From the Department of Neurology, Oregon Health & Science University, Portland, OR.

Abstract

• Objective: To review the clinical characteristics, epidemiology, and management of the most common neuropsychiatric symptoms (NPS) in Parkinson’s disease (PD).
• Methods: Literature review.
• Results: PD has traditionally been considered a disease of impaired motor function. However, neuropsychiatric complications, such as fatigue, depression, anxiety, psychosis, impulse control disorders, and apathy, frequently complicate the course of the illness. Although the development of new medication options in recent years has had a positive benefit on the management of these troublesome symptoms, responses are frequently suboptimal. The development of valid instruments to measure neuropsychiatric symptoms has been vital in research efforts to bridge the gaps in our understanding. Further elucidation of neuropsychiatric pathophysiologies will help to define treatment targets and has the potential to expand our therapeutic armamentarium.
• Conclusion: While NPS affect patients with established disease, recent investigations have demonstrated risk of symptoms in those with early untreated stages of PD; therefore, better understanding of NPS should be the goal of practitioners treating the entire continuum of PD.

Parkinson’s disease (PD) has traditionally been considered a disease of impaired motor function, but increased recognition of nonmotor symptoms and in particular neuropsychiatric symptoms, such as fatigue, depression, anxiety, psychosis, impulse control disorders, and apathy, offer new opportunities for better care of patients. While neuropsychiatric symptoms affect patients with established disease, recent investigations have clearly demonstrated risk of symptoms in those with early untreated stages of PD; therefore, better understanding of neuropsychiatric symptoms should be the goal of practitioners treating the entire continuum of PD. This review will focus on the clinical characteristics, epidemiology, and management of the most common neuropsychiatric symptoms in PD.

Impulse Control Disorders

The recognition that dopaminergic drugs were successful at treating many symptoms of PD was followed by the disturbing realization that impulse control disorders could be an unfortunate side effect in a substantial minority. Impulse control disorders as defined by DSM-IV [1] are disinhibited behaviors that are maladaptive and recurrent, causing personal and relationship consequences. The impulse control disorders that became associated with PD and medication intake, particularly dopamine agonist use, included gambling, hobbyism, punding (stereotyped, seemingly purposeless behaviors), excessive sexual behavior, shopping, hoarding, and less commonly, compulsive eating. The prevalence estimates of these behavioral disturbances range from 6% to 15.5%, compared with < 2% in the general population [2,3]. The addiction-like dopamine dysregulation syndrome, whereby patients self-medicate with high doses of levodopa and short-acting dopamine agonists beyond what is needed for motor control, can lead to significant impairment of the therapeutic alliance in addition to other patient personal relations. With the advent of surgical options to treat PD and its medication complications, it was observed that stimulation of the subthalamic nucleus could be associated with the spectrum of impulse control disorders [4].

Epidemiology/Risk Factors

In a recent systematic review of the literature of impulse control disorders in PD [5], the authors determined that dopaminergic therapy caused compulsive or impulsive behaviors in approximately 10% of PD patients in the course of their treatment, with pathologic gambling and hypersexuality most frequently experienced. Multiple impulse control disorders are not uncommon and may coexist in one-quarter of patients with compulsivity. There appeared to be more disordered behavior with higher comparable doses of agonists. The authors concluded that impulse control disorder symptoms tended to occur with initiation or dose increases of direct D₂/D₃ agonists, such as pramipexole and ropinirole. Importantly, impulse control disorder behavior improved if not resolved with discontinuation or reduction of dosage of the agonist, even if a compensatory levodopa dosage is added or increased. Perhaps not surprisingly, it was observed that if patients had a preexisting impulse control disorder prior to PD or the initiation of treatment, there was a high likelihood of worsening of symptoms. This small subgroup is estimated at about 1% of PD subjects, which corresponds to the prevalence of impulse control disorders in the general population. Other identified potential risk factors for impulse control disorder development include male gender, young age at onset, a personal or family history of addiction, novelty or risk seeking personality, and a concurrent diagnosis of depression [3]. In a recent study of early PD patients, the risk of developing an impulse control disorder became important once treatment with dopaminergic drugs began and continued for a year or more [6].

Pathogenesis

The pathogenesis is not fully understood, however, mesolimbic dopamine alterations are strongly suspected. It has been long speculated that the high doses of dopamine needed to replete the relatively depleted dorsal striatum overdose the “intact” ventral striatum and cause this neuropsychiatric disorder [7–9]. The additional cognitive impairments in PD, which can include problems with attention, working memory, planning, forethought and decision-making, are faculties that can markedly increase susceptibility to impulse control disorder [8].

The role of serotonin deficiency in the PD brain and its part in inhibiting the patient’s ability to delay rewards adds to the complexity of impulse control disorder pathogenesis. Dorsal raphe nuclei disease in PD results in loss of serotonin innervation to substantial portions of the prefrontal and motor cortices in addition to basal ganglia substructures like the striatum, pallidum and subthalamic nucleus [10]. Together with dopamine, serotonin may work to regulate risk-sensitive decision making, response inhibition, waiting for future rewards, and overall impulse control. Its relative loss therefore also likely contributes to tipping the balance towards impulse dyscontrol [11,12]. The role of other neurotransmitters such as opiate systems involved in the process of acquisition and maintenance of addictive behaviors like dopamine dysregulation syndrome remains to be fully understood.

Treatment

The most successful strategy to address this problem is to reduce or eliminate the offending medication, usually the dopamine agonist. This may be associated with worsening apathy, anxiety or depression; however, substituting levodopa can be a successful strategy in many cases [13]. Zonisamide was described to be possibly effective in a trial of 15 subjects; however, the open label nature of this evidence must be considered as with other case reports using valproate, donepezil, and selective serotonin reuptake inhibitors (SSRIs) [14–16].

Fatigue

An easy to understand operational definition of fatigue is that it is a state of extreme tiredness, weakness, or exhaustion, either physical or mental or both. Fatigue is not uncommon in the general population [17] but is increasingly recognized to occur in numerous disease conditions and is frequently encountered in PD and multiple sclerosis. The latter is of special significance in the consideration of the neurotransmission of fatigue, as it is not thought to be a disease of dopamine deficiency. The pathophysiology remains unclear, and it may differ depending on whether the fatigue is experienced as more physical or mental, or rather motor versus nonmotor as some authors propose.

Fatigue has been conceptualized as central or peripheral in character. Peripheral fatigue is best understood as muscular fatigue caused by repetitive muscular contraction or reduced force generation [18]. Central fatigue however, is divided into mental or physical fatigue. Mental fatigue can occur after sustained attentive or emotional activity. It may alternatively be provoked after boring repetitive tasks or lack of intellectually stimulating activity. Physical fatigue is the sense of body exhaustion or energy to perform physical tasks even though the ability to carry them out exists.

Epidemiology

As recognition of the problem of fatigue increased in the last 2 decades, the realization that one-third to one-half of patients experience it at some point has improved opportunities for recognition and treatment [19]. Fatigue may be the presenting symptom in one-third of patients prior to actual motor symptom onset [20]. Half of untreated PD patients in a biomarker cohort study reported fatigue [6]. Unfortunately, it is also described by patients as one of the most disabling symptoms, causing significant impact on quality of life [19]. Fatigue in PD is associated with higher rates of depressive symptoms, but occurs with higher prevalence in nondepressed patients [21]. Poor ability to initiate and sustain activity due to fatigue is different from depression, excessive sleepiness, or impaired motor function [22,23].

Pathophysiology

The pathophysiology of fatigue remains somewhat unclear, though physical fatigue is likely a significant part of the problem and related to dopamine deficiency based on studies of time and force generation of keyboard strikes in PD subjects before and after L-dopa administration. These subjects had declines in force and increased physical fatigue which improved after L-dopa [24]. In other studies using transcranial magnetic stimulation to study changes in cortical excitability, the degree of physical fatigue correlated with abnormalities in motor evoked potentials during fatiguing exercising. These studies also support the hypothesis that fatigue is a motor symptom [25,26]. In the ELLDOPA study, fatigue worsened more in PD subjects treated with placebo [27]. Other imaging studies have suggested suggested nondopaminergic mechanisms including serotonergic pathway abnormalities [28], thus the question behind the etiology and solution for all cases of fatigue remains to be settled.

Diagnosis

The diagnosis is fatigue may be challenging as it may mask as depression or apathy. There are a number of fatigue rating scales available; however, the validated Parkinson’s Fatigue Scale (PFS) supersedes many of the problems of using a generic scale which could overlap motor questions and potentially be confounding [29,30].

Treatment

Most important is awareness and vigilance for the symptoms of fatigue, depression, and apathy and effort to distinguish between them. It may require structured interviews or assessment tools to properly diagnose the problem. Treatment is less clear in that few studies have clearly indicated the best treatment options. In placebo-controlled trials, methylphenidate did improve fatigue as did levodopa [31]. Modafinil, a hypocretin modulator and a drug first approved by the FDA for treatment of narcolepsy, has demonstrated mixed results in recent years. It may reduce physical fatigue and reduce excessive daytime sleepiness but likely does not reduce subjective symptoms of fatigue [32]. L-dopa can significantly reduce fatigue in many patients, which would argue that it often is a motor symptom [33,24]. In a post-hoc analysis of the ADAGIO delayed start study, patients taking rasagiline 1 mg/day and 2 mg/day (the latter dose exceeds the usual clinical dosing) showed significantly less worsening of symptoms on the PFS compared to placebo over time [34]. It is important to realize that once motor symptoms are optimally treated with dopaminergic medications, while many patients will feel significant relief from fatigue some patients will continue to feel symptomatic.

Apathy

The definition of apathy has become more complicated and refined, incorporating findings from the study of brain disease and behavioral analysis. Marin’s classic elaboration of apathy as lack of motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress has been built upon by Levy and Dubois [35–37]. They suggest apathy may be better thought of as an observable behavioral syndrome characterized by a quantitative reduction of self-generated voluntary and purposeful behaviors. They suggest 3 apathetic subtypes: emotional, cognitive, and auto-activational, which reflect different disease states accounting for failure of normal goal-directed behavior.

Epidemiology

Prevalence estimates for apathy in PD vary. This is likely due to the varying recruitment criteria among studies, with some including patients with comorbid depression and dementia and others containing only “pure apathy.” Other reports may have had referral bias issues, as community-based studies report lower prevalences in general. In a group of newly diagnosed PD patients, using more restrictive criteria (apathy subscale of the neuropsychiatric inventory and the diagnostic consensus criteria for apathy validated in PD), Pedersen reported a prevalence of apathy of 14.3% [38]. In a 4-year prospective longitudinal cohort study, an annual incidence rate of 12.3% was reported, with apathy developing in 60% of the cohort by the study’s conclusion [39].

Apathy has been associated with longer disease duration, male gender [40], higher daily levodopa doses [41], more severe parkinsonism [38], and lower education status, though the latter feature remains under debate. Early cognitive deficits appear to be a risk factor for development of apathy [42]. The patterns of cognitive dysfunction and apathy remain unsettled in the literature.

Pathology

The pathology of atrophy remains unexplained and is unlikely to be reduced to a simple atrophy of one nucleus or the tone of one circuit. However, in a small neuroimaging study, severity of apathy correlated with atrophy of the bilateral nucleus accumbens [43], and it is notable that one major input to the nucleus accumbens is the amygdala. According to Braak staging, by stage 4 significant involvement of the amygdala by Lewy bodies has occurred. Others have found changes in grey matter density that could correlate with deficits of the prefrontal-basal ganglia circuitry to produce dysfunction of segregated frontal-subcortical loops. These may correlate with the “autoactivation” deficit pattern of apathy in which patients have a lack of self-initiated actions, even thoughts, though appear more normal when giving externally prompted responses [37,44].

Assessment

Clinically, the relationship between apathy and depression can be hard to disentangle, especially since many studies have found an association between them, especially with regards to apathy and anhedonia. Depression may feature negative self thoughts and sadness while apathy is notable for lack of initiation and effort. Viewed over a longer period of time, apathy tended to worsen in a linear fashion, where depression tended to fluctuate with improvements and exacerbations.

The Movement Disorders Society task force has recommended the Lille Apathy Rating Scale (LARS) for assessment of apathy; English and French versions have been validated in PD patients. It uses a semi-structured interview format assessing 4 dimensions of apathy: self awareness, intellectual curiosity, emotion, and action initiation [45–47].

The impact of apathy cannot be underestimated as this poor show of motivation or effort leads to lack of engagement in old activities or interest in new ones. Spouses may misinterpret this change in behavior as laziness or deliberate social withdrawal, or perhaps entitlement. It is not surprising that apathy routinely shows up on quality of life (QoL) questionnaires as highly impacting patients and families. In one study, apathy was the nonmotor symptom most likely to cause caregiver distress in PD [40,48–50].

Treatment

No approved drugs exist for treatment of apathy. However, clinical experience often confirms that dopaminergic modulation can be helpful in the treatment of apathy as indirect evidence suggests. A meta-analysis of controlled trials using pramipexole and Part I of the Unified Parkinson's disease rating scale (UPDRS) (secondary measure) showed the medication improved scores on this measure of motivation and mood in non-depressed subjects [51] with PD. Rare patients undergoing subthalamic deep brain stimulation have been reported to experience new and sometimes severe apathy after surgery [52]. This was posited at least in part to be the result of reduction of dopaminergic medication due to surgery.

Nondopaminergic pharmacotherapy of apathy is in its infancy. A recent controlled trial of rivastigmine in 31 French subjects with moderate to severe apathy based on LARS showed that 6 months of treatment at 9.5 mg/day improved average scores from –11.5 to –20 compared with placebo. While quality of life did not improve, caregiver burden did. The investigators found in this group of subjects that apathy was a possible herald for early dementia in PD [53].

A post-hoc analysis of the ADAGIO study (rasagiline or placebo in PD patients taking antidepressants) found that rasagiline use was associated with a nonsignificant slowing of apathy development during the trial [54].

Psychosis

Psychotic symptoms are a common occurrence in drug-treated patients, with visual hallucinations occurring in up to 30%, though over a 20-year period up to three-quarters of patients may develop visual hallucinations.After visual, the most common type of hallucination is auditory, followed by the other affected senses such as tactile, olfactory, or even taste [57]. Delusions, which tend to be paranoid in nature, occur in about 5% of patients [55–57]. The presence of psychotic symptoms is associated with poorer quality of life [58].

Symptomatology

The visual hallucinations of PD are usually quite stereotyped, and have been described as “minor” and “non-minor”[59]. Minor hallucinations refer to transient peripheral field stimuli that disappear when brought into central focus, “something flashed by,” a sense of a living being nearby, “a presence in the room,” or illusions whereby objects are transformed, eg, a bush in the yard is a deer.

Auditory hallucinations tend to be vague or indistinct sounds, like music in another room as opposed to voices speaking directly to the patient as might be experienced in a primary psychotic disorder. Tactile forms often involve insects or other animals crawling on the skin. Olfactory hallucinations may take the form of smelling perfume, toxic odors from room vents, etc.

Early in the experience, the visual hallucinations may be amusing in that they consistently remain nonthreatening, similar day to day, and sometimes oddly provide an aspect of comfort or companionship to the patient. More commonly, the hallucinations are bothersome to the patient because the experience indicates to the patient that there is something wrong with their mind. Visual hallucinations often begin in low-stimulus environments, often in the evening or other low-light conditions, but as the problem advances they can occur at any time of day. While visual hallucinations may initially occur for only seconds at a time many days apart, the frequency and duration can increase until they occur hours at a time every day and are accompanied by multiple other visual hallucinations, delusions, and confusion [60].

Delusions tend to be more distressing to patients and caregivers because they are often paranoid in nature. The patient is more likely to act out due to the anxiety the paranoia creates. For example, she may change passwords to online accounts due to a belief that unknown assailants are after her finances. He may go to great lengths trying to prove his wife is cheating.

Risk Factors

While the primary risk factor for psychotic symptom development is dementia [57], it occurs in nondemented patients. Other associations include reduced visual acuity [56], visual processing impairment [61–65], use of dopamine agonists, REM behavior disorder, duration of PD, axial rigidity subtype of disease [61,66–68]. The pathophysiology of psychosis in PD is likely complex and remains currently unexplained. The role of excess dopamine has been described above, but there is also data suggesting cholinergic deficits in the cortex may also contribute. Excess serotonin (increased 5HT2A receptor subtypes) in the temporal lobe within the visual processing pathway has been postulated to be of significance [69,70]. Hypometabolism in visual association areas of the brain in subjects with visual hallucinations has been demonstrated in PET and functional MRI studies [64,71]. This is similar to findings in patients with dementia with Lewy bodies [72].

This review focuses on the primary forms of PD-related psychosis, which occur with a clear sensorium and generally longer exposure to dopaminergic medication. It is important to distinguish 2 other common scenarios in which hallucinations or delusions may occur. In the common toxic-metabolic delirium, a clouded sensorium with attention deficits may be the only clue to the etiology of new onset confusion with visual hallucinations. It is highly likely that resolution of the underlying medical problem will lead to resolution of the new onset psychosis and encephalopathy. In a second scenario, hallucinations precede or occur very shortly after the onset of initiation of dopaminergic medication. This differs from the classic syndrome described earlier, in particular when visual hallucinations precede any initiation of medication, and likely represents the distinction between a diagnosis of Lewy body disease and PD [60].

Treatment

Management of psychosis is approachable, but often the outcome is unsatisfactory and associated with trade-offs in motor control. It is unfortunately true that psychotic symptoms are often associated with increased caregiver burden and are a cause of increased nursing home placements [73]. When considering the workup of psychotic symptoms, the differential diagnosis includes delirium, dream enactment (REM behavior disorder), or less commonly, Bonnet syndrome.

A delirium may be precipitated by a difficult to diagnose infection; new-onset confusion and psychotic symptoms may be the heralding presentation. Urinary tract or upper respiratory tract are common vulnerable sources of infection. Once infection is ruled out, the next practical step is to review the patient’s medication list and manage centrally acting drugs that could be contributing to the altered sensorium. A recent prescription of opioids for a dental treatment or a new muscle relaxant may be a culprit, though it is not that usual. A bladder anticholinergic could be suspect and is worth eliminating especially if its addition coincided with the appearance of the psychotic symptoms. Once the non-dopaminergic medications have been reduced/eliminated, then the PD medications should be considered. The general approach is to eliminate the medications that provide the least benefit while being more likely to contribute to psychotic symptoms. Anticholinergic medications, dopamine agonists, selegiline should all be uppermost in that consideration until one is left with L-dopa and COMT inhibitors (the latter function to increase levodopa availability). Then COMT inhibitors and levodopa can be reduced; however, at any point motor control can suffer with the loss of symptomatic therapies [74].

Clozapine is effective against psychotic symptoms in PD, at doses much lower than used in schizophrenia (300-600mg/day). The average dose in the US randomized controlled clinical trial was 25 mg/day, with no associated motor worsening. Patients in the United States are required by the FDA to be placed in a computer-based registry and monitored for agranulocytosis for the duration of clozapine therapy. This rare adverse event is not dose related. Orthostasis can occur at these low doses however. Fortunately the metabolic syndrome is not associated with this range of administration [75,76].

Quetiapine was not found to be effective in 3 blinded randomized controlled trials despite its rather common use for this purpose. It was not associated with motor worsening, however.

Other neuroleptic medications have not resulted in widespread use, because trials have been open label, or outcomes demonstrated motor worsening. Cholinesterase inhibitors have been the subject of a few positive case series, however results appear to be sporadic, the effect size is relatively small, and side effects of this medication class are common [77–79]. It is clear that there is an unmet need for a medication for psychotic symptoms. Clozapine is effective but onerous in its monitoring requirements. Practically speaking, there are relatively few PD patients who take advantage of it because of its feasibility challenges. Yet the problem of psychotic symptoms is a significant one that imposes important challenges to the patient and caregiver, and may limit the number of medications that the patient needs in order to optimize quality of life.

Pimavanserin, a novel medication which acts as a selective serotonin inverse agonist, is in the early application stages for FDA approval for treatment of psychotic symptoms in PD [80]. In its pivotal phase III controlled trial, the drug reduced not only positive symptoms (hallucinations/delusions) without causing motoric worsening, but also reduced caregiver burden. Pimavanserin improved certain sleep features without causing daytime sedation. If this drug meets final approval, it may present an exciting option for many patients for whom treatment was previously limited.

