ABC of Sleep Medicine (ABC Series)

Chapter 9

Sleep in Neurodegenerative Disease


·        Sleep–wake disturbance is seen as a major component of virtually every neurodegenerative disease

·        Symptoms arising from poor quality sleep and impaired daytime wakefulness may mimic those arising from the underlying neurodegenerative process

·        Patients with Parkinson's disease (PD) can develop virtually any type of sleep-related symptom, often in advance of physical or motor signs of the illness

·        Fragmented overnight sleep and narcoleptic levels of daytime sleepiness are relatively common in PD and increase with age

·        Motor symptoms responsive to dopaminergic therapy may account for many overnight symptoms in PD

·        Advanced PD with cognitive impairment is associated with very severe sleep disturbance, often with hallucinations and nocturnal confusion

·        Alzheimer's disease (AD) commonly leads to disturbed circadian rhythms and sleep–wake disturbance, often with minimal insight from the patient

·        Promoting daytime alertness by non-pharmacological means may improve quality of life in AD sufferers

·        In motor neuron disease (MND), an early sign of diaphragmatic weakness is poor quality overnight sleep with daytime lethargy secondary to nocturnal hypoventilation

·        Non-invasive ventilation is now an established and proven treatment for many MND patients with hypoventilation

Significant disturbance of the sleep–wake cycle is increasingly recognised as an integral, important and sometimes treatable element of all the common neurodegenerative disorders. The ability of carers to cope with poor or disturbed sleep in the home is often a major cause of concern, potentially leading to early institutionalised care. Many have also highlighted the inevitable rising prevalence of age-related sleep disorders as a consequence of ageing populations in developed countries.

The vast majority of neurodegenerative conditions reflect abnormal accumulation of mis-folded proteins within nerve cells, either as a pathological marker or a likely direct cause of eventual neuronal death. Preventing or slowing down this neurodegenerative process represents a future therapeutic ‘holy grail’. Results from basic science at the cellular level suggest that significant sleep deprivation or chronic poor quality sleep may actually accelerate abnormal protein accumulation within cells, potentially fuelling any neurodegenerative process. As a corollary, whether improving sleep quality could be ‘neuroprotective’ in those with underlying neurodegeneration remains a tantalising but entirely credible speculation.

At a practical level, optimising a subject's daytime alertness in the context of a neurodegenerative illness will, at the very least, have a positive influence on attention, cognition and possibly mood. Unfortunately, many drugs used in dementia and related disorders may have the opposite effects.

Parkinson's disease

Idiopathic Parkinson's disease (PD) is characterised primarily by rest tremor, rigidity and slowed movements with impaired gait and abnormal postural reflexes. These recognisable motor symptoms are variably responsive to dopaminergic medication, at least initially.

Numerous other non-motor symptoms affecting cognitive, neuropsychiatric and autonomic domains are now recognised in PD. These are often as debilitating as the motor aspects and frequently more difficult to manage. Their presence usually reflects more widespread neuronal death within the brain and undermines the simple notion that PD is merely due to a cerebral deficiency of dopamine.

Although initial clinical descriptions of the disease by James Parkinson himself described subjects as having ‘constant sleepiness’ and ‘extreme exhaustion’ (Box 9.1), the extensive and complex sleep-related problems in PD have only recently been characterised.

Box 9.1

Sleep becomes much disturbed; the tremulous motions of the limbs occur during sleep and augment until they awaken the patient. [in the final stages there is]…constant sleepiness with slight delirium and other marks of extreme exhaustion.

A quote from James Parkinson's original essay on the ‘Shaking Palsy’ written in 1817.

Indeed, the complete range of sleep-related symptoms may sometimes be seen in the same patient. It is difficult to define a typical patient profile, however, and any treatments should always be individualised.


Even allowing for age-related deterioration in sleep quality, an inability to stay asleep effectively is extremely common in PD. The potential causes are varied and multifactorial (Table 9.1). Nocturnal motor symptoms may predominate, especially if the subject is under-treated with dopaminergic drugs. Reported difficulties with turning in bed or limb tremor interfering with sleep continuity are particularly common complaints. Another indicator that dopaminergic medication effects are wearing off is severe pain in the latter part of the night, typically in the feet, reflecting dystonia. These various nocturnal motor and painful symptoms may respond to longer-acting drugs, particularly the dopamine agonists, taken before bed.

