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Progressive Dementia and Hypersomnolence With Dream-Enacting Behavior
Oneiric Dementia
Jean E. Cibula, MD;
Stephan Eisenschenk, MD;
Michael Gold, MD;
Thomas A. Eskin, MD;
Robin L. Gilmore, MD;
Kenneth M. Heilman, MD
Arch Neurol. 2002;59:630-634.
ABSTRACT
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Background Sleep disorders are associated with several types of degenerative dementias,
including Alzheimer and prion diseases. Animal models have demonstrated abolition
of rapid eye movement atonia, resulting in dream-enacting complex movements
termed oneiric behavior, and patients with fatal
familial insomnia may have vivid dreams that intrude on wakefulness.
Objective To describe a new form of progressive dementia with hypersomnia and
oneiric behavior.
Methods Neuropsychological and polysomnographic studies of a middle-aged woman
with a progressive dementia, excessive daytime sleepiness, and a vertical
gaze palsy.
Results Neuropsychological testing revealed decreased verbal fluency, impaired
attention and working memory, amnesia, poor recall, and bradyphrenia with
hypersomnia. Polysomnography revealed a rapid eye movement behavioral disorder
with complete absence of slow wave sleep. Prion protein analysis did not reveal
the mutation associated with fatal familial insomnia, and other diagnostic
test findings were unrevealing.
Conclusion Our patient had a previously unreported syndrome of progressive dementia
associated with rapid eye movement behavioral disorder and the absence of
slow wave sleep.
INTRODUCTION
THE CO-OCCURRENCE of sleep disorders with dementing illnesses has led
to recognition of several syndromes. Lugaresi et al1
described a "fatal familial insomnia" (FFI) characterized by progressive loss
of slow wave sleep (SWS) with autonomic dysfunction, motor dysfunction, and
dementia. Animal models have demonstrated abolition of rapid eye movement
(REM) atonia, resulting in dream-enacting complex movements termed oneiric behavior.2 In patients with
FFI, Tinuper et al3 described episodes of "sleep"
with vivid dreams that intruded spontaneously on wakefulness, described as
an "oneiric stuporous state." In addition, sleep disorders may also be associated
with diseases that induce dementia, such as Lewy body disease or Alzheimer
disease.4-5 We examined and studied
a patient with loss of SWS and REM atonia and progressive dementia without
the genetic deficit or postmortem findings associated with FFI. Therefore,
we suspect that this patient had a form of dementia with a sleep disorder
that has not been previously reported.
REPORT OF A CASE
The patient was a right-handed, 50-year-old woman who presented initially
to the University of Florida, Gainesville, in September 1995 with memory decline
and sleep difficulties. Her symptoms began in spring 1991 with horizontal
and vertical diplopia and severe depression. She underwent a psychiatric evaluation
and was believed to have an obsessive-compulsive disorder with severe depression.
She had daytime hypersomnia and fell asleep while driving. She also complained
of episodes of bilateral hand shaking and the inability to speak without loss
of awareness. She "talked and thrashed" during sleep and had fallen out of
bed, fractured her toes, and injured her husband. In January 1993, she underwent
polysomnography with a multiple sleep latency test. She demonstrated sleep
onset–REM periods in 4 of 5 naps. She was prescribed imipramine hydrochloride
for treatment of her neurologic and psychiatric disorders, but she discontinued
the medication because of weight gain. By summer 1993, she could not manage
her finances and was severely amnestic.
At the time of her evaluation at the University of Florida, she was
taking 100 mg of sertraline hydrochloride daily, as well as calcium and magnesium
supplements. Her history was significant only for colitis during her 20s.
She was adopted and her family history was unknown. She had achieved her bachelor's
degree in graphic arts, was married, but had no children. She had a 68 pack-year
history of smoking and acknowledged prior ethanol abuse, quitting 4 years
before her presentation to the hospital. She noted thinning and coarsening
of her hair and tinnitus. She was sleeping from 9 PM to 7 AM consistently
but was frequently falling asleep throughout the day. There was no snoring,
but intermittent movements were present during all periods of sleep.
On examination, she was initially asleep. While sleeping, she exhibited
diffuse asynchronous myoclonic twitches. Bell sign was present. She could
follow some commands during this episode but had no recall after awakening.
Her husband reported this as a typical sleep episode, lasting 5 to 10 minutes.
Her hair was coarse and thin. Otherwise, the general examination was normal.
Cranial nerve examination revealed a right exophoria with normal pupillary
responses. She could not make vertical eye (pursuit and saccadic) movements
except with an oculocephalic maneuver. Her horizontal movements were not restricted.