Depression

A study of early PD suggested that depression is often unrecognized and frequently untreated [1]. Indeed it is not unusual for depression to predate the diagnosis of PD by an average of 4 to 6 years [81]. Expanding to the larger PD population, it is generally accepted that about 30% to 50% of PD patients experience clinically significant depression, and once diagnosed may have a long term course, or may recur [82,83]. This is important as untreated depression is an important cause of poor quality of life in early PD. In addition depression can exacerbate motor disability, lead to earlier motor treatment with medication, and increase caregiver stress [83–85].

Diagnosis

A number of clinimetric rating scales for depression have been used and their advantages have been largely related to their objective nature (quantifiable); thus, they tend to be most useful in epidemiologic research studies or for larger scale screening purposes. Examples include the the Beck Depression Inventory, the Geriatric Depression Scale, and the Hamilton Depression Scale, all of which have been shown to be valid tools in PD (with the exception of the UPDRS Depression). It is important to note that they do not substitute for a diagnostic clinical interview [89].

Suicide is not common in PD, however suicidal ideation is estimated at about 11% in PD patients [90], and while there was concern initially after deep brain stimulation procedures began that suicide incidence was increased, evidence does not support this [91].

Pathophysiology

The pathophysiology of depression in PD is largely unknown however is thought to be less causally due to psychosocial factors and more etiologically driven by brainstem monoamine and serotonergic dysfunction [92]. Nonetheless, similar to other chronic conditions, PD patients can certainly develop fear of disability, guilt about impact on others, or other reactive mood changes. Overall, rates of depression are higher in PD compared with patients with similar conditions matched for disability [93].

Treatment

First, the clinician must determine if depression is a result of short-term fluctuations, chronic undertreatment of motor disease, or longer-term mood phenomenon. One important pattern to recognize are mood fluctuations, which can parallel motor OFF-ON cycling. It can be valuable to distinguish this as “subsyndromic” depression or anxiety (sometimes referred to as “OFF dysphoria”), as it can respond to improvement in antiparkinsonian medication dosing patterns that reduce fluctuations[94–96]. Similarly, elevating chronic motor undertreatment to goal therapy can result in mood normalization.

If symptoms persist despite optimization of motor/nonmotor fluctuations or chronic undertreatment and are severe enough to warrant treatment, then therapies used can range from nonpharmacologic education, support, and mental health referrals, as well as pharmacologic support in the form of medications.

A frequent but uncontrolled observation was that when undertreatment of motor disease was finally redressed, mood often improved. A multicenter randomized controlled trial of pramipexole in PD patients without motor fluctuations but with mild to moderate depressive symptoms showed the drug improved scores on the Beck Depression Inventory over a 12-week period. The improvement in mood was 6 points overall, but by 2 points over placebo, illustrating the importance of the size of the placebo effect [97]. Given the potential side effect profile of dopamine agonists, it may be useful to weigh the antidepressant effects only when their motor benefits are already being employed.

Controlled trials have demonstrated efficacy of both selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) antidepressants in PD. Clinical trials have demonstrated efficacy against placebo or with other antidepressant comparators. Examples of drugs with demonstrated efficacy include citalopram, paroxetine, venlafaxine, and nortriptyline. Results have attempted to illuminate the small unique differences between classes of antidepressants or dynamic properties between drugs within a class. For example, desipramine may nudge scores on a mood scale a few weeks sooner than a purer SSRI. Paroxetine (SSRI) versus venlafaxine (SNRI) improved mood scores comparably in a multicenter trial with a placebo comparator. In general, all have all been demonstrated to be effective and with a relatively low side-effect profile, comparable to the general population[98–102]. While case reports exist in the literature, the interaction of monoamine oxidase B inhibitors and SSRIs has not caused significant hypertensive crises or risk of serotonin syndrome [103,104]. Electroconvulsive therapy (ECT) can be used for severe refractory depression in PD as for non-PD patients, with case reports of very effective results. Due to the rarity of use, systematic evidence for its use is lacking [105,106].

Other novel agents and techniques such as omega-3 fatty acids [107] and repetitive transcranial magnetic stimulation [108] have been reported with promising early results. Cognitive behavioral therapy (CBT), which may involve stress management techniques, sleep hygiene, and caregiver support, additionally almost always provided improvement in measured outcomes, whether the trial was controlled or open label in design. In one RCT of CBT in PD of 14 weeks’ duration, there were significantly more treatment responders in the CBT group, with a number needed to treat of only 2 [109].

Anxiety

Anxiety is also common in PD, at least as common as depression considering that prevalence estimates suggest up to 50% of patients experience it [110–112]. Manifestations of anxiety may include panic attacks, generalized anxiety disorder, social anxiety, or other phobias [113]. Anxiety has an important negative impact on health-related quality of life and is often underrecognized by clinicians [114]. While reliable and valid scales to measure anxiety have been lacking in PD, a new effort has yielded the “Parkinson Anxiety Scale” though full clinimetric properties of the scale remain to be demonstrated (sensitivity to change) [115].

Anxiety that parallels the timing of motor OFF-ON cycling is important to recognize. This “subsyndromic” anxiety or anxiety disorder not otherwise specified (ie, the anxiety does not meet DSM-IV criteria) can respond to improvement in antiparkinsonian medication dosing patterns that reduce fluctuations [116,117]. Indeed, the presence of motor fluctuations is the principle marker of anxiety in many studies [118–120]. In an analogous manner, anxiety can predate PD by years and be part of the nonmotor amalgam of features heralding the disease [6,121].

Treatment

Systematic controlled trials of anxiolytic treatment for PD are lacking; therefore, SSRIs are prescribed for this purpose as in non-PD patients. Until SSRIs are demonstrated to be of benefit in anxiety, they are likely safer than use of benzodiazepines, which are associated with risk for falling, cognitive dysfunction, or autonomic dysregulation in PD patients when used during waking hours. Psychotherapy and other nonpharmacologic approaches are likely to be of benefit. A small study of neuromuscular (massage) therapy demonstrated improvement on the Beck Anxiety Inventory in PD [122]. A case report of ECT for severe anxiety has been published [123].

Conclusion

Neuropsychiatric symptoms are common in PD and new knowledge about clinical features, epidemiology, and treatment options has been gained in the last decade, though much remains to be discovered. The development of valid instruments to measure neuropsychiatric symptoms has been vital in these research efforts to bridge the gaps in our understanding. Further elucidation of the pathophysiologies of neuropsychiatric symptoms will help to define treatment targets and likely fuel drug development and the discovery of drugs with more potent benefit and fewer side effects.

Corresponding author: Kathryn A. Chung, MD, Department of Neurology, Oregon Health & Science University, Portland, OR, [email protected].

Financial disclosures: None.

From the Department of Neurology, Oregon Health & Science University, Portland, OR.

Abstract

• Objective: To review the clinical characteristics, epidemiology, and management of the most common neuropsychiatric symptoms (NPS) in Parkinson’s disease (PD).
• Methods: Literature review.
• Results: PD has traditionally been considered a disease of impaired motor function. However, neuropsychiatric complications, such as fatigue, depression, anxiety, psychosis, impulse control disorders, and apathy, frequently complicate the course of the illness. Although the development of new medication options in recent years has had a positive benefit on the management of these troublesome symptoms, responses are frequently suboptimal. The development of valid instruments to measure neuropsychiatric symptoms has been vital in research efforts to bridge the gaps in our understanding. Further elucidation of neuropsychiatric pathophysiologies will help to define treatment targets and has the potential to expand our therapeutic armamentarium.
• Conclusion: While NPS affect patients with established disease, recent investigations have demonstrated risk of symptoms in those with early untreated stages of PD; therefore, better understanding of NPS should be the goal of practitioners treating the entire continuum of PD.

Parkinson’s disease (PD) has traditionally been considered a disease of impaired motor function, but increased recognition of nonmotor symptoms and in particular neuropsychiatric symptoms, such as fatigue, depression, anxiety, psychosis, impulse control disorders, and apathy, offer new opportunities for better care of patients. While neuropsychiatric symptoms affect patients with established disease, recent investigations have clearly demonstrated risk of symptoms in those with early untreated stages of PD; therefore, better understanding of neuropsychiatric symptoms should be the goal of practitioners treating the entire continuum of PD. This review will focus on the clinical characteristics, epidemiology, and management of the most common neuropsychiatric symptoms in PD.

Impulse Control Disorders

The recognition that dopaminergic drugs were successful at treating many symptoms of PD was followed by the disturbing realization that impulse control disorders could be an unfortunate side effect in a substantial minority. Impulse control disorders as defined by DSM-IV [1] are disinhibited behaviors that are maladaptive and recurrent, causing personal and relationship consequences. The impulse control disorders that became associated with PD and medication intake, particularly dopamine agonist use, included gambling, hobbyism, punding (stereotyped, seemingly purposeless behaviors), excessive sexual behavior, shopping, hoarding, and less commonly, compulsive eating. The prevalence estimates of these behavioral disturbances range from 6% to 15.5%, compared with < 2% in the general population [2,3]. The addiction-like dopamine dysregulation syndrome, whereby patients self-medicate with high doses of levodopa and short-acting dopamine agonists beyond what is needed for motor control, can lead to significant impairment of the therapeutic alliance in addition to other patient personal relations. With the advent of surgical options to treat PD and its medication complications, it was observed that stimulation of the subthalamic nucleus could be associated with the spectrum of impulse control disorders [4].

Epidemiology/Risk Factors

In a recent systematic review of the literature of impulse control disorders in PD [5], the authors determined that dopaminergic therapy caused compulsive or impulsive behaviors in approximately 10% of PD patients in the course of their treatment, with pathologic gambling and hypersexuality most frequently experienced. Multiple impulse control disorders are not uncommon and may coexist in one-quarter of patients with compulsivity. There appeared to be more disordered behavior with higher comparable doses of agonists. The authors concluded that impulse control disorder symptoms tended to occur with initiation or dose increases of direct D₂/D₃ agonists, such as pramipexole and ropinirole. Importantly, impulse control disorder behavior improved if not resolved with discontinuation or reduction of dosage of the agonist, even if a compensatory levodopa dosage is added or increased. Perhaps not surprisingly, it was observed that if patients had a preexisting impulse control disorder prior to PD or the initiation of treatment, there was a high likelihood of worsening of symptoms. This small subgroup is estimated at about 1% of PD subjects, which corresponds to the prevalence of impulse control disorders in the general population. Other identified potential risk factors for impulse control disorder development include male gender, young age at onset, a personal or family history of addiction, novelty or risk seeking personality, and a concurrent diagnosis of depression [3]. In a recent study of early PD patients, the risk of developing an impulse control disorder became important once treatment with dopaminergic drugs began and continued for a year or more [6].

Pathogenesis

The pathogenesis is not fully understood, however, mesolimbic dopamine alterations are strongly suspected. It has been long speculated that the high doses of dopamine needed to replete the relatively depleted dorsal striatum overdose the “intact” ventral striatum and cause this neuropsychiatric disorder [7–9]. The additional cognitive impairments in PD, which can include problems with attention, working memory, planning, forethought and decision-making, are faculties that can markedly increase susceptibility to impulse control disorder [8].

The role of serotonin deficiency in the PD brain and its part in inhibiting the patient’s ability to delay rewards adds to the complexity of impulse control disorder pathogenesis. Dorsal raphe nuclei disease in PD results in loss of serotonin innervation to substantial portions of the prefrontal and motor cortices in addition to basal ganglia substructures like the striatum, pallidum and subthalamic nucleus [10]. Together with dopamine, serotonin may work to regulate risk-sensitive decision making, response inhibition, waiting for future rewards, and overall impulse control. Its relative loss therefore also likely contributes to tipping the balance towards impulse dyscontrol [11,12]. The role of other neurotransmitters such as opiate systems involved in the process of acquisition and maintenance of addictive behaviors like dopamine dysregulation syndrome remains to be fully understood.

Treatment

The most successful strategy to address this problem is to reduce or eliminate the offending medication, usually the dopamine agonist. This may be associated with worsening apathy, anxiety or depression; however, substituting levodopa can be a successful strategy in many cases [13]. Zonisamide was described to be possibly effective in a trial of 15 subjects; however, the open label nature of this evidence must be considered as with other case reports using valproate, donepezil, and selective serotonin reuptake inhibitors (SSRIs) [14–16].

Fatigue

An easy to understand operational definition of fatigue is that it is a state of extreme tiredness, weakness, or exhaustion, either physical or mental or both. Fatigue is not uncommon in the general population [17] but is increasingly recognized to occur in numerous disease conditions and is frequently encountered in PD and multiple sclerosis. The latter is of special significance in the consideration of the neurotransmission of fatigue, as it is not thought to be a disease of dopamine deficiency. The pathophysiology remains unclear, and it may differ depending on whether the fatigue is experienced as more physical or mental, or rather motor versus nonmotor as some authors propose.

Fatigue has been conceptualized as central or peripheral in character. Peripheral fatigue is best understood as muscular fatigue caused by repetitive muscular contraction or reduced force generation [18]. Central fatigue however, is divided into mental or physical fatigue. Mental fatigue can occur after sustained attentive or emotional activity. It may alternatively be provoked after boring repetitive tasks or lack of intellectually stimulating activity. Physical fatigue is the sense of body exhaustion or energy to perform physical tasks even though the ability to carry them out exists.

Epidemiology

As recognition of the problem of fatigue increased in the last 2 decades, the realization that one-third to one-half of patients experience it at some point has improved opportunities for recognition and treatment [19]. Fatigue may be the presenting symptom in one-third of patients prior to actual motor symptom onset [20]. Half of untreated PD patients in a biomarker cohort study reported fatigue [6]. Unfortunately, it is also described by patients as one of the most disabling symptoms, causing significant impact on quality of life [19]. Fatigue in PD is associated with higher rates of depressive symptoms, but occurs with higher prevalence in nondepressed patients [21]. Poor ability to initiate and sustain activity due to fatigue is different from depression, excessive sleepiness, or impaired motor function [22,23].

Pathophysiology

The pathophysiology of fatigue remains somewhat unclear, though physical fatigue is likely a significant part of the problem and related to dopamine deficiency based on studies of time and force generation of keyboard strikes in PD subjects before and after L-dopa administration. These subjects had declines in force and increased physical fatigue which improved after L-dopa [24]. In other studies using transcranial magnetic stimulation to study changes in cortical excitability, the degree of physical fatigue correlated with abnormalities in motor evoked potentials during fatiguing exercising. These studies also support the hypothesis that fatigue is a motor symptom [25,26]. In the ELLDOPA study, fatigue worsened more in PD subjects treated with placebo [27]. Other imaging studies have suggested suggested nondopaminergic mechanisms including serotonergic pathway abnormalities [28], thus the question behind the etiology and solution for all cases of fatigue remains to be settled.

Diagnosis

The diagnosis is fatigue may be challenging as it may mask as depression or apathy. There are a number of fatigue rating scales available; however, the validated Parkinson’s Fatigue Scale (PFS) supersedes many of the problems of using a generic scale which could overlap motor questions and potentially be confounding [29,30].

Treatment

Most important is awareness and vigilance for the symptoms of fatigue, depression, and apathy and effort to distinguish between them. It may require structured interviews or assessment tools to properly diagnose the problem. Treatment is less clear in that few studies have clearly indicated the best treatment options. In placebo-controlled trials, methylphenidate did improve fatigue as did levodopa [31]. Modafinil, a hypocretin modulator and a drug first approved by the FDA for treatment of narcolepsy, has demonstrated mixed results in recent years. It may reduce physical fatigue and reduce excessive daytime sleepiness but likely does not reduce subjective symptoms of fatigue [32]. L-dopa can significantly reduce fatigue in many patients, which would argue that it often is a motor symptom [33,24]. In a post-hoc analysis of the ADAGIO delayed start study, patients taking rasagiline 1 mg/day and 2 mg/day (the latter dose exceeds the usual clinical dosing) showed significantly less worsening of symptoms on the PFS compared to placebo over time [34]. It is important to realize that once motor symptoms are optimally treated with dopaminergic medications, while many patients will feel significant relief from fatigue some patients will continue to feel symptomatic.

Apathy

The definition of apathy has become more complicated and refined, incorporating findings from the study of brain disease and behavioral analysis. Marin’s classic elaboration of apathy as lack of motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress has been built upon by Levy and Dubois [35–37]. They suggest apathy may be better thought of as an observable behavioral syndrome characterized by a quantitative reduction of self-generated voluntary and purposeful behaviors. They suggest 3 apathetic subtypes: emotional, cognitive, and auto-activational, which reflect different disease states accounting for failure of normal goal-directed behavior.

Epidemiology

Prevalence estimates for apathy in PD vary. This is likely due to the varying recruitment criteria among studies, with some including patients with comorbid depression and dementia and others containing only “pure apathy.” Other reports may have had referral bias issues, as community-based studies report lower prevalences in general. In a group of newly diagnosed PD patients, using more restrictive criteria (apathy subscale of the neuropsychiatric inventory and the diagnostic consensus criteria for apathy validated in PD), Pedersen reported a prevalence of apathy of 14.3% [38]. In a 4-year prospective longitudinal cohort study, an annual incidence rate of 12.3% was reported, with apathy developing in 60% of the cohort by the study’s conclusion [39].

Apathy has been associated with longer disease duration, male gender [40], higher daily levodopa doses [41], more severe parkinsonism [38], and lower education status, though the latter feature remains under debate. Early cognitive deficits appear to be a risk factor for development of apathy [42]. The patterns of cognitive dysfunction and apathy remain unsettled in the literature.

Pathology

The pathology of atrophy remains unexplained and is unlikely to be reduced to a simple atrophy of one nucleus or the tone of one circuit. However, in a small neuroimaging study, severity of apathy correlated with atrophy of the bilateral nucleus accumbens [43], and it is notable that one major input to the nucleus accumbens is the amygdala. According to Braak staging, by stage 4 significant involvement of the amygdala by Lewy bodies has occurred. Others have found changes in grey matter density that could correlate with deficits of the prefrontal-basal ganglia circuitry to produce dysfunction of segregated frontal-subcortical loops. These may correlate with the “autoactivation” deficit pattern of apathy in which patients have a lack of self-initiated actions, even thoughts, though appear more normal when giving externally prompted responses [37,44].

Assessment

Clinically, the relationship between apathy and depression can be hard to disentangle, especially since many studies have found an association between them, especially with regards to apathy and anhedonia. Depression may feature negative self thoughts and sadness while apathy is notable for lack of initiation and effort. Viewed over a longer period of time, apathy tended to worsen in a linear fashion, where depression tended to fluctuate with improvements and exacerbations.

The Movement Disorders Society task force has recommended the Lille Apathy Rating Scale (LARS) for assessment of apathy; English and French versions have been validated in PD patients. It uses a semi-structured interview format assessing 4 dimensions of apathy: self awareness, intellectual curiosity, emotion, and action initiation [45–47].

The impact of apathy cannot be underestimated as this poor show of motivation or effort leads to lack of engagement in old activities or interest in new ones. Spouses may misinterpret this change in behavior as laziness or deliberate social withdrawal, or perhaps entitlement. It is not surprising that apathy routinely shows up on quality of life (QoL) questionnaires as highly impacting patients and families. In one study, apathy was the nonmotor symptom most likely to cause caregiver distress in PD [40,48–50].

Treatment

No approved drugs exist for treatment of apathy. However, clinical experience often confirms that dopaminergic modulation can be helpful in the treatment of apathy as indirect evidence suggests. A meta-analysis of controlled trials using pramipexole and Part I of the Unified Parkinson's disease rating scale (UPDRS) (secondary measure) showed the medication improved scores on this measure of motivation and mood in non-depressed subjects [51] with PD. Rare patients undergoing subthalamic deep brain stimulation have been reported to experience new and sometimes severe apathy after surgery [52]. This was posited at least in part to be the result of reduction of dopaminergic medication due to surgery.

Nondopaminergic pharmacotherapy of apathy is in its infancy. A recent controlled trial of rivastigmine in 31 French subjects with moderate to severe apathy based on LARS showed that 6 months of treatment at 9.5 mg/day improved average scores from –11.5 to –20 compared with placebo. While quality of life did not improve, caregiver burden did. The investigators found in this group of subjects that apathy was a possible herald for early dementia in PD [53].

A post-hoc analysis of the ADAGIO study (rasagiline or placebo in PD patients taking antidepressants) found that rasagiline use was associated with a nonsignificant slowing of apathy development during the trial [54].

