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Emergency presentations of Parkinson's disease: early recognition and treatment are crucial for optimum outcome
  1. R Ghosh,
  2. B J Liddle
  1. Robert Hadfield Wing, Northern General Hospital, Sheffield, UK
  1. Correspondence to Dr R Ghosh, Robert Hadfield Wing, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK; robinghosh{at}nhs.net

Abstract

Parkinson's disease (PD) is a debilitating condition associated with significant morbidity and mortality. Pathophysiologically the illness is due to a disruption of dopamine production in the basal ganglia and leads to a wide array of symptoms. These symptoms are not restricted to the nervous system; thus, the illness often presents acutely to a wide range of specialties, many of which may have limited experience in the condition. Patients often become unwell with illnesses unrelated to their PD. However, these conditions frequently lead to a deterioration in PD control. In addition, there exist certain acute complications of PD which are often difficult to recognise and carry significant mortality. Discussing the acute presentations of the illness under the umbrella of PD is important as it enables clinicians to focus upon the specific concerns involved in managing patients with the illness. A number of conditions are extremely common in PD and include falls, orthostatic hypotension, swallowing difficulties, psychosis, and hyperkinetic movement disorders. Optimal treatment of these conditions requires the consideration of issues specific to PD. Lesser recognised acute presentations of PD include the serotonin syndrome and neuroleptic malignant-like syndrome. While encountered less commonly, these conditions have been well described in the literature and untreated may prove fatal. They require urgent management, with their importance being further highlighted by the fact they may often mimic other illnesses, making diagnosis difficult. Therapeutic interventions aimed at treating PD and preventing its complications are evolving rapidly.

  • Parkinson's disease
  • emergencies
  • acute presentations
  • dyskinesia
  • falls
  • dysphagia
  • psychiatric
  • serotonin syndrome
  • neuroleptic malignant syndromes
  • clinical pharmacology
  • geriatric medicine
  • neurology
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Introduction

Parkinson's disease (PD) is a progressive neurodegenerative condition which impairs patients' motor skills, speech, and higher mental functioning. The risk of developing PD increases with age, having a prevalence of around 2% in those aged 80 years and over.1–3 Consequently, many patients are elderly and suffer with multiple comorbidities. The combination of a growing elderly population, alongside the increased morbidity of patients with PD, ensures that the number of patients with PD presenting acutely to hospital is likely to increase over coming years.4

While the pathophysiology of PD is of a neurodegenerative nature, the illness manifests clinically as a multisystem disease. In a study following a cohort of patients previously diagnosed with the illness, Woodford and Walker found patients were frequently admitted with a variety of presenting conditions, both related and unrelated to PD.5 In view of this, patients may present acutely to a range of specialties with varying experience in PD. Additionally, conditions unrelated to PD may also impact on a patient's health so as to cause a patient's PD control to deteriorate. Common manifestations include falls, swallowing difficulties, and the worsening of psychiatric symptoms. This highlights the importance of all physicians being made aware of the acute presentations of patients suffering with PD. Less commonly there exist a number of well recognised life threatening complications of the illness which require prompt diagnosis and treatment. These conditions may be precipitated by a deterioration in health due to unrelated illnesses, worsening of PD or medication changes. They include severe dyskinetic states, serotonin syndrome, and a condition mimicking neuroleptic malignant syndrome. Such complications require prompt diagnosis and treatment. This is often hindered by their non-specific presentation and a lack of awareness.

Our observation is that the acute complications of PD are often poorly recognised and treated. Potential reasons for this include the frequent presentation of patients to non-PD specialists and a lack of familiarity with some of the lesser known complications. This motivated our review of the literature in order to provide a clear account of these issues for physicians involved in the emergency care of such patients. Each acute presentation is discussed in terms of epidemiology, pathogenesis, symptoms, and treatment, initially focusing upon the common presentations which clinicians are likely to encounter. Latterly the article discusses the less common but well documented and potentially fatal complications—neuroleptic malignant-like syndrome (NMLS) and the serotonin syndrome. While recognised as conditions associated with PD, these complications are not unique to the illness. Consequently much of the previous literature discusses these disorders either in isolation or in the context of other clinical settings. Therefore, this review addresses these acute presentations with specific reference to PD. By including these rare but important conditions within the context of PD the article highlights their relevance to the physician treating acutely unwell patients.

