Recurrent offs

Almost everyone taking levodopa may develop response fluctuations.4 They typically appear after the so-called ‘honeymoon’ period, characterised by a favourable and stable levodopa response.5 Motor fluctuations comprise recurrent episodes of parkinsonism (off periods) of variable intensity that occur at different times in relation to levodopa intake (wearing off, delayed-on, no-on, unpredictable off).3

In some patients, especially those with younger onset or those taking higher doses of levodopa, motor fluctuations become severe, causing great discomfort.3 Severe off-related parkinsonism can manifest with a wide range of symptoms, especially severe tremor and unmanageable freezing of gait. These episodes are frequently associated with pain, profuse sweating and tachycardia, abdominal discomfort, and also psychiatric manifestations, particularly depression and anxiety.6

The treatment aims to reduce off time and severity by providing a more constant delivery of dopaminergic drug to the brain.6 By the time these problems develop, patients are taking multiple doses of levodopa and most have tried adjunctive treatments aiming to prolong levodopa effect: such adjuvant treatments include dopamine agonists, catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase B (MAO) inhibitors. Changing the levodopa dose through the day and adjusting the adjuvant medications can minimise the fluctuations and make them more predictable.5 However, about 10% of patients have severe medically refractory fluctuations; such patients require referral to specialised centres for consideration of device-aided therapies.3 However, age, cognitive status and the presence of psychotic symptoms frequently limit the use of these therapies.7

Dyskinesias

Involuntary movements (dyskinesias) can develop at different times in relation to the antiparkinsonian effect of levodopa (peak-dose and diphasic dyskinesia, or off-period painful dystonia).3 Although levodopa-induced dyskinesias are usually mild and focal in distribution, they can sometimes become generalised and interfere with sitting, walking and basic activities of daily living. This is more common in people with young-onset Parkinson’s disease.3 Patients then need urgent interventions to prevent consequences, such as falls and other injuries (ie, bone fractures). Moreover, severe dyskinesias, both peak-dose or diphasic, can occur at the end of the day in people taking slow-release formulations of oral levodopa, or in those receiving levodopa-carbidopa intestinal gel infusions.8

Treatment of dyskinesia is based on adjusting dopaminergic treatments. Peak-dose dyskinesias usually improve with redistributing the total daily levodopa intake into more frequent but smaller doses. Some patients need a lower total dose of levodopa (or lower dose of adjunctive therapies such as dopamine agonists, COMT inhibitors or MAO inhibitors). If these measures fail, then it is worth considering amantadine (300–400 mg daily).7

Managing diphasic dyskinesias is a major clinical challenge in advanced Parkinson’s disease.6 Modifying treatment, as would be done for peak-dose dyskinesias, may in fact worsen diphasic dyskinesias; sometimes the only suitable alternative is an intermittent ‘rescue’ subcutaneous injection of apomorphine immediately before an on/off state transition.6 9 In patients whose dyskinesias do not respond, it is worth considering one of the available continuous dopaminergic treatments or deep-brain stimulation.9

These strategies for managing wearing off and unpredictable on/off fluctuations also apply to off-period dystonia. Baclofen or injecting botulinum toxin into dystonic muscles can occasionally help.10

Clinical picture

This syndrome was first noted in people with advanced Parkinson’s disease undergoing ‘drug holidays’ to try to limit their levodopa-induced motor and neuropsychiatric complications.12 Patients deteriorated into an akinetic ‘off’ state, usually over a few days. The syndrome may also follow changes in dopaminergic treatment or be provoked by trauma, surgery, and pulmonary, gastrointestinal and urinary tract infections; although sometimes there is no apparent trigger.11 In severe cases, patients do not respond to dopaminergic rescue medications, with their parkinsonism deteriorating rapidly and becoming progressively more immobile and rigid.

