Psychiatric Issues in Pediatric Oncology: Diagnosis and Management


DSM5

Acute-onset, fluctuating, usually reversible, change in mental status

Disturbance in attention and awareness

Change in at least one domain of cognition (e.g., memory, orientation, language, perceptual disturbances)

Symptoms in infants and children (hypoactive, hyperactive, or both)

Disoriented (both)

Inattentive (both)

Disorganized sleep (both)

Sparse or delayed responses (hypoactive)

Oversleepy (hypoactive)

Refractory agitation (hyperactive)

Requiring escalating doses of sedation (hyperactive)

Pulling lines and tubes (hyperactive)

Withdrawal, flat affect (hypoactive)

Screening tools

Ages for use

Pediatric Anesthesia Emergence Delirium (PAED) (Sikich and Lerman 2004)

Pediatric Confusion Assessment Method (pCAM) (Smith et al. 2011)

Preschool Confusion Assessment Method (ps-CAM)

Cornell Assessment of Pediatric Delirium (CAPD) (Traube et al. 2014)

Over 18 months old

Over 5 years old

2–5 years old (pending publication)

From newborn and up (0–21 year)

Etiologies

Common

Anesthetics (except dexmedetomidine)

Antihistamines

Benzodiazepines (intoxication or withdrawal)

CNS disease

Infection (systemic or localized)

Metabolic/electrolyte derangements

Opiates (intoxication or withdrawal)

Scopolamine/anticholinergics

Seizure

Steroids (intoxication or withdrawal)

Less common

Biological therapy (antibody or cell therapies)

Catatonia

CNS vascular event (hemorrhagic or embolic)

Ifosfamide/other chemotherapy toxicities

NMDA receptor encephalitis

Other paraneoplastic encephalitis

Opsoclonus-myoclonus

Posterior reversible encephalopathy syndrome (PRES) (Kushner et al. 2013)

Severe vitamin deficiencies (or rapid repletion in refeeding)

Behavioral/environmental interventions

Use familiar toys, music, and caregivers

Primary nursing care

Frequent reorientation

Nonconfrontation of delusions/hallucinations

Encourage oral hydration

Reduction in stimulation

Diurnal cycle preservation

 Encourage awake in day, sleep in night

 Cluster nursing care to reduce unnecessary awakenings

 Timing of sedating medications

Early mobilization/encouragement of physical therapy



The differential diagnosis of delirium may include undertreatment of pain or other physical symptoms, emotional distress (depression vs. hypoactive delirium), tantrums, and traumatic symptoms (Creten et al. 2011; Turkel et al. 2006). Once identified, clinicians should first seek to reverse delirium by treating underlying medical etiologies and/or removing offending “deliriogenic” medications (Table 8.1). Medical workup of the newly identified delirious patient should include blood and urine cultures, physical exam, and routine laboratories. Other workup will depend on the specific symptoms and history of each patient. In immunocompromised patients, a high index of suspicion for infection should be present.

In pediatric oncology, the most common causes of delirium include: opiates (intoxication and withdrawal), anesthesia, benzodiazepines, antihistamines, steroids, and infection. In the case of opiates, changing to another opiate (“rotation”) may relieve symptoms as patients may be more sensitive to side effects of a particular drug and more tolerant of another. While most general anesthetics may be a risk factor, there is evidence that use of dexmedetomidine, during surgical procedures or for sedation in the PICU, may be protective against delirium (Dahmani et al. 2014).



Interventions for Delirium


The consulting psychiatrist can recommend a change in sedatives or anesthesia, after which dosing and management would be at the discretion of the intensivist or anesthesiologist. In addition to addressing underlying medical etiologies, staff can implement environmental changes that assist with comforting, reorienting, and promoting normal sleep for delirious patients. While environmental or sensory disruptions alone will not cause delirium, a calm and nonthreatening environment helps reduce distress and agitation in the disoriented patient and should be a goal for all hospitalized patients. When possible, clustering of nursing care (to reduce interruptions at night and preserve sleep), frequent reorientation of the patient, preservation of day/night cues (e.g., lights on in the day, off at night), early mobilization even in the PICU, and encouraging oral hydration can all improve sleep quality and reduce disorientation and agitation in delirious and at-risk patients (Silver et al. 2014).

