Identifying and Managing Drug Induced Parkinsonism: The Role of Neuroscience Nurses

Parkinsonism is an umbrella term for a clinical syndrome of bradykinesia (slowed irregular movements) with at least one of the following: muscle rigidity (stiffness), tremor and postural instability (balance problems) (Hughes, Daniel, Kilford, & Lees, 1992; Postuma et al., 2015). There are many different causes of parkinsonism and the most common is Parkinson’s disease, which affects about 1-5% of adults over 60; incidence increases with age but about 20% of people diagnosed with Parkinson’s are under 50 (Draoui, El Hiba, Aimrane, El Khiat, & Gamrani, 2020; Kowal, Dall, Chakrabarti, Storm, & Jain, 2013; Reeve, Simcox, & Turnbull, 2014).

It is a degenerative, progressive brain disorder whereby dopaminergic neurons projecting from the substantia nigra in the brainstem gradually die off and this leads to a pre-synaptic reduction of dopamine release in the striatum. In contrast, drug induced parkinsonism (DIP) occurs when dopamine receptor blocking agents, such as antipsychotic (neuroleptic) and antiemetic drugs, bind to post-synaptic receptors in the striatum and thus stop dopamine having a stimulating effect; see Figure 1. It is generally reversible once the offending drug is withdrawn.

Figure 1:

DIP is the second leading cause of parkinsonism (Rissardo & Caprara, 2023), accounting for about 11.9% of all cases with an estimated prevalence of 3.3 per 100,000 person years (Martí-Massó & Poza, 1998; Savica et al., 2017). However, DIP is under-recognised so calculations of prevalence are likely to be an underestimate of the true numbers (Undeberg, McKeirnan, & Easley, 2022). The similarity of its clinical phenotype with Parkinson’s disease results in common misdiagnosis with an estimated 6.8% of individuals initially diagnosed with Parkinson’s disease later diagnosed as having DIP (Mukilan, Praveen, Chowdary, & Aanandhi, 2018). High rates of misdiagnosis and similar presentations have resulted in a rise in the number of individuals with DIP presenting to movement disorder clinics, neuroscience wards and community-based services (Esper & Factor, 2008; Gershanik, 1994; Shin & Chung, 2012).

Neuroleptic drugs, which are also called anti-psychosis drugs, are the most common class of medication associated with DIP (de Germay, Montastruc, Carvajal, Lapeyre-Mestre, & Montastruc, 2020). Once limited to the mental health setting, specifically for schizophrenia and other causes of psychosis, the prescription of neuroleptics are now being increasingly indicated for a much wider range of conditions including depression, anxiety, insomnia, and post-traumatic stress disorder (Gallagher & Bouchard, 2023; Rogers, Hartigan, & Sanders, 2021). Neuroleptic drugs have a multitude of pharmacological actions but generally they all block dopamine receptors. As an estimated 15-60% of individuals on long-term neuroleptics will potentially develop DIP symptoms (Mukilan et al., 2018) this often associated with medication or dosage changes, it is vital that neuroscience nurses remain abreast of current research enabling them to provide appropriate and personalised care for those with parkinsonism. DIP sits in limbo between neurology and psychiatry, and it is this crossover of specialities that makes the diagnosis, management, and personalisation of DIP care particularly challenging. Furthermore, DIP is just one presentation in a range of neuroleptic induced movement disorders that include dystonia, akathisia, catatonia, neuroleptic malignant syndrome and tardive dyskinesia (Caroff et al., 2018); noting that aspects of these movement disorders may also occur in conjunction with DIP. It is imperative that all individuals presenting with new parkinsonism are assessed for DIP, given its high burden related not only to diagnostic workups, potential hospitalisations and healthcare expenditures, but also the personal costs including lost workdays, complications such as falls and poor quality of life (Pitton Rissardo & Caprara, 2023).

Neuroscience nurses play a pivotal role in improving health outcomes for those with parkinsonism. It is important that they know how to provide personalised care for individuals with DIP and lower the risk of complications. The purpose of this article is to provide information to neuroscience nurses about causative drugs and risk factors for DIP.

It also aims to highlight typical clinical characteristics and useful features that help distinguish DIP from Parkinson’s disease. Finally, this review will summarise investigations and discuss care and management.

The pharmaceutical mechanisms resulting in DIP are varied, but most causative drugs result in blockade of Dopamine D2 receptors in the striatum (Burkhard, 2014; López-Sendón, Mena, & G de Yébenes, 2013; Mukilan et al., 2018). The striatum is a cluster of interconnected nuclei that form a part of the basal ganglia and are critical in the control of motor, reward, and executive function (Bamford & Bamford, 2019). The propensity for a drug to cause DIP is related to its occupancy of D2 receptors (Hirose, 2006). Figure 1 is a schematic diagram of dopaminergic neurons in the striatum. The diagram illustrates the release and binding of dopamine in a healthy state compared to the differing pathophysiology in Parkinson’s disease and DIP. In Parkinson’s disease there is pre-synaptic degeneration and associated lack of dopamine, this compared to DIP where the post synaptic D2 receptors are blocked by the offending drug.

