Irritability

Irritability is a common experience among healthy individuals. Annoyance, impatience, anger, and loss of temper are manifestations of irritability and may be present in normal day-to-day life. However, these experiences may be exacerbated by brain injury and become sources of distress and functional impairment. Traumatic brain injury (TBI) may increase both the frequency and intensity of irritable episodes.

• •
  

  Irritability involves both subjective emotional components (e.g., feeling angry or annoyed) and outward manifestations of that feeling (e.g., demonstrating anger) (Alderman 2003).

  
  
• •
  

  Irritability is a common manifestation of posttraumatic emotional dysregulation.

  
  
  
  
  • •
    

    In its early form, posttraumatic irritability tends to manifest with “snappiness,” typically as a reaction to modest stressors or sources of frustration.

    
    
  • •
    

    Chronic forms of posttraumatic irritability involve recurrent and fleeting outbursts that are experienced as ego dystonic and constitute a change from preinjury patterns of response (Eames 2001).

  
  

Reported rates of posttraumatic irritability vary widely, likely as a consequence of the various definitions and methodologies employed across applicable investigations. Nonetheless, irritability is thought to be a common problem in the early recovery period, with most persons enjoying improvement over time (Yang et al. 2013).

Assessment for posttraumatic irritability needs to take into account injury severity and insight. Persons recovering from more severe injuries are often less aware of and able to report on irritability that is readily apparent to families and care providers. Hence, evaluators must consider the degree to which self-awareness is preserved when relying on patient self-report. In the setting of intact self-awareness, the Neurobehavioral Symptom Inventory (NSI) and the Irritability Questionnaire represent useful assessment tools.

When self-awareness is in question, informant-based assessment is preferred and is usefully guided by the Neuropsychiatry Inventory (NPI). Differential diagnosis in the setting of irritability requires recognizing the regularity with which irritability presents among even healthy persons; irritability is not necessarily indicative or a consequence of brain injury. Preexisting emotionality, various psychiatric disorders (especially depression, irritable mania, anxiety disorders, or posttraumatic stress disorder), substance use, pain, and medications may cause or contribute to irritability (Arciniegas and Wortzel 2014). These conditions, when identified, serve as appropriate initial targets for treatment rather than more direct management of irritability itself.

The treatment of irritability involves consideration of the severity of symptoms and cognitive status:

• •
  

  For mild to moderate irritability with intact cognition:

  
  
  
  
  • •
    

    Counseling and psychotherapy (Rees and Bellon 2007)

    
    
  • •
    

    Group therapy and manualized anger self-management training (Hart et al 2012)

  
  
  
  
• •
  

  For severe irritability and/or cognitive or behavioral impairment:

  
  
  
  
  • •
    

    Case reports describe sertraline, valproate, methylphenidate, carbamazepine, quetiapine, aripiprazole, buspirone, and propranolol as beneficial treatments (Arciniegas and Wortzel 2014).

    
    
  • •
    

    Selective serotonin reuptake inhibitors (SSRIs) are beneficial across a range of affective dysregulation disorders (except apathy), with modest side effect profiles, ease of use, and efficacy on comorbid conditions. They are considered first-line pharmacotherapy for posttraumatic irritability.

    
    
  • •
    

    Sertraline, citalopram, and escitalopram are preferred because of short half-lives, modest drug and CYP450 interactions, and modest side effect profiles.

    
    
  • •
    

    Amantadine has a relatively robust evidence base, including randomized controlled trials for posttraumatic irritability (Hammond et al. 2014, 2015, 2018), but caution is advised in the setting of cooccurring cognitive impairment.

    
    
  • •
    

    An open-label trial of quetiapine suggests that low doses may reduce posttraumatic irritability and aggression and improve cognition (Kim and Biljani 2006).

