Behavioral and Cognitive Neurology

Jeffrey Maneval

Seth Gale

Kirk R. Daffner

DISORDERS OF ATTENTION AND EXECUTIVE FUNCTIONS

Background

Definitions

1. Attention involves neural processes that help select which stimuli/thoughts will be the center of awareness, while filtering out distractors.
- a. Components of attention include arousal, orienting (shifting of the direction of sensory organs), selectivity (focusing on certain stimuli), and the capacity to sustain processing (vigilance) and divide resources (during dual or multiple tasks).
- b. Disruption of attention is likely to undermine most cognitive functions.
2. Executive functions are a set of complex cerebral processes that exert “top-down,” volitional control over cognition and behavior.
- a. Key executive functions include working memory, monitoring, inhibition, and initiation.
- b. Executive functions facilitate context-appropriate behavioral responses while inhibiting inappropriate ones, maintaining and shifting cognitive sets, and monitoring and adjusting ongoing mental activity. They mediate insight, judgment, and problem-solving skills.
- c. Executive functions are most closely linked to a person’s capacity to remain independent.

Presenting Syndromes

1. Acute confusional state (ACS)
- a. ACS is a disorder of higher cognitive function reflecting the loss of a normal, coherent stream of thought, which can also have features of illogical/abnormal behavior.
- b. Its salient feature is a disruption of a patient’s “attentional matrix.”
- c. “Delirium” is an alternative term for ACS.
- d. Delirium/ACS can be classified as “hyperactive,” “hypoactive,” or “mixed.” Hyperactive delirium can be accompanied by sympathetic overactivity, mood lability, agitation, and at times hallucinations; hypoactive delirium involves slowed psychomotor activity and can present with lethargy or sluggishness. Mixed delirium will have one or more features of both. Delirium often has a fluctuating course, with disturbances of sleep architecture.
2. Attention deficit hyperactivity disorder (ADHD)
- a. ADHD is defined by inappropriate levels of attention, impulsivity, or hyperactivity, with symptom onset prior to age 12; these difficulties must occur in more than one setting (home, school, etc.).
- b. Many children with ADHD have persistent symptoms in adulthood that may disrupt daily activities; these symptoms may include inattention, easy distractibility, disorganization, impulsivity, affective lability, learning problems, and impairment of executive functions.
3. Dysexecutive syndromes
- a. Cognitive: Impaired planning and decreased working memory, poor insight
- b. Behavioral: Impulsivity, disinhibition, perseveration
- c. Motivational: Apathy, abulia

Pathophysiology

Neuroanatomic Components

1. Frontal-subcortical circuits
- a. Frontal lobes → basal ganglia (caudate) → globus pallidus/substantia nigra → thalamus (dorsal medial/ventral anterior) →frontal lobes.
- b. Disruption anywhere along these circuits can lead to similar behavioral outcomes.
- c. Topographically distinct circuits exist with key nodes in dorsolateral frontal cortex, medial frontal cortex, and orbital frontal cortex.
- d. Most often, disruption of the dorsolateral frontal circuit is associated with cognitive signs, the medial frontal circuit with altered self-monitoring and motivation, and the orbital frontal circuit with decreased inhibitory control and affective lability.
2. Ascending neurotransmitter systems
- a. Norepinephrine from the locus ceruleus helps mediate arousal and improves signal-to-noise ratio (ie, reduces distractions).
- b. Dopamine from the ventral tegmental area is necessary for functioning of the prefrontal cortex and maintenance of appropriate behavioral engagement.
- c. Acetylcholine (ACh) from the basal forebrain and brainstem reticular systems may modulate activity of widespread regions of the thalamus and cortex and influence overall information processing capacity.

Disorders

1. Attention and executive functions can be undermined by a wide range of medical, neurologic, and psychiatric conditions.
2. Common causes include the following:
- a. Toxic-metabolic encephalopathy (including side effects of medications)
- b. Multifocal injury (including cerebrovascular disease (CVD), traumatic brain injury, multiple sclerosis)
- c. Developmental causes (eg, ADHD, Tourette syndrome)
- d. Degenerative diseases (including behavioral variant-frontotemporal dementia [bvFTD], vascular dementia, Alzheimer disease, demyelinating diseases such as multiple sclerosis, and Parkinson disease)
- e. Neuropsychiatric conditions (eg, anxiety, depression, hypomania/mania, schizophrenia)
- f. Disorders of arousal and sleep (including sleep apnea and narcolepsy)
- g. Mechanical causes (“brain sagging syndrome” from idiopathic intracranial hypotension or from CSF overshunting in patients with a ventriculoperitoneal shunt)

Prognosis

Prognosis is variable and depends on the underlying conditions.

