Second edition

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1993), sensitivity testing should be undertaken. If isoniazid
is used, consideration should be given to supplementation
with vitamin B6 to prevent the development of pellagra
(Ishii and Nishihara 1985), as discussed in Section 13.3.
Tuberculomas may be treated with the same drug regimen.
In some cases, excision is required.
14.18 WHIPPLE’S DISEASE
Whipple’s disease, first described by George Hoyt Whipple
in 1907 (Whipple 1907), is a rare disorder found mostly in
white males, which occurs secondary to infection with a
bacillus known as Tropheryma whippelii. Although Whipple’s
disease most commonly causes arthralgia and abdominal
complaints, the nervous system may be involved with, as
described below, a wide variety of signs and symptoms.
Clinical features
Whipple’s disease typically presents in middle years.
Migratory large-joint polyarthralgia is common and patients
also typically have abdominal pain, diarrhea, weight loss,
and mild fever. In a minority of cases the central nervous
system is involved and, although such involvement generally
occurs within the context of long-standing arthralgia
or abdominal symptomatology, there are definite cases in
which Whipple’s disease has presented with central nervous
system involvement alone (Adams et al. 1987; Lampert
et al. 1962; Pruss et al. 2007; Romanul et al. 1977).
When the central nervous system is involved (Gerard
et al. 2002; Louis et al. 1996; Manzel et al. 2000; Matthews
et al. 2005), patients typically present with a gradually progressive
dementia, delirium or personality change. In most
cases other symptoms are also present, including upper
motor neuron signs, ataxia, nystagmus, myoclonus, seizures,
supranuclear ophthalmoplegia, and various manifestations
of hypothalamic dysfunction including sleep disturbance
(with either hypersomnolence or, less commonly, insomnia),
hyperphagia, decreased libido or diabetes insipidus. A small
minority of patients may also display a very distinctive
abnormal movement known as oculomasticatory myorhythmia,
in which pendular eye movements occur in concert with
rhythmic jaw movements (Schwartz et al. 1986).
T2-weighted MRI may reveal multifocal areas of
increased signal intensity within the cerebral cortex, the
basal ganglia, thalamus, midbrain, and cerebellar cortex; in
some cases these lesions may show enhancement with
gadolinium.
The CSF may show either a lymphocytic pleocytosis or
an elevated total protein, or both, with a normal glucose.
In rare instances some of the white cells may be periodic
acid–Schiff (PAS) positive. PCR assay is typically, but not
always, positive for T. whippelii DNA.
The diagnosis may also be established by small bowel
biopsy, which may reveal not only PAS-positive macrophages
14.18 Whipple’s disease 513
but also a positive PCR assay; in this regard, however, it
must be kept in mind that, albeit rarely, central nervous
system Whipple’s disease can occur with a negative small
bowel biopsy (Pollock et al. 1981).
Course
Central nervous system involvement is a grave sign in
Whipple’s disease; in most cases there is a steady progression,
with death occurring within 6–12 months.
Etiology
Whipple’s disease, as noted, occurs secondary to infection
by T. whippelii (Raoult et al. 2000; Relman et al. 1992).
Within the central nervous system (Powers and Rawe
1979; Smith et al. 1965), focal areas of inflammation and
necrosis, along with glial scars, are found in the cerebral
cortex, basal ganglia, hypothalamus, brainstem (especially
the periaqueductal gray), and cerebellar cortex. PASpositive
macrophages are found in these areas, and electron
microscopy may reveal the bacillus within the
macrophage.
Differential diagnosis
The appearance of dementia, delirium, or personality
change in the context of long-standing polyarthralgia or
abdominal complaints is highly suggestive; in these cases,
consideration might also be given to Lyme disease or to
cerebrotendinous xanthomatosis. The differential for
dementia or delirium occurring with myoclonus is discussed
in Sections 5.1 and 5.3 respectively. Oculomasticatory
myorhythmia, although present in only a minority of cases,
is a particularly valuable sign as it is virtually pathognomonic
for this disease.
Vitamin B12 deficiency may occur in cases characterized
by severe diarrhea, making an independent contribution
to central nervous system symptomatology.
Treatment
The general treatment of dementia, delirium, and personality
change is discussed in Sections 5.1, 5.3, and 7.2
respectively. Although there are no controlled trials of
antibiotic treatment, most clinicians will begin with a
2-week course of ceftriaxone, followed by treatment with
trimethoprim–sulfamethoxazole. The CSF should be monitored
and treatment continued until the patient is clinically
stable and the CSF has normalized; in many cases this
may take up to 2 years. If antibiotics are discontinued the
patient should be closely monitored as relapses may occur;
in some cases indefinite treatment is required.