Second edition

09.qxd 3/10/08 9:39 AM Page 405
were, to replace infantile spasms but also as the first seizure
type in those patients whose seizures begin at a later age.
Mental retardation is seen in approximately two-thirds
of patients. Furthermore, and especially in those with frequent
seizures, there may be a progressive cognitive decline,
thus constituting a dementia. Autism may occur in up to
one-quarter of all patients (Alsen et al. 1994; Gutierrez et al.
1998; Lawlor and Maurer 1987), and is more likely in those
both with tubers in the temporal lobe and frequent seizures
of temporal lobe onset (Bolton and Griffiths 1997; Bolton
et al. 2002). In a very small minority of patients, hydrocephalus
may occur secondary to occlusion of the foramen
of Monro by a tuber or astrocytoma, with the development
of further cognitive decline accompanied by headache and
gait disturbance.
Other lesions include subungual fibromas, retinal
phakomas, renal angiomyolipomas and cysts, cardiac rhabdolipomas,
and pulmonary cysts.
Neuroimaging reveals the distinctive tubers. Tubers typically
undergo calcification and, when this occurs, they are
immediately apparent on skull radiographs or CT scanning.
Magnetic resonance scanning also reveals calcified tubers
and may also identify uncalcified ones, which may be
missed on CT scanning. The electroencephalogram (EEG)
is marked by slowing and interictal epileptiform activity,
which is often multifocal. Genetic testing is available.
Course
Tuberous sclerosis is a gradually progressive disease. Those
with an early childhood onset, especially those with severe
epilepsy, rarely survive for more than 15 years, eventually
succumbing to status epilepticus or cardiac or renal complications.
In adult-onset cases, the progression tends to be
much slower, and the disease may be compatible with a
normal lifespan.
Etiology
Tuberous sclerosis occurs secondary to mutations in either
one of two genes: TSC1 is located on chromosome 9 and
codes for a protein known as hamartin; TSC2 is on chromosome
16 and codes for tuberin (European Chromosome 16
Tuberous Sclerosis Consortium 1993; Fryer et al. 1987;
Hyman and Whittemore 2000). Hamartin and tuberin
function as tumor suppressor proteins, and it is presumably
a lack of this normal ‘suppression’ that allows for the development
of the tubers and other manifestations of the
disease. Approximately two-thirds of cases represent spontaneous
mutations, whereas in the remaining one-third the
disease is inherited on an autosomal dominant basis.
Tubers are nodules of varying size, ranging from millimeters
to 2 cm or more, and are composed of glia and enlarged,
‘ballooned’, neuronal elements. They are typically found
both in the cerebral cortex and in the subependymal white
9.3 Von Recklinghausen’s disease (neurofibromatosis type 1) 405
matter: in some cases subependymal tubers may protrude
into the ventricle and may be so numerous that they
impart a ‘candle guttering’ appearance to the surface of the
ventricle (Richardson 1991). Tubers, as noted, typically
undergo calcification, and the calcification may be so pronounced
as to produce ‘brain stones’ (Yakovlev and
Corwin 1939). Some tubers may undergo malignant transformation
into astrocytomas (Goh et al. 2004; Morimoto
and Mogami 1986), and tubers (or astrocytomas) adjacent
to the foramen of Monro may cause occlusion and noncommunicating
hydrocephalus.
Differential diagnosis
The classic triad of seizures, mental retardation, and adenoma
sebaceum is pathognomonic. As noted earlier, however,
about one-third of patients will have normal
intelligence, and such cases may present with seizures
alone in adult years (Kofman and Hyland 1959). In these
cases, diagnostic suspicion may be aroused by skin lesions,
such as ash leaf spots or adenoma sebaceum, or by finding
tubers on imaging.
Treatment
Seizure control is imperative. Infantile spasms may
respond to adrenocorticotropic hormone (ACTH) or vigabatrin.
Partial or grand mal seizures may be treated with
the usual AEDs, with, however, some caveats. In some
cases renal failure may occur, making the use of AEDs that
undergo primary renal excretion problematic. Other
AEDs, such as carbamazepine (Weig and Pollack 1993),
may precipitate cardiac block in patients with cardiac
lesions. In treatment-resistant cases in which there is a single,
well-localized epileptogenic zone, surgical resection
may be considered (Jarrar et al. 2004).
Obstructive hydrocephalus may respond to neurosurgical
intervention. Tubers that have undergone transformation
into astrocytomas may also respond to treatment
with rapamycin (Franz et al. 2006).
Mental retardation and autism are treated in the usual
fashion, as discussed in Sections 5.5 and 9.14 respectively.
When severe, adenoma sebaceum may be surgically
treated, but recurrences are the rule. Genetic counselling
should be offered, not only to patients but also, given that
some cases (perhaps manifest only by subtle skin lesions)
may go undetected, to relatives.
9.3 VON RECKLINGHAUSEN’S DISEASE
(NEUROFIBROMATOSIS TYPE 1)
Von Recklinghausen’s disease, also known as neurofibromatosis
type 1 or ‘peripheral’ neurofibromatosis, is a not
uncommon genetic disorder characterized by skin lesions