Other cranial nerves, muscle bulk, strength, tone, fine motor movements, gait,
sensation to all modalities, and deep tendon reflexes were normal.
On neurobehavioral testing, the patient was alert and oriented but was
mildly bradykinetic and bradyphrenic. She answered questions with monosyllabic
answers. Although no semantic or phonemic paraphasic errors were noted, her
husband had noted such errors at home. She scored 49 out of 60 on the Boston
Naming Test.6 Speech repetition was intact,
and she followed simple and sequential commands. In an abbreviated Controlled
Oral Word Association Test,7 she named 15 words
that began with the letter f in 1 minute. With categorical
naming, she named 22 fruits or vegetables in 1 minute, but she refused to
continue after naming 11 animals. On memory testing, she registered 3 out
of 3 objects immediately but did not recall any objects. On the Hopkins Verbal
Learning Test,8 she was given the same 12 words
to recall in 3 successive trials. Her scores were 5, 4, and 3. Her digit span
forward was 4. Contrasting programs, finger naming, and praxis were all intact,
but she had frequent errors when performing serial subtractions. A psychiatric
interview was performed that suggested depression with somatization.
A neuro-ophthalmologic evaluation demonstrated 20/20 visual acuity bilaterally.
Horizontal movements were full; however, vertical movements were present only
with the oculocephalic maneuver. There was a variable 6- to 8-diopter exotropia.
There were no Kayser-Fleischer rings. Her eye movements were believed to be
suggestive of Whipple disease, with ocular convergence movements synchronized
with facial contractions, primarily involving the jaw (oculomasticatory myorhythmia).9
DIAGNOSTIC EVALUATION
Magnetic resonance imaging revealed diffuse atrophy, most pronounced
in the mesial temporal region. Hexylmethylpropylene amineoxine single-photon
emission computed tomography revealed no areas of abnormal blood flow.
Polysomnography revealed a total absence of SWS and loss of REM atonia,
with demonstration of dream-enacting behavior, including simulating conduction
of an orchestra. No other sleep-related disorder was noted. She was admitted
to the Epilepsy Monitoring Unit. Over several days, medications were administered
in an attempt to induce SWS and sleep spindles on electroencephalographic
testing. These medications included diazepam, methohexital sodium, trihexyphenidyl
hydrochloride, methylphenidate hydrochloride, carbamazepine, valproic acid,
and dextroamphetamine sulfate. Electroencephalographic testing was performed
with the patient under light diprivan sedation with nitrous oxide. Serial
intravenous administration of 1 mg of pyrolite and 5 mg of neostigmine bromide
resulted in the observation of sleep spindles and abbreviated K complexes
on the electroencephalogram. Intravenous administration of 25 mg of methohexital
and 10 mg of diazepam resulted in the generation of frontal beta activity
and drug spindles following the recovery from methohexital administration.
Serum chemistries, complete blood cell count, liver functions, hemogram,
B12, free thyroxine, thyrotropin, serum treponemal antibody, and
folic acid levels showed no abnormalities. Additional study findings are summarized
in Table 1, with elevated serial
serum and urine gold levels for the patient and her husband shown in Table 2. An analysis of blood for FFI in
the laboratory of Pierluigi Gambetti, MD, at Case Western Reserve University,
Cleveland, Ohio, revealed that she was homozygous for methionine at codon
129, normally a polymorphic site in the prion protein gene associated with
sporadic Creutzfeldt-Jakob disease (CJD). This was believed to be a normal
variant. The aspartic acid to asparagine mutation at codon 178 associated
with FFI was not present.
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Table 1. Serum and Urine Laboratory Values Associated With Rare Causes
of Dementia and Insomnia*
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Table 2. Comparison of Serum and Urine Gold Levels for the Patient
and Spouse Over Time*
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Cerebrospinal fluid (CSF) revealed 20 red blood cells; 9 white blood
cells (all monocytes); protein, 0.05 g/dL; glucose, 3.8 mmol/L; IgG, 10.4
mg/dL; albumin, 0.04 g/dL; positive oligoclonal bands; and myelin basic protein
that was below detectable limits. Cerebrospinal fluid periodic acid–Schiff
stain was negative for particles associated with Whipple disease. Flow cytometry
for CSF cytology was negative.
Nerve conduction studies revealed no evidence of a peripheral neuropathy,
which has been reported with Morvan fibrillary chorea and with heavy metal
toxicity. A small bowel biopsy revealed no evidence of Whipple disease. A
bone marrow biopsy demonstrated a few sea-blue histiocytes but no foamy macrophages.