Treatment

General Principles

1. Review medications. Eliminate nonessential medications, being particularly mindful of those with anticholinergic, sedative, or extrapyramidal/parkinsonian side effects.
2. Review and treat systemic/medical conditions (eg, cardiac, pulmonary, renal, endocrine, pain, and sleep).
3. Identify and treat neuropsychiatric conditions that may be contributing to impaired attention and executive functions (eg, anxiety, depression, hypomania/mania, and psychosis).

Medications

Attentional Problems

1. Stimulant medications (Table 15-1): U.S. Food and Drug Administration (FDA) approval is limited to ADHD and narcolepsy. Side effects vary and can include insomnia, anorexia, exacerbation of tics, agitation, anxiety, psychotic symptoms, mood lability, and lowering of seizure threshold. Serious cardiovascular adverse events, including sudden death, have occurred in patients with significant heart problems, and there are reports of cerebro- and cardiovascular events in adults. Potential risks should be reviewed with the patient (and with the patient’s family, when appropriate). Monitor blood pressure, especially in patients with hypertension. Avoid concomitant use of monoamine oxidase inhibitors (MAOIs).
2. There are numerous stimulants currently available that vary in their pharmacokinetics, with short-acting, intermediate-acting, and longer-acting preparations. Patients may respond better to one stimulant than another. Duration of action is one of the key considerations in choice of a stimulant medication.
3. Modafinil has a different mechanism of action than stimulants. It involves the activation of the orexinergic system, inhibition of dopamine and norepinephrine transporters, elevation of extracellular catecholamines, glutamate, and serotonin, and diminution of γ-aminobutyric acid (GABA). It is approved for excessive daytime sleepiness related to narcolepsy, shift work sleep disorder, and as an adjunct treatment for obstructive sleep apnea. It may be effective in the treatment of ADHD in children and adults but does not have FDA approval for this. Potential side effects include insomnia, headache, nausea, nervousness, and hypertension. In addition, there is a risk of diminished appetite, weight loss, and significant dermatologic problems, especially in children and adolescents. The FDA has warned against its use in children.
4. Armodafinil, the enantiopure of modafinil, reaches its peak serum concentration more slowly than modafinil. Thus, it may be able to promote wakefulness for a longer time in some patients. First benefit may not be apparent until 150 mg.
5. Catecholamine “boosters”
- a. Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) that is approved in the United States for ADHD in children greater than 6 years,
  adolescents, and adults. Potential side effects include gastrointestinal distress, increased blood pressure, sexual dysfunction, urinary retention, possible cardiac problems, and increased risk of suicidal thinking in children and adults. It is less likely than stimulants to cause insomnia and is contraindicated in patients on MAOIs or with narrow-angle glaucoma.
- b. Bupropion: Although the precise neurochemical mechanisms are not known, it probably affects both the norepinephrine and dopamine systems. There is an increased risk of seizures with >450 mg/d, >150 mg of the immediate release formulation at one time, or if the patient has bulimia. Contraindication with MAOIs or in seizure disorders. Bupropion may be particularly helpful for inattentive patients with concomitant depression or nicotine dependence (see Table 15-2).
- c. α₂-Adrenergic agonists: There are abundant α₂-receptors in the prefrontal cortex, and studies have suggested that agonists may improve working memory, behavioral inhibition, and attentional focus. In adults, clonidine (0.1 mg/d, increase to bid, up to 0.6 mg/d) and guanfacine (1 mg/d, increase up to 3 mg/d) have FDA approval only for hypertension, but guanfacine ER is approved for ADHD in children ages 6 to 12 (1 mg/d, increase up to 4 mg/d) and 13 to 17 (up to 7 mg/d). These can be used as monotherapy or adjuncts to stimulants. Side effects include dry mouth, drowsiness, dizziness, constipation, and orthostatic hypotension. Guanfacine preferentially binds postsynaptic α_2A-adrenoreceptors in the prefrontal cortex and tends to be less sedating than clonidine.
6. Others (Table 15-2): Tricyclic antidepressants (TCAs) (eg, nortriptyline, desipramine), selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) (eg, venlafaxine) can be considered primary or adjunctive therapies for inattention, especially when patients exhibit concurrent problems with anxiety, depression, pain, or sleep disturbance.