Psychosis

Psychotic symptoms are a common occurrence in drug-treated patients, with visual hallucinations occurring in up to 30%, though over a 20-year period up to three-quarters of patients may develop visual hallucinations.After visual, the most common type of hallucination is auditory, followed by the other affected senses such as tactile, olfactory, or even taste [57]. Delusions, which tend to be paranoid in nature, occur in about 5% of patients [55–57]. The presence of psychotic symptoms is associated with poorer quality of life [58].

Symptomatology

The visual hallucinations of PD are usually quite stereotyped, and have been described as “minor” and “non-minor”[59]. Minor hallucinations refer to transient peripheral field stimuli that disappear when brought into central focus, “something flashed by,” a sense of a living being nearby, “a presence in the room,” or illusions whereby objects are transformed, eg, a bush in the yard is a deer.

Auditory hallucinations tend to be vague or indistinct sounds, like music in another room as opposed to voices speaking directly to the patient as might be experienced in a primary psychotic disorder. Tactile forms often involve insects or other animals crawling on the skin. Olfactory hallucinations may take the form of smelling perfume, toxic odors from room vents, etc.

Early in the experience, the visual hallucinations may be amusing in that they consistently remain nonthreatening, similar day to day, and sometimes oddly provide an aspect of comfort or companionship to the patient. More commonly, the hallucinations are bothersome to the patient because the experience indicates to the patient that there is something wrong with their mind. Visual hallucinations often begin in low-stimulus environments, often in the evening or other low-light conditions, but as the problem advances they can occur at any time of day. While visual hallucinations may initially occur for only seconds at a time many days apart, the frequency and duration can increase until they occur hours at a time every day and are accompanied by multiple other visual hallucinations, delusions, and confusion [60].

Delusions tend to be more distressing to patients and caregivers because they are often paranoid in nature. The patient is more likely to act out due to the anxiety the paranoia creates. For example, she may change passwords to online accounts due to a belief that unknown assailants are after her finances. He may go to great lengths trying to prove his wife is cheating.

Risk Factors

While the primary risk factor for psychotic symptom development is dementia [57], it occurs in nondemented patients. Other associations include reduced visual acuity [56], visual processing impairment [61–65], use of dopamine agonists, REM behavior disorder, duration of PD, axial rigidity subtype of disease [61,66–68]. The pathophysiology of psychosis in PD is likely complex and remains currently unexplained. The role of excess dopamine has been described above, but there is also data suggesting cholinergic deficits in the cortex may also contribute. Excess serotonin (increased 5HT2A receptor subtypes) in the temporal lobe within the visual processing pathway has been postulated to be of significance [69,70]. Hypometabolism in visual association areas of the brain in subjects with visual hallucinations has been demonstrated in PET and functional MRI studies [64,71]. This is similar to findings in patients with dementia with Lewy bodies [72].

This review focuses on the primary forms of PD-related psychosis, which occur with a clear sensorium and generally longer exposure to dopaminergic medication. It is important to distinguish 2 other common scenarios in which hallucinations or delusions may occur. In the common toxic-metabolic delirium, a clouded sensorium with attention deficits may be the only clue to the etiology of new onset confusion with visual hallucinations. It is highly likely that resolution of the underlying medical problem will lead to resolution of the new onset psychosis and encephalopathy. In a second scenario, hallucinations precede or occur very shortly after the onset of initiation of dopaminergic medication. This differs from the classic syndrome described earlier, in particular when visual hallucinations precede any initiation of medication, and likely represents the distinction between a diagnosis of Lewy body disease and PD [60].

Treatment

Management of psychosis is approachable, but often the outcome is unsatisfactory and associated with trade-offs in motor control. It is unfortunately true that psychotic symptoms are often associated with increased caregiver burden and are a cause of increased nursing home placements [73]. When considering the workup of psychotic symptoms, the differential diagnosis includes delirium, dream enactment (REM behavior disorder), or less commonly, Bonnet syndrome.

A delirium may be precipitated by a difficult to diagnose infection; new-onset confusion and psychotic symptoms may be the heralding presentation. Urinary tract or upper respiratory tract are common vulnerable sources of infection. Once infection is ruled out, the next practical step is to review the patient’s medication list and manage centrally acting drugs that could be contributing to the altered sensorium. A recent prescription of opioids for a dental treatment or a new muscle relaxant may be a culprit, though it is not that usual. A bladder anticholinergic could be suspect and is worth eliminating especially if its addition coincided with the appearance of the psychotic symptoms. Once the non-dopaminergic medications have been reduced/eliminated, then the PD medications should be considered. The general approach is to eliminate the medications that provide the least benefit while being more likely to contribute to psychotic symptoms. Anticholinergic medications, dopamine agonists, selegiline should all be uppermost in that consideration until one is left with L-dopa and COMT inhibitors (the latter function to increase levodopa availability). Then COMT inhibitors and levodopa can be reduced; however, at any point motor control can suffer with the loss of symptomatic therapies [74].

Clozapine is effective against psychotic symptoms in PD, at doses much lower than used in schizophrenia (300-600mg/day). The average dose in the US randomized controlled clinical trial was 25 mg/day, with no associated motor worsening. Patients in the United States are required by the FDA to be placed in a computer-based registry and monitored for agranulocytosis for the duration of clozapine therapy. This rare adverse event is not dose related. Orthostasis can occur at these low doses however. Fortunately the metabolic syndrome is not associated with this range of administration [75,76].

Quetiapine was not found to be effective in 3 blinded randomized controlled trials despite its rather common use for this purpose. It was not associated with motor worsening, however.

Other neuroleptic medications have not resulted in widespread use, because trials have been open label, or outcomes demonstrated motor worsening. Cholinesterase inhibitors have been the subject of a few positive case series, however results appear to be sporadic, the effect size is relatively small, and side effects of this medication class are common [77–79]. It is clear that there is an unmet need for a medication for psychotic symptoms. Clozapine is effective but onerous in its monitoring requirements. Practically speaking, there are relatively few PD patients who take advantage of it because of its feasibility challenges. Yet the problem of psychotic symptoms is a significant one that imposes important challenges to the patient and caregiver, and may limit the number of medications that the patient needs in order to optimize quality of life.

Pimavanserin, a novel medication which acts as a selective serotonin inverse agonist, is in the early application stages for FDA approval for treatment of psychotic symptoms in PD [80]. In its pivotal phase III controlled trial, the drug reduced not only positive symptoms (hallucinations/delusions) without causing motoric worsening, but also reduced caregiver burden. Pimavanserin improved certain sleep features without causing daytime sedation. If this drug meets final approval, it may present an exciting option for many patients for whom treatment was previously limited.

Depression

A study of early PD suggested that depression is often unrecognized and frequently untreated [1]. Indeed it is not unusual for depression to predate the diagnosis of PD by an average of 4 to 6 years [81]. Expanding to the larger PD population, it is generally accepted that about 30% to 50% of PD patients experience clinically significant depression, and once diagnosed may have a long term course, or may recur [82,83]. This is important as untreated depression is an important cause of poor quality of life in early PD. In addition depression can exacerbate motor disability, lead to earlier motor treatment with medication, and increase caregiver stress [83–85].

Diagnosis

A number of clinimetric rating scales for depression have been used and their advantages have been largely related to their objective nature (quantifiable); thus, they tend to be most useful in epidemiologic research studies or for larger scale screening purposes. Examples include the the Beck Depression Inventory, the Geriatric Depression Scale, and the Hamilton Depression Scale, all of which have been shown to be valid tools in PD (with the exception of the UPDRS Depression). It is important to note that they do not substitute for a diagnostic clinical interview [89].

Suicide is not common in PD, however suicidal ideation is estimated at about 11% in PD patients [90], and while there was concern initially after deep brain stimulation procedures began that suicide incidence was increased, evidence does not support this [91].

Pathophysiology

The pathophysiology of depression in PD is largely unknown however is thought to be less causally due to psychosocial factors and more etiologically driven by brainstem monoamine and serotonergic dysfunction [92]. Nonetheless, similar to other chronic conditions, PD patients can certainly develop fear of disability, guilt about impact on others, or other reactive mood changes. Overall, rates of depression are higher in PD compared with patients with similar conditions matched for disability [93].

Treatment

First, the clinician must determine if depression is a result of short-term fluctuations, chronic undertreatment of motor disease, or longer-term mood phenomenon. One important pattern to recognize are mood fluctuations, which can parallel motor OFF-ON cycling. It can be valuable to distinguish this as “subsyndromic” depression or anxiety (sometimes referred to as “OFF dysphoria”), as it can respond to improvement in antiparkinsonian medication dosing patterns that reduce fluctuations[94–96]. Similarly, elevating chronic motor undertreatment to goal therapy can result in mood normalization.

If symptoms persist despite optimization of motor/nonmotor fluctuations or chronic undertreatment and are severe enough to warrant treatment, then therapies used can range from nonpharmacologic education, support, and mental health referrals, as well as pharmacologic support in the form of medications.

A frequent but uncontrolled observation was that when undertreatment of motor disease was finally redressed, mood often improved. A multicenter randomized controlled trial of pramipexole in PD patients without motor fluctuations but with mild to moderate depressive symptoms showed the drug improved scores on the Beck Depression Inventory over a 12-week period. The improvement in mood was 6 points overall, but by 2 points over placebo, illustrating the importance of the size of the placebo effect [97]. Given the potential side effect profile of dopamine agonists, it may be useful to weigh the antidepressant effects only when their motor benefits are already being employed.

Controlled trials have demonstrated efficacy of both selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) antidepressants in PD. Clinical trials have demonstrated efficacy against placebo or with other antidepressant comparators. Examples of drugs with demonstrated efficacy include citalopram, paroxetine, venlafaxine, and nortriptyline. Results have attempted to illuminate the small unique differences between classes of antidepressants or dynamic properties between drugs within a class. For example, desipramine may nudge scores on a mood scale a few weeks sooner than a purer SSRI. Paroxetine (SSRI) versus venlafaxine (SNRI) improved mood scores comparably in a multicenter trial with a placebo comparator. In general, all have all been demonstrated to be effective and with a relatively low side-effect profile, comparable to the general population[98–102]. While case reports exist in the literature, the interaction of monoamine oxidase B inhibitors and SSRIs has not caused significant hypertensive crises or risk of serotonin syndrome [103,104]. Electroconvulsive therapy (ECT) can be used for severe refractory depression in PD as for non-PD patients, with case reports of very effective results. Due to the rarity of use, systematic evidence for its use is lacking [105,106].

Other novel agents and techniques such as omega-3 fatty acids [107] and repetitive transcranial magnetic stimulation [108] have been reported with promising early results. Cognitive behavioral therapy (CBT), which may involve stress management techniques, sleep hygiene, and caregiver support, additionally almost always provided improvement in measured outcomes, whether the trial was controlled or open label in design. In one RCT of CBT in PD of 14 weeks’ duration, there were significantly more treatment responders in the CBT group, with a number needed to treat of only 2 [109].

Anxiety

Anxiety is also common in PD, at least as common as depression considering that prevalence estimates suggest up to 50% of patients experience it [110–112]. Manifestations of anxiety may include panic attacks, generalized anxiety disorder, social anxiety, or other phobias [113]. Anxiety has an important negative impact on health-related quality of life and is often underrecognized by clinicians [114]. While reliable and valid scales to measure anxiety have been lacking in PD, a new effort has yielded the “Parkinson Anxiety Scale” though full clinimetric properties of the scale remain to be demonstrated (sensitivity to change) [115].

Anxiety that parallels the timing of motor OFF-ON cycling is important to recognize. This “subsyndromic” anxiety or anxiety disorder not otherwise specified (ie, the anxiety does not meet DSM-IV criteria) can respond to improvement in antiparkinsonian medication dosing patterns that reduce fluctuations [116,117]. Indeed, the presence of motor fluctuations is the principle marker of anxiety in many studies [118–120]. In an analogous manner, anxiety can predate PD by years and be part of the nonmotor amalgam of features heralding the disease [6,121].

Treatment

Systematic controlled trials of anxiolytic treatment for PD are lacking; therefore, SSRIs are prescribed for this purpose as in non-PD patients. Until SSRIs are demonstrated to be of benefit in anxiety, they are likely safer than use of benzodiazepines, which are associated with risk for falling, cognitive dysfunction, or autonomic dysregulation in PD patients when used during waking hours. Psychotherapy and other nonpharmacologic approaches are likely to be of benefit. A small study of neuromuscular (massage) therapy demonstrated improvement on the Beck Anxiety Inventory in PD [122]. A case report of ECT for severe anxiety has been published [123].

Conclusion

Neuropsychiatric symptoms are common in PD and new knowledge about clinical features, epidemiology, and treatment options has been gained in the last decade, though much remains to be discovered. The development of valid instruments to measure neuropsychiatric symptoms has been vital in these research efforts to bridge the gaps in our understanding. Further elucidation of the pathophysiologies of neuropsychiatric symptoms will help to define treatment targets and likely fuel drug development and the discovery of drugs with more potent benefit and fewer side effects.

Corresponding author: Kathryn A. Chung, MD, Department of Neurology, Oregon Health & Science University, Portland, OR, [email protected].

Financial disclosures: None.

From the Department of Neurology, Oregon Health & Science University, Portland, OR.

Abstract

• Objective: To review the clinical characteristics, epidemiology, and management of the most common neuropsychiatric symptoms (NPS) in Parkinson’s disease (PD).
• Methods: Literature review.
• Results: PD has traditionally been considered a disease of impaired motor function. However, neuropsychiatric complications, such as fatigue, depression, anxiety, psychosis, impulse control disorders, and apathy, frequently complicate the course of the illness. Although the development of new medication options in recent years has had a positive benefit on the management of these troublesome symptoms, responses are frequently suboptimal. The development of valid instruments to measure neuropsychiatric symptoms has been vital in research efforts to bridge the gaps in our understanding. Further elucidation of neuropsychiatric pathophysiologies will help to define treatment targets and has the potential to expand our therapeutic armamentarium.
• Conclusion: While NPS affect patients with established disease, recent investigations have demonstrated risk of symptoms in those with early untreated stages of PD; therefore, better understanding of NPS should be the goal of practitioners treating the entire continuum of PD.

Parkinson’s disease (PD) has traditionally been considered a disease of impaired motor function, but increased recognition of nonmotor symptoms and in particular neuropsychiatric symptoms, such as fatigue, depression, anxiety, psychosis, impulse control disorders, and apathy, offer new opportunities for better care of patients. While neuropsychiatric symptoms affect patients with established disease, recent investigations have clearly demonstrated risk of symptoms in those with early untreated stages of PD; therefore, better understanding of neuropsychiatric symptoms should be the goal of practitioners treating the entire continuum of PD. This review will focus on the clinical characteristics, epidemiology, and management of the most common neuropsychiatric symptoms in PD.

Impulse Control Disorders

The recognition that dopaminergic drugs were successful at treating many symptoms of PD was followed by the disturbing realization that impulse control disorders could be an unfortunate side effect in a substantial minority. Impulse control disorders as defined by DSM-IV [1] are disinhibited behaviors that are maladaptive and recurrent, causing personal and relationship consequences. The impulse control disorders that became associated with PD and medication intake, particularly dopamine agonist use, included gambling, hobbyism, punding (stereotyped, seemingly purposeless behaviors), excessive sexual behavior, shopping, hoarding, and less commonly, compulsive eating. The prevalence estimates of these behavioral disturbances range from 6% to 15.5%, compared with < 2% in the general population [2,3]. The addiction-like dopamine dysregulation syndrome, whereby patients self-medicate with high doses of levodopa and short-acting dopamine agonists beyond what is needed for motor control, can lead to significant impairment of the therapeutic alliance in addition to other patient personal relations. With the advent of surgical options to treat PD and its medication complications, it was observed that stimulation of the subthalamic nucleus could be associated with the spectrum of impulse control disorders [4].

Epidemiology/Risk Factors

In a recent systematic review of the literature of impulse control disorders in PD [5], the authors determined that dopaminergic therapy caused compulsive or impulsive behaviors in approximately 10% of PD patients in the course of their treatment, with pathologic gambling and hypersexuality most frequently experienced. Multiple impulse control disorders are not uncommon and may coexist in one-quarter of patients with compulsivity. There appeared to be more disordered behavior with higher comparable doses of agonists. The authors concluded that impulse control disorder symptoms tended to occur with initiation or dose increases of direct D₂/D₃ agonists, such as pramipexole and ropinirole. Importantly, impulse control disorder behavior improved if not resolved with discontinuation or reduction of dosage of the agonist, even if a compensatory levodopa dosage is added or increased. Perhaps not surprisingly, it was observed that if patients had a preexisting impulse control disorder prior to PD or the initiation of treatment, there was a high likelihood of worsening of symptoms. This small subgroup is estimated at about 1% of PD subjects, which corresponds to the prevalence of impulse control disorders in the general population. Other identified potential risk factors for impulse control disorder development include male gender, young age at onset, a personal or family history of addiction, novelty or risk seeking personality, and a concurrent diagnosis of depression [3]. In a recent study of early PD patients, the risk of developing an impulse control disorder became important once treatment with dopaminergic drugs began and continued for a year or more [6].

Pathogenesis

The pathogenesis is not fully understood, however, mesolimbic dopamine alterations are strongly suspected. It has been long speculated that the high doses of dopamine needed to replete the relatively depleted dorsal striatum overdose the “intact” ventral striatum and cause this neuropsychiatric disorder [7–9]. The additional cognitive impairments in PD, which can include problems with attention, working memory, planning, forethought and decision-making, are faculties that can markedly increase susceptibility to impulse control disorder [8].

The role of serotonin deficiency in the PD brain and its part in inhibiting the patient’s ability to delay rewards adds to the complexity of impulse control disorder pathogenesis. Dorsal raphe nuclei disease in PD results in loss of serotonin innervation to substantial portions of the prefrontal and motor cortices in addition to basal ganglia substructures like the striatum, pallidum and subthalamic nucleus [10]. Together with dopamine, serotonin may work to regulate risk-sensitive decision making, response inhibition, waiting for future rewards, and overall impulse control. Its relative loss therefore also likely contributes to tipping the balance towards impulse dyscontrol [11,12]. The role of other neurotransmitters such as opiate systems involved in the process of acquisition and maintenance of addictive behaviors like dopamine dysregulation syndrome remains to be fully understood.

Treatment

The most successful strategy to address this problem is to reduce or eliminate the offending medication, usually the dopamine agonist. This may be associated with worsening apathy, anxiety or depression; however, substituting levodopa can be a successful strategy in many cases [13]. Zonisamide was described to be possibly effective in a trial of 15 subjects; however, the open label nature of this evidence must be considered as with other case reports using valproate, donepezil, and selective serotonin reuptake inhibitors (SSRIs) [14–16].

Fatigue

An easy to understand operational definition of fatigue is that it is a state of extreme tiredness, weakness, or exhaustion, either physical or mental or both. Fatigue is not uncommon in the general population [17] but is increasingly recognized to occur in numerous disease conditions and is frequently encountered in PD and multiple sclerosis. The latter is of special significance in the consideration of the neurotransmission of fatigue, as it is not thought to be a disease of dopamine deficiency. The pathophysiology remains unclear, and it may differ depending on whether the fatigue is experienced as more physical or mental, or rather motor versus nonmotor as some authors propose.

Fatigue has been conceptualized as central or peripheral in character. Peripheral fatigue is best understood as muscular fatigue caused by repetitive muscular contraction or reduced force generation [18]. Central fatigue however, is divided into mental or physical fatigue. Mental fatigue can occur after sustained attentive or emotional activity. It may alternatively be provoked after boring repetitive tasks or lack of intellectually stimulating activity. Physical fatigue is the sense of body exhaustion or energy to perform physical tasks even though the ability to carry them out exists.

Epidemiology

As recognition of the problem of fatigue increased in the last 2 decades, the realization that one-third to one-half of patients experience it at some point has improved opportunities for recognition and treatment [19]. Fatigue may be the presenting symptom in one-third of patients prior to actual motor symptom onset [20]. Half of untreated PD patients in a biomarker cohort study reported fatigue [6]. Unfortunately, it is also described by patients as one of the most disabling symptoms, causing significant impact on quality of life [19]. Fatigue in PD is associated with higher rates of depressive symptoms, but occurs with higher prevalence in nondepressed patients [21]. Poor ability to initiate and sustain activity due to fatigue is different from depression, excessive sleepiness, or impaired motor function [22,23].