While addressing these factors, if symptom management is required for reasons of safety or distress (e.g., the child is pulling lines and tubes, hallucinating, or frightened), the off-label use of low-dose atypical antipsychotics is the recommended intervention in adults and children (Turkel and Hanft 2014). Use of atypical antipsychotics has been found to be safe in low doses and often allows for reduced use of other sedatives, which may be causing delirium and normalization of sleep/wake cycle. As sleep disruption is now understood to be a critical mechanism and core symptom of delirium, it is not surprising that studies are investigating use of melatonin to reset (or prevent disruption of) circadian rhythm in patients at risk or already experiencing delirium. Melatonin and melatonin agonist studies in adults, which have been small, have found they are well tolerated with modest benefit in prevention but not resolution of delirium. As melatonin is known to be safe and helpful in multiple types of pediatric sleep disorders, it is reasonable to consider its use in targeted cases of sleep disruption (Turkel and Hanft 2014; Chakraborti et al. 2014; Özcan and Dönmez 2014).

Since antihistamines and benzodiazepines are routinely used in daily pediatric oncology care, it is common to see children who have “paradoxical” reactions and become agitated, enraged, hyperactive, disinhibited or present with the full syndrome of delirium. In general, antihistamines and benzodiazepines should be avoided for children with a history of paradoxical reactions; however, sometimes these medications are unavoidable (e.g., blood transfusions requiring premedication with antihistamines) and concomitant use of a low-dose atypical antipsychotic may be needed to offset these adverse effects. Antipsychotics and other dopaminergic drugs like metoclopramide can induce extrapyramidal symptoms (EPS) (e.g., oculogyric crisis, torticollis) or akathisia (a type of psychomotor agitation, often described as “ants in pants” or a “restless leg” type of feeling all over the body). A careful history about the timing of medications and the development of symptoms can help differentiate these types of symptoms in a patient who may have an evolving delirium in the context of polypharmacy, which is very common. Further discussion of doses and scheduling follows in the Medications section.


Withdrawal Syndromes


Some patients with cancer experience chronic symptoms such as pain, nausea, and anxiety, which may necessitate long-term administration of habit-forming medications such as opiates or benzodiazepines. This can occur in an inpatient setting (e.g., during a prolonged critical illness or stem cell transplant) or with chronic comorbidities (e.g., avascular necrosis of joints related to corticosteroids, phantom limb pain, persistent nausea) of cancer therapy as an outpatient. Acute or subacute changes in a patient’s clinical status (for better or worse) may result in the rapid reduction of these medications and cause opiate or benzodiazepine withdrawal symptoms if a patient had developed physiological dependence to the drug. It is common for these sorts of dose changes, made 2–3 days prior to presentation of withdrawal symptoms, to be overlooked when a patient’s medical problems are complex, acute, and fluctuating. Therefore, careful review of the medications dispensed over the course of the symptoms is important.

While the classic syndrome of opiate withdrawal includes hypertension, tachycardia, vomiting, diarrhea, and diaphoresis, milder symptoms experienced by patients still on some dose of opiate often appear psychiatric in nature, including dysphoria, anxiety, emotional lability, tremulousness, fatigue, myalgias, and nausea. With the recognition of withdrawal, these symptoms can be easily treated and reversed. For patients on a short course of opiate therapy (less than 14 days), the World Health Organization (WHO) guidelines recommend discontinuation by a taper which decreases the original dose by 10–20 % every 8 hours, gradually increasing the time interval. However, for patients on opiates for longer periods, dose reduction should not exceed 10–20 % per week and management should include a measurement of withdrawal symptoms using a standard scoring system (World Health Organization 2012). The treatment of cancer-related and treatment-related pain in children is covered in Chap. 3 and in the WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses.

Benzodiazepine withdrawal can present similarly, with symptoms of nausea, agitation, anxiety, tremulousness, myalgia, tachycardia, and hypertension. Benzodiazepine withdrawal, like alcohol withdrawal, can cause dangerous hypertension and seizures and should be considered in any new onset seizure in a medically complex patient who has recent exposure to benzodiazepines. As with opiates, tapers in chronic users should be slow and based on prevention of objective signs of withdrawal (like the Withdrawal Assessment Tool (WAT-1) or the Sophia Observation Withdrawal Scale). Research in the area of monitoring and guidelines for tapering of sedation and other uses of opiates and benzodiazepines in pediatrics is urgently needed (Poh et al. 2014; Galinkin et al. 2014; Ista et al. 2013).


