicates cerebral amyloid angiopathy.
MELAS (mitochondrial encephalomyopathy, lactic acidosis,
and stroke-like episodes) may present in a fashion
similar to CADASIL, but is distinguished by deafness.
Treatment
At present, there is no specific treatment for CADASIL.
The general treatment of dementia is discussed in Section
5.1; genetic counselling should be offered.
10.8 GRANULOMATOUS ANGIITIS OF THE
CENTRAL NERVOUS SYSTEM
Granulomatous angiitis of the central nervous system is a
rare disorder characterized pathologically by a granulomatous
angiitis confined to the central nervous system, and
clinically by headache and delirium. An often used synonym
is primary angiitis of the central nervous system;
however, at times this term has also been used to refer to
other vasculitic processes and hence the reader should
examine any literature carefully, to ensure that, indeed,
granulomatous angiitis is the disorder in question.
Clinical features
Although the disease may present at any age, from childhood
to senescence, most patients are in their 30s or 40s.
The onset itself is generally subacute, spanning a few
weeks. Clinically (Abu-Shakara et al. 1994; Calabrese and
Mallek 1988; Case Records 1989; Hughes and Brownell
1966; Kolodny et al. 1968; Koo and Massey 1988; Lie 1992;
Moore 1989; Vollmer et al. 1993), patients typically have
severe, generalized headache, and in this setting they
develop a delirium that may be accompanied by focal
deficits or, uncommonly, seizures. Although focal deficits,
such as hemiparesis, may have a stroke-like onset, in most
cases they appear gradually. In some cases, the spinal cord
may be involved.