Search strategy and selection criteria

Medline (PubMed) and Embase data were searched under the keyword of Parkinson's disease combined with the terms: emergencies, acute presentations, dyskinesia, falls, serotonin syndrome, neuroleptic malignant syndrome, dysphagia, and psychiatric. Keywords were searched for within the titles and abstracts of documents. The keywords were chosen based upon our own observations of the important acute complications of PD, and were also guided by a previous paper which recorded the reason for admission of a cohort of patients with known PD over a 2 year period.5 The search was carried out between 1 January 2010 and 1 September 2010.

Due to a lack of published data in this field no restriction was made upon date of publication. Reference lists of identified articles were searched and included in the review.

Falls

Falls are common in PD, with around two thirds of patients falling each year.6 7 Common causes include poor PD control, postural instability, and orthostatic hypotension (table 1). It is common for complications to coexist. The clinical consequences of falls are substantial, carrying significant mortality and morbidity.8–10 Patients suffering with PD have specifically been found to be at increased risk of fractures, including fracture of the neck of femur.11 12 Such fractures carry a significant risk, with 1 year mortality in the range of 20–35%.13–15 Overall the prognosis for those suffering with PD may be worse than for fracture patients without the illness.16 Falls may also lead to a decrease in patient mobility and increased dependence.

Table 1

Common precipitants and complications of falls in Parkinson's disease (PD)

In view of this, there is a clear need for falls, their acute management and their prevention to be considered and treated as an emergency. This is reflected by the inclusion of a specific section on the management of falls in the current National Institute for Health and Clinical Excellence (NICE) guidelines for PD.2 These stress the importance of multidisciplinary input as well as specific medical issues such as poor control of PD, motor fluctuations, and orthostatic hypotension. The initial management of falls should focus upon the management of any acute precipitants and sequelae. Common precipitants and sequelae are listed in table 1.

Dyskinesia, psychosis, and delirium are discussed later in this article, while the optimisation of PD control should include the involvement of specialist care. The treatment of non-PD related complications is similar to those patients not suffering with PD.

Orthostatic hypotension is both a common cause of falls and a frequent complication of PD, being found in around 50% of patients with the illness.17 Orthostatic hypotension is multifactorial in PD, with causes including hypothalamic, brainstem, and peripheral nervous system degeneration. These are compounded by the hypotensive side effects of levodopa.2

The current NICE guidelines suggest a stepwise approach for the management of orthostatic hypotension aimed at alleviating the condition while minimalising interventions:

  • Step 1 Adjust/stop hypotensive medications

  • Step 2 Add salt retaining steroid (eg, fludrocortisone)

  • Step 3 Add direct acting sympathomimetics (eg, midodrine).

Midodrine is a short acting α agonist and should be given during ambulant hours only. This is usually upon waking, before lunch, and before tea. It is important to monitor for supine hypertension which may precipitate vascular complications. Dosage usually starts at 2.5 mg three times a day and can be increased to 10 mg three times a day.

In addition to the strategies discussed in the NICE guidelines, a number of studies have demonstrated benefit of the peripheral dopamine antagonist domperidone.18–20 The mechanism of action is via peripheral antagonism of the hypotensive effects of dopaminergic drugs, while the fact that the drug does not cross the blood–brain barrier ensures that parkinsonian symptoms are not worsened. The dosage of domperidone is 10–30 mg three times a day.

Where possible these measures should be undertaken in conjunction with conservative measures such as bed head elevation and increased salt and fluid intake.