On examination, patients may be confused with delirium, prominent global slowness and generalised muscle rigidity. They may develop hyperthermia and elevated serum muscle enzymes, following muscle damage from marked rigidity. Some patients develop dysautonomic features, such as tachycardia, unstable blood pressure and diaphoresis, resembling the clinical picture of neuroleptic malignant syndrome.13

Systemic complications may develop as the akinesia rapidly progresses, including aspiration pneumonia from decreased level of consciousness and rigidity; acute renal failure from rhabdomyolysis and dehydration; and thrombotic events such as deep vein thrombosis, pulmonary thromboembolism or (in severe cases) disseminated intravascular coagulation (box 1).

How to manage?

Early diagnosis is essential. Besides searching for and correcting the underlying cause, levodopa is the core of its management.11 14 If the syndrome was provoked by a decreased dose of dopaminergic treatment, the previous regimen should be immediately reinstated, and the oral levodopa dose gradually escalated. In patients with swallowing problems, a nasogastric tube can facilitate giving dopaminergic treatment. If increasing the levodopa dose fails, it is worth trying apomorphine (intermittent injections or continuous infusion), transdermal rotigotine or intravenous amantadine sulfate (only available in Germany, Austria and Hungary).13 The most refractory cases may be considered for nasogastric levodopa-carbidopa gel infusion with titrated dosing. Other treatments such as oral dantrolene sodium and oral bromocriptine are recommended but have no firm evidence of efficacy.12 Pulsed corticosteroid therapy (1 g daily of methylprednisolone until amelioration of symptoms) may help but again with only limited evidence of its effectiveness.15

Some patients need intensive care unit admission, for close monitoring of vital signs and supportive measures such as antipyretic treatment, fluid and electrolyte replacement, and prophylactic anticoagulants.2 Patients need routine checking of serum muscle enzymes, renal function (to identify deterioration) and clotting function (figure 1).

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Figure 1

Management of parkinsonism-hyperpyrexia syndrome. DA, dopamine agonist; LCIG, levodopa/carbidopa intestinal gel; LD, levodopa.; PHS, parkinsonism-hyperpyrexia syndrome

The prognosis is usually good with early treatment, although many patients do not return to their previous baseline level of function.12

Clinical picture

Patients typically present with prolonged episodes of generalised and exhausting dyskinetic movements that eventually cause motor collapse with consequent dehydration and rhabdomyolysis.16 17

This condition shares features with parkinsonism-hyperpyrexia syndrome: acute or subacute presentation, external trigger factors (infection and trauma) and systemic impairment (hyperthermia and rhabdomyolysis).2 Some patients may be refractory to treatment (limited response to reducing the dopaminergic medication or adding amantadine) but this is clearly less important than for parkinsonism-hyperpyrexia syndrome. Reducing dopaminergic drugs almost always improves dyskinesias in a short period of time.6 17

How to manage?

Besides promptly reducing the dopaminergic medication, patients may need general measures such as rehydration and electrolyte monitoring and repletion. In extreme cases, they may need sedation with propofol. Deep-brain stimulation may be a feasible long-term treatment.13

Clinical picture

Although serotonin syndrome shares many features with parkinsonism-hyperpyrexia syndrome and neuroleptic malignant-like syndrome (mental status decline and autonomic dysfunction; table 2), its onset is more rapid after starting or increasing the medication, usually within 6–12 hours.2 Its clinical manifestations vary but in addition to agitation and confusion there are four features that may help with the diagnosis: mixture of movement disorders (akathisia, tremor and myoclonus), hyperreflexia, mydriasis and diarrhoea.18

How to manage?

The cornerstone of treatment is to identify and withhold all drugs that could contribute to the hyperserotonergic state. Prompt and appropriate supportive care can be important for recovery, and adding non-selective 5-HT receptor antagonists (cyproheptadine and methysergide) may help.18

Acute psychosis

Psychotic symptoms occur in up to 30% of patients with Parkinson’s disease who take long-term dopaminergic treatment throughout the disease course; their occurrence suggests a poor prognosis and high mortality.19 Psychotic symptoms are well known to be an integral part of Parkinson’s disease, frequently triggered or aggravated by antiparkinsonian medications and a predictor of imminent cognitive decline.20