The pre-synaptic neurons project from the substantia nigra to the striatum and release dopamine into the synaptic cleft. In the healthy state, dopamine binds to post-synaptic dopamine (D) receptors and this stimulates the post-synaptic neuron. In Parkinson’s disease, there is a lack of dopamine due to pre-synaptic degeneration. In drug-induced parkinsonism, the offending drug typically blocks the post-synaptic D2 receptors, and this blocks the action of dopamine, which leads to less post-synaptic stimulation.

First-generation antipsychotic medications such as Chlorpromazine strongly block the receptors and are frequently associated with DIP (Burkhard, 2014; Pandey et al., 2023) whereas second generation, or so-called ‘atypical’ antipsychotics including Olanzapine and Risperidone have a lesser risk due to their lower affinity for D2 receptors (Druschky et al., 2020). Nevertheless up to 20% of individuals receiving long term treatment with atypical antipsychotics will develop DIP and, generally the higher the dose of any dopamine-receptor blocking drug, the higher the risk of DIP (Diaz-Martinez et al., 1998; Shin & Chung, 2012).

Not all drugs that cause DIP are directly related to D2 blockade though. For example Lithium Carbonate, which is increasingly common within the neuroscience setting, as it is used for the prevention of cluster headaches and augmentation of antidepressants (López-Sendón, Mena, & G de Yébenes, 2013), is thought to act by decreasing dopamine levels in the striatum or through increased cholinergic activity (Holroyd & Smith, 1995). Although Lithium Carbonate has an indirect dopamine effect, it has a high risk for potentiation and polypharmacy resulting in DIP (Beaulieu & Caron, 2008; Fountoulakis, Tohen, & Zarate Jr, 2022). Other drugs associated with DIP are outlined in Table 1 and include anti-emetics, antiepileptic drugs, antiarrhythmics, antidepressants, and many other compounds including recreational drugs (Burkhard, 2014; Gallagher & Bouchard, 2023; López-Sendón et al., 2013; Pandey et al., 2023).

The presenting symptoms and signs of DIP are variable, with an extrapyramidal syndrome of slowness and muscle stiffness the key consistent factors. A range of early clinical features include akinesia (freezing), bradykinesia (slowness and irregular rhythm of movements), postural instability, reduced facial expression and blink frequency, tremor, amimia (inability to express ideas by means of gestures or signs) and loss of arm swing when walking (Kumsa, Agenagnew, Alemu, & Girma, 2020; López-Sendón, Mena, & G de Yébenes, 2013). The neurological deficits that individuals experience can be distressing and significant enough to impact activities of daily life (Mukilan, Praveen, Chowdary, & Aanandhi, 2018) such as walking, driving, undertaking usual daily activities and living independently.

Whilst the motor symptoms of DIP and Parkinson’s disease may be similar, there are some features that may help differentiate the two.

For example, DIP more frequently presents with a symmetrical motor impairment whereas in Parkinson’s disease there is usually one side of the body more affected that the other (see Table 2).

Further, Parkinson’s disease is more likely to have a rest tremor in just one hand, whereas DIP often has no tremor or a postural symmetrical tremor (Mena & De Yébenes, 2006). Unlike Parkinson’s disease, where the onset of symptoms are typically slow and insidious, developing over months or years, the onset of DIP is fairly rapid and usually within days or weeks of starting a new medication, combining a new medication with an existing one, or following a dose increase (Ali, Sisay, Tariku, Mekuria, & Desalew, 2021; Blanchet & Kivenko, 2016; Kumsa et al., 2020; Undeberg, McKeirnan, & Easley, 2022).

It is useful for neuroscience nurses to be familiar with the risk factors for DIP so they can be particularly alert to identifying people at higher risk. Established risk factors for developing DIP include dose potency, duration of treatment, polypharmacy and pre-existing extrapyramidal symptoms (López-Sendón, Mena, & de Yébenes, 2012). The roles of demographic risk factors are less certain. For example older age has been identified in the literature as a risk for developing DIP but it is unclear if this may be due to the offending drug ‘un-masking’ subclinical Parkinson’s disease (Moleman et al., 1986). In contrast, other authors argue that younger individuals are at higher risk of DIP (Kasten et al., 2011). For example, Savica et al. (2017) reported that DIP accounted for 73% of parkinsonism presentations in adults aged less than 20 years in their cohort. Other potential risk factors include females which may be due to suppression of dopamine receptors by estrogen (Gordon, Gorski, Borison, & Diamond, 1980) although more recent data suggests males to be a risk (de Germay, Montastruc, Carvajal, Lapeyre-Mestre, & Montastruc, 2020). There may also be a familial and genetic predisposition (Kasten et al., 2011; Rissardo & Caprara, 2023).

