Psychiatric presentations and differentiating from neurologic disorders

All human emotions and behavior are generated by the brain. Unlike some neurologic signs (eg, hemiparesis, Broca’s aphasia), most behavioral signs and symptoms do not reliably localize to a single location, but rather to networks. The clinical challenge is discerning which behavioral disturbances represent a known neurologic disease and which represent idiopathic psychiatric disorders. Current classification systems like the Diagnostic and Statistical Manual of Mental Disorders 5 TR (01) and the International Classification of Diseases-10 (ICD-10) offer a good starting point and are necessary for consistency and reimbursement. However, they are simplified constructs of questionable validity (18). This section reviews the differential diagnosis for depression, mood lability, and psychosis.

Depression

When a patient presents with “depression,” the diagnosis may meet criteria for major depressive disorder defined by DSM-5 TR, but there are many other possibilities. For example, low mood may be a part of normal reactions like grief and demoralization, or an adjustment disorder from new devastating neurologic diagnoses. There are also instances where major depressive disorder is misdiagnosed when an underlying neurologic diagnosis is the cause.

An important distinction is apathy due to a neurologic disorder that disrupts the frontostriatal, reward, salience, or executive networks. Apathy may manifest with diminished goal-directed behavior, cognition, or emotions. Distinguishing the diminished initiative, interest, emotional expression, and responsiveness in apathy from the anhedonia, low motivation, poor concentration, and low energy of major depressive disorder can be difficult but important. An SSRI would be indicated in major depressive disorder, but an SSRI might worsen apathy as a side effect (emotional blunting). Key distinguishing features of major depressive disorder include the presence of high distress with at least some insight and active avoidance of activities that are less typical of apathy. Table 1 provides additional characteristics to consider.

Table 1. Comparison of a Major Depressive Episode and Apathy

Neuropsychological testing for patients with depression, anxiety, and psychotic disorders often involves multiple cognitive domains, especially processing speed, memory retrieval, working memory, attention, and executive functioning. These memory and concentration complaints should be distinguished from neurologic causes, such as neurodegenerative disorders because the treatment differs. Previously termed “pseudodementia,” other terms like “cognitive impairment due to depression” or “depression-related cognitive dysfunction” are more prevalent now. Table 2 lists features to help distinguish the cognitive profile between depression and Alzheimer dementia.

Table 2. Comparison of Cognitive Impairment Due to Depression and Alzheimer Dementia

Mood lability

Changes in emotion lie on a spectrum that includes normal reactivity. Pathologic elation or irritability with high energy may be due to mania from a psychiatric disorder, which is diagnosed using the DSM-5 TR criteria. The presence of a manic episode not due to a medical disease, substance, or medication is diagnostic of bipolar I disorder, and the presence of hypomania and depressive episodes is diagnostic of bipolar II disorder. Associated symptoms for a manic episode include distractibility, indiscretion (eg, spending an excessive amount of money), grandiosity, flight of ideas, increased goal-directed activities, decreased need for sleep, and talkativeness.

Manic-like presentations may be due to neurologic etiologies. For example, disinhibition, aggression, and impulsivity can be seen from frontal dysfunction (eg, frontal brain tumor). A particular frontal syndrome termed “Witzelsucht” is characterized by excessive jocularity in the form of making puns and telling inappropriate jokes. Bursts of uncontrollable laughing, especially if stereotyped and associated with confusion, may be an ictal presentation of gelastic seizures (eg, from a hypothalamic hamartoma). The equivalent manifestation of seizure in the form of crying may represent dacrystic seizures.

Another disorder that can manifest with either or both laughing and crying is pseudobulbar affect. Pseudobulbar affect is also known as involuntary emotional expression disorder, pathological laughing and crying, and emotional incontinence. In pseudobulbar affect, the external emotional expression (affect) is incongruent with or disproportionate to the internal emotional state (mood reported by the patient). This is caused by the disruption to the cerebro-ponto-cerebellar pathways due to damage from stroke, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, Parkinson disease dementia, and other insults to the brain. Treatment for pseudobulbar affect includes SSRIs, SNRIs, and TCAs, especially if there is co-morbid depression or anxiety. The FDA-approved medication combination of dextromethorphan and quinidine also helps reduce the severity and frequency of episodes.