Hallucinations (mainly visual with well-formed images and rarely auditory) and delusions (commonly paranoid, implying negative beliefs, especially towards relatives) are the hallmark of Parkinson’s disease psychosis.20 Loss of insight, particularly when having delusions, is very stressful for caregivers, and increases the likelihood of nursing home placement. In addition, hospitalised patients with Parkinson’s disease often develop other psychiatric symptoms such as confusion/delirium, typically accompanied by a fluctuating level of attention, disorganised speech and behavioural changes.19

Dopaminergic treatment, advanced age, visual problems and concomitant dementia are important factors that contribute to psychosis in Parkinson’s disease. Psychotic symptoms may appear in relation to underlying systemic conditions such as infection, toxic-metabolic derangements, surgery and other neurological disorders (ie, subdural haematoma related to falls). Changes in antiparkinsonian drugs frequently trigger psychotic symptoms; importantly, drugs such as antidepressants and painkillers can also trigger or aggravate these symptoms.

Psychosis usually presents gradually, allowing for gradual implementation of treatment changes (reduction in dopaminergic medication, and/or addition of antipsychotic drug). However, sometimes psychosis evolves subacutely with prominent agitation and challenging behaviour constituting a serious psychiatric emergency.

In the most severe cases, when the patient’s physical integrity is compromised, patients need acute psychiatric admission. The management includes intensive antipsychotic treatment, such as bucodispersable risperidone or intramuscular aripiprazole, although worsening of parkinsonism must be expected. Benzodiazepines can help if anxiety dominates the clinical picture. Containment measures are a last resort.21

In addition to reviewing medication changes, it is important to exclude external precipitant factors. Patients with suspected urinary tract infection or pneumonia require urine analysis and chest X-ray. It is important to try to reduce antiparkinsonian medication. Drug changes must be implemented cautiously and gradually, as motor symptoms may deteriorate significantly. A common strategy is first to reduce anticholinergic drugs, then MAO inhibitors, amantadine, dopamine agonist, COMT inhibitors and eventually levodopa, but the order of dose reduction or withdrawal may need to be individualised.22 It is also important to minimise polypharmacy, if possible reducing mainly tricyclic antidepressants, opioids and dopaminergic drugs.

If significant psychotic symptoms persist, and drug reduction is not advisable or poorly tolerated, it is worth considering an atypical antipsychotic drug (box 2). Typical antipsychotics should be avoided as they can precipitate a significant deterioration of motor symptoms, and a neuroleptic malignant syndrome.4 Clozapine and quetiapine are the most frequently used antipsychotics for treating psychotic symptoms in Parkinson’s disease; both improve psychosis without motor worsening. Pimavanserin, a selective-serotonin inverse agonist, has recently been approved by the Food and Drug Administration (FDA) for treating psychosis in Parkinson’s disease but there is only limited experience with this drug.23 24

In routine clinical practice, quetiapine is often the first-tried drug, owing to its easy dosing and low rates of adverse events. Its most common adverse effects are excessive sleepiness, orthostatic hypotension and metabolic syndrome. In severe cases, and if symptoms persist despite quetiapine dose exceeding 200 mg/day, clinicians should consider clozapine (12.5–50 mg) and pimavanserin, if available. Clozapine’s adverse effects include sedation, drooling and orthostatic hypotension; it occasionally causes neutropenia, and so requires intensive blood monitoring, its main drawback.25

Cholinesterase inhibitors (donepezil and rivastigmine) were shown to reduce Parkinson’s disease hallucinations and ziprasidone was effective for psychosis in Parkinson’s disease in two small studies (open-label and a case series), but an exacerbation of parkinsonism can be expected.22

Impulse-control disorders and dopamine-dysregulation syndrome

Impulse-control disorders are a sort of behavioural addiction. Patients do not often report them because of embarrassment or cultural barriers. They include pathological gambling, compulsive shopping, abnormal sexual behaviours or binge eating.26 Patients with this disorder are compelled to repeat these actions excessively in ways that can be dangerous for themselves and others, frequently causing devastating economic, legal and personal repercussions.