The diagnosis of DIP is based on history, examination and a review of medications (Factor, 2004). Standard imaging and pathology examinations are usually unremarkable. In terms of history, the clinician will specifically ask about typical positive features of DIP such as sudden onset or rapid onset of parkinsonism, symmetry of symptoms/signs and how the symptoms relate to the timing of new medications and dose escalation. They will also seek evidence of historical features that may suggest another cause of parkinsonism such as, for example, REM sleep behaviour disorder and a decreased sense of small (hyposmia), that typically begin years before the motor signs in Parkinson’s disease, or visual hallucinations and urinary incontinence that may occur with another parkinsonian conditions such as Dementia with Lewy Bodies (DLB).

The clinician will examine carefully for clinical signs of DIP such as symmetry of extrapyramidal signs; they will look for evidence of bradykinesia, which is often examined through repetitive finger taps, foot taps and gait – and manifests as slow irregular and small movements. Copying of spiral drawings and handwriting provides a useful record of bradykinesia and tremor, that may aid monitoring of improvement over time (Alty, Cosgrove, Thorpe, & Kempster, 2017). The face may have less expression, the voice may be soft and quiet and there may be reduced blink frequency, but these are signs of bradykinesia in general and do not discriminate DIP from PD. They will also examine for muscle rigidity, which is examined by gently moving the limbs, head and trunk whilst assessing tone, again looking to see if this is symmetrical (more common in DIP) or asymmetric (more common in Parkinson’s). Tremor is less commonly seen in DIP and when it does occur, tends to be a symmetric ‘postural’ tremor that is worse when the hands are held outstretched, or when performing an action. The clinician will also perform a careful neurological examination, looking for other rarer causes of parkinsonism such as abnormal eye movements seen in Progressive Supranuclear Palsy (PSP), cerebellar signs seen in Multiple System Atrophy (MSA), and cortical sensory loss and myoclonus seen in corticobasal syndrome (CBS). Any ‘red flags’ such as an abnormal sensory exam, abnormal eye movements or autonomic dysfunction would alert the clinician to look harder for a secondary diagnosis as DIP would not entirely explain these findings (recognising that it is possible to have DIP and a second neurological diagnosis); see Table 3.

Vascular parkinsonism deserves a special mention as this condition can present almost identically to DIP and may occur concurrently. It is caused by a combination of small vessel disease and small strokes that disrupt the fronto-striatal pathways. It typically presents with a symmetrical parkinsonism, that may be of sudden/rapid onset, but may be differentiated from DIP in that it tends to cause “lower half parkinsonism”; this manifest as gait being disproportionately impaired with small, slowed steps which have been termed “magnetic gait” or “walk of the little steps” (‘marche a petit pas’) whereas the upper limbs and face may appear relatively unaffected (Korczyn, 2015). Individuals with vascular parkinsonism may also have other frontal lobe motor and cognitive features such as impaired executive cognitive function and primitive reflexes such as a palmarmental reflex or grasp reflex (Benítez-Rivero et al., 2014).

A prompt diagnosis is imperative as a delayed diagnosis is associated with ineffective treatment and reduced quality of life (Pitton Rissardo & Caprara, 2023). The gold standard for diagnosing DIP is to cease the offending agent and to monitor the individual for improvements and a reversal of symptoms (Lim et al., 2013). However, there is a lack of consensus regarding the duration of recovery post the cessation of a potentially causative drug. The remittance period, to allow motor symptoms to recover, is estimated to be within days to weeks. However an estimated 30% of individuals may continue to show persisting symptoms beyond this time (Blanchet & Kivenko, 2016; López-Sendón, Mena, & de Yébenes, 2012) ; see Case Study box . The reversal of symptoms may be further complicated by an individual’s clinical dependence on a medication, and it is often a balancing act between alleviating symptoms of DIP and managing the underlying condition, particularly in the setting of chronic severe mental health diagnoses where the interruption of treatment is not generally advisable unless under direct medical supervision in an inpatient setting (Galoppin et al., 2020).