Psychosis

In psychiatric diagnoses, psychotic symptoms are generally defined by the positive symptoms of hallucinations (sensory perceptions not based on reality) or delusions (fixed false beliefs). These symptoms may present exclusively during a mood episode, like in major depressive disorder with psychotic features, or if the psychosis occurs for at least 2 weeks outside a major mood episode, schizoaffective disorder. Primary psychotic disorders like schizophrenia may additionally have disorganized speech, disorganized or catatonic behavior, or negative symptoms like amotivation and social withdrawal. The specific criteria can be found in the DSM 5 TR (01). Hallucinations and delusions, when due to brain pathology, may localize to frontal, temporal, or more diffuse brain areas with many possible etiologies.

Perceptual disturbances. Perceptual disturbances can be divided into illusions and hallucinations. Illusions are distortions or misinterpretations of real environmental stimuli (eg, seeing a person when it is just a coat rack). Hallucinations are perceptions generated without an external stimulus (eg, seeing a person in an empty room). Perceptual disturbances can occur in any sensory modality. Although non-ill persons experience occasional perceptual disturbances, the presence of frequent or intense aberrations often indicates a neuropsychiatric disorder.

In primary psychiatric disorders, auditory hallucinations are more common than visual hallucinations. The auditory hallucinations in psychiatric disorders are often distressing and may involve voices that make commentary on what the patient is doing, talk to each other, or tell the patient to do something. The presence of visual hallucinations should be carefully reviewed for medical etiologies. For example, simple hallucinations like a flashing light may be due to retinal pathology, migraine with visual aura, or occipital lobe seizures. If the localization of the ictal focus is beyond the primary visual cortex, the hallucinations can also be more complex (eg, people or scenes) but are typically stereotyped and short-lived (seconds to 2 minutes). A more benign etiology is visual release (also known as Charles Bonnet syndrome), where the brain produces visual hallucinations due to a lack of stimuli from poor visual acuity. Patients generally retain insight unless there is delirium or dementia. If the hallucination only occurs briefly on awakening (hypnopompic) or falling asleep (hypnogogic), these could be normal or a part of narcolepsy due to REM intrusion into wakefulness. In peduncular hallucinosis, a lesion to the midbrain or pons (eg, stroke) can cause complex movie-like hallucinations. Finally, intoxication (eg, psychedelics), withdrawal syndromes (eg, alcohol), and any cause of delirium can produce hallucinations.

Table 3. Types of Perceptual Disturbances

Delusions. Delusions are fixed and false beliefs that are not amenable to evidence to the contrary and are outside the patient’s cultural belief system. The content can vary, from mundane to fantastic, from simple to systemic and elaborate. Table 4 lists types of delusions, and any delusion can be found in either psychiatric or neurologic disorders. The most common delusions in schizophrenia are delusions of persecution, but ideas of reference and thought insertion or withdrawal and control are also common. When there’s a mood disorder, delusions can be mood-congruent (eg, delusions of guilt and nihilism in depression) or mood-incongruent (eg, delusions of grandeur in depression). Some syndromes may have other names or eponyms. For example, delusional parasitosis is also known as Ekbom syndrome, and if focused on removing fibers or filaments from the skin, Morgellons disease. When two people share the same delusion, this is termed folie à deux. Delusions of misidentification are often associated with right frontal lesions.

Table 4. Types of Delusions

Catatonia

Catatonia is a psychomotor syndrome defined in the DSM, but can have both primary psychiatric (major depressive disorder, bipolar, schizophrenia) and neurologic or medical etiologies. DSM-5 defines catatonia by the presence of at least three of the 12 core features listed in Table 5, but there are various other diagnostic criteria and even differences in the definition of terms. The most widely used rating scale to screen or monitor symptom severity is the Bush Francis Catatonia Scale (06). Catatonia can go underrecognized or be difficult to diagnose, given the overlap with other entities like delirium and its various presentations. Key features include a seemingly purposeless lack of movement, excessive movement, or abnormal movement in a fully conscious patient. When there is autonomic instability (fever, tachycardia, hypertension), this is termed malignant catatonia. Some also place neuroleptic malignant syndrome as a type of malignant catatonia, one that is induced by the use of antipsychotics or dopamine blockers. First-line treatment is lorazepam, and if this is ineffective, electroconvulsive therapy. It is important to conceptualize catatonia as a syndrome that may be responsive to said treatment, but a simultaneous search for and treatment of the underlying etiology is crucial for long-term recovery.