Swallowing difficulties

Difficulty in swallowing occurs to a varying degree in nearly all patients with PD.21 Dysphagia is due to catecholamine degeneration and Lewy body formation within the brainstem, resulting in a deterioration of bulbar function.22 The spectrum of symptoms ranges from simple drooling to life threatening complications such as aspiration pneumonia and malnutrition.21 23

An important consequence of swallowing difficulties is their potential to lead to aspiration pneumonia. Occult dysphagia may often go unrecognised until the development of this, highlighting the importance of screening patients presenting with bronchopneumonia or lower respiratory tract infections. Screening methods include speech and language therapy assessment, video fluoroscopy, and fibreoptic examination. Although it may not be possible to correct the underlying problem fully, treatments such as attenuated diets, optimal feeding positions, and tube feeding may help avoid complications. Long term tube feeding often requires the insertion of percutaneous gastrojejunostomy feeding tubes.

A further problem is where the patient's dysphagia deteriorates while admitted to hospital for unrelated conditions. This may be due to the generalised effects of any intercurrent illness or an inability to swallow PD medications. The latter issue has the potential to form a vicious circle where a further inability to swallow medications may lead to further deterioration. Rapid assessment of the patient's swallowing with timely appropriate management may reduce complications such as aspiration pneumonia, suboptimal nutritional status, and NMLS (discussed later). Alternative forms of PD medication delivery include the nasogastric delivery of the patient's usual medications, apomorphine infusions, and transdermal delivery.

Lastly, advanced PD is often a terminal illness with pneumonia being a leading cause of death.24 In view of this it is important to recognise when swallowing issues herald the onset of the terminal phase of the illness. Early identification and appropriate palliative management avoids unnecessary patient suffering and use of resources.

Acute hyperkinetic disorders

The most important of these disorders is levodopa induced dyskinesia. This is an abnormality of the voluntary control of muscles, and occurs to a varying degree in around 50% of patients treated for over 5 years with levodopa.25 The aetiology of this potentially debilitating disorder is not fully understood; however, current opinion suggests that the pulsatile delivery of pharmacological levodopa, reduced buffering capacity of the remaining neurons, and aberrant compensatory mechanisms play significant roles.25 26

Dyskinesia may be precipitated by medication changes and intercurrent illness, with implicated drugs including levodopa preparations and catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone.27 28 COMT inhibitors induce dyskinesia by increasing the bioavailability of levodopa.

The condition may occur in a number of forms, including chorea, choreoathetosis, dystonia, and myoclonus. Diagnosis of these involuntary movements may be difficult for those unfamiliar with the condition. Dyskinesia may be incorrectly identified as a severe tremor and the authors have experienced episodes where the condition was misdiagnosed as seizures. One instance resulted in a patient being managed as a case of status epileptics and being sedated and intubated on the intensive care unit before referral to the PD team. Often dyskinesia is an insidious process progressing over many years. However, patients may rapidly deteriorate leading to a critical life threatening condition. Such precipitous presentations are often due to intercurrent illness or medication changes. Continued dyskinetic movements of the limbs may lead to exhaustion, trauma, dehydration, and rhabdomyolysis.29

Combined with the appropriate management of any intercurrent illness, the treatment approach involves the careful adjustment of levodopa.30 Levodopa adjustments are tailored to individual patient needs and should only be undertaken by physicians familiar with their use. An important consideration in adjusting the levodopa dosage is the potential detrimental effects of subtherapeutic dopaminergic therapy. In these situations parenteral apomorphine may be used in combination with reducing the dose of levodopa.31 Apomorphine is a short acting dopamine agonist which should be given under specialist supervision.