Table 15-1 Stimulant and Related Medications

Medication	Starting Dose	Dosing Range^a
Short Acting (3-6 h)
Methylphenidate (Methylin, Ritalin)	5 mg bid-tid	Up to 60 mg/d
Dexmethylphenidate IR	2.5 mg bid	Up to 20 mg/d
Amphetamine-dextroamphetamine	5 mg qd-bid	Up to 40 mg/d
Intermediate Acting (4-8 h)
Methylphenidate SR (eg, Ritalin SR)	20 mg q am	Up to 60 mg/d
Dexmethylphenidate ER	10 mg q am	Up to 40 mg/d
Amphetamine-dextroamphetamine ER	10 mg q am	Up to 30 mg/d
Longer Acting (8-12 h)
Methylphenidate ER (eg, Concerta)	18 mg q am	72 mg/d
Methylphenidate patch (eg, Datytrana)	10 mg (on for 9, off for 15 h)_	Up to 60 mg/d
Methylphenidate PM (eg, Jornay PM)	20 mg q pm	Up to 100 mg
Lisdexamfetamine	30 mg q am	Up to 70 mg/d
Other (Nonstimulants)^b
Modafinil	100 mg qd	Up to 400 mg/d
Armodafinil	150 mg qd	Up to 250 mg/d
Atomoxetine	40 mg qd	Up to 100 mg/d
bid, twice a day; tid, three times a day; ER or XR, extended release; LA, long acting; qd, every day; SR, slow release.
^aSome clinicians increase these medications to even higher doses, while carefully monitoring the clinical status of their patients. ^bModafinil and atomoxetine have different mechanisms of action from stimulants.

Table 15-2 Selected Antidepressant Medications

Medication	Starting Dose	Dosing Range
SSRIs
Fluoxetine	10-20 mg/d	Up to 80 mg/d
Sertraline	25-50 mg/d	Up to 200 mg/d
Paroxetine	10 mg/d	Up to 50 mg/d
Citalopram	10-20 mg/d	Up to 40 mg/d^a
Escitalopram	5-10 mg/d	Up to 20 mg/d
Vortioxetine	5-10 mg/d	Up to 20 mg/d
5-HT₂ Antagonists
Trazodone	25-50 mg qhs	Up to 300 mg/d (divided doses)
Nefazodone	100 mg bid	Up to 600 mg/d
TCAs
Nortriptyline	25 mg qhs	Up to 200 mg/d
Desipramine	25 mg qd	Up to 300 mg
SSNIs
Venlafaxine ER	37.5 mg	Up to 225 mg/d
Duloxetine	40 mg qd	Up to 120 mg/d
Milnacipran	25 mg bid	Up to 100 mg/bid
Levomilnacipran	20 mg/d	120 mg/d
Other
Mirtazapine	7.5^b-15 mg qhs	Up to 45 mg/d
Bupropion	75-150 mg/d	Up to 450 mg/d^c
Bupropion SR	100-150 mg/d	Up to 300 mg/d
Bupropion ER/XL	150 mg/d	Up to 450 mg/d
^aDoses >20 mg for age >60, and doses >40 mg for all adults, are generally not recommended, due to risk of QT prolongation. ^bAs a sleep aid, 7.5 or 15 mg may be most effective, as the somnolence side effect is stronger at lower doses. ^cDo not exceed 150 mg per dose.
For elderly patients, appropriate starting doses may be lower. bid, twice a day; ER or XL, extended release; tid, three times a day; qhs, every night; SSNIs, selective serotonin-norepinephrine reuptake inhibitors; SR, sustained release; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

Executive Dysfunction

1. Dopamine agonists (DAs)/modulators (Table 15-3) may increase motivation, diminish apathy, and improve working memory or other executive functions. Evidence supports the notion that there is an optimal level of dopamine activity, with too little or too much leading to dysfunction. These medications predominantly affect dopaminergic neurons in the brainstem (eg, substantia nigra, ventral tegmental area) and along cortical-subcortical pathways (eg, nigrostriatal, tuberoinfundibular, mesocorticolimbic).
- a. Approval in the United States for most of these medications is limited to the treatment of Parkinson disease or restless leg syndrome. Clinicians can consider “empiric” treatment of dysexecutive symptoms with these agents. In such circumstances, it is crucial to closely monitor whether symptoms are improving and assess the potential effect of negative side effects.
- b. Begin with the lowest dose possible and increase very slowly.
- c. Patient response and side effects should be followed regularly with objective metrics (eg, number of days patient dressed without assistance, number of emotional outbursts in the prior week, body weight, standing blood pressure). Potential side effects include sedation, postural hypotension, hallucinations, gastrointestinal symptoms (eg, nausea), and peripheral edema. Amantadine is also associated with anticholinergic-like side effects.
- d. Often, the doses used are lower than what is typically prescribed for Parkinson disease. However, in cases of profound abulia, very high doses of these medications can be tried, with caution.
2. Cholinesterase inhibitors (Table 15-4) may augment cholinergic tone from basal forebrain to frontal cortex, with the potential to improve attention and executive functions. They have been most studied in Alzheimer disease and dementia with Lewy bodies (DLB).

Table 15-3 Dopaminergic Agents

Medication	Starting Dose	Dosing Range
Pramipexole	0.125 mg qd-tid	Up to 4.5 mg/d
Bromocriptine	1.25 qd-bid	Up to 30 mg/d
Ropinirole	0.25 qd-tid	Up to 24 mg/d
Amantadine IR	100 mg qd-bid	Up to 300 mg/d
Amantadine ER	137 qd	Up to 274 mg/d
Selegiline (MAO inhibitor)	5 mg	5-10 mg/d
Selegiline transdermal	6 mg/24 h	Up to 12 mg/24 h
bid, twice a day; MAO, monoamine oxidase inhibitor; qd, every day; tid, three times a day.