Pathophysiology

The pathophysiology of fatigue remains somewhat unclear, though physical fatigue is likely a significant part of the problem and related to dopamine deficiency based on studies of time and force generation of keyboard strikes in PD subjects before and after L-dopa administration. These subjects had declines in force and increased physical fatigue which improved after L-dopa [24]. In other studies using transcranial magnetic stimulation to study changes in cortical excitability, the degree of physical fatigue correlated with abnormalities in motor evoked potentials during fatiguing exercising. These studies also support the hypothesis that fatigue is a motor symptom [25,26]. In the ELLDOPA study, fatigue worsened more in PD subjects treated with placebo [27]. Other imaging studies have suggested suggested nondopaminergic mechanisms including serotonergic pathway abnormalities [28], thus the question behind the etiology and solution for all cases of fatigue remains to be settled.

Diagnosis

The diagnosis is fatigue may be challenging as it may mask as depression or apathy. There are a number of fatigue rating scales available; however, the validated Parkinson’s Fatigue Scale (PFS) supersedes many of the problems of using a generic scale which could overlap motor questions and potentially be confounding [29,30].

Treatment

Most important is awareness and vigilance for the symptoms of fatigue, depression, and apathy and effort to distinguish between them. It may require structured interviews or assessment tools to properly diagnose the problem. Treatment is less clear in that few studies have clearly indicated the best treatment options. In placebo-controlled trials, methylphenidate did improve fatigue as did levodopa [31]. Modafinil, a hypocretin modulator and a drug first approved by the FDA for treatment of narcolepsy, has demonstrated mixed results in recent years. It may reduce physical fatigue and reduce excessive daytime sleepiness but likely does not reduce subjective symptoms of fatigue [32]. L-dopa can significantly reduce fatigue in many patients, which would argue that it often is a motor symptom [33,24]. In a post-hoc analysis of the ADAGIO delayed start study, patients taking rasagiline 1 mg/day and 2 mg/day (the latter dose exceeds the usual clinical dosing) showed significantly less worsening of symptoms on the PFS compared to placebo over time [34]. It is important to realize that once motor symptoms are optimally treated with dopaminergic medications, while many patients will feel significant relief from fatigue some patients will continue to feel symptomatic.

Apathy

The definition of apathy has become more complicated and refined, incorporating findings from the study of brain disease and behavioral analysis. Marin’s classic elaboration of apathy as lack of motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress has been built upon by Levy and Dubois [35–37]. They suggest apathy may be better thought of as an observable behavioral syndrome characterized by a quantitative reduction of self-generated voluntary and purposeful behaviors. They suggest 3 apathetic subtypes: emotional, cognitive, and auto-activational, which reflect different disease states accounting for failure of normal goal-directed behavior.

Epidemiology

Prevalence estimates for apathy in PD vary. This is likely due to the varying recruitment criteria among studies, with some including patients with comorbid depression and dementia and others containing only “pure apathy.” Other reports may have had referral bias issues, as community-based studies report lower prevalences in general. In a group of newly diagnosed PD patients, using more restrictive criteria (apathy subscale of the neuropsychiatric inventory and the diagnostic consensus criteria for apathy validated in PD), Pedersen reported a prevalence of apathy of 14.3% [38]. In a 4-year prospective longitudinal cohort study, an annual incidence rate of 12.3% was reported, with apathy developing in 60% of the cohort by the study’s conclusion [39].

Apathy has been associated with longer disease duration, male gender [40], higher daily levodopa doses [41], more severe parkinsonism [38], and lower education status, though the latter feature remains under debate. Early cognitive deficits appear to be a risk factor for development of apathy [42]. The patterns of cognitive dysfunction and apathy remain unsettled in the literature.

Pathology

The pathology of atrophy remains unexplained and is unlikely to be reduced to a simple atrophy of one nucleus or the tone of one circuit. However, in a small neuroimaging study, severity of apathy correlated with atrophy of the bilateral nucleus accumbens [43], and it is notable that one major input to the nucleus accumbens is the amygdala. According to Braak staging, by stage 4 significant involvement of the amygdala by Lewy bodies has occurred. Others have found changes in grey matter density that could correlate with deficits of the prefrontal-basal ganglia circuitry to produce dysfunction of segregated frontal-subcortical loops. These may correlate with the “autoactivation” deficit pattern of apathy in which patients have a lack of self-initiated actions, even thoughts, though appear more normal when giving externally prompted responses [37,44].

Assessment

Clinically, the relationship between apathy and depression can be hard to disentangle, especially since many studies have found an association between them, especially with regards to apathy and anhedonia. Depression may feature negative self thoughts and sadness while apathy is notable for lack of initiation and effort. Viewed over a longer period of time, apathy tended to worsen in a linear fashion, where depression tended to fluctuate with improvements and exacerbations.

The Movement Disorders Society task force has recommended the Lille Apathy Rating Scale (LARS) for assessment of apathy; English and French versions have been validated in PD patients. It uses a semi-structured interview format assessing 4 dimensions of apathy: self awareness, intellectual curiosity, emotion, and action initiation [45–47].

The impact of apathy cannot be underestimated as this poor show of motivation or effort leads to lack of engagement in old activities or interest in new ones. Spouses may misinterpret this change in behavior as laziness or deliberate social withdrawal, or perhaps entitlement. It is not surprising that apathy routinely shows up on quality of life (QoL) questionnaires as highly impacting patients and families. In one study, apathy was the nonmotor symptom most likely to cause caregiver distress in PD [40,48–50].

Treatment

No approved drugs exist for treatment of apathy. However, clinical experience often confirms that dopaminergic modulation can be helpful in the treatment of apathy as indirect evidence suggests. A meta-analysis of controlled trials using pramipexole and Part I of the Unified Parkinson's disease rating scale (UPDRS) (secondary measure) showed the medication improved scores on this measure of motivation and mood in non-depressed subjects [51] with PD. Rare patients undergoing subthalamic deep brain stimulation have been reported to experience new and sometimes severe apathy after surgery [52]. This was posited at least in part to be the result of reduction of dopaminergic medication due to surgery.

Nondopaminergic pharmacotherapy of apathy is in its infancy. A recent controlled trial of rivastigmine in 31 French subjects with moderate to severe apathy based on LARS showed that 6 months of treatment at 9.5 mg/day improved average scores from –11.5 to –20 compared with placebo. While quality of life did not improve, caregiver burden did. The investigators found in this group of subjects that apathy was a possible herald for early dementia in PD [53].

A post-hoc analysis of the ADAGIO study (rasagiline or placebo in PD patients taking antidepressants) found that rasagiline use was associated with a nonsignificant slowing of apathy development during the trial [54].

Psychosis

Psychotic symptoms are a common occurrence in drug-treated patients, with visual hallucinations occurring in up to 30%, though over a 20-year period up to three-quarters of patients may develop visual hallucinations.After visual, the most common type of hallucination is auditory, followed by the other affected senses such as tactile, olfactory, or even taste [57]. Delusions, which tend to be paranoid in nature, occur in about 5% of patients [55–57]. The presence of psychotic symptoms is associated with poorer quality of life [58].

Symptomatology

The visual hallucinations of PD are usually quite stereotyped, and have been described as “minor” and “non-minor”[59]. Minor hallucinations refer to transient peripheral field stimuli that disappear when brought into central focus, “something flashed by,” a sense of a living being nearby, “a presence in the room,” or illusions whereby objects are transformed, eg, a bush in the yard is a deer.

Auditory hallucinations tend to be vague or indistinct sounds, like music in another room as opposed to voices speaking directly to the patient as might be experienced in a primary psychotic disorder. Tactile forms often involve insects or other animals crawling on the skin. Olfactory hallucinations may take the form of smelling perfume, toxic odors from room vents, etc.

Early in the experience, the visual hallucinations may be amusing in that they consistently remain nonthreatening, similar day to day, and sometimes oddly provide an aspect of comfort or companionship to the patient. More commonly, the hallucinations are bothersome to the patient because the experience indicates to the patient that there is something wrong with their mind. Visual hallucinations often begin in low-stimulus environments, often in the evening or other low-light conditions, but as the problem advances they can occur at any time of day. While visual hallucinations may initially occur for only seconds at a time many days apart, the frequency and duration can increase until they occur hours at a time every day and are accompanied by multiple other visual hallucinations, delusions, and confusion [60].

Delusions tend to be more distressing to patients and caregivers because they are often paranoid in nature. The patient is more likely to act out due to the anxiety the paranoia creates. For example, she may change passwords to online accounts due to a belief that unknown assailants are after her finances. He may go to great lengths trying to prove his wife is cheating.

Risk Factors

While the primary risk factor for psychotic symptom development is dementia [57], it occurs in nondemented patients. Other associations include reduced visual acuity [56], visual processing impairment [61–65], use of dopamine agonists, REM behavior disorder, duration of PD, axial rigidity subtype of disease [61,66–68]. The pathophysiology of psychosis in PD is likely complex and remains currently unexplained. The role of excess dopamine has been described above, but there is also data suggesting cholinergic deficits in the cortex may also contribute. Excess serotonin (increased 5HT2A receptor subtypes) in the temporal lobe within the visual processing pathway has been postulated to be of significance [69,70]. Hypometabolism in visual association areas of the brain in subjects with visual hallucinations has been demonstrated in PET and functional MRI studies [64,71]. This is similar to findings in patients with dementia with Lewy bodies [72].

This review focuses on the primary forms of PD-related psychosis, which occur with a clear sensorium and generally longer exposure to dopaminergic medication. It is important to distinguish 2 other common scenarios in which hallucinations or delusions may occur. In the common toxic-metabolic delirium, a clouded sensorium with attention deficits may be the only clue to the etiology of new onset confusion with visual hallucinations. It is highly likely that resolution of the underlying medical problem will lead to resolution of the new onset psychosis and encephalopathy. In a second scenario, hallucinations precede or occur very shortly after the onset of initiation of dopaminergic medication. This differs from the classic syndrome described earlier, in particular when visual hallucinations precede any initiation of medication, and likely represents the distinction between a diagnosis of Lewy body disease and PD [60].

Treatment

Management of psychosis is approachable, but often the outcome is unsatisfactory and associated with trade-offs in motor control. It is unfortunately true that psychotic symptoms are often associated with increased caregiver burden and are a cause of increased nursing home placements [73]. When considering the workup of psychotic symptoms, the differential diagnosis includes delirium, dream enactment (REM behavior disorder), or less commonly, Bonnet syndrome.

A delirium may be precipitated by a difficult to diagnose infection; new-onset confusion and psychotic symptoms may be the heralding presentation. Urinary tract or upper respiratory tract are common vulnerable sources of infection. Once infection is ruled out, the next practical step is to review the patient’s medication list and manage centrally acting drugs that could be contributing to the altered sensorium. A recent prescription of opioids for a dental treatment or a new muscle relaxant may be a culprit, though it is not that usual. A bladder anticholinergic could be suspect and is worth eliminating especially if its addition coincided with the appearance of the psychotic symptoms. Once the non-dopaminergic medications have been reduced/eliminated, then the PD medications should be considered. The general approach is to eliminate the medications that provide the least benefit while being more likely to contribute to psychotic symptoms. Anticholinergic medications, dopamine agonists, selegiline should all be uppermost in that consideration until one is left with L-dopa and COMT inhibitors (the latter function to increase levodopa availability). Then COMT inhibitors and levodopa can be reduced; however, at any point motor control can suffer with the loss of symptomatic therapies [74].

Clozapine is effective against psychotic symptoms in PD, at doses much lower than used in schizophrenia (300-600mg/day). The average dose in the US randomized controlled clinical trial was 25 mg/day, with no associated motor worsening. Patients in the United States are required by the FDA to be placed in a computer-based registry and monitored for agranulocytosis for the duration of clozapine therapy. This rare adverse event is not dose related. Orthostasis can occur at these low doses however. Fortunately the metabolic syndrome is not associated with this range of administration [75,76].

Quetiapine was not found to be effective in 3 blinded randomized controlled trials despite its rather common use for this purpose. It was not associated with motor worsening, however.

Other neuroleptic medications have not resulted in widespread use, because trials have been open label, or outcomes demonstrated motor worsening. Cholinesterase inhibitors have been the subject of a few positive case series, however results appear to be sporadic, the effect size is relatively small, and side effects of this medication class are common [77–79]. It is clear that there is an unmet need for a medication for psychotic symptoms. Clozapine is effective but onerous in its monitoring requirements. Practically speaking, there are relatively few PD patients who take advantage of it because of its feasibility challenges. Yet the problem of psychotic symptoms is a significant one that imposes important challenges to the patient and caregiver, and may limit the number of medications that the patient needs in order to optimize quality of life.

Pimavanserin, a novel medication which acts as a selective serotonin inverse agonist, is in the early application stages for FDA approval for treatment of psychotic symptoms in PD [80]. In its pivotal phase III controlled trial, the drug reduced not only positive symptoms (hallucinations/delusions) without causing motoric worsening, but also reduced caregiver burden. Pimavanserin improved certain sleep features without causing daytime sedation. If this drug meets final approval, it may present an exciting option for many patients for whom treatment was previously limited.

Depression

A study of early PD suggested that depression is often unrecognized and frequently untreated [1]. Indeed it is not unusual for depression to predate the diagnosis of PD by an average of 4 to 6 years [81]. Expanding to the larger PD population, it is generally accepted that about 30% to 50% of PD patients experience clinically significant depression, and once diagnosed may have a long term course, or may recur [82,83]. This is important as untreated depression is an important cause of poor quality of life in early PD. In addition depression can exacerbate motor disability, lead to earlier motor treatment with medication, and increase caregiver stress [83–85].

Diagnosis

A number of clinimetric rating scales for depression have been used and their advantages have been largely related to their objective nature (quantifiable); thus, they tend to be most useful in epidemiologic research studies or for larger scale screening purposes. Examples include the the Beck Depression Inventory, the Geriatric Depression Scale, and the Hamilton Depression Scale, all of which have been shown to be valid tools in PD (with the exception of the UPDRS Depression). It is important to note that they do not substitute for a diagnostic clinical interview [89].

Suicide is not common in PD, however suicidal ideation is estimated at about 11% in PD patients [90], and while there was concern initially after deep brain stimulation procedures began that suicide incidence was increased, evidence does not support this [91].

Pathophysiology

The pathophysiology of depression in PD is largely unknown however is thought to be less causally due to psychosocial factors and more etiologically driven by brainstem monoamine and serotonergic dysfunction [92]. Nonetheless, similar to other chronic conditions, PD patients can certainly develop fear of disability, guilt about impact on others, or other reactive mood changes. Overall, rates of depression are higher in PD compared with patients with similar conditions matched for disability [93].

Treatment

First, the clinician must determine if depression is a result of short-term fluctuations, chronic undertreatment of motor disease, or longer-term mood phenomenon. One important pattern to recognize are mood fluctuations, which can parallel motor OFF-ON cycling. It can be valuable to distinguish this as “subsyndromic” depression or anxiety (sometimes referred to as “OFF dysphoria”), as it can respond to improvement in antiparkinsonian medication dosing patterns that reduce fluctuations[94–96]. Similarly, elevating chronic motor undertreatment to goal therapy can result in mood normalization.

If symptoms persist despite optimization of motor/nonmotor fluctuations or chronic undertreatment and are severe enough to warrant treatment, then therapies used can range from nonpharmacologic education, support, and mental health referrals, as well as pharmacologic support in the form of medications.

A frequent but uncontrolled observation was that when undertreatment of motor disease was finally redressed, mood often improved. A multicenter randomized controlled trial of pramipexole in PD patients without motor fluctuations but with mild to moderate depressive symptoms showed the drug improved scores on the Beck Depression Inventory over a 12-week period. The improvement in mood was 6 points overall, but by 2 points over placebo, illustrating the importance of the size of the placebo effect [97]. Given the potential side effect profile of dopamine agonists, it may be useful to weigh the antidepressant effects only when their motor benefits are already being employed.

Controlled trials have demonstrated efficacy of both selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) antidepressants in PD. Clinical trials have demonstrated efficacy against placebo or with other antidepressant comparators. Examples of drugs with demonstrated efficacy include citalopram, paroxetine, venlafaxine, and nortriptyline. Results have attempted to illuminate the small unique differences between classes of antidepressants or dynamic properties between drugs within a class. For example, desipramine may nudge scores on a mood scale a few weeks sooner than a purer SSRI. Paroxetine (SSRI) versus venlafaxine (SNRI) improved mood scores comparably in a multicenter trial with a placebo comparator. In general, all have all been demonstrated to be effective and with a relatively low side-effect profile, comparable to the general population[98–102]. While case reports exist in the literature, the interaction of monoamine oxidase B inhibitors and SSRIs has not caused significant hypertensive crises or risk of serotonin syndrome [103,104]. Electroconvulsive therapy (ECT) can be used for severe refractory depression in PD as for non-PD patients, with case reports of very effective results. Due to the rarity of use, systematic evidence for its use is lacking [105,106].

Other novel agents and techniques such as omega-3 fatty acids [107] and repetitive transcranial magnetic stimulation [108] have been reported with promising early results. Cognitive behavioral therapy (CBT), which may involve stress management techniques, sleep hygiene, and caregiver support, additionally almost always provided improvement in measured outcomes, whether the trial was controlled or open label in design. In one RCT of CBT in PD of 14 weeks’ duration, there were significantly more treatment responders in the CBT group, with a number needed to treat of only 2 [109].

Anxiety

Anxiety is also common in PD, at least as common as depression considering that prevalence estimates suggest up to 50% of patients experience it [110–112]. Manifestations of anxiety may include panic attacks, generalized anxiety disorder, social anxiety, or other phobias [113]. Anxiety has an important negative impact on health-related quality of life and is often underrecognized by clinicians [114]. While reliable and valid scales to measure anxiety have been lacking in PD, a new effort has yielded the “Parkinson Anxiety Scale” though full clinimetric properties of the scale remain to be demonstrated (sensitivity to change) [115].

Anxiety that parallels the timing of motor OFF-ON cycling is important to recognize. This “subsyndromic” anxiety or anxiety disorder not otherwise specified (ie, the anxiety does not meet DSM-IV criteria) can respond to improvement in antiparkinsonian medication dosing patterns that reduce fluctuations [116,117]. Indeed, the presence of motor fluctuations is the principle marker of anxiety in many studies [118–120]. In an analogous manner, anxiety can predate PD by years and be part of the nonmotor amalgam of features heralding the disease [6,121].

Treatment

Systematic controlled trials of anxiolytic treatment for PD are lacking; therefore, SSRIs are prescribed for this purpose as in non-PD patients. Until SSRIs are demonstrated to be of benefit in anxiety, they are likely safer than use of benzodiazepines, which are associated with risk for falling, cognitive dysfunction, or autonomic dysregulation in PD patients when used during waking hours. Psychotherapy and other nonpharmacologic approaches are likely to be of benefit. A small study of neuromuscular (massage) therapy demonstrated improvement on the Beck Anxiety Inventory in PD [122]. A case report of ECT for severe anxiety has been published [123].

Conclusion

Neuropsychiatric symptoms are common in PD and new knowledge about clinical features, epidemiology, and treatment options has been gained in the last decade, though much remains to be discovered. The development of valid instruments to measure neuropsychiatric symptoms has been vital in these research efforts to bridge the gaps in our understanding. Further elucidation of the pathophysiologies of neuropsychiatric symptoms will help to define treatment targets and likely fuel drug development and the discovery of drugs with more potent benefit and fewer side effects.

Corresponding author: Kathryn A. Chung, MD, Department of Neurology, Oregon Health & Science University, Portland, OR, [email protected].

Financial disclosures: None.

A 25-year-old woman is concerned about lesions on the dorsum of her right foot that first appeared about four months ago. Initially, there was one red lesion; several similarly colored lesions manifested within a few weeks. The original lesion darkened from red to brown before gradually fading to its current appearance. All the lesions are asymptomatic.

The patient denies injury to the foot. She denies any history of skin problems, including any similar lesions elsewhere on her body. She describes her general health as “quite good,” aside from mild seasonal allergies. She is taking no medications of any kind.

EXAMINATION
Three macular patches—each about 2.4 cm and roughly round, with sharp margins—are seen on the dorsum of her right foot. There is no palpable component to any of them, nor increased warmth or tenderness. Two are dark reddish brown, with nonblanchable redness. The middle lesion looks quite different—brownish gray—but it too is totally macular. Elsewhere, her type IV Hispanic skin is free of any notable lesions.

A shave biopsy is taken from one of the active (red) lesions. The pathology results indicate capillaritis.

What is the diagnosis?