Current theory proposes that the development of dyskinesia relates to pulsatile rather than continuous dopaminergic stimulation, with intravenous delivery of levodopa having previously been shown to stabilise motor fluctuations.32–36 Therefore, novel techniques are being developed in order to achieve this. A current area of interest is the use of duodenal infusions of levodopa which avoid erratic gastric emptying and the resulting unpredictable dopaminergic stimulation.37–40

Dyskinesia as a cause of breathing difficulties and choking attacks

Due to its high mortality, laryngeal dystonia merits specific mention.41 This often causes nocturnal stridor and episodes of choking.42 Diagnosis is via direct laryngeal examination and electromyography. Treatment increases patient survival, with options including nocturnal continuous positive airways pressure ventilation, laryngeal adductor botulinum injections, and tracheostomy.42–44

Psychosis

Psychotic symptoms affect up to 40% of patients with PD, often leading to hospitalisation and even suicide attempts.45 46 Psychosis in PD is associated with dopaminergic stimulation, poor motor status, sleep disorders, and depression.47 It may also be precipitated by intercurrent illness or medication changes.48 49 Potential consequences include falls, poor compliance with treatment, and distress to both patients and relatives. In past years the development of psychotic symptoms carried a grave prognosis in PD; however, the development of the newer ‘atypical’ antipsychotic drugs have since notably improved the outlook for patients.50

As psychosis may be precipitated by intercurrent illness, searching for and treating any underlying metabolic or infectious precipitant is mandatory. Standard treatment approaches regarding delirium are also relevant, in particular the importance of consistent nursing care, a reality orientation approach, and an appropriate sensory environment.51

In terms of specific considerations relating to PD, a common approach is to review the PD medications. Common practice is to stop the last medication prescribed before the symptoms arose (‘last one in, first one out approach’). Failing this, the common order for stopping medications is usually anticholinergics, monoamine oxidase inhibitors (MAOIs), amantadine, dopamine agonists, and levodopa.52 However, a major limitation of this strategy is the deterioration of the patient's motor function. Where a further deterioration in motor function is not desirable, consideration should be give to the addition of a neuroleptic medication.

Recent years have seen the increasing use of atypical neuroleptics in clinical practice. These are of particular relevance to PD as extrapyramidal side effects are less of a problem than with earlier neuroleptics. Two commonly used neuroleptics in this scenario are clozapine and quetiapine. Clozapine has been demonstrated to have a significant benefit compared to placebo, with no worsening of parkinsonian symptoms.52–56 The starting dose is 12.5 mg/day, with therapeutic doses usually <50 mg/day. However, its use is limited by the need to monitor leucocyte counts due to idiosyncratic agranulocytosis. Alternatively, quetiapine may be used, with usual starting doses of 12.5–25 mg/day which may be increased sequentially at 25–50 mg intervals.57–61 Despite the evidence for its efficacy being less unequivocal than that of clozapine,53 62 due to clozapine's risk of agranulocytosis, quetiapine is generally used as first line therapy, with clozapine reserved for more difficult cases. Although occasionally being associated with extrapyridimal side effects,63 the authors have rarely found this a clinically significant issue, with symptoms often being minimal.

The recent development of cholinesterase inhibitors has also proved useful for patients suffering with coexistent dementia. Dementia is found in around 40% of patients with PD, where the cholinesterase inhibitor rivastigmine has been found to improve psychotic symptoms and behavioural problems.64 Rivastigmine should be started at a low dose of 3 mg/day, increased as tolerated to 12 mg/day. It can be given either in divided doses orally or via a transdermal patch. In our experience rivastigmine may be used in conjunction with the atypical neuroleptics, although it may often take several weeks to work. Figure 1 illustrates an approach to the patient with PD presenting with psychotic symptoms.

Figure 1

Flow diagram for the assessment and treatment of acute psychosis in Parkinson's disease (PD). MAOI, monoamine oxidase inhibitors.

Neuroleptic malignant-like syndrome (NMLS)

NMLS, or parkinsonism hyperpyrexia syndrome, is a life threatening disorder seen in patients where dopamine concentrations are suddenly reduced. Despite being rare, the condition is potentially fatal and may often go unrecognised. Early diagnosis is hindered by a lack of awareness and the fact it may mimic other conditions. This raises the possibility of its true incidence being higher than currently recognised. Recently, the occurrence of this syndrome when PD medications were stopped intentionally before deep brain stimulation surgery has been observed.65 As this field expands, the condition may be encountered more frequently in the future.