Table 9.1 Potential causes of impaired sleep maintenance in Parkinson's disease (PD).

Mechanisms of insomnia in PD


Nocturnal motor symptoms

Bradykinesia, tremor, dystonia (usually early morning)

Primary sleep disorders

Due to PD pathology in brainstem ‘sleep centres’, restless legs syndrome, sleep apnoea

Effects of medication

All PD treatments may disturb overnight sleep


Often not recognised in PD, partly due to lack of facial expression

Abnormal circadian timing

A theoretical but credible cause of poor sleep in PD


Often reflects bladder instability and can be a major cause of concern

Fragmentation of sleep is almost certainly also secondary to the underlying disease process in PD. This is not surprising given that many areas of the brainstem, including key nuclei involved in sleep control, carry the characteristic pathological hallmark of PD, the Lewy body. Long-term hypnotic medication to improve sleep continuity may, therefore, often be justified if significant sleep maintenance insomnia is seen in PD.

Nocturia is also a major issue for many patients, particularly as they may physically struggle with mobilising to the bathroom. It probably partly reflects the increased bladder instability seen in PD, although it may also simply result from spontaneous awakenings due to the underlying disease process. Agents to suppress detrusor hyper-reflexia sometimes help although their anticholinergic properties may worsen any associated nocturnal confusion. In males, the provision of an overnight urinary sheath often improves sleep considerably.

Leg restlessness is also a common nocturnal symptom in PD. It is debatable whether this is a form of restless legs syndrome or more related to underlying PD and its treatment.

Anxiety and depression are probably extremely common in PD but can be difficult to recognise. If sleep disruption is thought to result partly from mood problems, sedating antidepressants such as trazodone or mirtazapine may help. Side effects are likely to be commoner in the PD population, however, and elderly patients, in particular, should be monitored closely.

Excessive daytime sleepiness (EDS)

Significant daytime sleepiness is frequently seen in PD, probably affecting well over 30% of subjects. The patients themselves often appear not to recognise the extent of their excessive sleepiness, making corroborative history from a spouse or family members important. Sudden ‘sleep attacks’ may occur in severe cases, resembling the levels of sleepiness seen in conditions such as narcolepsy.

The causes of EDS in PD are often complex and multifactorial (Table 9.2). In some, it may largely reflect poor quality nocturnal sleep. Treatable conditions such as obstructive sleep apnoea should always be considered.

Table 9.2 Causes of excessive daytime sleepiness (EDS) in Parkinson's disease (PD).

Mechanisms of hypersomnia in PD


Poor quality nocturnal sleep

Any cause of secondary insomnia in PD

Primary sleep disorder

PD pathology in ‘sleep centres’, sleep apnoea, periodic limb movements during sleep

Medication effects

Most PD drugs, especially the dopamine agonists, may cause sleepiness although mechanisms remain obscure


Often not recognised

Impaired circadian timing

A theoretical consideration

A minority of patients experience severe EDS as an idiosyncratic reaction to dopaminergic medication, particularly at low doses of the newer agonist agents. As with sleep maintenance insomnia, EDS in some subjects is likely to reflect pathological damage to the brain's sleep centres. Furthermore, disruption of circadian sleep–wake rhythms seems a likely factor in advanced disease although this remains speculative.

Once overnight sleep has been optimised, wake-promoting medication is sometimes appropriate and successful in PD. Selegiline, traditionally used to help the motor symptoms of PD, is metabolised to amphetamine and may have an alerting effect. Modafinil, the wake-promoting agent most commonly used in narcolepsy, is also beneficial in some patients at standard doses although response rates are unpredictable.

Parasomnias and hallucinations

Disturbing nocturnal behaviours are frequently reported in PD, usually by the bed partner (Table 9.3). Violent dream enactment or REM sleep behaviour disorder (discussed in Chapter 7) affects over 30% of patients and may pre-date the development of motor symptoms by many years. Clonazepam before bed is the most widely used treatment although some evidence suggests melatonin may also reduce the abnormal limb movements.