Table 15-4 Cholinesterase Inhibitors

Medication	Starting Dose	Dosing Objective	Comments
Donepezil	5 mg	Increase to 10 mg after 2-4 wk (can increase higher in selected patients; there is a 23 mg tablet)	Once per day dosing
Rivastigmine	1.5 mg bid	Increase by 3 mg q 2-4 wk (as tolerated), up to 6 mg bid	Possible effect of its butyl cholinesterase activity on ↓AD progression
Rivastigmine patch	4.6 mg/d	9.5 mg/d (or 13.3/d in selected patients)	Especially useful if GI intolerance with orals
Galantamine	4 mg bid	Increase by 8 mg/d q4 weeks up to 12 mg bid	Possible effect of its modulation of nicotinic receptor on symptoms and ↓ AD disease progression
Galantamine ER	8 mg/d	Up to 24 mg/d
Huperzine A	50 μg bid	Up to 400 μg/d	100 μg ˜ 5 mg of donepezil
Donepezil, rivastigmine, and galantamine are also available as oral solutions. AD, Alzheimer disease; bid, twice a day.

Apathy

1. Apathy is defined as a disorder of motivation; a decrease in goal-directed behaviors, emotional unresponsiveness, and disengagement from the environment. It may lead to a loss of independence in one or more instrumental activities of daily livings, such as shopping, driving, using public transportation, or handling finances. Apathy must be distinguished from depression, but these two disorders may be concurrent.
- a. Abulia can be viewed as a more extreme presentation of apathy, with marked limitations in initiating purposeful behaviors.
- b. Akinesia reflects a disorder of initiating movement.
2. Dopamine agonists may be helpful (Table 15-3).
3. Stimulant medications may also be used (Table 15-1). A clinical trial using methylphenidate 10 mg twice a day was a safe and effective treatment of apathy in Alzheimer disease.

Behavioral/Environmental

Depends on the severity of the impairments.

1. General principles
- a. Organizational strategies/time-management techniques, and executive function skills training.
- b. External support/guidance.
- c. Increased structure (including cleaning and organizing the patient’s living quarters).
- d. Psychotherapy techniques including cognitive-behavioral therapy (CBT) and Mindfulness-based meditation.
- e. Stable routines.
- f. Concrete rewards and consequences to the patient’s actions.
- g. Planning for the patient’s future.
- h. Education and support of caregivers.
2. Referrals
- a. Occupational therapist, speech and language pathologist, or other rehabilitation specialist to work on behavioral strategies and organizational techniques.
- b. Social worker to help ensure adequate safety, future planning, and caregiver support.

DISORDERS OF AROUSAL AND WAKEFULNESS

Background

An appropriate level of arousal is necessary, but not sufficient, for awareness and the performance of all cognitive tasks.

Prognosis

Prognosis is variable and depends on the underlying conditions.

DISORDERS OF MEMORY

Background

1. Declarative Memory: Conscious recall of events/information. Can be grouped into Episodic Memory (recalling one’s experience of an event) and Semantic Memory (memories of facts, words, ideas, concepts). Nondeclarative memory
includes unconscious memories that affect behavior (procedural, conditioning, priming).
2. Amnestic syndrome is characterized by recall deficits with relatively well-preserved attention; anterograde memory loss; and retrograde memory loss—events that occurred closest to the onset of memory loss are recalled least (Ribot law).

Pathophysiology

1. Neuroanatomic components: The limbic system and frontal lobes play a crucial role in episodic memory.
- a. Limbic system: Acetylcholine, involved in pathways from the basal forebrain to limbic structures, facilitates the process. In general, a rapid rate of forgetting (with loss of stored data and reduced ability to even “recognize” previously learned information when tested by multiple-choice questions) strongly suggests impairment within the limbic system.
- b. Frontal lobes: Activation-retrieval difficulties, marked by preserved recognition in the setting of poor recall, may indicate problems with frontal network functioning.
2. Disorders:
- a. Degenerative dementias (see below).
- b. Transient global amnesia (TGA): a syndrome of reversible anterograde amnesia, etiology often unknown (possibly vascular, epileptic, or migrainous), with typical duration range of 6 to 24 hours and clinically characterized by profound disorientation, repetitive question asking, and inability for new memory formation. This may be associated with transient single or multiple punctate foci of diffusion restriction on diffusion-weighted imaging (DWI)/ADC sequences in the CA1 region of the hippocampus.
- c. Other damage to limbic system or frontal networks (eg, TBI), anoxia, Korsakoff syndrome (see below “Vitamin Deficiency States/Toxins”), limbic encephalitis (eg, herpes simplex encephalitis, paraneoplastic encephalitis), temporal lobe epilepsy, CVD).
- d. Opioid-associated amnestic syndrome is characterized by acute onset of memory loss in the setting of opioid use, typically fentanyl or heroin, with bilateral hippocampal diffusion restriction on neuroimaging.