CLINICAL COURSE
By May 1996, she had difficulty with ocular convergence. Mild rigidity
was also present. She was treated with 50/200 mg of carbidopa-levodopa extended
release 4 times a day, without improvement. By January 1997, vertical and
horizontal movements in response to optokinetic nystagmus were lost. In an
attempt to treat her sleep disorder, she was prescribed pemoline, 37.5 mg
twice daily, but this induced no improvement in her somnolence.
The patient's dementia continued to progress, and she developed incontinence
of urine and bowel. She was treated with tacrine hydrochloride, 10 mg/d, but
no improvement was seen. She had poor insight into her difficulties. She received
sertraline, 150 mg/d, with little benefit. She eventually required assistance
with all activities of daily living. The motor and sensory examinations remained
essentially unchanged except for the increasing prominence of frontal release
signs. The patient died in July 1998.
POSTMORTEM FINDINGS
The postmortem examination was limited to her brain, which weighed 1020
g. On gross examination, there was regional cerebral atrophy, most prominent
in the anterior frontal and anteromedial temporal lobes, with moderate to
marked ex vacuo hydrocephalus, most prominent in the temporal horns and third
ventricle.
Microscopic examination demonstrated widespread but variable areas of
astroglial and microglial reaction, most prominent in layers 1 through 3 of
the cortex. There were small glial nodules that included pleomorphic microglia
and histiocytes with scattered lymphocytes or plasma cells. In addition to
these nodules, there was perivascular lymphocytic infiltration that was also
seen in deep cerebral white matter, most prominently in frontal, insular,
and temporal regions. Inflammatory cells were also seen around leptomeningeal,
subpial, and superficial cortical blood vessels. In deeper cortical layers,
rodlike microglia were seen in association with reactive astrocytes. Hippocampal
pyramidal neurons, particularly in CA1, were frequently eosinophilic with
inflammatory changes similar to those observed in the neocortex. Examination
of the amygdalae revealed a residual spongy tissue composed of reactive astroglia
with rare surviving neurons; however, no residual inflammation or microglial
reaction was present. The surrounding white matter was atrophic and gliotic
with prominent corpora amylacea. Basal ganglia and thalami appeared to be
spared, but the midbrain tectum, periaqueductal gray, paramedian pontine tegmentum,
and ventral paramedian medulla showed the same glial and perivascular changes.
Cerebellar gray and white matter were minimally affected with a few pleomorphic
microglia in the roof nuclei. There was no evidence of cortical beta amyloid
immunoreactivity. No neurofibrillary degeneration (tau immunoperoxidase) or
Lewy bodies (ubiquitin immunoperoxidase) were present. Luxol fast blue and
periodic acid–Schiff stain revealed no evidence of demyelination. Frozen
specimens of the cerebellum sent to Gambetti's laboratory for prion protein
analysis were negative.
COMMENT
Compared with age-matched controls, patients with dementia have a greater
disruption of sleep, with more frequent arousals and decreased sleep efficiency,
and may have increased stage 1 and decreased SWS.4-5,10
Patients with Alzheimer disease often have dysregulation of their circadian
rhythms, sleep excessively during the day, have nighttime awakening, and may
have alteration of REM latency.4, 10
Patients with Lewy body dementia may have REM behavioral disorder.5 The sleep disorder described in this patient is not
associated with degenerative dementias, such as Alzheimer, Lewy body, or Pick
disease, because the absence of SWS and REM atonia and the presence of sleep
onset–REM periods are not characteristic of these degenerative dementias.
The postmortem examination was also not compatible with these dementias.
As in this patient's case, patients with Parkinson disease may have
persistence of muscle tone, leading to loss of REM atonia,11-14
and patients with progressive supranuclear palsy may present with horizontal
and vertical gaze palsies. Although patients with Parkinson disease and the
Parkinson-plus syndromes may have a reduction of SWS and REM sleep, they have
not been reported to have absent SWS. In addition, the postmortem examination
did not demonstrate depigmentation of the substantia nigra, and no neurofibrillary
tangles were noted.
This woman demonstrated a supranuclear gaze palsy and complained of
excessive flatus and loose stools, which have been reported in patients with
Whipple disease.15 Our patient, however, did
not demonstrate other signs associated with Whipple disease, including uveitis,
arthralgias, malabsorption, fevers, and lymphadenopathy.15-16
The dementia of Whipple disease has been described as progressive short-term
memory difficulties, with diffuse abnormalities on neuropsychological testing.16 Whipple disease is caused by Tropheryma
whippelii, diagnosable on polymerase chain reaction analysis of CSF.17 Unfortunately, this test was not available when we
evaluated this patient, but the absence of periodic acid–Schiff stain–positive
macrophages in CSF, on a small bowel biopsy, and in postmortem tissue is not
consistent with the diagnosis of Whipple disease.