Table 9.3 Potential causes of excessive nocturnal motor activity in Parkinson's disease (PD).

Mechanisms of excess motor activity and behavioural problems at night


Motor symptoms of PD

Tremor can persist into light non-REM sleep

REM sleep behaviour disorder

Violent or agitated dream enactment is seen in at least 30% of subjects

Medication effects

Extra movements (dyskinesias) may persist during sleep due to excess dopaminergic medication

Nocturnal confusion

May cause abnormal arousals resembling sleepwalking

Vivid dreams and nightmares can be linked to increases in dopaminergic treatment. If troublesome, it may be appropriate to reduce doses, especially if there are associated hallucinations during drowsy wakefulness.

In those with cognitive impairment or frank dementia (PD dementia or dementia with Lewy bodies), prolonged episodes of nocturnal confusion with or without hallucinatory intrusions present a difficult management problem. Leaving the bed and engaging in complex but inappropriate tasks may even mimic a form of agitated sleepwalking. Routine hypnotics often worsen the situation and exacerbate confusion. Atypical neuroleptic agents such as quetiapine or clozapine (usually under psychiatric supervision) may improve the apparent psychotic elements as may anticholinesterase inhibitors such as rivastigmine. However, these drugs have variable effects on improving sleep continuity and may worsen motor symptoms such as tremor.

Complex parkinsonian disorders

Multiple system atrophy (MSA) is a neurodegenerative disease which may mimic the motor symptoms of PD but is less responsive to standard drug therapy. Although the pathology is different to PD, it most often produces a picture of progressive parkinsonism with prominent rigidity. Variable combinations of cerebellar and autonomic dysfunction also complicate the clinical picture.

Most likely as a consequence of widespread brainstem pathology, overnight breathing may become seriously disturbed in MSA. Vocal cord dysfunction potentially causing life-threatening stridor is the most serious consequence but obstructive and central sleep apnoeas are also very common. If overnight breathing problems are suspected, specialist intervention with overnight polysomnographic recording is recommended, especially if inspiratory stridor is reported. It has been suggested that tracheostomy may be required in such cases to prevent sudden death rather than simple positive airway pressure masks.

In MSA, dream enactment and REM sleep behaviour disorder are extremely common and may even aid with early diagnosis if recognised. Of interest, the striking male bias for this phenomenon seen in PD appears much less obvious in MSA.

Progressive supranuclear palsy (PSP) is a rarer parkinsonian disorder with prominent gait disturbance and axial rigidity. Reduced eye movements, particularly in the vertical plane, are a pathognomonic physical sign. Sleep continuity is usually very poor in advanced patients in the absence of any specific abnormalities. When recorded, there is often a dramatic reduction in sleep spindles, the EEG marker for light non-REM sleep. Sleep-disordered breathing and dream enactment are comparatively rare, however. Technical difficulties make it difficult to measure REM sleep but severe disturbances are very likely in this patient group.

Alzheimer's disease

Alzheimer's disease (AD) typically presents initially with short-term memory failure prior to a slow and progressive deterioration in all domains of intellectual and social functioning. The sleep–wake cycle may become significantly disturbed at any time during the course of the illness. Nocturnal insomnia, daytime sleepiness, agitated wanderings at night may occur in any combination, usually with reduced insight from the patients themselves. Significant sleep disturbances might also contribute directly to a subject's cognitive decline and, at the very least, produce considerable burden to the care-giver.

Depression may be difficult to recognise in demented patients but can present as an agitated sleep disturbance. Trials of standard anti-depressant therapy are often justifiable. Tricyclic agents should be used with extreme caution due to anti-cholinergic effects which may exacerbate confusion.

Night-time sedation is a controversial and difficult area in the management of AD. Benzodiazepines often worsen nocturnal confusion and contribute both to daytime somnolence and gait unsteadiness on waking. Agents such as low dose quetiapine may improve sleep quality without major side effects. However, there have been concerns raised over the use of neuroleptic agents in demented populations with an increased incidence of strokes seen in some studies. Anticonvulsant drugs such as sodium valproate have also been used empirically to improve behavioural dyscontrol at night, with limited success.