Prognosis

Prognosis is variable and depends on the underlying conditions.

Treatment

Medications

1. Cholinesterase inhibitors (Table 15-4)
- a. Increase the availability of acetylcholine.
- b. Currently, approval in the United States includes the treatment of Alzheimer disease dementia and Parkinson disease dementia.
- c. Cholinesterase inhibitors have been shown to result in a modest improvement in cognitive function relative to placebo in many trials. In addition to improved cognitive functioning, there is evidence of a beneficial effect on activities of daily living (ADLs) and reduction of behavioral/neuropsychiatric symptoms, especially apathy, and overall milder symptoms.
- d. Patients with DLB/Parkinson disease may have significant improvements in cognition and noncognitive symptoms such as orthostasis, hallucinations, and sleep disturbances.
- e. There have been studies indicating the efficacy of cholinesterase inhibitors in treating patients with vascular dementia and mixed-type (neurodegenerative/vascular) dementia.
- f. Clinicians can consider “empiric” treatment with cholinesterase inhibitors for other conditions with memory disturbance (eg, TBI).
- g. Donepezil is a reversible acetylcholinesterase inhibitor (AChEI) dosed once a day. Rivastigmine inhibits both acetylcholinesterase (neuronal) and butyl cholinesterase (plasma) activity and a transdermal formulation may reduce the risk of GI-related side effects. Galantamine is an AChEI and also exhibits allosteric binding to nicotinic receptors; the clinical benefits of this additional mechanism have not been proven.
- h. Rivastigmine and galantamine are given in bid dosing. Rivastigmine is also available as a once-a-day patch and galantamine has a long-acting, once-a-day tablet. There is no clear evidence that one agent is more efficacious than another. Patients vary in terms of the medication that is better tolerated.
- i. Potential side effects of cholinesterase inhibitors include: gastrointestinal distress (eg, nausea, anorexia, diarrhea, vomiting, and weight loss), insomnia, vivid dreams, agitation, dizziness, and muscle cramps. Sometimes initial side effects diminish or resolve after days/weeks. Some patients have intolerable side effects with one medication but tolerate another, so may be beneficial to switch to a different agent in this class.
- j. Huperzine A, a herbal AChEI, is an alternative for patients who prefer a “natural” treatment. It has shown modest efficacy in some trials for Alzheimer disease, with even less clear benefit for vascular dementia, and ADHD. It is not approved in the United States for any indication. It comes in tablets of 50 μg. A typical dosage is 100 μg per day (bid dosing). Up to 400 μg daily may be used if tolerated and necessary for optimal therapeutic benefit.
2. Herbal substances
- a. These have not been subject to the same scrutiny as FDA-approved medications.
- b. Ginkgo biloba may have antioxidant properties, increase cerebral blood flow, inhibit platelet-activating factor, and have mild stimulating effects. Some combination of these actions may be relevant to their potential efficacy in the treatment of dementia. Doses range from 120 to 360 mg daily in divided doses. Several studies have shown that 240 mg/d can modestly improve cognitive performance and measures of global function over 22 to 26 weeks. Ginkgo appears to be safe for use, with no excess side effects compared with placebo. Ginkgo does not slow the rate of developing dementia in patients with mild cognitive impairment (MCI) and in normal older adults.
3. Memantine, a chemical relative of amantadine, is a moderate-affinity, uncompetitive N-methyl D-aspartate (NMDA) receptor antagonist and weak booster of dopamine. It has a greater NMDA antagonist effect at high levels of receptor activation than at low ones. The symptomatic improvement of cognition may
result from improved “signal-to-noise” transmission across NMDA (and possibly AMPA) receptors and/or protection against glutamate-induced excitotoxicity. It comes in both 10-mg tablets and a long-acting, once-a-day (extended release, XR) dose with 7, 14, 21, and 28 mg tablets. Typical doses are 20 mg, one 10 mg tablet twice daily, or 28 mg, one tablet once daily (FDA-suggested), but doses up to 40 mg/d (divided doses) have been studied. It is approved in the United States for moderate to severe Alzheimer disease, but studies support potential efficacy in vascular dementia and mixed-type Alzheimer disease/vascular dementia. Combined treatment with cholinesterase inhibitors seems to be tolerated and may be more effective than using cholinesterase inhibitors alone.

Behavioral/Environmental Strategies for Memory Disorders

1. Mnemonic devices
2. Increasing depth of encoding
3. Rehearsal
4. External cueing to assist with retrieval
5. Use of written cues

BEHAVIORAL DYSREGULATION/OUTBURSTS

Background

Agitation, aggression, and outbursts of intense emotional behavior are among the most socially undesirable and dangerous manifestations of neuropsychiatric disorders.