DISCUSSION
When red inflammatory processes fail to blanch with digital pressure, we know that red blood cells (RBCs) have likely leaked from damaged blood vessels and stained the interstitial spaces. Generically, we call this purpura. On occasion, purpura can be an ominous sign, indicating a vasculitis such as leukocytoclastic vasculitis (LCV), in which an immune complex damages the walls of blood vessels that supply vital organs. This can occur in the context of a connective tissue disease, such as lupus, or an allergic reaction to an ingestant (food, drink, or medicine).

But there are specific histologic criteria (eg, nuclear dust from white blood cells that have expended themselves in attacking blood vessel walls and extravasated RBCs from these same leaky walls) for the diagnosis of LCV that were missing in this case. Significantly, the affected blood vessels in this case were capillaries, which are not affected by LCV.

The histologic and clinical findings put us squarely into a relatively benign group of conditions called capillaritis. Collectively, these are known as pigmented purpuris dermatoses; the most common is Schamberg disease (progressive pigmentary dermatosis). These dermatoses are characterized by extravasation of RBCs with marked hemosiderin deposition.

In this case, however, we’re looking at another common form, lichen aureus (LA). The lesions of LA are round to polygonal, sometimes shiny, and brownish red (which can look darker in patients with darker skin).

Schamberg lesions are said to resemble sprinkled cayenne pepper. They typically start on the lower legs and move upward to just below the knee, then slowly descend and resolve. This entire process will occur within a period of several months.

The cause of this family of dermatoses is unknown, but, thankfully, they are all asymptomatic and self-limited. Topical and systemic treatment does not help.

The differential also includes granulomatous disease (eg, granuloma annulare) and fixed drug eruption. Biopsy, as in this case, is often warranted.

TAKE-HOME LEARNING POINTS
• Lichen aureus and Schamberg disease are the most common forms of capillaritis, a benign condition usually affecting the legs and feet.

• These forms of capillaritis are caused by extravasation of red blood cells (RBCs) from damaged capillaries.

• They typically manifest with brownish red macules and patches that do not blanch with digital pressure.

• The cause of capillaritis is unknown, although it is clear that it results from damage to capillary vessel walls that allows RBCs to leak into the interstitial tissues.

• The main item in the differential is leukocytoclastic vasculitis (LCV), which is of more acute onset and usually has a petichial appearance. Since it has systemic implications, suspected LCV must be confirmed or ruled out with biopsy. 

A 25-year-old woman is concerned about lesions on the dorsum of her right foot that first appeared about four months ago. Initially, there was one red lesion; several similarly colored lesions manifested within a few weeks. The original lesion darkened from red to brown before gradually fading to its current appearance. All the lesions are asymptomatic.

The patient denies injury to the foot. She denies any history of skin problems, including any similar lesions elsewhere on her body. She describes her general health as “quite good,” aside from mild seasonal allergies. She is taking no medications of any kind.

EXAMINATION
Three macular patches—each about 2.4 cm and roughly round, with sharp margins—are seen on the dorsum of her right foot. There is no palpable component to any of them, nor increased warmth or tenderness. Two are dark reddish brown, with nonblanchable redness. The middle lesion looks quite different—brownish gray—but it too is totally macular. Elsewhere, her type IV Hispanic skin is free of any notable lesions.

A shave biopsy is taken from one of the active (red) lesions. The pathology results indicate capillaritis.

What is the diagnosis?

DISCUSSION
When red inflammatory processes fail to blanch with digital pressure, we know that red blood cells (RBCs) have likely leaked from damaged blood vessels and stained the interstitial spaces. Generically, we call this purpura. On occasion, purpura can be an ominous sign, indicating a vasculitis such as leukocytoclastic vasculitis (LCV), in which an immune complex damages the walls of blood vessels that supply vital organs. This can occur in the context of a connective tissue disease, such as lupus, or an allergic reaction to an ingestant (food, drink, or medicine).

But there are specific histologic criteria (eg, nuclear dust from white blood cells that have expended themselves in attacking blood vessel walls and extravasated RBCs from these same leaky walls) for the diagnosis of LCV that were missing in this case. Significantly, the affected blood vessels in this case were capillaries, which are not affected by LCV.

The histologic and clinical findings put us squarely into a relatively benign group of conditions called capillaritis. Collectively, these are known as pigmented purpuris dermatoses; the most common is Schamberg disease (progressive pigmentary dermatosis). These dermatoses are characterized by extravasation of RBCs with marked hemosiderin deposition.

In this case, however, we’re looking at another common form, lichen aureus (LA). The lesions of LA are round to polygonal, sometimes shiny, and brownish red (which can look darker in patients with darker skin).

Schamberg lesions are said to resemble sprinkled cayenne pepper. They typically start on the lower legs and move upward to just below the knee, then slowly descend and resolve. This entire process will occur within a period of several months.

The cause of this family of dermatoses is unknown, but, thankfully, they are all asymptomatic and self-limited. Topical and systemic treatment does not help.

The differential also includes granulomatous disease (eg, granuloma annulare) and fixed drug eruption. Biopsy, as in this case, is often warranted.

TAKE-HOME LEARNING POINTS
• Lichen aureus and Schamberg disease are the most common forms of capillaritis, a benign condition usually affecting the legs and feet.

• These forms of capillaritis are caused by extravasation of red blood cells (RBCs) from damaged capillaries.

• They typically manifest with brownish red macules and patches that do not blanch with digital pressure.

• The cause of capillaritis is unknown, although it is clear that it results from damage to capillary vessel walls that allows RBCs to leak into the interstitial tissues.

• The main item in the differential is leukocytoclastic vasculitis (LCV), which is of more acute onset and usually has a petichial appearance. Since it has systemic implications, suspected LCV must be confirmed or ruled out with biopsy. 

A 25-year-old woman is concerned about lesions on the dorsum of her right foot that first appeared about four months ago. Initially, there was one red lesion; several similarly colored lesions manifested within a few weeks. The original lesion darkened from red to brown before gradually fading to its current appearance. All the lesions are asymptomatic.

The patient denies injury to the foot. She denies any history of skin problems, including any similar lesions elsewhere on her body. She describes her general health as “quite good,” aside from mild seasonal allergies. She is taking no medications of any kind.

EXAMINATION
Three macular patches—each about 2.4 cm and roughly round, with sharp margins—are seen on the dorsum of her right foot. There is no palpable component to any of them, nor increased warmth or tenderness. Two are dark reddish brown, with nonblanchable redness. The middle lesion looks quite different—brownish gray—but it too is totally macular. Elsewhere, her type IV Hispanic skin is free of any notable lesions.

A shave biopsy is taken from one of the active (red) lesions. The pathology results indicate capillaritis.

What is the diagnosis?

DISCUSSION
When red inflammatory processes fail to blanch with digital pressure, we know that red blood cells (RBCs) have likely leaked from damaged blood vessels and stained the interstitial spaces. Generically, we call this purpura. On occasion, purpura can be an ominous sign, indicating a vasculitis such as leukocytoclastic vasculitis (LCV), in which an immune complex damages the walls of blood vessels that supply vital organs. This can occur in the context of a connective tissue disease, such as lupus, or an allergic reaction to an ingestant (food, drink, or medicine).

But there are specific histologic criteria (eg, nuclear dust from white blood cells that have expended themselves in attacking blood vessel walls and extravasated RBCs from these same leaky walls) for the diagnosis of LCV that were missing in this case. Significantly, the affected blood vessels in this case were capillaries, which are not affected by LCV.

The histologic and clinical findings put us squarely into a relatively benign group of conditions called capillaritis. Collectively, these are known as pigmented purpuris dermatoses; the most common is Schamberg disease (progressive pigmentary dermatosis). These dermatoses are characterized by extravasation of RBCs with marked hemosiderin deposition.

In this case, however, we’re looking at another common form, lichen aureus (LA). The lesions of LA are round to polygonal, sometimes shiny, and brownish red (which can look darker in patients with darker skin).

Schamberg lesions are said to resemble sprinkled cayenne pepper. They typically start on the lower legs and move upward to just below the knee, then slowly descend and resolve. This entire process will occur within a period of several months.

The cause of this family of dermatoses is unknown, but, thankfully, they are all asymptomatic and self-limited. Topical and systemic treatment does not help.

The differential also includes granulomatous disease (eg, granuloma annulare) and fixed drug eruption. Biopsy, as in this case, is often warranted.

TAKE-HOME LEARNING POINTS
• Lichen aureus and Schamberg disease are the most common forms of capillaritis, a benign condition usually affecting the legs and feet.

• These forms of capillaritis are caused by extravasation of red blood cells (RBCs) from damaged capillaries.

• They typically manifest with brownish red macules and patches that do not blanch with digital pressure.

• The cause of capillaritis is unknown, although it is clear that it results from damage to capillary vessel walls that allows RBCs to leak into the interstitial tissues.

• The main item in the differential is leukocytoclastic vasculitis (LCV), which is of more acute onset and usually has a petichial appearance. Since it has systemic implications, suspected LCV must be confirmed or ruled out with biopsy. 

The bispecific factor VIII–mimetic antibody ACE910 has a longer half-life than current hemophilia A treatments, potentially offering a more convenient once-weekly, subcutaneous injection, based on a study published in Blood.

In a phase I study, ACE910 was well tolerated at doses up to 1 mg/kg, with an average half life of 28 to 34 days. Based on tests in FVIII-depleted plasma, ACE910 shortened activated partial thromboplastin time (APTT) and increased peak height of thrombin generation, and exhibited a long-lasting response throughout the 24-week study period. ACE910 at 1 mg/kg resulted in APTT similar to that seen in normal plasma, although the peak height of thrombin generation did not reach normal levels.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The findings suggest “that ACE910 has the potential to reduce bleeding frequency in patients with severe hemophilia A to that of patients with mild hemophilia A, even at less frequent dosing, compared with existing FVIII and bypassing drugs. Furthermore, ACE910 may change the treatment paradigm from the current approach of maintaining trough levels of FVIII:C greater than 1% to a new approach of maintaining a constant hemostatic activity corresponding to a mild hemophilia A level,” wrote Dr. Naoki Uchida of Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, and colleagues (Blood. 2016 Apr 7. doi: 10.1182/blood-2015-06-650226).

Adverse events were comparable with those of placebo; 13 of 48 subjects who received ACE910 reported 15 adverse events, compared with 6 adverse events reported by 4 of 16 subjects who received placebo. Except for moderate nasopharyngitis reported in one subject, all adverse events were mild, were not dose dependent, and were similar for Japanese and white subjects. Clinical and laboratory findings showed normal coagulability with ACE910 administered at any dose.

An anti-drug antibody response was observed in 2 of 48 patients (1 Japanese, 1 white) both at 0.1 mg/kg ACE910. The anti-drug antibody responses were not IgE mediated, and no allergic symptoms were observed.

The bispecific factor VIII–mimetic antibody ACE910 has a longer half-life than current hemophilia A treatments, potentially offering a more convenient once-weekly, subcutaneous injection, based on a study published in Blood.

In a phase I study, ACE910 was well tolerated at doses up to 1 mg/kg, with an average half life of 28 to 34 days. Based on tests in FVIII-depleted plasma, ACE910 shortened activated partial thromboplastin time (APTT) and increased peak height of thrombin generation, and exhibited a long-lasting response throughout the 24-week study period. ACE910 at 1 mg/kg resulted in APTT similar to that seen in normal plasma, although the peak height of thrombin generation did not reach normal levels.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The findings suggest “that ACE910 has the potential to reduce bleeding frequency in patients with severe hemophilia A to that of patients with mild hemophilia A, even at less frequent dosing, compared with existing FVIII and bypassing drugs. Furthermore, ACE910 may change the treatment paradigm from the current approach of maintaining trough levels of FVIII:C greater than 1% to a new approach of maintaining a constant hemostatic activity corresponding to a mild hemophilia A level,” wrote Dr. Naoki Uchida of Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, and colleagues (Blood. 2016 Apr 7. doi: 10.1182/blood-2015-06-650226).

Adverse events were comparable with those of placebo; 13 of 48 subjects who received ACE910 reported 15 adverse events, compared with 6 adverse events reported by 4 of 16 subjects who received placebo. Except for moderate nasopharyngitis reported in one subject, all adverse events were mild, were not dose dependent, and were similar for Japanese and white subjects. Clinical and laboratory findings showed normal coagulability with ACE910 administered at any dose.

An anti-drug antibody response was observed in 2 of 48 patients (1 Japanese, 1 white) both at 0.1 mg/kg ACE910. The anti-drug antibody responses were not IgE mediated, and no allergic symptoms were observed.

The bispecific factor VIII–mimetic antibody ACE910 has a longer half-life than current hemophilia A treatments, potentially offering a more convenient once-weekly, subcutaneous injection, based on a study published in Blood.

In a phase I study, ACE910 was well tolerated at doses up to 1 mg/kg, with an average half life of 28 to 34 days. Based on tests in FVIII-depleted plasma, ACE910 shortened activated partial thromboplastin time (APTT) and increased peak height of thrombin generation, and exhibited a long-lasting response throughout the 24-week study period. ACE910 at 1 mg/kg resulted in APTT similar to that seen in normal plasma, although the peak height of thrombin generation did not reach normal levels.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The findings suggest “that ACE910 has the potential to reduce bleeding frequency in patients with severe hemophilia A to that of patients with mild hemophilia A, even at less frequent dosing, compared with existing FVIII and bypassing drugs. Furthermore, ACE910 may change the treatment paradigm from the current approach of maintaining trough levels of FVIII:C greater than 1% to a new approach of maintaining a constant hemostatic activity corresponding to a mild hemophilia A level,” wrote Dr. Naoki Uchida of Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, and colleagues (Blood. 2016 Apr 7. doi: 10.1182/blood-2015-06-650226).

Adverse events were comparable with those of placebo; 13 of 48 subjects who received ACE910 reported 15 adverse events, compared with 6 adverse events reported by 4 of 16 subjects who received placebo. Except for moderate nasopharyngitis reported in one subject, all adverse events were mild, were not dose dependent, and were similar for Japanese and white subjects. Clinical and laboratory findings showed normal coagulability with ACE910 administered at any dose.

An anti-drug antibody response was observed in 2 of 48 patients (1 Japanese, 1 white) both at 0.1 mg/kg ACE910. The anti-drug antibody responses were not IgE mediated, and no allergic symptoms were observed.

Okay, let’s try this one more time. We agree that vaccine rates are declining and that the outbreak of measles believed to have spread from an index case at Disneyland is an example of the risk this country faces from those declining rates. In the last few years, there has been at least one study that found that providing vaccine-hesitant families with factual provaccine information failed to change parental attitudes. In fact, the educational effort backfired in some cases, and hesitant parents found other arguments to support their flawed positions. An equally discouraging study presented in the last year suggests that parents have already decided whether they will vaccinate even before they enter into childbearing, long before pediatricians have an opportunity to present their case.

In the face of this dismal landscape of antiscience, some pediatricians have decided to discharge vaccine-refusing families from their practices. Although this approach may create a thin shell of protection against some malpractice suits, and provide their youngest patients a shred of protection from waiting-room acquired infection, it has no effect on the larger problem facing this country.

A study from the University of Illinois published in the Proceedings of the National Academy of Sciences entitled, “Countering anti-vaccine attitudes” (PNAS 2015 Aug 18;112[33]:10321-4) suggests that we may have been too timid in choosing our strategies to combat the antivaccine epidemic. From a group of more than 800 individuals across a broad economic base, a smaller group of 315 was culled using several strategies to ensure that the participants were paying attention. They were then divided into three subgroups whose pretest vaccine attitudes did not differ.

One group was presented with materials that included photographs of ill children with rashes and a testimonial from the mother whose child had had measles. A second group was presented with articles exposing the myth of a relationship between autism and the measles-mumps-rubella vaccine. This group was labeled the “autism correction” group. The control group was presented with several scientific articles unrelated to vaccines.

The researchers found that while the control group and the autism correction group showed no change in their attitudes to vaccines, those individuals presented with graphic evidence of the risk of disease did demonstrate a significant change in attitude. So, the message would seem to be that scaring parents might work.

I’m not sure why pediatricians have been so hesitant to employ scare tactics in the past. While you and I may be more easily convinced by science-based evidence than the average parent, we also have seen children with vaccine-preventable diseases or at least seen pictures and heard their horrible histories. I suspect that our provaccine attitudes are colored more by the horrors that we have seen and heard than by our lip service to the sanctity of science.

We may have been too worried about being labeled as fear mongers if we showed graphic pictures of sick and dying children and promoted tear-jerking testimonials from parents. If we were a business whose bottom line depended on selling vaccines, our marketing and advertising folks would have sent us on the fear-generating pathway long ago.

It is time to ask ourselves if the situation is so dire that it is time to stop pussyfooting around with soft educational messages and begin trying to scare the vaccine deniers into protecting their children – and everyone else’s.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

Okay, let’s try this one more time. We agree that vaccine rates are declining and that the outbreak of measles believed to have spread from an index case at Disneyland is an example of the risk this country faces from those declining rates. In the last few years, there has been at least one study that found that providing vaccine-hesitant families with factual provaccine information failed to change parental attitudes. In fact, the educational effort backfired in some cases, and hesitant parents found other arguments to support their flawed positions. An equally discouraging study presented in the last year suggests that parents have already decided whether they will vaccinate even before they enter into childbearing, long before pediatricians have an opportunity to present their case.

In the face of this dismal landscape of antiscience, some pediatricians have decided to discharge vaccine-refusing families from their practices. Although this approach may create a thin shell of protection against some malpractice suits, and provide their youngest patients a shred of protection from waiting-room acquired infection, it has no effect on the larger problem facing this country.

A study from the University of Illinois published in the Proceedings of the National Academy of Sciences entitled, “Countering anti-vaccine attitudes” (PNAS 2015 Aug 18;112[33]:10321-4) suggests that we may have been too timid in choosing our strategies to combat the antivaccine epidemic. From a group of more than 800 individuals across a broad economic base, a smaller group of 315 was culled using several strategies to ensure that the participants were paying attention. They were then divided into three subgroups whose pretest vaccine attitudes did not differ.

One group was presented with materials that included photographs of ill children with rashes and a testimonial from the mother whose child had had measles. A second group was presented with articles exposing the myth of a relationship between autism and the measles-mumps-rubella vaccine. This group was labeled the “autism correction” group. The control group was presented with several scientific articles unrelated to vaccines.

The researchers found that while the control group and the autism correction group showed no change in their attitudes to vaccines, those individuals presented with graphic evidence of the risk of disease did demonstrate a significant change in attitude. So, the message would seem to be that scaring parents might work.

I’m not sure why pediatricians have been so hesitant to employ scare tactics in the past. While you and I may be more easily convinced by science-based evidence than the average parent, we also have seen children with vaccine-preventable diseases or at least seen pictures and heard their horrible histories. I suspect that our provaccine attitudes are colored more by the horrors that we have seen and heard than by our lip service to the sanctity of science.

We may have been too worried about being labeled as fear mongers if we showed graphic pictures of sick and dying children and promoted tear-jerking testimonials from parents. If we were a business whose bottom line depended on selling vaccines, our marketing and advertising folks would have sent us on the fear-generating pathway long ago.

It is time to ask ourselves if the situation is so dire that it is time to stop pussyfooting around with soft educational messages and begin trying to scare the vaccine deniers into protecting their children – and everyone else’s.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

Okay, let’s try this one more time. We agree that vaccine rates are declining and that the outbreak of measles believed to have spread from an index case at Disneyland is an example of the risk this country faces from those declining rates. In the last few years, there has been at least one study that found that providing vaccine-hesitant families with factual provaccine information failed to change parental attitudes. In fact, the educational effort backfired in some cases, and hesitant parents found other arguments to support their flawed positions. An equally discouraging study presented in the last year suggests that parents have already decided whether they will vaccinate even before they enter into childbearing, long before pediatricians have an opportunity to present their case.

In the face of this dismal landscape of antiscience, some pediatricians have decided to discharge vaccine-refusing families from their practices. Although this approach may create a thin shell of protection against some malpractice suits, and provide their youngest patients a shred of protection from waiting-room acquired infection, it has no effect on the larger problem facing this country.

A study from the University of Illinois published in the Proceedings of the National Academy of Sciences entitled, “Countering anti-vaccine attitudes” (PNAS 2015 Aug 18;112[33]:10321-4) suggests that we may have been too timid in choosing our strategies to combat the antivaccine epidemic. From a group of more than 800 individuals across a broad economic base, a smaller group of 315 was culled using several strategies to ensure that the participants were paying attention. They were then divided into three subgroups whose pretest vaccine attitudes did not differ.

