Extreme sleep pattern in Lewy body dementia: a hypothalamic matter?

Abstract

Excessive sleep during the night and for >2 hours during the day is part of the fluctuating wakefulness criterion of dementia with Lewy bodies (DLB). The phenomenon ‘sleep days’ is not uncommon in nursing homes. Here, we describe a woman who, for months, slept for 3 days and nights in a row and thereafter was awake for 3 days and nights. Electroencephalogram (EEG) showed slow background activity and increased delta activity. No epileptiform activity was detected. Polysomnography showed a severely disturbed, markedly fragmented sleep pattern. On her death, neuropathology revealed degeneration and loss of neurons along with α-synuclein-containing Lewy body inclusions and neurites in the substantia nigra, locus coeruleus, hypothalamus, and neocortex, thus fulfilling the criteria of DLB, cortical type. We propose that the hypothalamic degeneration contributed significantly to the clinical profile in this case. We suggest that patients with sleep days should be investigated for other DLB signs.

Background

Cognitive disorders impose a great burden on the individual, caregivers and society in terms of care and costs.¹ The most common degenerative neurocognitive disorder is Alzheimer’s disease (AD) followed by dementia with Lewy bodies (DLB).² The latter is under-recognised, which is a disadvantage for patients because correct treatment may ameliorate the symptoms whereas the wrong treatment could be fatal.³ The term Lewy body dementia (LBD) includes Parkinson’s disease (PD) with dementia and DLB. The neuropathological background of LBD involves misfolding of the neurotoxic protein α-synuclein, which aggregates to form Lewy bodies, and Lewy neurites that are deposited in a fairly regular pattern throughout the brain and brainstem.

DLB is characterised by the core criteria (1) parkinsonism, (2) fluctuations in attention and wakefulness, (3) visual hallucinations and (4) Rapid Eye Movement (REM) sleep behaviour disorder (RBD).⁴ The fluctuations in attention and wakefulness are described as easily falling asleep despite engaging in something interesting, as well as sleeping many hours at night while still having to sleep more than 2 hours in the daytime.

The clinical symptoms of DLB depend on the anatomical involvement of the α-synuclein deposits.⁵ Involvement of neurotransmitter-producing cells, such as those in the nucleus basalis of Meynert, results in cholinergic deficiency with symptoms such as disturbed wakefulness and attention, and visual hallucinations.^6–8 Involvement of the substantia nigra results in dopamine deficiency, which is clinically manifested as parkinsonism. Pathology in the locus coeruleus results in norepinephrine deficiency and, among other symptoms, depression and anxiety. α-Synuclein deposits may also affect the peripheral nervous system; for example, deposits in sympathetic ganglia cause bradycardia and possibly orthostatic hypotension and deposits in the intestinal parasympathetic ganglia can cause constipation.⁹ The treatment of DLB attempts mainly to balance deficiencies in acetylcholine, dopamine and norepinephrine by prescribing acetylcholinesterase inhibitors, l-DOPA and antidepressants often complemented with memantine, respectively. The latter may also have a beneficial effect on RBD.¹⁰

The pathophysiology of human sleep disorders is not totally clear. It is known that both the sleep and waking states involve a complicated interplay of neuronal networks in the human brain, such as the ascending reticular activating system, and neurotransmitter influences such as the orexin/hypocretin system, all of which are regulated by centres in the hypothalamus, including the biological clock in the nucleus suprachiasmaticus.¹¹ The activating system has constituents in the lateral hypothalamus, monoaminergic neurons from the locus coeruleus (norepinephrine), raphe nuclei (serotonin) and periaqueductal grey matter (dopamine). These can be modified by orexin/hypocretin produced in the lateral and posterior hypothalamus.

Lesions along the activating system, situated mainly in the posterior lateral hypothalamus and adjacent midbrain, induce excessive daytime sleepiness and even coma.¹¹ Excessive daytime sleepiness is a common symptom in patients with neurodegenerative disorders such as AD, Lewy body disorders, Multiple system atrophy, progressive supranuclear palsy and in normal ageing¹²; this symptom is most frequently seen in patients with Lewy body disorders.