Pathophysiology

1. Neuroanatomic components: Behavioral regulation is dependent on the appropriate functioning of limbic structures (eg, hypothalamus, amygdala) and frontal networks (eg, orbitofrontal cortex). Many neurochemicals, including serotonin, ACh, GABA, norepinephrine, dopamine, and androgens, play an important modulatory role.
2. Disorders: A wide range of disorders can be associated with behavioral dysregulation, including delirium/ACS, dementia, hyperthyroidism, CVD, TBI, developmental disorders, and psychiatric illnesses such as schizophrenia, mania, psychotic depression, and personality disorders.

Prognosis

Prognosis is variable and depends on the underlying conditions.

Treatment

General Principles

1. Evaluate and treat concurrent illnesses (eg, toxic-metabolic state, infection, pain, constipation, endocrine disorders, sleep disturbance), especially in cognitively vulnerable patients (eg, patients with dementia or intellectual disabilities).
2. Identify and treat neuropsychiatric symptoms and disorders that may be contributing (eg, depression, anxiety, hypomania/mania, thought disorder).
3. Simplify medication regimen, if possible.
4. Medication treatment depends on the urgency/acuteness of the situation.
- a. If a patient is wildly agitated and dangerous, haloperidol 5 mg intramuscularly (IM) or intravenously (IV) alone or in combination with lorazepam 1 to 2 mg IM/IV is widely available.
- b. For most agitation, aggression, and emotional outbursts associated with cognitive/behavioral disorders, second-generation antipsychotics are recommended. Acutely, olanzapine (IM) 10 mg or oral disintegrating tablet (10-20 mg) may also be effective; onset of action is 15 to 45 min. Ziprasidone IM or po 10 to 20 mg or Risperidone 0.5 to 4 mg oral or sublingual disintegrating tablets may be considered.
- c. Repeat as necessary until the behavior is under control. For older or cognitively disabled patients, much lower doses are appropriate, but the ratio of benzodiazepine to neuroleptic should be approximately the same.
- d. Closely monitor the patient’s vital signs and obtain an electrocardiogram when feasible at baseline and serially to check for QT prolongation due to neuroleptic medication use (especially IV haloperidol).
- e. As with all treatments, the aim is to try to maximize efficacy and safety while minimizing untoward side effects. Behavioral strategies are often the first line intervention and may reduce or eliminate the need for medication; these should be instituted initially and then concurrently with medication.
5. Mood stabilizers
- a. Antiseizure medications (Table 15-5) have been used for more than three decades for their mood-stabilizing and potentially behavior-stabilizing properties. Of note, no randomized controlled trials have demonstrated their efficacy in treating agitation and other neuropsychiatric symptoms associated with dementia.
  - 1) Valproic acid, usually given as divalproex sodium, has FDA approval for the treatment of acute mania in bipolar disorder and is commonly used in maintenance therapy. Evidence for use in neurodegenerative diseases is scant, and should not be used as a first line therapy. However, in select cases, adjunctive use can be helpful.
  - 2) Gabapentin may have some benefit for behavioral dysregulation, especially in patients with anxiety disorders or peripheral neuropathy.
  - 3) Carbamazepine has a long history of use in the treatment of emotional outbursts and explosive behavior. Its extended-release formulation has FDA approval for the treatment of acute mania or mixed episodes associated with bipolar disorder. It has modest effects on agitation/aggression in dementia; drug-drug interactions and potential for anemia or agranulocytosis must be monitored.
  - 4) Oxcarbazepine probably has similar effects to carbamazepine and does not have the risk of hematologic derangement; periodic screening for Syndrome of inappropriate antidiuretic hormone secretion/hyponatremia is needed.
  - 5) Lamotrigine has approval in United States for maintenance therapy in bipolar disorder.
  - 6) Other anticonvulsants have been studied using varying degrees of experimental control.
  - 7) In general, aim for doses and therapeutic levels similar to those appropriate for the treatment of epilepsy, although benefits are often seen at lower doses.
- b. Lithium should be used very cautiously in patients with overt brain disease (eg, TBI, degenerative dementia). Levels of 1.0 are needed for the best outcomes in primary bipolar disorder, but a level of 2.0 causes neurotoxic symptoms in most patients. Common side effects of long-term lithium use include hypothyroidism and nephrogenic diabetes insipidus. Both conditions can aggravate neurologic impairment. Kidney function should be monitored as least weekly during dosage adjustment and at least quarterly thereafter. Thyrotropin and T₄ should be checked every 3 to 6 months and again if the patient develops new symptoms compatible with hypothyroidism.
6. Sympatholytics (catecholamine blockers)
- a. Behavioral dysregulation and hyperresponsiveness may arise from some level of increased CNS adrenergic activity, with increased post-synaptic release of norepinephrine.
- b. Propranolol (beta-blocker) 20 to 480 mg/d may be particularly effective for those with intellectual disabilities or autism spectrum disorder. Follow patient for signs of hypotension and bradycardia. Asthma is a relative contraindication. Improvement may not be noticeable for weeks.