NMLS was first described in Japan in 1981, where a patient not exposed to neuroleptics had their dopaminergic medications discontinued abruptly.66 The syndrome may also arise where it is difficult to deliver patients' PD medications.66–68 The syndrome is clinically indistinguishable from neuroleptic malignant syndrome (NMS), differing only in its aetiology (table 2).69 70 NMS is an idiosyncratic reaction to antipsychotic medications. While NMLS is usually due to the withdrawal of dopaminergic drugs, it has also been reported upon withdrawal of non-dopaminergic drugs, including amantadine and anticholinergics.67 NMLS can often be difficult to differentiate from serotonin syndrome (table 2).

Table 2

Comparison of serotonin syndrome, neuroleptic malignant syndrome (NMS), and neuroleptic malignant-like syndrome (NMLS)

The clinical presentation is one of rigidity, fever, dysautonomia, and decreased level of consciousness (table 2). Dysphagia, hypersalivation, and akinesia are characteristic symptoms which clinically help differentiate NMLS from serotonin syndrome. Patients usually deteriorate slowly over a number of days. Case reports have recorded the development of rhabdomyolysis with raised creatine kinase concentrations and the presence of myoglobulinuria.65 Further potential complications include acute renal failure (secondary to rhabdomyolysis and dehydration), aspiration pneumonia (secondary to rigidity and decreased conscious level), and coagulation sequelae such thromboembolism and disseminated intravascular coagulation.71 Studies have demonstrated a mortality of between 10–30%, with those patients with pre-morbid memory impairment or physical illness carrying the highest risk.70 72 The diagnosis is made via a compatible presentation and medication history, supported by biochemical tests (table 2).

Early supportive treatment with intravenous fluids and external body cooling are essential for good recovery.73 Specific treatment involves dopaminergic replacement. Levodopa may be taken orally or nasogastrically, and should be given at the patient's previous dose. In cases where the syndrome has been precipitated by an intentional reduction in medication, the patient should be given the dose before this reduction. Parenteral apomorphine may also be used, initially as periodic subcutaneous injections and if necessary as an infusion.70 73 Recent years have also seen the development of transdermally delivered dopamine agonists. As well as being of potential use as a treatment for NMLS, these also offer an alternative to avoid disruption of PD medication delivery, thus potentially avoiding the complication.

Serotonin syndrome

Serotonin syndrome is an iatrogenic condition caused by the hyperstimulation of 5-hydroxytryptamine (5-HT) receptors. Similarly to NMLS, the condition is rare but potentially fatal.74 Also consistent with NMLS, there is a clear risk of the syndrome being under diagnosed due to a lack of familiarity and its potential to mimic other conditions. The hyperserotonergic state can be triggered by the co-administration of therapeutic doses of MAOIs, selective serotonin reuptake inhibitors (SSRIs), and opiates.75–79 MAOI inhibitors used in PD include selegiline and rasagiline, while many patients with PD also suffer co-existent depression and are therefore often prescribed SSRIs.80 81 The potential for drug interaction is further propagated by the common use of opiates in clinical practice. In view of these issues, patients with PD are at increased risk of developing serotonin syndrome.

Although several symptoms are similar to NMLS, onset in <24 h, myoclonus, hypereflexia, diarrhoea, and mydriasis are characteristic signs of serotonin syndrome not typical of NMLS (table 2).70 74 Biochemical tests are similar to NMLS. The mortality rate of serotonin syndrome is difficult to determine accurately, largely due to difficulties in diagnosis and the fact that patients may have varying comorbidities. However, an accepted figure lies between 10–15%.82

Diagnosis hinges upon a compatible history, clinical presentation, and laboratory tests (table 2). A recognised approach to the diagnosis of serotonin syndrome is the Hunter Serotonin Toxicity Criteria.83 These yield a sensitivity of 97% and specificity of 84% (figure 2).