One group was presented with materials that included photographs of ill children with rashes and a testimonial from the mother whose child had had measles. A second group was presented with articles exposing the myth of a relationship between autism and the measles-mumps-rubella vaccine. This group was labeled the “autism correction” group. The control group was presented with several scientific articles unrelated to vaccines.

The researchers found that while the control group and the autism correction group showed no change in their attitudes to vaccines, those individuals presented with graphic evidence of the risk of disease did demonstrate a significant change in attitude. So, the message would seem to be that scaring parents might work.

I’m not sure why pediatricians have been so hesitant to employ scare tactics in the past. While you and I may be more easily convinced by science-based evidence than the average parent, we also have seen children with vaccine-preventable diseases or at least seen pictures and heard their horrible histories. I suspect that our provaccine attitudes are colored more by the horrors that we have seen and heard than by our lip service to the sanctity of science.

We may have been too worried about being labeled as fear mongers if we showed graphic pictures of sick and dying children and promoted tear-jerking testimonials from parents. If we were a business whose bottom line depended on selling vaccines, our marketing and advertising folks would have sent us on the fear-generating pathway long ago.

It is time to ask ourselves if the situation is so dire that it is time to stop pussyfooting around with soft educational messages and begin trying to scare the vaccine deniers into protecting their children – and everyone else’s.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

Steatosis may be present in at least half of liver transplant recipients, and the prevalence increases significantly over time, according to data from a retrospective study of 548 adult patients.

Although steatosis is common after transplantation, the prevalence, risk factors, and impact on patient survival has not been well studied, wrote Dr. Irena Hejlova of the Institute for Clinical and Experimental Medicine in Prague, Czech Republic, and her colleagues.

Courtesy of Wikimedia / Nephron / Creative Commons License

“Our study was the first to document that the prevalence of steatosis in LT [liver transplant] recipients may be far higher than previously reported,” they said.

The researchers reviewed liver biopsies and patient survival data and found steatosis in 309 (56%) of the patients, including 93 (17%) with significant steatosis (defined as greater than 33%). Pretransplant factors associated with significant steatosis included cirrhosis caused by alcohol consumption as well as a high body mass index. Post-transplant risk factors associated with increased risk of significant steatosis included increased body mass index, increased serum triglycerides, alcohol consumption, and type 2 diabetes. However, “Although patients transplanted for alcoholic cirrhosis are at an increased risk, the vast majority of post-transplant steatosis is nonalcohol-related,” the researchers noted.

The overall prevalence of steatosis increased from 30% at 1 year after transplant to 48% at 10 years after transplant. Post-transplant steatosis was not associated with worse patient survival in the short term, but the long-term survival of patients with significant steatosis tended to be worse.

Read the full study here (Liver Transpl. 2016 Apr 5. doi: 10.1002/lt.24393).

Steatosis may be present in at least half of liver transplant recipients, and the prevalence increases significantly over time, according to data from a retrospective study of 548 adult patients.

Although steatosis is common after transplantation, the prevalence, risk factors, and impact on patient survival has not been well studied, wrote Dr. Irena Hejlova of the Institute for Clinical and Experimental Medicine in Prague, Czech Republic, and her colleagues.

Courtesy of Wikimedia / Nephron / Creative Commons License

“Our study was the first to document that the prevalence of steatosis in LT [liver transplant] recipients may be far higher than previously reported,” they said.

The researchers reviewed liver biopsies and patient survival data and found steatosis in 309 (56%) of the patients, including 93 (17%) with significant steatosis (defined as greater than 33%). Pretransplant factors associated with significant steatosis included cirrhosis caused by alcohol consumption as well as a high body mass index. Post-transplant risk factors associated with increased risk of significant steatosis included increased body mass index, increased serum triglycerides, alcohol consumption, and type 2 diabetes. However, “Although patients transplanted for alcoholic cirrhosis are at an increased risk, the vast majority of post-transplant steatosis is nonalcohol-related,” the researchers noted.

The overall prevalence of steatosis increased from 30% at 1 year after transplant to 48% at 10 years after transplant. Post-transplant steatosis was not associated with worse patient survival in the short term, but the long-term survival of patients with significant steatosis tended to be worse.

Read the full study here (Liver Transpl. 2016 Apr 5. doi: 10.1002/lt.24393).

Steatosis may be present in at least half of liver transplant recipients, and the prevalence increases significantly over time, according to data from a retrospective study of 548 adult patients.

Although steatosis is common after transplantation, the prevalence, risk factors, and impact on patient survival has not been well studied, wrote Dr. Irena Hejlova of the Institute for Clinical and Experimental Medicine in Prague, Czech Republic, and her colleagues.

Courtesy of Wikimedia / Nephron / Creative Commons License

“Our study was the first to document that the prevalence of steatosis in LT [liver transplant] recipients may be far higher than previously reported,” they said.

The researchers reviewed liver biopsies and patient survival data and found steatosis in 309 (56%) of the patients, including 93 (17%) with significant steatosis (defined as greater than 33%). Pretransplant factors associated with significant steatosis included cirrhosis caused by alcohol consumption as well as a high body mass index. Post-transplant risk factors associated with increased risk of significant steatosis included increased body mass index, increased serum triglycerides, alcohol consumption, and type 2 diabetes. However, “Although patients transplanted for alcoholic cirrhosis are at an increased risk, the vast majority of post-transplant steatosis is nonalcohol-related,” the researchers noted.

The overall prevalence of steatosis increased from 30% at 1 year after transplant to 48% at 10 years after transplant. Post-transplant steatosis was not associated with worse patient survival in the short term, but the long-term survival of patients with significant steatosis tended to be worse.

Read the full study here (Liver Transpl. 2016 Apr 5. doi: 10.1002/lt.24393).

Some types of human papillomavirus (HPV) that are implicated in a variety of cancers have been suggested as a risk factor for esophageal cancer. However, the frequency of HPV infection in patients with esophageal premalignant lesions or carcinomas varies as widely as 0% to 88% in different studies, say researchers from Affiliated Cancer Hospital of Zhengzhou University, in Zhengzhou, China.

The most common high-risk oncogenic subtypes are HPV-16 and HPV-18. One meta-analysis found HPV-16 in 38% of esophageal cancer cases. But HPV-18 is less defined, the researchers say. They conducted a meta-analysis to determine the prevalence of HPV-18 in China, which has one of the highest rates in the world of esophageal cancer as well as one of the highest rates of HPV prevalence in esophageal squamous cell carcinoma.

Related: Tracking a Tumor

Their analysis of 19 studies included 2,556 cases of esophageal cancer. Overall, the prevalence of HPV-18 was > 4%—less than cervical cancer (15.3%), ovarian cancer (12.2%), laryngeal cancer (6.2%), bladder cancer (5.9%), and lung cancer (5.6%). The estimates of HPV prevalence in esophageal cancer varied widely, the researchers found, by geographic region.

Related: Promising Method to Evaluate Response to Treatment

Although their study doesn’t answer the question of etiology of HPV and esophageal cancer, the researchers say it is an important preliminary step toward evaluating the relationship. They add that their findings could also give some indication of the effect of the HPV vaccine against esophageal cancer.

Source:Guo LW, Zhang SK, Liu SZ, et al. Epidemiol Infect. 2016;144(3):469-477.doi: 10.1017/S0950268815001703.

Some types of human papillomavirus (HPV) that are implicated in a variety of cancers have been suggested as a risk factor for esophageal cancer. However, the frequency of HPV infection in patients with esophageal premalignant lesions or carcinomas varies as widely as 0% to 88% in different studies, say researchers from Affiliated Cancer Hospital of Zhengzhou University, in Zhengzhou, China.

The most common high-risk oncogenic subtypes are HPV-16 and HPV-18. One meta-analysis found HPV-16 in 38% of esophageal cancer cases. But HPV-18 is less defined, the researchers say. They conducted a meta-analysis to determine the prevalence of HPV-18 in China, which has one of the highest rates in the world of esophageal cancer as well as one of the highest rates of HPV prevalence in esophageal squamous cell carcinoma.

Related: Tracking a Tumor

Their analysis of 19 studies included 2,556 cases of esophageal cancer. Overall, the prevalence of HPV-18 was > 4%—less than cervical cancer (15.3%), ovarian cancer (12.2%), laryngeal cancer (6.2%), bladder cancer (5.9%), and lung cancer (5.6%). The estimates of HPV prevalence in esophageal cancer varied widely, the researchers found, by geographic region.

Related: Promising Method to Evaluate Response to Treatment

Although their study doesn’t answer the question of etiology of HPV and esophageal cancer, the researchers say it is an important preliminary step toward evaluating the relationship. They add that their findings could also give some indication of the effect of the HPV vaccine against esophageal cancer.

Source:Guo LW, Zhang SK, Liu SZ, et al. Epidemiol Infect. 2016;144(3):469-477.doi: 10.1017/S0950268815001703.

Some types of human papillomavirus (HPV) that are implicated in a variety of cancers have been suggested as a risk factor for esophageal cancer. However, the frequency of HPV infection in patients with esophageal premalignant lesions or carcinomas varies as widely as 0% to 88% in different studies, say researchers from Affiliated Cancer Hospital of Zhengzhou University, in Zhengzhou, China.

The most common high-risk oncogenic subtypes are HPV-16 and HPV-18. One meta-analysis found HPV-16 in 38% of esophageal cancer cases. But HPV-18 is less defined, the researchers say. They conducted a meta-analysis to determine the prevalence of HPV-18 in China, which has one of the highest rates in the world of esophageal cancer as well as one of the highest rates of HPV prevalence in esophageal squamous cell carcinoma.

Related: Tracking a Tumor

Their analysis of 19 studies included 2,556 cases of esophageal cancer. Overall, the prevalence of HPV-18 was > 4%—less than cervical cancer (15.3%), ovarian cancer (12.2%), laryngeal cancer (6.2%), bladder cancer (5.9%), and lung cancer (5.6%). The estimates of HPV prevalence in esophageal cancer varied widely, the researchers found, by geographic region.

Related: Promising Method to Evaluate Response to Treatment

Although their study doesn’t answer the question of etiology of HPV and esophageal cancer, the researchers say it is an important preliminary step toward evaluating the relationship. They add that their findings could also give some indication of the effect of the HPV vaccine against esophageal cancer.

Source:Guo LW, Zhang SK, Liu SZ, et al. Epidemiol Infect. 2016;144(3):469-477.doi: 10.1017/S0950268815001703.

The management of symptomatic uterine fibroids in the patient desiring conservative surgical therapy can be challenging at times. The advent of robot-assisted laparoscopy has provided surgeons with an enabling tool and patients with the option for a minimally invasive approach to myomectomy.

This month’s video was produced in order to demonstrate a systematic approach to the robot-assisted laparoscopic myomectomy in patients who are candidates. The example case is removal of a 5-cm, intrauterine posterior myoma in a 39-year-old woman (G3P1021) with heavy menstrual bleeding who desires future fertility.

Key objectives of the video include:

Also integrated into this video is the application of the ExCITE technique—a manual cold knife tissue extraction technique utilizing an extracorporeal semi-circle “C-incision” approach—for tissue extraction. This technique was featured in an earlier installment of the video channel.¹

I hope that you find this month’s video helpful to your surgical practice.

Vidyard Video

 

Share your thoughts on this video! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The management of symptomatic uterine fibroids in the patient desiring conservative surgical therapy can be challenging at times. The advent of robot-assisted laparoscopy has provided surgeons with an enabling tool and patients with the option for a minimally invasive approach to myomectomy.

This month’s video was produced in order to demonstrate a systematic approach to the robot-assisted laparoscopic myomectomy in patients who are candidates. The example case is removal of a 5-cm, intrauterine posterior myoma in a 39-year-old woman (G3P1021) with heavy menstrual bleeding who desires future fertility.

Key objectives of the video include:

Also integrated into this video is the application of the ExCITE technique—a manual cold knife tissue extraction technique utilizing an extracorporeal semi-circle “C-incision” approach—for tissue extraction. This technique was featured in an earlier installment of the video channel.¹

I hope that you find this month’s video helpful to your surgical practice.

Vidyard Video

 

Share your thoughts on this video! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The management of symptomatic uterine fibroids in the patient desiring conservative surgical therapy can be challenging at times. The advent of robot-assisted laparoscopy has provided surgeons with an enabling tool and patients with the option for a minimally invasive approach to myomectomy.

This month’s video was produced in order to demonstrate a systematic approach to the robot-assisted laparoscopic myomectomy in patients who are candidates. The example case is removal of a 5-cm, intrauterine posterior myoma in a 39-year-old woman (G3P1021) with heavy menstrual bleeding who desires future fertility.

Key objectives of the video include:

Also integrated into this video is the application of the ExCITE technique—a manual cold knife tissue extraction technique utilizing an extracorporeal semi-circle “C-incision” approach—for tissue extraction. This technique was featured in an earlier installment of the video channel.¹

I hope that you find this month’s video helpful to your surgical practice.

Vidyard Video

 

Share your thoughts on this video! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Diagnosis: Lymphomatoid papulosis

Lymphomatoid papulosis is a rare, chronic, and benign papulonodular or papulonecrotic skin disorder. LyP affects people of all ages, and its peak incidence occurs in the 5th decade. It generally has no predilection for a particular sex; however, some have reported a slight predominance in males. Patients of all races may be diagnosed with LyP, although it is less common in black patients. In addition, 10% of LyP cases are associated with anaplastic large cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin’s lymphoma.

Patients typically present with multiple erythematous papules that evolve into red-brown papulopustular or papulovesicular lesions. The papules may be mildly pruritic or asymptomatic and can be few in number to hundreds at presentation. The lesions usually appear in crops that resolve within 2-8 weeks with or without scarring, and can continue this cyclic process for months to years. The arms, legs, and trunk are most commonly affected, although LyP can present anywhere on the body.

The diagnosis of LyP is classically based upon histopathologic examination. Hematoxylin and eosin staining reveals a dense dermal infiltrate of atypical lymphocytes along with numerous eosinophils and neutrophils; lymphocytes are CD30+. Vessels in the dermis also appear with fibrin deposition, endothelial edema, and red blood cell extravasation. In addition, LyP can be classified as type A, type B, type C, and/or type D. These subtypes are determined by the size of atypical lymphocytes, type of atypical cells, location and amount of infiltrate, and CD30 and CD8 staining.

The differential diagnosis of LyP includes anaplastic large cell lymphoma, cutaneous T-cell lymphoma, folliculitis, insect bites, Langerhans cell histiocytosis, leukemia cutis, milia, miliaria, and scabies.

The etiology of LyP is unknown. It is unclear whether the proliferation of T cells is a benign and chronic disorder initiated by a stimulus or an indolent T-cell malignancy that the immune system monitors and only allows for localized, cutaneous involvement.

Mild forms of LyP can often be managed with topical corticosteroids. However, other therapies such as intralesional corticosteroids, phototherapy (UVB or PUVA), tetracycline antibiotics, and methotrexate are effective in treating cases of more persistent and widespread disease.

Our patient’s biopsy showed an irregular epidermis with scale, focal ulceration, scattered eosinophils, and dermal lymphocytes and histiocytes present in a perivascular pattern. Many of the lymphoid cells were enlarged, hyperchromatic, and irregular. Immunohistochemical staining was CD30+. These histologic changes were most consistent with lymphomatoid papulosis. 

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].

Diagnosis: Lymphomatoid papulosis

Lymphomatoid papulosis is a rare, chronic, and benign papulonodular or papulonecrotic skin disorder. LyP affects people of all ages, and its peak incidence occurs in the 5th decade. It generally has no predilection for a particular sex; however, some have reported a slight predominance in males. Patients of all races may be diagnosed with LyP, although it is less common in black patients. In addition, 10% of LyP cases are associated with anaplastic large cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin’s lymphoma.

Patients typically present with multiple erythematous papules that evolve into red-brown papulopustular or papulovesicular lesions. The papules may be mildly pruritic or asymptomatic and can be few in number to hundreds at presentation. The lesions usually appear in crops that resolve within 2-8 weeks with or without scarring, and can continue this cyclic process for months to years. The arms, legs, and trunk are most commonly affected, although LyP can present anywhere on the body.

The diagnosis of LyP is classically based upon histopathologic examination. Hematoxylin and eosin staining reveals a dense dermal infiltrate of atypical lymphocytes along with numerous eosinophils and neutrophils; lymphocytes are CD30+. Vessels in the dermis also appear with fibrin deposition, endothelial edema, and red blood cell extravasation. In addition, LyP can be classified as type A, type B, type C, and/or type D. These subtypes are determined by the size of atypical lymphocytes, type of atypical cells, location and amount of infiltrate, and CD30 and CD8 staining.

The differential diagnosis of LyP includes anaplastic large cell lymphoma, cutaneous T-cell lymphoma, folliculitis, insect bites, Langerhans cell histiocytosis, leukemia cutis, milia, miliaria, and scabies.

The etiology of LyP is unknown. It is unclear whether the proliferation of T cells is a benign and chronic disorder initiated by a stimulus or an indolent T-cell malignancy that the immune system monitors and only allows for localized, cutaneous involvement.

Mild forms of LyP can often be managed with topical corticosteroids. However, other therapies such as intralesional corticosteroids, phototherapy (UVB or PUVA), tetracycline antibiotics, and methotrexate are effective in treating cases of more persistent and widespread disease.

Our patient’s biopsy showed an irregular epidermis with scale, focal ulceration, scattered eosinophils, and dermal lymphocytes and histiocytes present in a perivascular pattern. Many of the lymphoid cells were enlarged, hyperchromatic, and irregular. Immunohistochemical staining was CD30+. These histologic changes were most consistent with lymphomatoid papulosis. 

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].

Diagnosis: Lymphomatoid papulosis

Lymphomatoid papulosis is a rare, chronic, and benign papulonodular or papulonecrotic skin disorder. LyP affects people of all ages, and its peak incidence occurs in the 5th decade. It generally has no predilection for a particular sex; however, some have reported a slight predominance in males. Patients of all races may be diagnosed with LyP, although it is less common in black patients. In addition, 10% of LyP cases are associated with anaplastic large cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin’s lymphoma.

Patients typically present with multiple erythematous papules that evolve into red-brown papulopustular or papulovesicular lesions. The papules may be mildly pruritic or asymptomatic and can be few in number to hundreds at presentation. The lesions usually appear in crops that resolve within 2-8 weeks with or without scarring, and can continue this cyclic process for months to years. The arms, legs, and trunk are most commonly affected, although LyP can present anywhere on the body.

The diagnosis of LyP is classically based upon histopathologic examination. Hematoxylin and eosin staining reveals a dense dermal infiltrate of atypical lymphocytes along with numerous eosinophils and neutrophils; lymphocytes are CD30+. Vessels in the dermis also appear with fibrin deposition, endothelial edema, and red blood cell extravasation. In addition, LyP can be classified as type A, type B, type C, and/or type D. These subtypes are determined by the size of atypical lymphocytes, type of atypical cells, location and amount of infiltrate, and CD30 and CD8 staining.

The differential diagnosis of LyP includes anaplastic large cell lymphoma, cutaneous T-cell lymphoma, folliculitis, insect bites, Langerhans cell histiocytosis, leukemia cutis, milia, miliaria, and scabies.

The etiology of LyP is unknown. It is unclear whether the proliferation of T cells is a benign and chronic disorder initiated by a stimulus or an indolent T-cell malignancy that the immune system monitors and only allows for localized, cutaneous involvement.

Mild forms of LyP can often be managed with topical corticosteroids. However, other therapies such as intralesional corticosteroids, phototherapy (UVB or PUVA), tetracycline antibiotics, and methotrexate are effective in treating cases of more persistent and widespread disease.

Our patient’s biopsy showed an irregular epidermis with scale, focal ulceration, scattered eosinophils, and dermal lymphocytes and histiocytes present in a perivascular pattern. Many of the lymphoid cells were enlarged, hyperchromatic, and irregular. Immunohistochemical staining was CD30+. These histologic changes were most consistent with lymphomatoid papulosis. 

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].

CHICAGO – The largest-ever randomized trial of catheter ablation of atrial fibrillation has ended in a draw between radiofrequency and cryoballoon ablation in safety and efficacy – and that actually represents a win for cryoablation, a simpler and far more easily mastered procedure, Dr. Karl-Heinz Kuck said at the annual meeting of the American College of Cardiology.

“We can teach physicians how to do cryoablation much more easily. That will allow more patients with atrial fibrillation to get access to catheter ablation, which is what we really need,” according to Dr. Kuck, principal investigator in the poetically named FIRE AND ICE trial and head of cardiology at St. Georg Hospital in Hamburg (Germany).