- c. Prazosin (α₁-blocker) is FDA approved for hypertension, but has also been used for nightmares, PTSD, and agitation/aggression in dementia.
7. Dextromethorphan/quinidine is a sigma-1 agonist and weak NMDA-antagonist, which is FDA-approved for the treatment of pseudobulbar affect. Some evidence has shown benefit for severe agitation in dementia, and may be reasonable to try to avoid the need for antipsychotics.
8. Atypical neuroleptics (Table 15-6)
- a. These have FDA approval for the psychotic symptoms and agitation associated with schizophrenia. Many have FDA approval for acute mania or mixed episodes associated with bipolar disorder as well as for maintenance therapy. Brexpiprazole was the first FDA-approved treatment for agitation associated with dementia due to Alzheimer disease.
- b. Atypical neuroleptics also have been widely used in the treatment of patients whose behaviors are potentially dangerous to themselves and others. They also may have benefit for treating psychosis or agitation in dementia. Consider risperidone, quetiapine, or olanzapine. There is less experience with newer neuroleptic medications at the current time.
- c. All the first-generation atypical neuroleptics block D₂ dopamine and 5-HT₂ serotonergic receptors, as well as other dopamine and serotonin receptors to varying degrees. These medications have differing affects on histaminic, γ-adrenergic, and cholinergic receptors. In general, potential side effects of neuroleptics include somnolence, dizziness, orthostatic hypotension, akathisia, extrapyramidal signs, dystonia, neuroleptic malignant syndrome, and tardive dyskinesia. Although the neurologic side effects are less frequent and less severe with the atypical rather than typical neuroleptics, all of them can occur and patients with preexisting brain disorders are most vulnerable to experiencing them.
- d. Extrapyramidal side effects (EPS) can be addressed with low doses of amantadine, pramipexole, or bromocriptine (Table 15-3), while monitoring for worsening of the underlying behavioral problems. Dystonia can be managed by anticholinergic agents, either IV or po (eg, diphenhydramine 50 mg or benztropine 2 mg). Akathisia may be helped by propranolol 20 to 40 mg tid.
- e. Metabolic syndrome (obesity, hypertriglyceridemia, low high-density lipoprotein, hypertension, hyperglycemia) can be checked for by monitoring weight, waist circumference, fasting serum glucose, lipid profile, and blood pressure.
- f. There is evidence that typical and atypical neuroleptic medications are associated with an increased risk of death and cardiovascular events, especially in the elderly. The risk may increase at higher doses of the medication.
- g. Randomized trials have suggested that atypical neuroleptics (eg, olanzapine, risperidone) have some degree of efficacy in treating behavioral symptoms in elderly patients with dementia. However, the benefits may be outweighed by side effects.
- h. We suggest avoiding this class of medication, when feasible, in treating elderly patients with dementia; discussing the risks/benefits/uncertainties with caregivers; using the lowest dose possible; and discontinuing the medication if ineffective.
9. Benzodiazepines: An increase in GABA activity may reduce anxiety and have a calming effect. However, there is a risk of reducing inhibition, causing a paradoxical increase in behavioral dysregulation.
10. Buspirone, a 5-hydroxytryptamine 1A (5-HT_1A) agonist, is FDA-approved for generalized anxiety disorder and may also reduce aggressive behaviors. Begin 2.5 mg or 5 mg/d, up to tid. Increase up to 60 mg/d in divided doses. Consider lower doses for those with any prior brain injury. The effects are often delayed. Side effects tend to be minor and include headaches and nausea. Buspirone does not suppress respiratory drive, so it can be used in patients with lung disease.
11. SSRIs (Table 15-2) may reduce irritability and behavioral outbursts, especially in patients with concomitant anxiety and dysphoria. Some SSRIs (eg, sertraline and especially citalopram) have been shown to reduce behavioral problems in elderly patients with dementia. For the behavioral problems associated with FTD, clinical experience and case series suggest that SSRIs are among the most effective. Vortioxetine seems to have benefits for cognitive enhancement in patients with major depression and those with mild cognitive impairment. Further studies are needed on patients with dementia or other neurologic disorders. Low doses of the serotonin antagonist and reuptake inhibitor trazodone (see below) may also be effective.
- a. Potential side effects of SSRIs include sexual dysfunction, increased apathy, restless leg syndrome/periodic limb movements, akathisia, agitation, sleep disturbances, and the serotonin syndrome (a medical emergency involving a change in mental state, autonomic instability, and neuromuscular hyperactivity).
- b. Clinicians have used a variety of treatments for SSRI-induced sexual dysfunction, including sildenafil (50-100 mg as needed), bupropion (75-150 mg/d), and buspirone (15-30 mg bid). Less well-studied options include cyproheptadine (4-12 mg as needed), amantadine (100-300 mg/d), or other dopaminergic agents (Table 15-3).
12. Trazodone is a 5-HT₂ (serotonin) antagonist and reuptake inhibitor; 25 to 300 mg/d has been used to help manage agitated patients. This medication can be sedating and cause headaches.
13. Cholinesterase inhibitors (Table 15-4) have been shown to have beneficial effects on behavior and neuropsychiatric symptoms (usually of milder severity) in patients with probable Alzheimer disease.