The sleep disorders associated with DLB are RBD, excessive daytime sleepiness and symptomatic narcolepsy. However, the affected anatomical region seems to be more important than the type of underlying pathology per se.¹² If motor inhibition during REM sleep fails to be initiated, RBD occurs. For the bed partner, RBD is experienced as acting out of wild dreams with kicking, shouting and hitting. The patient often describes nightmares with a scary content.¹³ A certain anatomical structure responsible for RBD has not been identified, although the findings in individual cases suggest involvement of the sublaterodorsal and locus coeruleus–precoeruleus areas in the periaqueductal grey matter.¹⁴

At the Memory Clinic in Malmö, Sweden, DLB patients receive annual follow-ups in a standardised way, a procedure that has been ongoing for over 10 years. In this setting, we have noted five patients who developed extreme sleep–wake cycles not previously described. These cycles, which the relatives refer to as ‘sleep-days’, can be irregular but, more interestingly, they occur in some patients as a repeated set pattern of sleep and wakefulness. This is illustrated by the following case.

Case presentation

The following clinical description is presented with the family’s permission. The patient was 81 years old when she was referred to the Memory Clinic. She was a retired school teacher who, since widowed, had lived with one of her two adult daughters. She was diagnosed with PD (hypokinetic non-tremulous rigid type) at the age of 71 years, and cognitive decline was clearly apparent from the age of 76 years. She was treated with L-dopa initially 300 mg daily successively increasing to 800 mg daily. The clinical diagnosis was PD dementia. The main symptom displayed when she attended the Memory Clinic was visual hallucinations, in which she visualised unidentified young children and the family dog, which had been dead for years. At age 75, she had several months of nightmares involving loud screaming at night. When the patient was 81, her daughter confirmed that she talked and shouted while asleep at night (a sign of RBD) and also complained of unusual tiredness during the day.

At age 84, she developed a particularly disturbed sleep pattern after recovering from a hip fracture. According to the daughter, the patient slept very heavily and breathed with long and deep breaths until the afternoon. This occurred at the start of what became a prolonged period of profound sleep disturbance. The sleep-ins occurred once every 7–10 days, and the deep ‘comatose’ sleep became successively longer. After some months of this pattern, she would wake in the late afternoon but continue to sleep until the evening. During these sleep-ins, it was impossible to wake the patient up. For example, she continued sleeping despite the presence of a carpenter hammering in the apartment and she slept as if she did not hear anything. Before falling asleep she was often in a delirious state which was cleared after waking up.

Eventually, the sleeping days lengthened, first to 36 hours and then to 48 hours and, after 1 year, to 72 hours. During this time, she would also be awake for 72 hours continuously. Trying to modulate the sleeping time pharmacologically with mirtazapine, zopiclone, zolpidem and later melatonin made the patient anxious. Cholinesteras inhibitor was tried twice but aggravated the difficulties to fall asleep. The pattern of 72 hours sleep and wakefulness persisted until she died at the age of 89 years. It was as if her 24 hour biological clock had changed to a 144 hour pattern. In the initial stages, the daughter was able to feed the patient with soup or porridge during the sleep days. However, in some months, the patient was completely unarousable during these days and the daughter described her as if she was ‘in a comatose state’. At this point, treatment with intravenous fluids a few times was a necessary life-saving measure.

Her most extreme sleep period was 5 days and nights of sleep followed by 7 days and nights of wakefulness.

Investigations

The patient was followed at the Memory Clinic with planned visits once a year when cognitive tests were performed. The results of the Mini Mental State Examination indicate the successive cognitive decline: at 81 years, 24/30; 82 years, 14/30; 83 years, 15/30; 85 years, 13/30; 86 years, 13/30 and 87 years, 5/30.