Other Iatrogenic Symptoms



Case Vignette

Lucy, a 3-year-old girl with acute myelogenous leukemia (AML), who receives steroids for 1 week each month, has been exhibiting worsening irritability over the 7-day course of steroids each cycle. Her pediatric oncologist requests child psychiatry consultation to assess her mood and behavior. Parents report escalating outbursts to rageful tantrums in which she is inconsolable, irrational, screaming, and throwing herself on the floor for up to 90 minutes regardless of any intervention by parents. Parents note that despite offering her whatever she wants she doesn’t stop until she “cries herself to sleep.” She also has started threatening to pull out her central line when agitated. Her sleep is erratic, waking during the night crying and hungry. The symptoms escalate over the week and finally dissipate 2–3 days after steroids are stopped. Diagnosis: Substance (corticosteroid)-induced mood disorder. Recommendation: Start risperidone at 0.25 mg at bedtime and titrate up to 0.25 mg in AM and 0.5 mg at bedtime during steroid courses only. Outcome: The patient responded well with better sleep at night and fewer, self-limited tantrums lasting less than 5 minutes with consolable irritability. Mother reports patient still has personality changes the week on steroids, but they are much more manageable. The patient’s appetite is ravenous during the day due to the additive effects of steroids and risperidone, but with safety concerns and sleep both greatly improved, her mother feels this is acceptable.

Many cancer treatments cause iatrogenic psychiatric symptoms. Administration of corticosteroids, which is commonly used for the treatment of ALL and lymphoma, causes varying degrees of irritability, mood lability, impulsivity, lethargy and/or insomnia (Ularntinon et al. 2010). These changes can be intense but are usually limited to the duration of the treatment. Psychoeducation may be sufficient in supporting a patient and family through their course of corticosteoids, but if significant impairment is present, a short-acting agent like risperidone can be extremely helpful in reducing impairment and distress. If chronic steroid use is needed for graft versus host disease (GVHD) or other illnesses, frank clinical depression or anxiety disorders may develop which warrant other targeted therapies.

Another medication that warrants close monitoring of psychiatric symptoms is isotretinoin (Accutane), most commonly used for severe cystic acne, but due to its effect on inhibition of tumorigenesis, it has also been used in regimens treating neuroblastoma, medulloblastoma, and other skin and brain cancers. Prescription of isotretinoin in the United States can only occur if patient is registered and monitored on an FDA-administered website due to its side effects of severe teratogenicity, blood dyscrasias, and psychiatric effects, which include depression and mood lability and, rarely, suicidal ideation or completed suicide. It is often well tolerated. If needed, atypical antipsychotics can be useful for offsetting any mild to moderate psychiatric effects, but the presentation of severe psychiatric symptoms warrants reevaluating the risks and benefits of the treatment.

Interferon alpha (IFN-alpha), an immunotherapy used for treatment of metastatic melanoma, hepatitis B and C, giant cell tumors, and rarely other disorders, carries significant side effects including flu-like symptoms, fatigue, anorexia, and neuropsychiatric symptoms like depression, mania, and psychosis. It is generally better tolerated in children than adults but symptoms, if present, often respond well to targeted therapy with antidepressant, antimanic, or antipsychotic medication.


Neurocognitive Impairment


The evaluation and management of neurocognitive adverse effects of cancer illness and therapy in children and adolescents are discussed in Chap. 10. As part of a differential diagnosis during psychiatric evaluation, neurocognitive symptoms may include impairment of any domain of cognition, in particular, memory, attention, processing speeds, and visual motor integration (Castellino et al. 2014). A patient with acquired neurocognitive impairment may present to psychiatric evaluation with secondary anxiety or frustration with daily tasks (e.g., due to reduced ability to attend or process information), amotivation, or underachievement in academics. For the assessment of inattention and other cognitive symptoms after cancer treatments, an ADHD framework is insufficient, as many at-risk patients will not meet diagnostic criteria (Kahalley et al. 2011). Of note, depression, anxiety, and PTSD can also have cognitive symptoms like attention impairment and should be ruled out. Neuropsychological testing is an essential part of evaluation and treatment planning for patients with these types of symptoms. Some patients with attentional issues due to ADHD or acquired cognitive deficits may benefit from stimulant therapy to improve performance on focused tasks (Pao et al. 2006). In pediatric cancer survivors who received CNS directed therapy (ALL with cranial radiation and brain tumors), response to methylphenidate (MPH) is less robust (45 %) than in the ADHD population (75 %) . A history of preexisting inattention/ADHD is the best predictor of response. Given that the safety and tolerability are favorable, and similar to the ADHD population, and nearly half will have a response, Conklin et al. recommend a trial of methylphenidate with a slow titration and close monitoring of treatment response and side effects (Conklin et al. 2014). See Table 8.5, Stimulants, for specific medication information.