Figure 2

Diagnosis of serotonin syndrome.59 MAOI, monoamine oxidase inhibitors; SSRI, selective serotonin reuptake inhibitor.

It is important to exclude mimics of the syndrome such as metabolic, infectious, and neurological conditions.

Treatment

Appropriate supportive care and discontinuation of serotonergic medications form the cornerstone of treatment, superseding the need for specific pharmacotherapy. Supportive care includes passive and active cooling, sedation, airway management, fluid balance titration, and muscle paralysis.84

Many cases improve with the discontinuation of precipitating medications combined with supportive treatment. Benzodiazepines may also be used to ease agitation.85 There is also evidence for the use of chlorpromazine, and the antihistamine and serotonin antagonist cyproheptadine.82 86 While chlorpromazine has been used in the treatment of serotonin syndrome, the authors would not recommend its use in this scenario due to its adverse impact on PD control. Most cases improve within 24 h; however those patients who develop multiorgan failure carry a higher morbidity.

Discussion

The ageing population, combined with the higher prevalence of PD in the elderly, ensure that acute presentations of the disease are likely to be seen more commonly over the coming years. This may frequently occur to specialties unfamiliar with PD, necessitating a wider appreciation of these issues. The accurate and timely assessment of patients, coupled with appropriate treatment, is essential in limiting morbidity and mortality.

Patients living with PD often suffer multiple comorbidities, where a deterioration in PD or health in general may precipitate a decline in the other. Therefore, it is important to ensure that any patient evaluation is thorough in its search for alternative explanations of a patient's condition, or indeed any other precipitants of the acute parkinsonian syndrome. There are also rare but potentially serious complications associated with PD which may mimic other conditions, notably NMLS and the serotonin syndrome.

These acute presentations require specific therapies targeted at treating the underlying disorder and managing complications. While it is important for non-specialists to be able to identify these issues promptly, their management is complex and should involve clinicians familiar with PD and its treatments.

Main messages

  • Patients with Parkinson's disease (PD) frequently present acutely to hospital.

  • Presentations not related to the illness may still cause a deterioration in PD control.

  • Stopping patients' PD medications abruptly should be avoided and where necessary alternative routes of delivery should be sought.

  • Clinicians admitting patients with PD should have a low threshold to involve a PD specialist.

  • While a feverish illness in a patient with PD is most likely secondary to infection, it is important to consider other parkinsonian acute conditions such as neuroleptic malignant-like syndrome (NMLS) and the serotonin syndrome.

Current research questions

  • Will the advent of newer medications aimed at continuous dopaminergic stimulation reduce the risk of developing dyskinesia and other complications?

  • What is the optimum medication regimen in those diagnosed early with PD to minimalise later complications?

Key references

▶ Katzenschlager R, Hughes A, Evans A, et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges. Mov Disord 2005;20:151–7.

▶ Quinn N, Marsden CD, Parkes JD. Complicated response fluctuations in Parkinson's disease: response to intravenous infusion of levodopa. Lancet 1982;2:412–15.

▶ Parkinson's Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med 1999;340:757–63.

▶ Keyser DL, Rodnitzky RL. Neuroleptic malignant syndrome in parkinson's disease after withdrawal or alteration of dopaminergic therapy. Arch Intern Med 1991;151:794–6.

▶ Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100–9.

Self assessment questions (True/False; answers after the references)

  1. Current opinion suggests that the pulsatile delivery of pharmacological levodopa is a major factor in the development of dyskinesia in patients with PD.

  2. Neuroleptic medications should be initiated early in the treatment of psychosis in PD.

  3. Patients unable to take oral dopaminergic medications may be given transdermal or subcutaneous alternatives.

  4. Dysphagia and hypersalivation are classical symptoms of the serotonin syndrome and help differentiate it from neuroleptic malignant syndrome.

  5. Patients presenting with bronchopneumonia who suffer with PD should be screened for aspiration.

Answers

  1. True

  2. False

  3. True

  4. False

  5. True

References

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Footnotes

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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