Case Records of the Massachusetts General Hospital

nosis was confirmed by the transmission of disease
to primates have survived as long as 15 years. 10
Distinctive clinicopathological variants of Creutzfeldt–Jakob
disease include the Heidenhain variant
(characterized by early cortical blindness and visual
agnosia, with striking involvement of the occipital cortex),
the Brownell–Oppenheimer variant (prominent
ataxia, with severe cerebellar involvement and relatively
little cognitive impairment), the Stern–Garcia
variant (prominent involvement of the basal ganglia
and thalamus), the panencephalitic variant (disproportionate
involvement of white matter in Japanese patients),
and a poliodystrophic form. 20 These clinical
descriptions will continue to be useful in recognizing
the many presentations of Creutzfeldt–Jakob disease,
but there is no doubt that the disease is rapidly
being redefined on a genetic basis.
Cerebellar dysfunction, as seen in this case, is relatively
common in Creutzfeldt–Jakob disease. Ataxia
is present initially in approximately a third of patients
and develops eventually in up to two thirds. 20 The
basal ganglia are involved in over half the patients,
but involuntary movements typically decrease as the
disease runs its course. 20 Myoclonus eventually appears
in up to 84 percent of patients. 20 A dramatic
startle reflex is often demonstrated at the bedside, but
it is by no means a constant feature of the disease.
Although this patient had a spastic quadriparesis,
a predominance of lower-motor-neuron signs is unusual
in Creutzfeldt–Jakob disease. The true range
of anterior-horn-cell involvement remains controversial,
but in recent surveys lower-motor-neuron findings
have been reported in only about 10 percent of
patients. 10,21,22
Other than the MRI findings, are there any noninvasive
tests that support a clinical diagnosis of
Creutzfeldt–Jakob disease? The importance of assigning
a presumptive diagnosis based on the clinical
triad of dementia, myoclonus, and triphasic waves
on electroencephalography has been emphasized in
the past. The earliest electroencephalographic changes
often consist of either diffuse or lateralized slowing
of the background. Focal slowing and periodic
lateralized epileptiform discharges are typically early,
transient findings. Triphasic waves, spike-and-wave
complexes, or both may appear subsequently, followed
by the development of bilateral synchronous,
high-voltage, periodic sharp-wave complexes. These
complexes are initially intermittent but later become
continuous, with a periodicity of approximately one
per second. In up to 80 percent of cases, these bisynchronous,
periodic sharp-wave discharges are present
by the middle-to-late stages of the disease. In the
terminal stage of the disease, they may become less
prominent and may be superimposed on a slower,
lower-voltage background. In this case, the absence
of periodic sharp-wave complexes, especially in combination
with the longer-than-average duration of the
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The New England Journal of Medicine
disease and the predominant involvement of subcortical
structures on MRI, underscores the fact that an
absence of paroxysmal sharp-wave complexes does
not rule out the diagnosis of Creutzfeldt–Jakob disease.
In addition, the various electroencephalographic
complexes are not pathognomonic for Creutzfeldt–
Jakob disease; they have been associated with toxic
effects of drugs (lithium, phencyclidine, tricyclic antidepressants,
and barbiturates), other infections (subacute
sclerosing panencephalitis and herpes simplex
encephalitis), metabolic or anoxic encephalopathies,
epilepsy, and postictal states — all of which have
been mistaken for Creutzfeldt–Jakob disease.
23,24
The remainder of the ancillary tests currently at
our disposal are much less useful in identifying cases
of Creutzfeldt–Jakob disease. In this case, a singlephoton-emission
CT scan revealed a bifrontal decrease
in glucose metabolism, which is not surprising in view
of the clinical predominance of frontal-lobe signs.
In the absence of an obvious clinical picture or revealing
MRI findings, single-photon-emission CT
scans are occasionally useful in identifying the best
site for biopsy, since hypoperfusion parallels the areas
of greatest neuropathological involvement. The most
frequently reported chemical abnormality in Creutzfeldt–Jakob
disease is an increase in the total protein
in the cerebrospinal fluid (usually less than 100 mg per
deciliter and rarely as high as 500 mg per deciliter).
A variety of other cerebrospinal fluid tests have
been proposed as aids in the differential diagnosis of
Creutzfeldt–Jakob disease. However, at present, I believe
that all these “markers” serve mainly to corroborate
the clinically observed tempo when there is a
high a priori clinical suspicion of Creutzfeldt–Jakob
disease. The most promising strategies for antemortem
diagnosis may eventually be based on the development
of assays with conformation-dependent
monoclonal antibodies that recognize PrPSc-specific
epitopes. 27,28
Familial Creutzfeldt–Jakob disease is associated
with mutations of the gene coding for prion protein
( PRNP).
Point mutations on the short arm of chromosome
20 (codons 178, 183, 200, 210, and 232)
and octapeptide-repeat insertions in the open reading
frame (codons 67, 75, and 83) have been linked
to the disease. 13 Most patients with inherited prion
disease are heterozygous for these mutations and presumably
have both wild-type and mutant prion protein.
29 From a genetic perspective, when the diagnosis
of familial Creutzfeldt–Jakob disease is being considered,
the appropriate clinical picture, coupled with
the finding of a known PRNP mutation, establishes
the diagnosis. Sporadic Creutzfeldt–Jakob disease has
not yet been consistently linked with specific mutations
in the PRNP gene, although there have been
isolated reports of cases associated with point mutations
or substitutions. 30,31 The likelihood of uncovering
a novel causative mutation in this gene is low.
The New England Journal of Medicine
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