The results of the neuropsychiatric inventory at age 85 years were as follows: total score, 42/144; delusions, 4/12; hallucinations, 6/12; agitation, 6/12; anxiety, 6/12; apathy, 9/12; aberrant motor behaviour, 2/12; sleep 9/12. The scores at 86 years were: Total score, 35/144; delusions, 9/12; hallucinations, 8/12; agitation, 6/12; sleep, 12/12.

CT at 81 years showed minor frontal periventricular white matter changes but was otherwise normal. A dopamine transporter scan obtained at age 81 years showed bilateral reduced dopamine reuptake capacity in the basal ganglia.

Electroencephalogram (EEG) at age 88 years showed a marked slowing of the EEG background and no epileptiform activity.

Prolonged polysomnography at age 89 years (figure 1) obtained during a clinically wakeful period showed the absence of obvious diurnal rhythm. The wake pattern was interrupted irregularly by short periods of drowsiness/light sleep and periods of REM sleep.

Figure 1.

Prolonged polysomnography for 60 h (A, B). (C–E) 10 s epochs of recording. Traces from above: EEG left, EEG right, eye movements (orange) and muscle electromyography (EMG) activity (green). Note the absence of diurnal rhythm. Wake patterns (C) are interrupted by short periods of drowsiness/light sleep, N1 (D). Note the irregular appearance of REM sleep periods with rapid eye movements and muscle relaxation (E).

Outcome and follow-up

The patient died in her home at age 89 years. An autopsy with subsequent neuropathological examination was performed. The brain showed no atrophy on the exterior and weighed 1400 g. All brain regions were assessed: the neocortex, limbic system, basal ganglia and hypothalamus, white matter, cerebellum and brainstem.

Routine H&E staining for microscopy showed mild degeneration visible in the frontal and insular cortex, hypothalamus, and hippocampus–entorhinal cortex compatible with Braak stage V but not in any other region of the cerebrum. Immunohistochemical staining for α-synuclein showed abnormalities that were prominent in the hippocampus, insular cortex and hypothalamus. In the hypothalamus, most neurons were severely degenerated or absent (figure 2).

Figure 2.

Microphotographs of part of the hypothalamus in our patient (left) and a case of mild disease, Lewy body dementia of limbic type (right). Note the reduction and atrophy of neurons (left, upper row) compared with preserved and densely packed cells (right). H&E staining. Synuclein protein deposits are numerous in our patient (left, lower row) compared with the case with mild limbic disease (right). α-Synuclein staining. For comparison, a control case normal hypothalamus, centre. H&E staining. The corresponding alpha-synuclein staining was blank.

The neuropathology also revealed degeneration in the substantia nigra of the mesencephalon and locus coeruleus of the pons; both nuclei exhibited nearly total degeneration and loss of neurons; ischaemic lesions in the basal ganglia with small lacunar infarcts on both sides were also found. Inconclusion, we judge the hypothalamus to be of a little more than intermediate degree of degeneration—it is not mild, but not of maximum severity where basically no neurons are found. Hence there were neurons, but clearly of impaired condition, of decreased numbers and also with an attenuations of the surrounding matrix.

Discussion

In our clinical experience, staff at nursing homes frequently report on patients having a phenomenon they call sleep days described as periods of time when a patient spends both day and night in bed and thereafter returns to their normal state. This behaviour and the physiological background are not well known among physicians. It is known that sleep disturbances are common in the α-synucleinopathies and appear in the form of RBD, excessive daytime sleepiness, and symptomatic narcolepsy.¹⁴ Individuals with other neurodegenerative disorders such as AD may exhibit reduced sleep efficiency, increased number of awakenings, and sleep–wake rhythm disturbances, allegedly caused by a functional disconnection between the suprachiasmatic nucleus and the pineal gland.¹⁵

LBD patients have a monoaminergic–cholinergic imbalance, which causes reduced levels of acetylcholine which may partially explain the disturbed sleep patterns since acetylcholine promotes alertness and wakefulness.¹⁶ However, norepinephrine may also be involved, which is why cell loss in the locus coeruleus is of interest.