FIRE AND ICE included 769 patients in eight European countries. The participants, all of whom had antiarrhythmic drug–refractory paroxysmal atrial fibrillation (AF), were randomized to radiofrequency ablation – the long-time standard – or to cryoablation, a newer technology. Radiofrequency ablation was guided by three-dimensional electroanatomic mapping, while cryoablation utilized fluoroscopic guidance.

The primary efficacy endpoint was the 1-year rate of clinical failure, defined as an occurrence of AF, atrial flutter, or atrial tachycardia lasting for at least 30 seconds, or repeat ablation or the use of antiarrhythmic drugs following a 90-day postprocedural blanking period. The clinical failure rate was 34.6% in the cryoballoon group and similar at 35.9% in the radiofrequency group.

Serious treatment-related adverse events occurred in 10.2% of the cryoballoon group and 12.8% of the radiofrequency group, a nonsignificant difference. No procedural deaths occurred in the study.

There were, however, several significant procedural differences. Procedure time averaged 124 minutes in the cryoablation group, nearly 20 minutes less than the 142 minutes for radiofrequency ablation. However, the 17-minute fluoroscopy time in the radiofrequency group was 5 minutes shorter than for cryoablation.

Dr. Kuck said the study underestimates the true procedural differences because FIRE AND ICE was carried out by extremely experienced operators. In routine clinical practice involving non-elite operators, it’s not unusual for radiofrequency ablation fluoroscopy times to be two or even three times longer than the 17 minutes seen in the study. Plus, FIRE AND ICE was conducted when the procedure entailed two applications of the cryoballoon. Now only one application is recommended, cutting an additional 12 minutes off the total procedure time, he added.

Radiofrequency ablation takes longer because it entails creating a series of point-to-point lesions in a circle to isolate the pulmonary veins. With cryoablation, the balloon is moved into position, inflated, and a 3-minute-freeze is administered to create a circle of necrotic tissue in a single-step procedure.

Discussant Dr. Hugh G. Calkins praised the FIRE AND ICE investigators’ use of a rigorous definition of recurrence that required as little as a 30-second episode of atrial arrhythmia.

“That’s a very high bar, so I think the results are very impressive,” said Dr. Calkins, professor of medicine and of pediatrics and director of the cardiac arrhythmia service at Johns Hopkins University, Baltimore.

He commented that “this study is a clear reminder that 90% success rates just don’t happen in this field,” despite what some practitioners have claimed.

Asked how he predicts the study results will influence the field of AF ablation, Dr. Kuck replied that he foresees much wider adoption of cryoablation and a stronger endorsement of the technology in updated guideline recommendations.

“I personally believe this will be the most important development in our field in the next several years,” he added.

The electrophysiologist noted that even though current guidelines give a class Ia recommendation to catheter ablation of paroxysmal AF that’s refractory to at least one antiarrhythmic drug, at present only 4% of such patients actually undergo the procedure.

“Having just 4% of patients with AF undergo catheter ablation cannot be what we are looking for as physicians,” Dr. Kuck said. “I believe if we want to roll out catheter ablation for AF, we need simple and safe tools. This trial elegantly shows that with a simpler device that allows single-shot isolation of the pulmonary veins, we can get the same safety and efficacy as with radiofrequency ablation. I often tell people that radiofrequency ablation of atrial fibrillation is the most challenging procedure in all cardiology. We do this procedure from the groin in a moving heart. It’s a very complex technology.”

His dream, he continued, is that cryoablation will eventually enable patients with atrial fibrillation to be managed the same way electrophysiologists treat patients with Wolff-Parkinson-White syndrome; with the first episode, the patient goes to the electrophysiology catheterization lab for an ablation procedure.

“I think there’s a great message here: The cryoballoon will move catheter ablation from a niche procedure performed in specialized centers by the few guys in the world who can do it really well out into the broader world. To do that you need a tool that is safe, simple, and can be handled by the average doctor,” Dr. Kuck said.

Discussant Dr. Anthony DeMaria commented that it would be premature at this point to start thinking about cryoablation as a first approach to new-onset AF, given the roughly 35% clinical failure rate at 1 year seen in FIRE AND ICE. That rate doubtless would have been even higher had patients been equipped with implantable loop recorders, added Dr. DeMaria, professor of medicine at the University of California, San Diego.

Dr. Kuck conceded that the high recurrence rate is one of the great unsolved limitations of catheter ablation of AF.

“We don’t know how to get the pulmonary veins permanently isolated,” he said. “We can create acute lesions, but over time what we’ve seen is recovery of tissue and then reconduction by the pulmonary veins. I believe that 20% of the 40% recurrence rate is due to reconduction from the pulmonary veins, and the rest is probably due to triggers coming from other sites.”

The FIRE AND ICE trial was funded in part by Medtronic, which markets the Arctic Front Advance cryoablation catheter used in the study. Dr. Kuck reported serving on a speakers’ bureau for Medtronic and acting as a consultant to Biosense Webster, Edwards, and St. Jude.

Simultaneous with Dr. Kuck’s presentation at ACC 16, the results of FIRE AND ICE were published online (N Engl J Med. 2016 Apr 4. doi: 10.1056/NEJMoa1602014).

[email protected]

CHICAGO – The largest-ever randomized trial of catheter ablation of atrial fibrillation has ended in a draw between radiofrequency and cryoballoon ablation in safety and efficacy – and that actually represents a win for cryoablation, a simpler and far more easily mastered procedure, Dr. Karl-Heinz Kuck said at the annual meeting of the American College of Cardiology.

“We can teach physicians how to do cryoablation much more easily. That will allow more patients with atrial fibrillation to get access to catheter ablation, which is what we really need,” according to Dr. Kuck, principal investigator in the poetically named FIRE AND ICE trial and head of cardiology at St. Georg Hospital in Hamburg (Germany).

FIRE AND ICE included 769 patients in eight European countries. The participants, all of whom had antiarrhythmic drug–refractory paroxysmal atrial fibrillation (AF), were randomized to radiofrequency ablation – the long-time standard – or to cryoablation, a newer technology. Radiofrequency ablation was guided by three-dimensional electroanatomic mapping, while cryoablation utilized fluoroscopic guidance.

The primary efficacy endpoint was the 1-year rate of clinical failure, defined as an occurrence of AF, atrial flutter, or atrial tachycardia lasting for at least 30 seconds, or repeat ablation or the use of antiarrhythmic drugs following a 90-day postprocedural blanking period. The clinical failure rate was 34.6% in the cryoballoon group and similar at 35.9% in the radiofrequency group.

Serious treatment-related adverse events occurred in 10.2% of the cryoballoon group and 12.8% of the radiofrequency group, a nonsignificant difference. No procedural deaths occurred in the study.

There were, however, several significant procedural differences. Procedure time averaged 124 minutes in the cryoablation group, nearly 20 minutes less than the 142 minutes for radiofrequency ablation. However, the 17-minute fluoroscopy time in the radiofrequency group was 5 minutes shorter than for cryoablation.

Dr. Kuck said the study underestimates the true procedural differences because FIRE AND ICE was carried out by extremely experienced operators. In routine clinical practice involving non-elite operators, it’s not unusual for radiofrequency ablation fluoroscopy times to be two or even three times longer than the 17 minutes seen in the study. Plus, FIRE AND ICE was conducted when the procedure entailed two applications of the cryoballoon. Now only one application is recommended, cutting an additional 12 minutes off the total procedure time, he added.

Radiofrequency ablation takes longer because it entails creating a series of point-to-point lesions in a circle to isolate the pulmonary veins. With cryoablation, the balloon is moved into position, inflated, and a 3-minute-freeze is administered to create a circle of necrotic tissue in a single-step procedure.

Discussant Dr. Hugh G. Calkins praised the FIRE AND ICE investigators’ use of a rigorous definition of recurrence that required as little as a 30-second episode of atrial arrhythmia.

“That’s a very high bar, so I think the results are very impressive,” said Dr. Calkins, professor of medicine and of pediatrics and director of the cardiac arrhythmia service at Johns Hopkins University, Baltimore.

He commented that “this study is a clear reminder that 90% success rates just don’t happen in this field,” despite what some practitioners have claimed.

Asked how he predicts the study results will influence the field of AF ablation, Dr. Kuck replied that he foresees much wider adoption of cryoablation and a stronger endorsement of the technology in updated guideline recommendations.

“I personally believe this will be the most important development in our field in the next several years,” he added.

The electrophysiologist noted that even though current guidelines give a class Ia recommendation to catheter ablation of paroxysmal AF that’s refractory to at least one antiarrhythmic drug, at present only 4% of such patients actually undergo the procedure.

“Having just 4% of patients with AF undergo catheter ablation cannot be what we are looking for as physicians,” Dr. Kuck said. “I believe if we want to roll out catheter ablation for AF, we need simple and safe tools. This trial elegantly shows that with a simpler device that allows single-shot isolation of the pulmonary veins, we can get the same safety and efficacy as with radiofrequency ablation. I often tell people that radiofrequency ablation of atrial fibrillation is the most challenging procedure in all cardiology. We do this procedure from the groin in a moving heart. It’s a very complex technology.”

His dream, he continued, is that cryoablation will eventually enable patients with atrial fibrillation to be managed the same way electrophysiologists treat patients with Wolff-Parkinson-White syndrome; with the first episode, the patient goes to the electrophysiology catheterization lab for an ablation procedure.

“I think there’s a great message here: The cryoballoon will move catheter ablation from a niche procedure performed in specialized centers by the few guys in the world who can do it really well out into the broader world. To do that you need a tool that is safe, simple, and can be handled by the average doctor,” Dr. Kuck said.

Discussant Dr. Anthony DeMaria commented that it would be premature at this point to start thinking about cryoablation as a first approach to new-onset AF, given the roughly 35% clinical failure rate at 1 year seen in FIRE AND ICE. That rate doubtless would have been even higher had patients been equipped with implantable loop recorders, added Dr. DeMaria, professor of medicine at the University of California, San Diego.

Dr. Kuck conceded that the high recurrence rate is one of the great unsolved limitations of catheter ablation of AF.

“We don’t know how to get the pulmonary veins permanently isolated,” he said. “We can create acute lesions, but over time what we’ve seen is recovery of tissue and then reconduction by the pulmonary veins. I believe that 20% of the 40% recurrence rate is due to reconduction from the pulmonary veins, and the rest is probably due to triggers coming from other sites.”

The FIRE AND ICE trial was funded in part by Medtronic, which markets the Arctic Front Advance cryoablation catheter used in the study. Dr. Kuck reported serving on a speakers’ bureau for Medtronic and acting as a consultant to Biosense Webster, Edwards, and St. Jude.

Simultaneous with Dr. Kuck’s presentation at ACC 16, the results of FIRE AND ICE were published online (N Engl J Med. 2016 Apr 4. doi: 10.1056/NEJMoa1602014).

[email protected]

CHICAGO – The largest-ever randomized trial of catheter ablation of atrial fibrillation has ended in a draw between radiofrequency and cryoballoon ablation in safety and efficacy – and that actually represents a win for cryoablation, a simpler and far more easily mastered procedure, Dr. Karl-Heinz Kuck said at the annual meeting of the American College of Cardiology.

“We can teach physicians how to do cryoablation much more easily. That will allow more patients with atrial fibrillation to get access to catheter ablation, which is what we really need,” according to Dr. Kuck, principal investigator in the poetically named FIRE AND ICE trial and head of cardiology at St. Georg Hospital in Hamburg (Germany).

FIRE AND ICE included 769 patients in eight European countries. The participants, all of whom had antiarrhythmic drug–refractory paroxysmal atrial fibrillation (AF), were randomized to radiofrequency ablation – the long-time standard – or to cryoablation, a newer technology. Radiofrequency ablation was guided by three-dimensional electroanatomic mapping, while cryoablation utilized fluoroscopic guidance.

The primary efficacy endpoint was the 1-year rate of clinical failure, defined as an occurrence of AF, atrial flutter, or atrial tachycardia lasting for at least 30 seconds, or repeat ablation or the use of antiarrhythmic drugs following a 90-day postprocedural blanking period. The clinical failure rate was 34.6% in the cryoballoon group and similar at 35.9% in the radiofrequency group.

Serious treatment-related adverse events occurred in 10.2% of the cryoballoon group and 12.8% of the radiofrequency group, a nonsignificant difference. No procedural deaths occurred in the study.

There were, however, several significant procedural differences. Procedure time averaged 124 minutes in the cryoablation group, nearly 20 minutes less than the 142 minutes for radiofrequency ablation. However, the 17-minute fluoroscopy time in the radiofrequency group was 5 minutes shorter than for cryoablation.

Dr. Kuck said the study underestimates the true procedural differences because FIRE AND ICE was carried out by extremely experienced operators. In routine clinical practice involving non-elite operators, it’s not unusual for radiofrequency ablation fluoroscopy times to be two or even three times longer than the 17 minutes seen in the study. Plus, FIRE AND ICE was conducted when the procedure entailed two applications of the cryoballoon. Now only one application is recommended, cutting an additional 12 minutes off the total procedure time, he added.

Radiofrequency ablation takes longer because it entails creating a series of point-to-point lesions in a circle to isolate the pulmonary veins. With cryoablation, the balloon is moved into position, inflated, and a 3-minute-freeze is administered to create a circle of necrotic tissue in a single-step procedure.

Discussant Dr. Hugh G. Calkins praised the FIRE AND ICE investigators’ use of a rigorous definition of recurrence that required as little as a 30-second episode of atrial arrhythmia.

“That’s a very high bar, so I think the results are very impressive,” said Dr. Calkins, professor of medicine and of pediatrics and director of the cardiac arrhythmia service at Johns Hopkins University, Baltimore.

He commented that “this study is a clear reminder that 90% success rates just don’t happen in this field,” despite what some practitioners have claimed.

Asked how he predicts the study results will influence the field of AF ablation, Dr. Kuck replied that he foresees much wider adoption of cryoablation and a stronger endorsement of the technology in updated guideline recommendations.

“I personally believe this will be the most important development in our field in the next several years,” he added.

The electrophysiologist noted that even though current guidelines give a class Ia recommendation to catheter ablation of paroxysmal AF that’s refractory to at least one antiarrhythmic drug, at present only 4% of such patients actually undergo the procedure.

“Having just 4% of patients with AF undergo catheter ablation cannot be what we are looking for as physicians,” Dr. Kuck said. “I believe if we want to roll out catheter ablation for AF, we need simple and safe tools. This trial elegantly shows that with a simpler device that allows single-shot isolation of the pulmonary veins, we can get the same safety and efficacy as with radiofrequency ablation. I often tell people that radiofrequency ablation of atrial fibrillation is the most challenging procedure in all cardiology. We do this procedure from the groin in a moving heart. It’s a very complex technology.”

His dream, he continued, is that cryoablation will eventually enable patients with atrial fibrillation to be managed the same way electrophysiologists treat patients with Wolff-Parkinson-White syndrome; with the first episode, the patient goes to the electrophysiology catheterization lab for an ablation procedure.

“I think there’s a great message here: The cryoballoon will move catheter ablation from a niche procedure performed in specialized centers by the few guys in the world who can do it really well out into the broader world. To do that you need a tool that is safe, simple, and can be handled by the average doctor,” Dr. Kuck said.

Discussant Dr. Anthony DeMaria commented that it would be premature at this point to start thinking about cryoablation as a first approach to new-onset AF, given the roughly 35% clinical failure rate at 1 year seen in FIRE AND ICE. That rate doubtless would have been even higher had patients been equipped with implantable loop recorders, added Dr. DeMaria, professor of medicine at the University of California, San Diego.

Dr. Kuck conceded that the high recurrence rate is one of the great unsolved limitations of catheter ablation of AF.

“We don’t know how to get the pulmonary veins permanently isolated,” he said. “We can create acute lesions, but over time what we’ve seen is recovery of tissue and then reconduction by the pulmonary veins. I believe that 20% of the 40% recurrence rate is due to reconduction from the pulmonary veins, and the rest is probably due to triggers coming from other sites.”

The FIRE AND ICE trial was funded in part by Medtronic, which markets the Arctic Front Advance cryoablation catheter used in the study. Dr. Kuck reported serving on a speakers’ bureau for Medtronic and acting as a consultant to Biosense Webster, Edwards, and St. Jude.

Simultaneous with Dr. Kuck’s presentation at ACC 16, the results of FIRE AND ICE were published online (N Engl J Med. 2016 Apr 4. doi: 10.1056/NEJMoa1602014).

[email protected]

In 1966, Dr. Charles Hammond was wrapping up a 2-year stint at the National Institutes of Health where he served at the behest of the military draft board. He had graduated from medical school just 5 years prior, and was in the middle of his ob.gyn. residency training at Duke University in Durham, N.C. when he was called to serve.

His experience wasn’t unusual for the time.

Courtesy Dr. Charles Hammond

“When the draft board called, you went,” he said in an interview.

When he returned, he picked up where he left off. Residencies at that time were an “open-ended thing,” sometimes lasting 5 or 6 years, depending on staffing needs and other considerations.

Dr. Hammond, now an emeritus professor at Duke, regards his public service commission as an opportunity that advanced his academic career – despite the interruption of his residency training.

Such draft-related interruptions ended in the wake of the Vietnam War, of course, but the late 1960s and the 1970s ushered in a whole new era of changes in ob.gyn. residency training programs.

By 1968, residencies lasted 4 years, and fellowships were for 2 years. Ob.gyn. subspecialties hadn’t yet been introduced, explained Dr. Sandra A. Carson, vice president for education at the American College of Obstetricians and Gynecologists.

“That is essentially how things worked for a long time,” she said in an interview.

That’s not to say there weren’t numerous other changes taking place in the specialty. In a series of interviews with physicians and educators who discussed the myriad ways that residency training has evolved over the last 50 years, a number of themes emerged.

Women in medicine

A striking change over the past 5 decades has been the increasing number of women in medicine. Nowhere has that been in greater evidence than in obstetrics and gynecology.

“There were a few – but very few,” Dr. Hammond said of women in medicine in the 1960s.

There was “a philosophy that men did it better,” he said, adding, “That has been nicely shown to be inaccurate.”

Currently, about 80% of first-year ob.gyn. residents are women, compared with 15% in 1975.

“Maybe even 83% now,” Dr. Carson said, noting that even in the early 1980s when she was in training, women were “few and far between.”

According to a 2011 workforce report by Dr. William F. Rayburn, obstetrics and gynecology has the highest percentage of women residents of any medical specialty – 80% in 2009 versus an average of 46% for other specialties combined, and that figure has remained fairly constant.

Dr. Kasandra Scales, a fourth-year resident at the State University of New York, Syracuse, said she is glad to be part of this era of the specialty where women play an integral role in the advancement of women’s health care.

Courtesy Dr. Kasandra Scales

“I believe our voice and unique perspective to relate with common experiences, such as the physical birth of a child or personal choices in contraception... has enhanced our specialty,” she said.

That said, the fact that men are noticeably absent from the pool of ob.gyn. applicants and residents concerns her. “There should be a balance, she said. “I think it is important to have diversity of all types in the healthcare system.”

Dr. Hammond looked back on his days in residency training and recalled pockets of resistance to the increasing number of women in medicine, but the ultimate effect was good for the specialty, he said, explaining that the quality of the resident pool improved steadily, because the number of qualified candidates increased.

“It has been an interesting interval to watch,” he said, specifically mentioning the demands that women faced in terms of family obligations, childbirth, and childrearing.

Restrictions on work hours instituted in residency programs in more recent years may have played an important role in opening the door to more women, he said.

Work hours down, learning curve up

Dr. Carson agreed that work-hour restrictions instituted in 2003 and updated in 2011, which cap the work week at 80 hours and also apply limits on shift hours, likely encouraged more women to enter the field. One constant over the last 50 years is the biological clock, she said, explaining that the pressures and demands of residency before limits were put in place may have steered women away.

Work-hour restrictions provide more flexibility, but they aren’t without controversy.

Dr. Hammond said he sees the value in work hour restrictions, but working long hours as a resident – sometimes as many as 110 hours per week – had its benefits, too.

“I remember one time when I’d been on call for about 2 and a half days, and up and working the whole time,” Dr. Hammond said. “I left the hospital, walked out to a bench, sat down, and fell asleep. I woke up and distinctly remember thinking, ‘Why am I doing this?’ But I did do it, and that fatigue helped me with learning to endure. You learned from it.”

Not only have long hours been viewed as a rite of passage in medicine, he said, but there were concerns initially that the level of education would diminish and that the risk of patient errors would increase as patients were handed off from one shift to the next, he said.