  
  

Affective lability

Affective (or emotional) lability involves:

• •
  

  Contextually congruent, albeit exaggerated, emotional reactions to personally meaningful stimuli

  
  
• •
  

  Episodes are provoked, variable in intensity, and only partially susceptible to voluntary control or distraction (Arciniegas and Wortzel 2014)

  
  
• •
  

  Episodes may involve partially stereotyped outbursts of anger, anxiety, crying, elation, irritability, or laughing

Affective lability by definition occurs periodically and involves relatively brief emotional shifts that are independent of any underlying persisting depressive, bipolar, or anxiety disorders, which are also common after traumatic brain injury and add to diagnostic complexity (Ponsford et al 2018). Determinations regarding prevalence after brain injury are complicated by various definitions and assessment methods employed across investigations (Arciniegas and Wortzel 2014).

That said, one investigation reports rates for mild TBI (mTBI) as high as 28% in the 1-week to 3-month postinjury period (Villemure et al 2011). Higher rates and the propensity for persistent problems occur with injuries of greater severity. In the setting of moderate to severe TBI, prevalence rates may range from 33% to 46% in the early postinjury period and from 14% to 62% more chronically (Arciniegas and Wortzel 2019).

Once again, evaluation necessitates consideration for cognitive deficits—more specifically, the capacity for self-awareness. Accordingly, evaluation for affective lability may be facilitated via either clinician-administered scales, such as the Neuropsychiatric Inventory-Clinician (NPI-C) or the Neurobehavioral Rating Scale-Revised (NRS-R), or via self-assessment tools such as the Affective Lability Scale or the Center for Neurologic Study-Lability Scale (CNS-LS) (Arciniegas and Wortzel 2019).

Affective lability is a feature shared across many neuropsychiatric conditions and thus is not necessarily indicative of or referable to brain injury. Considerations regarding differential diagnosis should involve a broad range of conditions spanning medicine and psychiatry, including depression, mania, substance abuse, and personality disorder.

The treatment of affective lability involves:

• •
  

  Behavioral interventions such as counseling, patient and family education, and/or psychotherapy

  
  
• •
  

  First-line pharmacotherapy options for severe or persisting symptoms include sertraline, citalopram, or escitalopram (Arciniegas and Wortzel 2014)

  
  
• •
  

  Second-line interventions are typically guided by comorbidities:

  
  
  
  
  • •
    

    With inattention and/or slow processing speed: methylphenidate

    
    
  • •
    

    With comorbid irritability and/or aggression: amantadine

    
    
  • •
    

    With irritability/anger or aggression (at self or others): valproate or carbamazepine

    
    
  • •
    

    With a comorbid seizure disorder: lamotrigine

  
  

Pathological laughing and crying

PLC is the prototypical disorder of emotional dyscontrol. The clinical manifestations may involve numerous disconnects between stimuli and emotional response in terms of both valance and intensity and disparity between demonstrated affect verses internal emotional experience. Other terms encountered in the medical literature to describe PLC include pseudobulbar affect , emotional incontinence, and involuntary emotional expression disorder .

• •
  

  PLC is characterized by frequent and brief episodes of stereotyped, intense, and uncontrollable laughing or crying that are exaggerated in comparison with the stimulus and may be contextually inappropriate (e.g., laughing induced by somber circumstances) (Wortzel et al 2008).

  
  
• •
  

  The internal emotional experience may bear little resemblance to the associated affective display (e.g., crying may occur absent associated sadness).

PLC is a relatively uncommon neuropsychiatric manifestation of TBI, especially compared with irritability and affective lability. Unlike these latter two forms of emotional dyscontrol, which frequently present in the setting of psychiatric illness and may even occur in healthy persons, PLC occurs in the setting of an underlying neurological condition (e.g., multiple sclerosis, stroke, and various neurodegenerative conditions). In essence, neurologic insults compromise the networks that integrate internal emotional states with affective displays and that instill elements of volitional control.

TBI is among the neurologic insults that may yield PLC. Prevalence of pathological laughter and crying ranges in the literature from 5% to 21% in the first year postinjury, with more severe injuries carrying greater risk of PLC. Pathological crying is four times more prevalent than pathological laughing after severe TBI (Roy et al 2015).