These symptoms are a frequent adverse effect of dopamine-replacement therapy. A recent study found a cumulative incidence of impulse-control disorders in 46% patients taking dopamine agonists; the association between this drug and impulse-control disorders relates to both dose and treatment duration.27 Since its treatment is challenging, minimising the use of dopamine agonists is the best approach to lessen the problem, especially in those people at particularly high risk for developing impulse-control disorders, such young men with histories of obsessive-compulsive disorder, impulsive and addictive personality traits.28

Reducing dopamine agonists is the first (and usually effective) treatment. In refractory cases, adding an atypical antipsychotic, such as quetiapine, sometimes helps this reduction.26 Deep-brain stimulation of the subthalamic nucleus29 and levodopa carbidopa intestinal gel30 can help by allowing dopaminergic dosage reduction.

Rapid reduction or suppression of dopamine agonists may lead to a serious condition known as dopamine agonist withdrawal syndrome.31 Its clinical picture resembles a psychostimulant withdrawal syndrome, with combined psychiatric symptoms (panic attacks, depression, agitation and drug craving), autonomic features (diaphoresis, orthostatic hypotension) and motor worsening due to the reduction in dopaminergic therapy. Besides the prior diagnosis of impulse-control disorders, other risk factors are a high baseline dose of dopamine agonist and a high cumulative drug exposure. Other dopaminergic drugs, antidepressants or benzodiazepines typically do not help.32

A less frequent psychiatric complication related to levodopa is ‘dopamine-dysregulation syndrome’. It comprises a levodopa dependence syndrome and involves all the typical symptoms of craving, with impulsivity, compulsivity and mood changes.33 Its prevalence is probably underestimated because less severe cases are rarely reported.6 It can coexist with impulse-control disorder and should be suspected when patients indiscriminately increase their levodopa dose without medical authorisation and exceed the required dose to restore their motor functionality. Patients may increase their levodopa dose to avoid unpleasant feelings, typically non-motor symptoms related to off episodes.33

The management of dopamine-dysregulation syndrome typically involves gradually reducing the levodopa and immediately withdrawing ‘booster’ doses of medications, such as apomorphine subcutaneous boluses and rapid-acting levodopa formulations. Deep-brain stimulation may help to facilitate dose reduction of levodopa.26

Symptomatic orthostatic hypotension

Orthostatic hypotension can result from both neurogenic (failure of the autonomic nervous system from postganglionic sympathetic nerves) and non-neurogenic disorders (dehydration, dopaminergic and antihypertensive drugs, and cardiac dysfunction such as arrhythmia). Neurogenic orthostatic hypotension in Parkinson’s disease results from a lack of the normal compensatory norepinephrine released from sympathetic postganglionic nerves that causes vasoconstriction and maintains blood pressure in the standing position. In Parkinson’s disease this compensatory mechanism is attenuated or absent.34

Orthostatic hypotension causes symptoms in about 10% of cases.35 Patients usually describe light-headedness with blurry vision on standing or walking. Concentration difficulties, postprandial head/neck discomfort, and even a frozen posture akin to a levodopa-related off episode may also occur.35 In the most severe cases, typically when the blood pressure drops abruptly, patients may lose consciousness. Such cases require exclusion of anaemia or an underlying cardiac disorder.

Syncope caused by orthostatic hypotension can have serious consequences, including falls and injuries.36 Identifying the drug that might be contributing is not easy since almost all dopaminergic treatments can induce or trigger orthostatic hypotension: MAO inhibitors, dopamine agonists and, less so, levodopa. Other medications, such as antihypertensives, sildenafil or α-blockers also need to be considered.

Appropriate steps to avoid symptomatic orthostatic hypotension involve hygienic dietary measures, mainly high-salt diet, plenty of isotonic fluid and elastic stockings. When symptoms persist, medications can be tried, including pyridostigmine (25 mg two times per day), fludrocortisone (0.1 mg one to three times a day), domperidone (10 mg three times a day), droxidopa (300 mg three times a day), and midodrine, a selective α-adrenergic agonist that induces vasoconstriction and increases blood pressure, (2.5–10 mg three times a day).