Table 5. DSM-5 Features of Catatonia

Neurologic disorders and their associated psychiatric disorders

Movement disorders

Parkinson disease. Nonmotor neuropsychiatric symptoms significantly impact disease course in Parkinson disease and result in higher levels of disability if left unaddressed. These symptoms often overlap with diagnostic criteria for mood, psychotic, and behavioral disturbances seen in primary psychiatric illnesses, making diagnosis challenging yet critical for optimal management of these patients.

Mood and anxiety disorders. Mood and anxiety disorders in Parkinson disease are more prevalent than in the general population and diagnosed using the DSM-5 criteria. Common nonmotor symptoms in Parkinson disease can include anhedonia, apathy (loss of motivation leading to reduced goal-directed behaviors), sleep disturbance, fatigue, cognitive difficulties, and psychomotor retardation, all of which are also part of the DSM-5 criteria for major depressive disorder and bipolar depression. Depressive symptoms are estimated to affect 35% to 50% of patients with Parkinson disease, with about 17% meeting criteria for major depressive disorder (29). These symptoms may precede the development of motor symptoms in up to a third of cases or develop at any point in the disease course; risk factors include female sex, onset of motor symptoms before 40 years of age, and severe cognitive impairment. Mania and hypomania can also occur in Parkinson disease. Although the manic symptoms can mirror those of bipolar disorder, they are more commonly linked to dopamine replacement therapy in the absence of a prior diagnosis of bipolar disorder. Additionally, anxiety can be a common comorbidity in Parkinson disease. It often occurs during the “off” period but can also occur in the “on” state or more consistently outside the nonmotor fluctuations.

Treatment options for depression and anxiety are similar to those available to the general population. Nonpharmacologic options include cognitive behavioral therapy and exercise therapy. Pharmacotherapy can include SSRIs and SNRIs as first-line agents. Caution should be exercised with TCAs, given the risks of worsening constipation and orthostatic hypotension, and benzodiazepines for anxiety, given the risk of falls and cognitive impairment. ECT is effective in patients with Parkinson disease and treatment-resistant depression and can even improve motor symptoms temporarily. Apathy (outside of a larger depressive syndrome) can be addressed with behavioral therapy, physical exercise, or dopamine agonists. Unique to Parkinson disease is the importance of evaluating the role of the antiparkinsonian regimen in mood variability, as many patients can experience dysphoria, (hypo)mania, anxiety, impulsive behaviors, and panic with excessive dopaminergic therapy or during the “off” periods.

Dopaminergic medication-related disorders. Use of dopaminergic medications, especially dopamine agonists, may lead to impulse control disorder in 15% to 20% of patients with Parkinson disease (28). Classic impulsive behaviors include binge eating, excessive sexual behaviors or shopping, and gambling. A related phenomenon is punding, which manifests as repetitive handling, sorting, arranging, or examining of objects. Another dopaminergic medication-related issue is dopamine dysregulation syndrome. In dopamine dysregulation syndrome, the patient experiences an addiction-like compulsive need to use excessive dopaminergic medications despite side effects of dyskinesia, aggression, euphoria, and even psychosis. The treatment for these conditions is a gradual reduction of dopaminergic medications, usually starting with the dopamine agonists, and sometimes the use of atypical antipsychotics. Caregiver intervention and education, cognitive behavioral therapy, and psychotherapy can also be helpful.