Table 15-5 Antiseizure Medications and Others as Potential Mood/Behavior Stabilizers

Medication	Starting dose	Therapeutic Range	Comments
Valproic acid	125-250 mg qd-bid	750-1250- mg/d, divided doses	Follow LFTs, CBC, platelets, weight gain, sedation, GI distress, tremor; IV prep available
Carbamazepine	100 mg qd-bid	400-600 mg/d	Follow LFTs, CBC, Na, sedation, ataxia, dizziness
Oxcarbazepine	300 mg bid	Up to 2,400 mg/d in divided doses	Follow Na
Lamotrigine	25-50 mg/d	300-500 mg/d in divided doses	Risk of Stevens-Johnsons syndrome/rash (reduced by very slow dose titration)
Gabapentin	100-300 mg qhs	Up to 1,200 mg tid	Sedation
Tiagabine	2-4 mg/d	Up to 32 mg in divided doses	Dizziness, sedation, may increase anxiety
Prazosin	1 mg qhs	3-15 mg qhs	Avoid with cardiac disease/arrhythmias, dysautonomia, or orthostatic intolerance
Dextromethorphan/Quinidine	20/10 mg	Up to 40 mg/20 mg (divided doses)	Most studied in pseudobulbar affect, but may have benefit for agitation in dementia
Lithium	300 mg qd	Levels of 0.8-1.2 mEq/L	Low therapeutic index; check kidney function weekly during titration, thyroid function every 3-6 mo or more
bid, twice a day; CBC, complete blood count; ER, extended release; GI, gastrointestinal; IV, intravenous; LFTs, liver function tests; Na, sodium; qd, every day; qhs, at night; tid, three times a day.

Table 15-6 Atypical Neuroleptic Medications

Medication	Starting Dose	Dosing Range	Comments
Clozapine	6.25-25 mg/d	25-300 mg bid	Minimal extrapyramidal effects. Risk of BM suppression (check frequent CBCs), seizures at higher doses. Patients with PD and psychosis may respond to very low doses. Disintegrating tablets and IM prep available
Olanzapine	1.25-5.0 mg qhs	2.5-20 mg/d	Weight gain; glucose intolerance; disintegrating tablets and IM prep available
Risperidone	0.25-1.0 mg qd-bid	0.5-4 mg bid	Of the atypical neuroleptics, may be most effective in agitation in dementia; most likely to cause extrapyramidal effects; disintegrating tablets and IM prep available
Quetiapine	12.5-25 mg qd-bid	25-600 mg/d	Weight gain; sedation. At low doses, less dopamine blocking activity than other antipsychotics
Ziprasidone	10-40 mg qd-bid	20-160 mg/d	↑ QTc interval of unclear clinical significance; weight neutral; IM prep available
Aripiprazole	10-15 mg/d	15-30 mg/d	Weight neutral; Akathisia common; adjunct to SSRIs for depression; IM prep available
Brexpiprazole	0.5 mg qd.	2-3 mg/d	FDA approved for treatment of agitation associated with Alzheimer disease
Pimavanserin	17-34 mg/d	34 mg/d	Approved for PD psychosis; selective 5-HT2A receptor antagonism (lack of D2 antagonism) may limit EPS
bid, twice a day; BM, bone marrow; CBCs, complete blood counts; EPS, extrapyramidal side effects; IM, intramuscular; PD, Parkinson disease; qd, every day; qhs, at night.

Behavioral/Environmental

1. Safety: protect the patient from self-harm. Protect the caregivers from potentially injurious behaviors.
2. Try to identify and avoid precipitating events.
3. Educate caregivers about management (eg, gentle distraction).
4. Reduce excessive environmental stimulation and establish a calm and “predictable” environment and routine.
5. Ensure patients do not have access to firearms.
6. Improve sensory fidelity when feasible (eg, glasses, hearing aids).
7. Improve sleep hygiene.
8. Ensure adequate fluid and nutritional intake.
9. Try to establish an exercise regimen.

OTHER NEUROPSYCHIATRIC DISORDERS

Neurologists often care for patients who suffer from a range of neuropsychiatric disorders. They should be aware of diagnostic issues and be prepared to provide initial treatment. However, patients at high risk of violence or self-injury, those with complex psychiatric or neuropsychiatric histories, or those resistant to first-line treatments should usually be referred to qualified psychiatrists with special expertise in this area.

Only gold members can continue reading. Log In or Register to continue