Niemann-Pick type C is a progressive disorder that may have a late onset
and may also present with vertical supranuclear ophthalmoplegia. This disorder
is often associated with psychiatric disease, progressive dementia, dystonia,
dysarthria, ataxia, and hepatosplenomegaly.18-19
Of the greatest relevance to our patient is the description of 7 patients
with a combination of cataplexy and variants of Niemann-Pick disease.20 However, our patient's bone marrow and postmortem
examination findings were not compatible with this diagnosis.
Morvan fibrillary chorea is a rare condition manifested by severe insomnia,
hallucinations, and loss of REM sleep, with frequent arousals.21
Our patient, however, had excessive sleepiness and loss of SWS. Chronic gold
and mercury exposure has been implicated in the pathogenesis of Morvan fibrillary
chorea. Initial gold levels were high in our patient but were later also noted
to be elevated in her asymptomatic husband (Table 2). No source of gold for ingestion or other intake was discovered,
and the levels returned to normal 6 months later, without any sign of clinical
improvement. Bismuth encephalopathy has also been implicated in a similar
sleep disorder, but none was detected on laboratory studies, and there was
no evidence for peripheral neuropathy, the most common manifestation of chronic
heavy metal toxicity.
Depressive pseudodementia may be associated with reduced sleep efficiency,
SWS, and REM latency.22-23 Reduced
REM latency and other REM sleep factors have been used to evaluate patients
with depression alone and with depression in conjunction with dementia, and
sleep onset–REM periods on multiple sleep latency tests have not been
consistently reported in depression.23 In addition,
the complete absence of SWS and lack of REM atonia during polysomnography
in this patient are not typical of depression.
Prion diseases are characterized by deposition of an abnormal isoform
of the cellular prion protein. The sporadic forms account for more than three
fourths of all cases of spongiform encephalopathy. Lugaresi et al1 initially described a heritable disease that presented
with progressive insomnia and dysautonomia, which they called FFI. Subsequent reports have noted phenotypic variability in FFI,24-25 and one would suspect that variability
of spontaneous mutations may produce syndromes clinically similar to FFI without
the same genotypic findings, including 5 subjects with clinical and histopathological
manifestations that were virtually identical to FFI.26
Prion protein PrP(Sc) type 2 was present in all subjects in an amount and
a distribution similar to those of FFI. The clinical course and duration were
similar, lasting 15 to 24 months. However, PrP(Sc) did not show the striking
underrepresentation of the unglycosylated isoform of the protein that is characteristic
of FFI. Moreover, none of the subjects had the prion protein gene D178N PRNP mutation, but all were homozygous for methionine at
codon 129. The presence or absence of SWS was not reported for the individual
patients; however, REM behavioral disorder appeared to be a feature of these
cases. The authors concluded that this likely represented a sporadic form
of FFI, which they termed sporadic fatal insomnia.26
Whereas patients with FFI may have a loss of SWS and a progressive dementia,
as in our patient, this patient did not have the genetic defects associated
with this disorder.1, 24, 27
Analysis of blood for FFI revealed that our patient was homozygous for methionine
at codon 129. This is normally a polymorphic site in the prion protein gene,
which has associations with sporadic CJD,24, 28
but was believed to be a normal variant. The aspartic acid to asparagine mutation
at codon 178 associated with FFI was not present in our patient.24
Other differences include the prolonged duration of illness in our patient,
lasting at least 7 years.
Precocious loss of physiologic sleep has also been reported in CJD.29 Although FFI has been primarily associated with a
pathogenic mutation at codon 178 in the PRNP gene,
coupled with methionine at codon 129, a patient has been described with familial
CJD who was affected by severe insomnia and was heterozygous for the pathogenic
lysine mutation at codon 200 and homozygous for methionine at codon 129 of
the PRNP gene.30 At
autopsy, the patient had significant involvement of the thalamus, as previously
described in subjects affected by FFI with the codon 178 mutation.24 The authors concluded that the case demonstrated
the wide variability of the clinical expressions of the codon 200 mutation,
which may include insomnia and thalamic pathologic abnormality.30
Further reports have contrasted the phenotypic, genotypic, and pathologic
findings between CJD and FFI.24, 28
The pathogenesis of FFI would suggest that the limbic thalamus has an
integral role in the central autonomic network, which coordinates the limbic
cortical regions and the lower brainstem, regulating the body's homeostasis
and sleep-wake cycle in an integrated fashion.1, 24, 31-32
Fatal familial insomnia characteristically affects the mediodorsal and anteroventral
thalamic nuclei most severely, with the basal ganglia, cerebellum, and brain
stem typically unaffected. In this woman, the basal ganglia and thalamus appeared
to be spared. The midbrain tectum, periaqueductal gray, paramedian pontine
tegmentum, and ventral paramedian medulla showed glial and perivascular inflammatory
changes. Microscopic examination demonstrated widespread, but variable, areas
of astroglial and microglial reaction. Only the amygdala revealed a residual
spongy tissue composed of reactive astroglia with rare surviving neurons;
however, no residual inflammation or microglial reaction was present.