Although the patient described here had received the initial diagnosis of PD at the age of 71 years, it appears that it was not classical PD but more of a hypokinetic, non-tremulous and rigid type often seen in DLB. Cognitive dysfunction was not investigated with cognitive testing until she was 76, which makes it difficult to know when it started in relation to the motor symptoms and therefore impossible to determine with certainty whether the illness was congruent with DLB rather than PD dementia. The strenuous disability to fall asleep probably enhanced the episodic confusion within the disease and led to delirious episodes in conjunction to the phase of falling asleep.

For practical reasons, polysomnography was not possible until late in the patient’s illness. The fragmented deep sleep was probably an ageing phenomenon, but the absence of obvious diurnal rhythm was pathological. Even though the recording was extended to 48 hours, it was not possible to capture the EEG pattern while she was clinically asleep. The interpretation of the neuropathological findings in this patient is that the involvement of the hypothalamus, together with severe degeneration and cell loss in the substantia nigra and locus coeruleus, may explain the sleep disturbance. The hypothalamic damage probably contributed to the difficulties of both falling asleep and waking up in this extreme case.

Hypothalamic lesions regularly occur in DLB, although their extent may vary between patients. These lesions can accompany the particular pathology of the pigmented brainstem nuclei, which is always significant. Others have found that hypothalamic synucleinopathy is common in PD and incidental Lewy body cases.^{17 18} Another study investigated hypothalamic pathology in PD and non-motor symptoms such as weight loss and autonomic failure, but could not find any relationships.¹⁹ This suggests that because α-synuclein deposits may be found in many different areas of the nervous system,⁵ symptoms in individual patients may vary according to the specific anatomical structures affected.

Patient’s perspective.

The daughter described the situation as follows.

Earlier, when the wakeful period was longer than the sleep period, my mother could be more like her old self, especially on the second wake day. She would sit in her wheelchair and enjoy being outdoors. On the third wake day, she was totally exhausted and increasingly confused, and began behaving like a ‘zombie’: turning over in bed, fighting to get to sleep. When she finally slept, she did not seem to suffer. For the first 24 hours, she looked almost amused. Her sleep was interrupted by periods when she would scream and speak in a loud and decisive manner for up to 2 hours non-stop. This strongly contrasted with her usual quiet personality.

When sleeping, she also behaved more childlike: making monotonic sounds and pursing her lips. She sometimes screamed very loudly, but she looked pleased and content. She only stopped screaming when I played the piano or combed her hair. In the last month of her life, the 6-day-and-night rhythm was prolonged, and it took even more days for her to wake up from her very deep sleep. The tragic part was that she was conscious of the situation and tried to find ways to make it easier to fall asleep. For example, she would say, ‘If I stay up long enough maybe it will be easier for me to fall asleep’. She would also say, ‘Why can’t I sleep like normal people?’

When she finally slept and then awoke, she was not aware of having slept longer than a normal night’s sleep. She also noticed that people and characters from her dreams would be present during her wake time, although she was aware that these characters were not actually real.

I was often met with suspicion when I had to cancel her appointments because of her deep sleep. Even healthcare providers asked questions like, ‘Can’t you just wake her up?’ No one seemed to have heard of a state like this!

Learning points.

• Extreme sleep–wakefulness patterns should not initially be explained by the dementia with Lewy bodies (DLB) disease. Other reasons, which may be treatable or preventable, should be considered first. These other conditions include epileptic seizures/states, cerebrovascular insults or low blood pressure. If another disorder cannot be found, we suggest that this disturbed sleep pattern is a possible alternative manifestation of the fluctuating alertness and wakefulness generally associated with DLB disorders.

• To establish the neurophysiological background to the disturbed sleep pattern, we recommend investigation using polysomnography.

• In nursing homes, the phenomenon of sleep days is not uncommon. We suggest that these patients should be investigated for other DLB signs. If cerebrovascular disease and epilepsy are ruled out, the phenomenon does not need emergency care but could be interpreted as part of the disturbed attention and wakefulness of DLB.