PLC is often apparent based on clinical interview, collateral information from caregivers, and direct observation. That said, various measures may aid in diagnosis and provide a means for quantifying symptom severity and to monitor progress with treatment. When self-awareness is preserved, the Pathological Laughter and Crying Scale is a good option (Arciniegas and Wortzel 2019). When insight is limited, a clinician-administered approach using the NPI-C is more useful (Arciniegas and Wortzel 2019). PLC frequently cooccurs with depressive disorders, anxiety disorders, posttraumatic stress disorder (PTSD), and behavioral dyscontrol (i.e., aggression) after TBI (Roy et al. 2015; Tateno et al. 2004).

PLC should be distinguished from normal emotionality, essential crying (Green et al. 1987), and personality disorders (e.g., borderline and/or histrionic personality disorder). Importantly, seizures may yield episodes of ictal laughing (gelastic seizures) or crying (dacrystic or quiritarian seizure). Altered consciousness and postictal confusion (which do not feature in PLC) are clues suggestive of seizures (Chahine and Chemali 2006).

Treatment of pathological laughter and crying includes:

• •
  

  Education regarding the nature and underlying causes of PLC for patients and families, to reduce distress and embarrassment

  
  
• •
  

  First-line medication options include SSRIs such as citalopram, escitalopram, or sertraline (Wortzel et al 2008)

  
  
• •
  

  Augmentation options, when results are insufficient, include amantadine, carbamazepine, lamotrigine, methylphenidate, or valproate (Arciniegas and Wortzel 2014)

  
  
• •
  

  Although approved by the US Food and Drug Administration (FDA) for pseudobulbar affect, dextromethorphan/quinidine (Nuedexta) is more appropriate when SSRIs prove ineffective, as combination therapy or augmentation (Hammond et al 2018).

Apathy

Apathy is appropriately regarded as a syndrome involving diminished goal-directed cognition, emotion, and behavior as a consequence of insult or injury to the brain that is not better accounted for by another cognitive or emotional condition.

Apathy manifests as a loss of motivation causing diminished ability to respond to stimuli (both internal and external) with goal-directed responses (Reekum and Reekum 2013). Apathy may affect cognition, behavior, and emotion (i.e., the capacity to think, do, or feel).

Apathy complicates a number of neuropsychiatric conditions, including TBI, and is associated with poor response to rehabilitation and other therapies along with increased caregiver burden. A variety of terms are used to describe apathy across a spectrum of severity, with the term akinetic mutism used to denote the near-complete loss of voluntary responses to stimuli in the setting of intact sensorimotor functions and arousal. The medical literature presents a wide range of prevalence estimations for apathy in the setting of TBI, from 20% to 71% (Worthington and Wood 2018).

Diminished motivation features across a wide variety of neuropsychiatric conditions, many of which may occur after TBI. Clinicians must be particularly vigilant to differentiate apathy from depression, because pharmacologic therapies typically used for depression (e.g., SSRIs) may exacerbate apathy. Unlike depression, apathy features diminished or blunted emotions as opposed to dysphoric emotional states (e.g., persistent sadness, hopelessness, helplessness).

Given the nature of apathy and diminished drive to act, patients struggling with apathy frequently lack the ability or drive to offer complaints in relation to this experience. Hence, informant-based interview is often necessary and should seek information regarding motivational behaviors, flattened affect, lack of initiation, and diminished interest or participation in activities (Reekum and Reekum 2013). Diagnostic assessment may be facilitated by the Apathy Assessment Scale (Marin 1991) or the NPI.

The treatment of posttraumatic apathy involves:

• •
  

  Nonpharmacologic interventions, such as verbal cueing, task checklists, computer retraining, cognitive interventions, music therapies, structured activity kits, multisensory stimulation environments

  
  
• •
  

  Medications that target dopamine systems:

  
  
  
  
  • •
    

    Methylphenidate or dextroamphetamine is an appropriate first-line options for TBI-related apathy.

    
    
  • •
    

    Bromocriptine and amantadine have been reported to be beneficial for apathy in the setting of TBI.