Circadian problems

Reversal of the day–night rhythm is very common in AD. It may reflect Alzheimer pathology in the ‘clock’ region of the hypothalamus although it also results from environmental factors. Nursing homes may not provide exercise or mental stimulation during the day. Early bedtimes may also be encouraged, often simply to facilitate staff changeovers. A frequent lack of daylight exposure is also proposed as a cause of impaired circadian timing. Trials of phototherapy during the day and melatonin at night have produced variable results across AD populations but no doubt help individual patients.

The phenomenon of ‘sundowning’ is well recognised in AD and refers to agitated confusional episodes around early evening or dusk. There may be an underlying circadian abnormality to explain the problem. Management with drug treatment is particularly difficult.

Intercurrent medical problems

The new development of nocturnal confusion or worsening sleepiness in a patient with dementia should raise the possibility of an intercurrent illness. Such patients are at risk of acute confusional states or delirium resulting from minor ailments such as subclinical bladder infections. Similarly, anaemia, metabolic upset or even constipation may present in unusual ways in patients unable to give clear medical histories.

Other sleep disorders

Given their increasing prevalence with age, obstructive sleep apnoea (OSA) and restless legs syndrome (RLS) should always be considered in elderly AD patients. Indeed, successful treatment of OSA with nasal mask therapy has occasionally dramatically improved cognitive function in individual patients. Furthermore, severe OSA itself is associated with signs of cognitive impairment and reduced cortical grey matter on detailed brain imaging. Whether severe sleep deprivation, intermittent hypoxia or both are the major contributing factors is unknown. Similarly, how reversible the scan changes are with appropriate therapy remains speculative.

If excessive leg restlessness appears to fuel a demented patient's sleep, even in the absence of a clear history, a therapeutic trial of a dopaminergic drug at low dose may be justified. These agents are generally well tolerated although increased nocturnal hallucinations or worsening insomnia need to be monitored.

Motor neuron disease

Typical cases of motor neuron disease (MND) will affect many muscle groups and progress inexorably, eventually involving respiratory muscles. Indeed, death is usually secondary to respiratory failure. In some, however, respiratory insufficiency may occur early in the disease course and develop insidiously. Because clinical examination of centre core muscles such as the diaphragm is difficult, weakness can remain unrecognised until lung function (e.g. forced vital capacity) is severely compromised.

The first signs of respiratory insufficiency often occur at night with hypoventilation and hypoxaemia when lying flat, particularly during REM sleep. Resulting disturbed or unrefreshing sleep is associated with early morning carbon dioxide retention causing headache. Daytime sleepiness is also a common consequence and usually pre-dates frank breathlessness or orthopnoea as an indicator of respiratory muscle weakness.

Nocturnal ventilation using a positive pressure mask has been shown convincingly to improve sleep continuity and quality of life in MND patients with significant diaphragmatic weakness. Survival has also been shown to improve even in patients with advanced disease. Mask tolerability and dealing with upper airways secretions are often difficult issue as patients enter a palliative phase of their illness.

Further reading

Altena, E., Ramautar, J.R., Van Der Warf, Y.D. and Van Someren, E.J. (2010) Do sleep complaints contribute to age-related cognitive decline? Prog Brain Res185, 181–205.

Arnulf, I., Leu, D. and Oudiette, D. (2008) Abnormal sleep and sleepiness in Parkinson's disease. Curr Opin Neurol21, 472–477.

Bliwise, D.L., Mercaldo, N.D., Avidan, A.Y. et al. (2011) Sleep disturbance in dementia with Lewy bodies and Alzheimer's disease: a multicentre analysis. Dement Geriatr Cogn Disord31, 239–246.

Boeve, B.F., Silber, M.H., Ferman, T.J. et al. (1998) REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology51, 363–370.

Radunovic, A., Annane, D., Jewitt, K. and Mustfa, N. (2009) Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 4 (Art. No.: CD004427). doi: 10.1002/14651858.CD004427.pub2.

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