It is important to accurately diagnose DIP as it is usually completely reversible once the causative medication is removed. It is clinically recommended that any new parkinsonism presentation be assessed for potential pharmaceutical causes, this necessitating a complete medication evaluation of all individuals presenting with suspected parkinsonism symptoms. (DeMaagd & Philip, 2015). It is estimated that DIP represents 3-12% of all parkinsonism presentations within the neuroscience setting (Alves et al., 2009; Martí-Massó & Poza, 1998; Meara, Bhowmick, & Hobson, 1999; Savica et al., 2017). Of these presentations, the rates of initial misdiagnosis for DIP are estimated to be as high as 40-75%, with the time to diagnosis averaging 1.8 years (Esper & Factor, 2008a; Friedman, Fernandez, & Trieschmann, 2004; Hansen, Brown, Weigel, & Casey, 1992; Stephen & Williamson, 1984). Contributing to these high rates of misdiagnosis is a wide variation in individual susceptibility and initial presentation. When the diagnosis is uncertain, and the symptoms could be indicative of Parkinson’s disease, (Kaegi, Bhatia, & Tolosa, 2010) the use of dopamine transporter imaging such as DaT Scans (see Figure 2 example) may aid differentiation of DIP from degenerative causes of parkinsonism (Rissardo & Caprara, 2023). In degenerative parkinsonism, these scans show a reduction in the presynaptic striatal terminals but in DIP these scans are normal. However, it is important to note that these imaging modalities are not specific for PD and will also be abnormal in other neurodegenerative disorders such as PSP, MSA, CBS and DLB. This imaging technology is an effective means to support an accurate diagnosis. However, it remains unattainable for most due to high costs, lack of availability (with most imaging technology located in larger cities) and it is also invasive, requiring the injection of a radionuclide.

Figure 2.

In all presentations that do not resolve, a differential diagnosis needs to be considered. It is possible that DIP may occur together with a second diagnosis, especially vascular parkinsonism, and Parkinson’s disease, and that withdrawing the offending drug will thus only relieve part of the clinical features. Table. 4 outlines the potential differential diagnoses for DIP.

Treatment of DIP should be individualised and consider varied vulnerabilities and medication priorities as well as the impact on activities of daily living and quality of life. The primary treatment of DIP specifically focuses on prevention, avoidance and the cessation of the offending drugs (Powell, Gallur, Koopowitz, & Hayes, 2020). Neuroscience nurses are critical and play a key role in promoting health, managing complications, and assisting individuals to adapt to the limitations of their disease (Chen, Lu, Jiang, & Huang, 2021).

The avoidance of causative drugs, or substitution with drugs that have a safer profile, is not always tenable as individuals may be clinically dependent on medications, and there is often a delicate balance between ameliorating parkinsonism symptoms and avoiding relapse of the underlying conditions such as depression or schizophrenia. Ultimately an individual may advocate for the continued prescription of the potential causative agent due to the underlying severity and refractory nature of their illness. In this case individual wishes need to be respected, however ongoing monitoring and counselling should occur (Undeberg, McKeirnan, & Easley, 2022), noting that some individuals may not be forthcoming with details related to their symptoms in fear of their medication regime changing.

It is imperative that potentially causative medications are reviewed and discontinued where possible, as outcome is dependent on drug exposure and early discontinuation is associated with more positive outcomes (Anand et al., 2023) than a delayed reduction or cessation of the drug (Rissardo & Caprara, 2023). Regular reviews of medication profiles should also occur with potentially causative agents flagged for potential discontinuation or change to an alternative agent as new therapies become available (Undeberg et al., 2022). Once a causative agent is discontinued, parkinsonism symptoms usually resolve within six months (Brigo, Erro, Marangi, Bhatia, & Tinazzi, 2014; Tachibana et al., 2020).

Pharmacological approaches to DIP commonly involve the use of centrally acting anti-cholinergic agents such as Benztropine or Amantadine that are used to improve rigidity (Friedman, 2014). Despite the longstanding history of anticholinergic use in the treatment of DIP, there is a lack of data to support their effectiveness and treatment decisions needs to be on an individual basis (Ahlenius & Ericson, 2001). In the setting of refractory DIP there is anecdotal evidence that electroconvulsive therapy can temporarily ameliorate parkinsonism and may also aid in the treatment of psychosis and depression (Baez & Avery, 2011; Faber & Trimble, 1991). The use of Levodopa generally produces a limited response in DIP due to striatal D2 receptor blockage (Burkhard, 2014; López-Sendón, Mena, & de Yébenes, 2012).

Psychological support is imperative as individuals are often vulnerable due to pre-existing mental illness and traumatised by the rapid onset of motor symptoms. A multidisciplinary team approach is intuitive for personalised care and neuroscience nurses fulfill several vital roles including the enabling of an integrated flow of care (Prell et al., 2020; Radder et al., 2019). The key components of any care model is that it is holistic, interdisciplinary, integrated, patient centred and personalised (van Munster et al., 2022).

This paper addresses knowledge gaps and aids neuroscience nurses in the timely identification of DIP, its treatment and care. This requires knowledge of possible offending drugs and the signs and symptoms of both DIP and Parkinson’s disease. Neuroscience nurses have a duty to remain vigilant to the possibility of DIP and to have the skills to manage it appropriately when present. Nurses can work with individuals throughout the course of their illness. The prevalence of DIP is increasing and despite this it is a frequently overlooked and a neglected topic.