Data on the effects of work-hour rules have been conflicting. In one study, Dr. Roger P. Smith found little overall effect on total technical experience among residents before and after the restrictions were put in place (there was no statistically significant difference in the average of median total cases in the 3 years before and after). Previous studies had documented increased costs and reduced faculty job satisfaction, while still others had shown no significant changes in 30-day readmission rates, in-hospital mortality, patient length of stay, or resident performance, he noted. “What is emerging is that both the great hopes and the great fears surrounding resident work-hour restrictions have not come to pass,” Dr. Smith wrote (Obstet Gynecol. 2010 Jun;115[6]:1166-71).

Dr. Scales, who is currently chair of the Junior Fellow District II Advisory Council for ACOG, comes down on the side of wishing for more hours.

“[The restrictions] do limit the things we can do and the exposure we may otherwise have,” she said, noting that it’s frustrating to have to leave when she’d rather stay and “see a cool case.”

“It’s a nice idea in principle, but the same amount of work has to be done. It’s not real life,” she said of work-hour restrictions. “It’s hard, at least for me, to want to give up my patients. Our job is to take in as much as you can before you leave to go out into the big bad world.”

It may be difficult to determine the actual impact of work hour limits on patient outcomes because the field of obstetrics and gynecology has changed so much over time.

Dr. David Forstein, vice chair of clinical operations in the department of obstetrics and gynecology at the University of South Carolina, Greenville, and a member of the Accreditation Council for Graduate Medical Education’s task force on work hours said that, for one thing, patients are generally sicker now than ever before, due in part to the obesity epidemic.

Further, changing trends mean that residents are getting less exposure to some procedures like operative vaginal deliveries, while also having to learn more ways to perform hysterectomy. Residents aren’t necessarily less prepared. They’re just having to work very hard because of the depth and breadth of the required knowledge has increased, Dr. Forstein said. “There’s a lot more to learn.”

Dr. Carson agreed that the approach to education has changed, and that those changes are largely a reflection of overall shifts in education and technology.

Technology trends

Every physician interviewed for this article cited laparoscopy and robotic surgery as key technological advances. Fifty years ago, the surgical tools were simpler, Dr. Carson said. Now residents must learn four approaches to hysterectomy: vaginal, abdominal, laparoscopic, and robotic-assisted laparoscopic hysterectomy.

From ultrasound and birth control to genetic screening and robotic surgery, the evolution of the field has been astounding during this time period. The effects of the birth control pill on family planning alone forced an expansion of curriculum not only to the physiology of these things, but also to the treatment of women as a whole person and often as part of a family unit, she said.

Many of the technologies have dramatically changed the landscape, both in terms of how learning is accomplished (for example, simulation), and how physicians interact with patients, Dr. Hammond agreed. With ultrasound, for example, there was a sense that part of the physician-patient relationship was lost.

“To a point, some of us old guys felt like they were doing ultrasound assessment of patients rather than the tried-and-true ‘talk to them and examine them’ [approach],” he said. “I guess whichever generation you are in seems to be the right one, but it’s probably somewhere in between.”

Residency in 2016

If Dr. Scales is any indication, concerns about the loss of a personal touch are unfounded. She says that for her, that’s what it’s all about.

“We were exposed to [technology] since we were 5 or 6 – it’s all we know,” she said of herself and her fellow residents. “It’s not a disadvantage. It’s about efficiency.”

“We have to get things done as quickly as possible and technology helps us with that,” said Dr. Scales, the daughter of a teacher and blue collar worker, who spent most of her life “surrounded by the underprivileged.”

She always desired to help lift that population up, and while she didn’t have a draft board directing her toward public service, she had her own calling of sorts. As a premed major in college, she worked with a nonprofit organization, and later she worked with Hurricane Katrina survivors.

“I liked that aspect of medicine. I wanted to be able to identify with people on an individual level,” she said.

Technology, work-hour restrictions, gender distribution – they’re just part of the journey.

“I’m glad I chose ob.gyn.,” she said. “Sometimes you go through ... reflection ... Am I ready? My answer is yes. I’m excited about the next step, I’m comfortable in the skill I learned in my residency program, I’m excited about the work I do every day, and I’m very excited about the next chapters.”

[email protected]

In 1966, Dr. Charles Hammond was wrapping up a 2-year stint at the National Institutes of Health where he served at the behest of the military draft board. He had graduated from medical school just 5 years prior, and was in the middle of his ob.gyn. residency training at Duke University in Durham, N.C. when he was called to serve.

His experience wasn’t unusual for the time.

Courtesy Dr. Charles Hammond

“When the draft board called, you went,” he said in an interview.

When he returned, he picked up where he left off. Residencies at that time were an “open-ended thing,” sometimes lasting 5 or 6 years, depending on staffing needs and other considerations.

Dr. Hammond, now an emeritus professor at Duke, regards his public service commission as an opportunity that advanced his academic career – despite the interruption of his residency training.

Such draft-related interruptions ended in the wake of the Vietnam War, of course, but the late 1960s and the 1970s ushered in a whole new era of changes in ob.gyn. residency training programs.

By 1968, residencies lasted 4 years, and fellowships were for 2 years. Ob.gyn. subspecialties hadn’t yet been introduced, explained Dr. Sandra A. Carson, vice president for education at the American College of Obstetricians and Gynecologists.

“That is essentially how things worked for a long time,” she said in an interview.

That’s not to say there weren’t numerous other changes taking place in the specialty. In a series of interviews with physicians and educators who discussed the myriad ways that residency training has evolved over the last 50 years, a number of themes emerged.

Women in medicine

A striking change over the past 5 decades has been the increasing number of women in medicine. Nowhere has that been in greater evidence than in obstetrics and gynecology.

“There were a few – but very few,” Dr. Hammond said of women in medicine in the 1960s.

There was “a philosophy that men did it better,” he said, adding, “That has been nicely shown to be inaccurate.”

Currently, about 80% of first-year ob.gyn. residents are women, compared with 15% in 1975.

“Maybe even 83% now,” Dr. Carson said, noting that even in the early 1980s when she was in training, women were “few and far between.”

According to a 2011 workforce report by Dr. William F. Rayburn, obstetrics and gynecology has the highest percentage of women residents of any medical specialty – 80% in 2009 versus an average of 46% for other specialties combined, and that figure has remained fairly constant.

Dr. Kasandra Scales, a fourth-year resident at the State University of New York, Syracuse, said she is glad to be part of this era of the specialty where women play an integral role in the advancement of women’s health care.

Courtesy Dr. Kasandra Scales

“I believe our voice and unique perspective to relate with common experiences, such as the physical birth of a child or personal choices in contraception... has enhanced our specialty,” she said.

That said, the fact that men are noticeably absent from the pool of ob.gyn. applicants and residents concerns her. “There should be a balance, she said. “I think it is important to have diversity of all types in the healthcare system.”

Dr. Hammond looked back on his days in residency training and recalled pockets of resistance to the increasing number of women in medicine, but the ultimate effect was good for the specialty, he said, explaining that the quality of the resident pool improved steadily, because the number of qualified candidates increased.

“It has been an interesting interval to watch,” he said, specifically mentioning the demands that women faced in terms of family obligations, childbirth, and childrearing.

Restrictions on work hours instituted in residency programs in more recent years may have played an important role in opening the door to more women, he said.

Work hours down, learning curve up

Dr. Carson agreed that work-hour restrictions instituted in 2003 and updated in 2011, which cap the work week at 80 hours and also apply limits on shift hours, likely encouraged more women to enter the field. One constant over the last 50 years is the biological clock, she said, explaining that the pressures and demands of residency before limits were put in place may have steered women away.

Work-hour restrictions provide more flexibility, but they aren’t without controversy.

Dr. Hammond said he sees the value in work hour restrictions, but working long hours as a resident – sometimes as many as 110 hours per week – had its benefits, too.

“I remember one time when I’d been on call for about 2 and a half days, and up and working the whole time,” Dr. Hammond said. “I left the hospital, walked out to a bench, sat down, and fell asleep. I woke up and distinctly remember thinking, ‘Why am I doing this?’ But I did do it, and that fatigue helped me with learning to endure. You learned from it.”

Not only have long hours been viewed as a rite of passage in medicine, he said, but there were concerns initially that the level of education would diminish and that the risk of patient errors would increase as patients were handed off from one shift to the next, he said.

Data on the effects of work-hour rules have been conflicting. In one study, Dr. Roger P. Smith found little overall effect on total technical experience among residents before and after the restrictions were put in place (there was no statistically significant difference in the average of median total cases in the 3 years before and after). Previous studies had documented increased costs and reduced faculty job satisfaction, while still others had shown no significant changes in 30-day readmission rates, in-hospital mortality, patient length of stay, or resident performance, he noted. “What is emerging is that both the great hopes and the great fears surrounding resident work-hour restrictions have not come to pass,” Dr. Smith wrote (Obstet Gynecol. 2010 Jun;115[6]:1166-71).

Dr. Scales, who is currently chair of the Junior Fellow District II Advisory Council for ACOG, comes down on the side of wishing for more hours.

“[The restrictions] do limit the things we can do and the exposure we may otherwise have,” she said, noting that it’s frustrating to have to leave when she’d rather stay and “see a cool case.”

“It’s a nice idea in principle, but the same amount of work has to be done. It’s not real life,” she said of work-hour restrictions. “It’s hard, at least for me, to want to give up my patients. Our job is to take in as much as you can before you leave to go out into the big bad world.”

It may be difficult to determine the actual impact of work hour limits on patient outcomes because the field of obstetrics and gynecology has changed so much over time.

Dr. David Forstein, vice chair of clinical operations in the department of obstetrics and gynecology at the University of South Carolina, Greenville, and a member of the Accreditation Council for Graduate Medical Education’s task force on work hours said that, for one thing, patients are generally sicker now than ever before, due in part to the obesity epidemic.

Further, changing trends mean that residents are getting less exposure to some procedures like operative vaginal deliveries, while also having to learn more ways to perform hysterectomy. Residents aren’t necessarily less prepared. They’re just having to work very hard because of the depth and breadth of the required knowledge has increased, Dr. Forstein said. “There’s a lot more to learn.”

Dr. Carson agreed that the approach to education has changed, and that those changes are largely a reflection of overall shifts in education and technology.

Technology trends

Every physician interviewed for this article cited laparoscopy and robotic surgery as key technological advances. Fifty years ago, the surgical tools were simpler, Dr. Carson said. Now residents must learn four approaches to hysterectomy: vaginal, abdominal, laparoscopic, and robotic-assisted laparoscopic hysterectomy.

From ultrasound and birth control to genetic screening and robotic surgery, the evolution of the field has been astounding during this time period. The effects of the birth control pill on family planning alone forced an expansion of curriculum not only to the physiology of these things, but also to the treatment of women as a whole person and often as part of a family unit, she said.

Many of the technologies have dramatically changed the landscape, both in terms of how learning is accomplished (for example, simulation), and how physicians interact with patients, Dr. Hammond agreed. With ultrasound, for example, there was a sense that part of the physician-patient relationship was lost.

“To a point, some of us old guys felt like they were doing ultrasound assessment of patients rather than the tried-and-true ‘talk to them and examine them’ [approach],” he said. “I guess whichever generation you are in seems to be the right one, but it’s probably somewhere in between.”

Residency in 2016

If Dr. Scales is any indication, concerns about the loss of a personal touch are unfounded. She says that for her, that’s what it’s all about.

“We were exposed to [technology] since we were 5 or 6 – it’s all we know,” she said of herself and her fellow residents. “It’s not a disadvantage. It’s about efficiency.”

“We have to get things done as quickly as possible and technology helps us with that,” said Dr. Scales, the daughter of a teacher and blue collar worker, who spent most of her life “surrounded by the underprivileged.”

She always desired to help lift that population up, and while she didn’t have a draft board directing her toward public service, she had her own calling of sorts. As a premed major in college, she worked with a nonprofit organization, and later she worked with Hurricane Katrina survivors.

“I liked that aspect of medicine. I wanted to be able to identify with people on an individual level,” she said.

Technology, work-hour restrictions, gender distribution – they’re just part of the journey.

“I’m glad I chose ob.gyn.,” she said. “Sometimes you go through ... reflection ... Am I ready? My answer is yes. I’m excited about the next step, I’m comfortable in the skill I learned in my residency program, I’m excited about the work I do every day, and I’m very excited about the next chapters.”

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In 1966, Dr. Charles Hammond was wrapping up a 2-year stint at the National Institutes of Health where he served at the behest of the military draft board. He had graduated from medical school just 5 years prior, and was in the middle of his ob.gyn. residency training at Duke University in Durham, N.C. when he was called to serve.

His experience wasn’t unusual for the time.

Courtesy Dr. Charles Hammond

“When the draft board called, you went,” he said in an interview.

When he returned, he picked up where he left off. Residencies at that time were an “open-ended thing,” sometimes lasting 5 or 6 years, depending on staffing needs and other considerations.

Dr. Hammond, now an emeritus professor at Duke, regards his public service commission as an opportunity that advanced his academic career – despite the interruption of his residency training.

Such draft-related interruptions ended in the wake of the Vietnam War, of course, but the late 1960s and the 1970s ushered in a whole new era of changes in ob.gyn. residency training programs.

By 1968, residencies lasted 4 years, and fellowships were for 2 years. Ob.gyn. subspecialties hadn’t yet been introduced, explained Dr. Sandra A. Carson, vice president for education at the American College of Obstetricians and Gynecologists.

“That is essentially how things worked for a long time,” she said in an interview.

That’s not to say there weren’t numerous other changes taking place in the specialty. In a series of interviews with physicians and educators who discussed the myriad ways that residency training has evolved over the last 50 years, a number of themes emerged.

Women in medicine

A striking change over the past 5 decades has been the increasing number of women in medicine. Nowhere has that been in greater evidence than in obstetrics and gynecology.

“There were a few – but very few,” Dr. Hammond said of women in medicine in the 1960s.

There was “a philosophy that men did it better,” he said, adding, “That has been nicely shown to be inaccurate.”

Currently, about 80% of first-year ob.gyn. residents are women, compared with 15% in 1975.

“Maybe even 83% now,” Dr. Carson said, noting that even in the early 1980s when she was in training, women were “few and far between.”

According to a 2011 workforce report by Dr. William F. Rayburn, obstetrics and gynecology has the highest percentage of women residents of any medical specialty – 80% in 2009 versus an average of 46% for other specialties combined, and that figure has remained fairly constant.

Dr. Kasandra Scales, a fourth-year resident at the State University of New York, Syracuse, said she is glad to be part of this era of the specialty where women play an integral role in the advancement of women’s health care.

Courtesy Dr. Kasandra Scales

“I believe our voice and unique perspective to relate with common experiences, such as the physical birth of a child or personal choices in contraception... has enhanced our specialty,” she said.

That said, the fact that men are noticeably absent from the pool of ob.gyn. applicants and residents concerns her. “There should be a balance, she said. “I think it is important to have diversity of all types in the healthcare system.”

Dr. Hammond looked back on his days in residency training and recalled pockets of resistance to the increasing number of women in medicine, but the ultimate effect was good for the specialty, he said, explaining that the quality of the resident pool improved steadily, because the number of qualified candidates increased.

“It has been an interesting interval to watch,” he said, specifically mentioning the demands that women faced in terms of family obligations, childbirth, and childrearing.

Restrictions on work hours instituted in residency programs in more recent years may have played an important role in opening the door to more women, he said.

Work hours down, learning curve up

Dr. Carson agreed that work-hour restrictions instituted in 2003 and updated in 2011, which cap the work week at 80 hours and also apply limits on shift hours, likely encouraged more women to enter the field. One constant over the last 50 years is the biological clock, she said, explaining that the pressures and demands of residency before limits were put in place may have steered women away.

Work-hour restrictions provide more flexibility, but they aren’t without controversy.

Dr. Hammond said he sees the value in work hour restrictions, but working long hours as a resident – sometimes as many as 110 hours per week – had its benefits, too.

“I remember one time when I’d been on call for about 2 and a half days, and up and working the whole time,” Dr. Hammond said. “I left the hospital, walked out to a bench, sat down, and fell asleep. I woke up and distinctly remember thinking, ‘Why am I doing this?’ But I did do it, and that fatigue helped me with learning to endure. You learned from it.”

Not only have long hours been viewed as a rite of passage in medicine, he said, but there were concerns initially that the level of education would diminish and that the risk of patient errors would increase as patients were handed off from one shift to the next, he said.

Data on the effects of work-hour rules have been conflicting. In one study, Dr. Roger P. Smith found little overall effect on total technical experience among residents before and after the restrictions were put in place (there was no statistically significant difference in the average of median total cases in the 3 years before and after). Previous studies had documented increased costs and reduced faculty job satisfaction, while still others had shown no significant changes in 30-day readmission rates, in-hospital mortality, patient length of stay, or resident performance, he noted. “What is emerging is that both the great hopes and the great fears surrounding resident work-hour restrictions have not come to pass,” Dr. Smith wrote (Obstet Gynecol. 2010 Jun;115[6]:1166-71).

Dr. Scales, who is currently chair of the Junior Fellow District II Advisory Council for ACOG, comes down on the side of wishing for more hours.

“[The restrictions] do limit the things we can do and the exposure we may otherwise have,” she said, noting that it’s frustrating to have to leave when she’d rather stay and “see a cool case.”

“It’s a nice idea in principle, but the same amount of work has to be done. It’s not real life,” she said of work-hour restrictions. “It’s hard, at least for me, to want to give up my patients. Our job is to take in as much as you can before you leave to go out into the big bad world.”

It may be difficult to determine the actual impact of work hour limits on patient outcomes because the field of obstetrics and gynecology has changed so much over time.

Dr. David Forstein, vice chair of clinical operations in the department of obstetrics and gynecology at the University of South Carolina, Greenville, and a member of the Accreditation Council for Graduate Medical Education’s task force on work hours said that, for one thing, patients are generally sicker now than ever before, due in part to the obesity epidemic.

Further, changing trends mean that residents are getting less exposure to some procedures like operative vaginal deliveries, while also having to learn more ways to perform hysterectomy. Residents aren’t necessarily less prepared. They’re just having to work very hard because of the depth and breadth of the required knowledge has increased, Dr. Forstein said. “There’s a lot more to learn.”

Dr. Carson agreed that the approach to education has changed, and that those changes are largely a reflection of overall shifts in education and technology.

Technology trends

Every physician interviewed for this article cited laparoscopy and robotic surgery as key technological advances. Fifty years ago, the surgical tools were simpler, Dr. Carson said. Now residents must learn four approaches to hysterectomy: vaginal, abdominal, laparoscopic, and robotic-assisted laparoscopic hysterectomy.

From ultrasound and birth control to genetic screening and robotic surgery, the evolution of the field has been astounding during this time period. The effects of the birth control pill on family planning alone forced an expansion of curriculum not only to the physiology of these things, but also to the treatment of women as a whole person and often as part of a family unit, she said.

Many of the technologies have dramatically changed the landscape, both in terms of how learning is accomplished (for example, simulation), and how physicians interact with patients, Dr. Hammond agreed. With ultrasound, for example, there was a sense that part of the physician-patient relationship was lost.

“To a point, some of us old guys felt like they were doing ultrasound assessment of patients rather than the tried-and-true ‘talk to them and examine them’ [approach],” he said. “I guess whichever generation you are in seems to be the right one, but it’s probably somewhere in between.”

Residency in 2016

If Dr. Scales is any indication, concerns about the loss of a personal touch are unfounded. She says that for her, that’s what it’s all about.

“We were exposed to [technology] since we were 5 or 6 – it’s all we know,” she said of herself and her fellow residents. “It’s not a disadvantage. It’s about efficiency.”

“We have to get things done as quickly as possible and technology helps us with that,” said Dr. Scales, the daughter of a teacher and blue collar worker, who spent most of her life “surrounded by the underprivileged.”

She always desired to help lift that population up, and while she didn’t have a draft board directing her toward public service, she had her own calling of sorts. As a premed major in college, she worked with a nonprofit organization, and later she worked with Hurricane Katrina survivors.

“I liked that aspect of medicine. I wanted to be able to identify with people on an individual level,” she said.

Technology, work-hour restrictions, gender distribution – they’re just part of the journey.

“I’m glad I chose ob.gyn.,” she said. “Sometimes you go through ... reflection ... Am I ready? My answer is yes. I’m excited about the next step, I’m comfortable in the skill I learned in my residency program, I’m excited about the work I do every day, and I’m very excited about the next chapters.”

[email protected]