Medications



Antidepressants (Table 8.2)





Table 8.2
Preparations and dosages of antidepressant medications in children





































































Medication

Prescribing information

(Starting dose – general range)

Routes of administration

FDA indication in children

Psycho-oncology uses and specific notes

Selective serotonin reuptake inhibitors (SSRIs)
   
Depression

Anxiety

Caution with linezolid (MAOI)

Note p450 interactions

Black box warning

Citalopram (Celexa®)

Escitalopram (Lexapro®)

5–40 mg/day, increase by 5–10 mg/day

POa

5–20 mg/day

Increase by 5–10 mg/day

POa

No

12 years and older for depression

Few drug-drug interactions; EKG changes above 40 mg

Few drug–drug interactions

Fluoxetine (Prozac®)

5–60 mg/day

Increase by 5–10 mg/day

POa

8 years and older for depression; 7 years and older for OCD

Long half-life, p450 issues

Fluvoxamine (Luvox®)

25–200 mg/day, increase by 25 mg/day

Max 300 mg

PO

8 years and older for OCD

Sedation, dry mouth, tachycardia

Paroxetine (Paxil®)

5–20 mg/day, increase by 5 mg/day

PO

No

Prohibited in Europe under 18, short half-life, increased rate of discontinuation symptoms

Sertraline (Zoloft®)

12.5–150 mg/day,

Increase by 12.5–25 mg/day

Max 200 mg

POa

Yes, 6 years and older for OCD
 

Other antidepressants
     

Bupropion (Wellbutrin®)

37.5–300 mg/day, increase by 37.5–50 mg/day

Max 450 mg

PO

No

Depression

Anxiety

ADHD (3rd line)

Decreases seizure threshold

Duloxetine (Cymbalta®)

20–60 mg/day, increase by 10–20 mg/day

Max 120 mg

PO

7 years or older for generalized anxiety disorder

Depression

Anxiety

Pain

Mirtazapine

(Remeron®)

7.5–45 mg/day, increase by 7.5–15 mg/day

Max 45 mg

POb

No

Depression

Anxiety

Boosts appetite (weight gain), antiemetic, helps sleep (sedation) at lower doses

Venlafaxine (Effexor®)

18.75–300 mg/day, increase by 18.75–37.5 mg/day

Max 375 mg

PO

No

Depression

Anxiety

Pain

Monitor blood pressure (hypertension) and heart rate (tachycardia)


PO per os/by mouth, IM intramuscular, IV intravenous

aLiquid form available

bOral disintegrating tablet available http://​www.​micromedexsoluti​ons.​com/​accessed 1/19/2015

Retrospective reviews of antidepressant use in pediatric oncology patients have been conducted (Pao et al. 2006; Portteus et al. 2006; Kersun and Elia 2007; Phipps et al. 2012). In most centers, pediatric oncologists prescribe antidepressants, but fewer than 10 % of the oncologists report specifically assessing for suicidal ideation despite the institution of a black box warning on use of selective serotonin reuptake inhibitors (SSRIs) in adolescents (Phipps et al. 2012). Consultation with a child psychiatrist by the pediatric oncology medical team is encouraged for the selection and monitoring of psychotropic medications for pediatric oncology patients. There are no randomized controlled trials (RCTs) in children with cancer and depression using antidepressants including SSRIs, the current antidepressant treatment of choice in children and adolescents (Valluri et al. 2012). In the United States, only fluoxetine and escitalopram have pediatric Food and Drug Administration (FDA) indications for depression (see Table 8.2 Antidepressants). Two small open-label trials of antidepressants have been reported in children with cancer (DeJong and Fombonne 2007; Gothelf et al. 2005).

Other medications used in the treatment of depression include mirtazapine and stimulants. Mirtazapine is a noradrenergic and specific serotonin agent that is a partial 5HT-3 receptor antagonist. Its use off-label has become more popular as it is sedating, causes weight gain, has antiemetic properties, and has few significant drug interactions, but it is not FDA approved for use in children. Children and adolescents who cannot tolerate antidepressants may, assuming cardiac stability, benefit from a trial of stimulants for depression and apathy. Tricyclic antidepressants do not have demonstrated efficacy for depression in children but may be useful for headache prophylaxis or enuresis (Daly and Wilens 1998). It is important to note they can be dangerously cardiotoxic in overdose and have anticholinergic side effects (e.g., dry mouth, sedation) at therapeutic doses.