Patients with FFI who underwent detailed neuropsychological testing
at different stages of the disease were noted to have early impairment of
attention and vigilance, with defective memory (predominantly defective encoding
and ordering of events) and marked variation in vigilance levels from one
moment to another.33 These disturbances of
attention and concentration are consistent with other types of subcortical
dementias; however, patients with FFI generally have no personality changes.
Our patient was noted to become more obsessive-compulsive in addition to her
other deficits, which included decreased attention and concentration (decreased
digit span, serial 7s, and refusal to continue testing), with a decline on
recall. Despite this, she did well on word association tasks, and no deficits
in comprehension were noted.
Loss of REM atonia with dream-enacting complex behavior during sleep
has been described in animals with pontine lesions.2
In humans, patients with FFI have been noted to demonstrate an "oneiric stuporous
state" during wakefulness, attributed to intrusion of vivid dreams.3 Although our patient did not have the genetic profile
consistent with FFI, she demonstrated spontaneous intrusion of purposeful
dreamlike behavior during her clinical evaluation and loss of REM atonia,
with dream-enacting behavior during polysomnography. Her clinical and postmortem
examinations did not appear compatible with any previously reported diseases
known to induce a progressive dementia associated with a sleep disorder characterized
by a loss of SWS and REM atonia. The pathological changes found on postmortem
examination were most consistent with a chronic meningoencephalitis. Although
a definitive diagnosis could not be made on the basis of the clinical profile,
laboratory studies, or postmortem examination, a viral infection or autoimmune
response was believed to be the most likely cause. We propose a syndrome termed oneiric dementia, consisting of (1) signs of progressive
dementia, supranuclear gaze palsy, and progressive hypersomnia accompanied
by oneiric behavior, (2) polysomnographic evidence of sleep onset–REM
periods, loss of SWS, and absence of REM atonia, and (3) pathological evidence
of chronic meningoencephalitis affecting primarily the brainstem. Future studies
should elucidate the etiology and treatment of this disorder.
AUTHOR INFORMATION
Accepted for publication November 13, 2001.
Author contributions: Study concept and design (Drs Cibula, Eisenschenk, and Heilman); acquisition of
data (Drs Cibula, Eisenschenk, Gold, Eskin, and Gilmore); analysis and interpretation of data (Drs Cibula,
Eisenschenk, Gilmore, and Heilman); drafting of the manuscript (Drs Cibula, Eisenschenk, and Eskin); critical revision
of the manuscript for important intellectual content (Drs
Eisenschenk, Gold, Gilmore, and Heilman); administrative, technical,
and material support (Drs Cibula and Gilmore); and
study supervision (Drs Eisenschenk, Gold, Gilmore, and Heilman).
We wish to acknowledge the helpful comments and discussions with Pierluigi
Gambetti, MD, Cleveland, Ohio; Pietro Cortelli, MD, and Elio Lugaresi, MD,
Bologna, Italy; and Emilia Sforza, MD, Strasbourg, France, during this patient's
clinical evaluation and postmortem evaluation.
Corresponding author: Stephan Eisenschenk, MD, Department of Neurology,
McKnight Brain Institute at the University of Florida College of Medicine,
100 S Newell Dr, Room L3-100, Gainesville, FL 32610-0236 (e-mail: eisensj{at}neurology.ufl.edu).
From the Departments of Neurology, University of Kentucky College of
Medicine, Lexington (Dr Cibula), McKnight Brain Institute at the University
of Florida College of Medicine, Gainesville (Drs Eisenschenk, Gilmore, and
Heilman), University of South Florida College of Medicine, Tampa (Dr Gold);
and Department of Pathology, University of Florida College of Medicine (Dr
Eskin), and the Malcolm Randall Veterans Administration Medical Center, Gainesville
(Dr Heilman).
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