Gastrointestinal complications

Dysphagia is common in Parkinson’s disease, typically in its late stages.1 It results from the loss of coordination in the normal steps of deglutition as well as oropharyngeal bradykinesia. Dysphagia may cause malnutrition with weight loss, high levels of anxiety during each meal for both the patient and carer, impaired medication intake and reduced social contact. It is associated with a high rate of mortality, mainly because of aspiration pneumonia.37 Early suspicion is essential to avoid these complications. Signs of neurogenic dysphagia include frequent coughing, choking or nasal regurgitation during meals, as well as frequent respiratory infections and drooling. When present, video fluoroscopy and fibreoptic endoscopic evaluation of swallowing should be considered.2 Management of dysphagia involves a personalised swallowing therapy, depending on the severity. Percutaneous gastrostomy may be a possibility, but it has to be implemented with caution.

A recent review showed how to manage dysphagia that interferes with oral intake of medication. Furthermore, alternative methods of oral levodopa are provided with conversion rates to rotigotine patch from other dopamine agonists and levodopa.38

Intestinal pseudo-obstruction, also known as paralytic ileus, is a serious condition that sometimes accompanies severe constipation. It seems to be relatively uncommon (2.4%).39 Abdominal distension, pain, nausea and vomiting characterise intestinal pseudo-obstruction, but in advanced patients with cognitive deterioration it can be difficult to diagnose, presenting with a prominent confusional state and poor response to levodopa.

During the acute phase, urgent endoscopic repositioning will be necessary. More severe cases may be complicated by intestinal perforation requiring surgical treatment.37 Preventive treatment of constipation with prokinetic drugs may help to prevent recurrences.

Excessive daytime sleepiness and sleep attacks

Excessive daytime sleepiness is inappropriate and undesirable sleepiness during waking hours even after adequate night-time sleep. It occurs in about 30% of patients with Parkinson’s disease, frequently in those with cognitive decline, and rarely in untreated patients.40 It can manifest during a conversation or a meal. Depending on when patients fall asleep, it can be a potential source of caregiver distress.

Sudden-onset-sleep or ‘sleep attacks’ comprise abrupt episodes of unplanned sleep during activities of daily living (ie, eating, driving). They can have disastrous consequences, particularly when they occur during activities that involve a risk for them and/or others, as with driving. Car accidents, falls and traumas may occur in the context of sleep attacks. Reports in the literature cite a prevalence of 13% for sleep attacks in patients under dopaminergic drugs, typically dopamine agonists and less commonly levodopa.40 Patients need to be warned about sleep attacks as a common adverse effect of dopaminergic treatment before starting these.

Clinicians should try to identify the main precipitant for excessive daytime sleepiness and sleep attacks. Obstructive sleep apnoea and other causes of poor nocturnal sleep need to be considered. Management is usually to reduce or withdraw those drugs likely to be causing the problem.

REM-sleep behaviour disorder

Rapid Eye Movement (REM)-sleep behaviour disorder is characterised by unpleasant dreams (eg, being attacked or robbed) and vigorous behaviours in which the patients appear to enact their dreams (eg, punching, jumping out of bed, shouting). It occurs in 25%–65% of patients with Parkinson’s disease.41

Protective measures such as bed rails or chair barricades may help to prevent falling from bed during vigorous dreams. Figure 2 illustrates the consequences of vivid dreams and their subsequent protective measures. Some patients hit their partner during sleep. Clonazepam is the treatment of choice for this sleep disorder despite the lack of randomised, placebo-controlled trials to evaluate its efficacy and safety. The starting dose is 0.25 mg or 0.5 mg at bedtime, increased progressively to a usual dose of 1–2 mg per night. It can aggravate sleep apnoea and so must be used with caution. When clonazepam is ineffective or not well tolerated, melatonin may be considered.42

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Figure 2

(A) Arm contusion in a patient with Parkinson's disease with REM-sleep behaviour disorder after falling out of bed while enacting a dream during REM-sleep. (B) Protection measures during the night to avoid falls and injuries during the episodes. (Courtesy of Dr. Alex Iranzo [42]). PD, Parkinson's disease; REM, rapid eye movement.