  
  
  
  
• •
  

  Medications that augment the cholinergic system:

  
  
  
  
  • •
    

    Acetylcholinesterase inhibitors such as donepezil, rivastigmine, or galantamine

  
  
  
  
• •
  

  Medications that target other neurotransmitters systems with stimulating effect, such as modafinil, carbidopa-levodopa, bupropion, venlafaxine, protriptyline, and selegiline

  
  
• •
  

  Treatment with antidepressants, such as SSRIs, may exacerbate apathy (Reekum and Reekum 2013).

Review questions

• 1.
  

  A 46-year-old male building contractor with a history of posttraumatic epilepsy presents for evaluation 12 weeks after a traumatic brain injury (TBI) with loss of consciousness (LOC) for 40 minutes when he was struck with an iron beam during a residential construction project. His wife accompanies him and reports that he has lost interest in their favorite TV shows, and she has a much harder time getting him to help around the house. When he is asked about this, he reports a general disinterest in his usual activities. He and his spouse deny any apparent dysphoric emotions but instead report he is emotionally muted, consistent with his affectively blunted presentation. The most appropriate first-line intervention for this patient’s condition would be

  
  
  
  
  • a.
    

    methylphenidate.

    
    
  • b.
    

    paroxetine.

    
    
  • c.
    

    carbamazepine.

    
    
  • d.
    

    bupropion.

  
  
  
  
• 2.
  

  A 23-year-old woman with a history of migraine headaches presents with her boyfriend for worsened headaches and increased emotionality after a low-velocity motor vehicle collision in which she was a restrained driver with no loss of consciousness. During evaluation, she is very talkative and superficial with history and details, hushes her boyfriend when he attempts to provide any history, has very expressive nonverbal communication, and portrays congruent but exaggerated emotional expressivity across a full range of emotional states and topics. Her affect is most consistent with:

  
  
  
  
  • a.
    

    apathy.

    
    
  • b.
    

    affective lability.

    
    
  • c.
    

    histrionic personality disorder.

    
    
  • d.
    

    pathological laughing and crying.

  
  
  
  
• 3.
  

  The son of a 52-year-old man accompanying his father to clinic requests an evaluation for his father’s mood changes. He has noted over the past few months, his father has inappropriate outbursts of childlike laughter during sad movies and serious conversations. These outbursts have caused conflict in his family, leading to increased tension between the patient and his wife. The patient reports he is unable to control it and wants to regain control of his emotions and repair his relationship with his wife. A US Food and Drug Administration (FDA)–approved treatment for his condition is

  
  
  
  
  • a.
    

    clonidine.

    
    
  • b.
    

    dextromethorphan/quinidine.

    
    
  • c.
    

    topiramate.

    
    
  • d.
    

    escitalopram.

  
  

Answers on page 396.

Access the full list of questions and answers online.

Available on ExpertConsult.com

• 4.
  

  A 25-year-old woman is about 5 weeks out from an uncomplicated mild TBI and says irritability that she feels is interfering with her friendships and rapport with her colleagues at work. The most appropriate initial therapeutic approach would be

  
  
  
  
  • a.
    

    divalproate.

    
    
  • b.
    

    escitalopram.

    
    
  • c.
    

    amantadine.

    
    
  • d.
    

    counseling or psychotherapy.

  
  
  
  
• 5.
  

  A 65-year-old newly retired attorney was involved in a skiing accident 3 months ago and was knocked unconscious after colliding with a tree. He presents to clinic several months after his injury reporting low energy and irritability. Over the past 6 weeks, he finds himself snapping more frequently at his wife, sleeping and eating more, and generally feeling depressed, in particular about how his retirement has been going thus far. He endorses little motivation to socialize and has also been procrastinating on completing paperwork for his last few clients at his law firm. This patient’s spectrum of symptoms is most consistent with

  
  
  
  
  • a.
    

    apathy.

    
    
  • b.
    

    major depressive disorder.

    
    
  • c.
    

    affective lability.

    
    
  • d.
    

    irritability.