Primary considerations in antidepressant selection include drug-drug interactions and side effect profiles. Practitioners must be aware that some antibiotics commonly used in resistant infections such as linezolid, a weak monoamine oxidase inhibitor, have a small but documented risk of leading to serotonin syndrome when combined with SSRI use. Serotonin syndrome is characterized by change in mental status, autonomic instability, and neuromuscular abnormalities and can be lethal if not identified and treated by discontinuation of the SSRI and providing autonomic support. Clinicians may have to decide to discontinue either linezolid or SSRI in situations in which both medications are present. Similarly, when patients must undergo prolonged periods of no intake by mouth during transplant or postoperatively, a clinical decision as to the severity of the depression may warrant continuation of the antidepressant via liquid form or per nasogastric tube.


Antipsychotics (Table 8.3)





Table 8.3
Preparations and dosages of antipsychotic medications in children






















































Medication

Prescribing information

(Starting dose – general range)

Maximum dose allowed

Routes of administration

FDA indication in children

Psycho-oncology uses and specific notes

Atypical antipsychotics
   
Need to monitor QT intervals

Aripiprazole (Abilify®)

2 mg–15 mg/day, increase by 5 mg/day

Max 30 mg

POa, b, IM

6–17 years agitation in autism; 10 years or older in bipolar I; 6–18 years in Tourette’s; 13–17 years in schizophrenia

Delirium (hypoactive, adults primarily); long half-life

Olanzapine (Zyprexa®, Zydis®)

2.5–10 mg/day, increase by 2.5–5 mg/day

Max 20 mg

POb, IM

13–17 years bipolar I acute, schizophrenia; depressed bipolar I with fluoxetine 10–17 years

Delirium

Nausea

Steroid-related mood problems

Quetiapine (Seroquel®)

12.5–50 mg/day, increase by 12.5–25 mg/day

Max 600–800 mg

PO

10–17 years bipolar mania; 13–17 years acute schizophrenia

Delirium

Agitation

Used in low doses (<200 mg/day)

Risperidone

(Risperdal®, Risperdal Consta®, Risperidone M-Tab®)

0.25–3 mg/day, increase 0.25–0.5 mg/day

Max 6 mg/day

POa, b, IM

5 years or older irritability in autism; 10 year or older bipolar I; 13 years or older schizophrenia

Delirium

Agitation

Steroid-related mood problems

Typical antipsychotics
   
Need to monitor QT intervals

Chlorpromazine (Thorazine®)

0.25 mg/lb body weight – 50 mg

(Titrate by weight)

PO, IM

6 months to 12 years for nausea and vomiting; severe problem behavior; 1–12 years tetanus

Delirium

Hiccups

Agitation; highly sedating

Haloperidol (Haldol®)

0.25–5 mg/day

PO, IM, IV

3 years or older Tourette’s, hyperactive or severe behavioral problems, schizophrenia

Delirium

Agitation


PO per os/by mouth, IM intramuscular, IV intravenous

aLiquid form available

bOral disintegrating tablet available http://​www.​micromedexsoluti​ons.​com/​accessed 1/19/2015

Off-label use of antipsychotics, particularly atypical antipsychotics, may be beneficial for symptom management for children with cancer in several clinical scenarios. As discussed above in the section on pediatric delirium, atypical antipsychotics are the recommended treatment for symptoms of agitation or distress in delirious infants and children. Their use in this setting may reduce exposure to other offending agents causing delirium, decrease time the patient is delirious, decrease traumatic disorientation and distress, and reduce length of stay in the PICU and hospital. Quetiapine and risperidone have been most commonly cited. Dose ranges have been anecdotally reported (Turkel and Hanft 2014; Silver et al. 2010) (Table 8.3), but studies are needed to determine the safest and most efficacious dosing regimens in medically ill children. In situations where a child is unable to take oral medications, low-dose intravenous haloperidol may be used.

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Oct 31, 2016 | Posted by in PEDIATRICS | Comments Off on Psychiatric Issues in Pediatric Oncology: Diagnosis and Management

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