Psychotic symptoms. Psychotic symptoms are common and disabling in Parkinson disease and can include delusions, a sense of presence, illusions, and hallucinations (26). These are associated with higher mortality, caregiver burnout, and nursing home placement. The prevalence increases as the disease progresses. Visual hallucinations are the most common, with delusions developing later in the disease course. Insight is typically preserved until the advanced stages. These symptoms can result from the underlying disease itself, dopaminergic medications, or a combination.

Treatment is considered if these symptoms become bothersome and distressing. Anticholinergics, dopamine agonists, amantadine, COMT inhibitors, and levodopa can be reduced or discontinued. If this is not an option or is ineffective, oral antipsychotics can be considered. Because dopamine blockade can worsen motor symptoms, atypical antipsychotics are preferred. Pimavanserin is approved to treat Parkinson disease psychosis without worsening motor function. Quetiapine is another commonly used option. Clozapine can also be effective but requires significant monitoring due to potential hematologic and cardiac side effects. If cognitive impairment is present, cholinesterase inhibitors may also improve psychotic symptoms.

Cognitive impairment. Cognitive dysfunction and Parkinson disease dementia are common and can affect several cognitive domains, with executive and visuospatial domains typically affected earlier in the course. Mild cognitive impairment is estimated to occur in about one third of patients with Parkinson disease, and approximately 75% of individuals with Parkinson disease for 10 or more years develop dementia (08). Onset is typically insidious. Progression is slow with prominent cognitive fluctuations often noted by family members. Parkinson disease dementia, by definition, is diagnosed when the cognitive symptoms develop at least a year after emergence of motor symptoms. In Dementia with Lewy bodies, cognitive symptoms precede or occur within a year of motor symptoms. Management options for Parkinson disease with dementia include cholinesterase inhibitors and behavioral, environmental, and caregiver interventions. Memantine has also been studied with mixed results and is sometimes used. Caregiver support is paramount.

Sleep disturbance. Sleep disorders in Parkinson disease include insomnia, excessive daytime sleepiness, circadian rhythm disorders, obstructive sleep apnea, restless leg syndrome, and rapid eye movement sleep behavior disorder (14).

REM sleep behavior disorder is characterized by loss of atonia during REM sleep and results in dream-enactment behaviors. It is thought to be an early biomarker of synucleinopathy, and the estimated risk of developing a neurodegenerative disease for a patient with REM sleep behavior disorder is approximately 80% at 10 years (10). It is estimated to be present in about 25% to 50% of patients with Parkinson disease, with 20% of these preceding the onset of parkinsonism. Management of REM sleep behavior disorder includes measures to create a safe sleeping environment. Pharmacotherapy starts with melatonin and, if needed, low-dose clonazepam.

Huntington disease. Huntington disease is a complex autosomal dominant neurodegenerative disorder causing abnormal movements in addition to significant neuropsychiatric and cognitive symptoms. Management of motor symptoms, depression, anxiety, suicidal ideation, apathy, agitation, psychosis, and cognitive impairment requires collaboration and a multidisciplinary approach (02).

Mood and anxiety disorders. Apathy (loss of motivation leading to reduced goal-directed behaviors) is one of the most disabling and progressive symptoms in Huntington disease, affecting 90% of patients. There is often an overlap with depression and cognitive impairment. Depression can affect up to half to three quarters of people with Huntington’s disease, and the risk of suicide is elevated two to six times in this population (11). Suicidality is not always a manifestation of depression and can also be a result of impulsivity or perseverative symptoms. It can be more prominent around times of genetic diagnosis and the start of functional dependency, but the risk is present throughout the disease course, so all patients should be screened. Additionally, medications used in the management of chorea (VMAT2 inhibitors) may increase depressive symptoms and suicidality. Careful titration and close monitoring are recommended. Anxiety is also common and often underrecognized. Perseverative ideation and obsessive-compulsive disorder are seen and can lead to significant distress.

There are no evidence-based guidelines available for treatment, but SSRIs and SNRIs are the most common agents used to manage depression, anxiety, irritability, perseverative, and obsessive-compulsive disorder-like symptoms. Higher doses of SSRIs are often necessary when obsessive-compulsive disorder is present. Nonpharmacologic interventions and caregiver coaching are also utilized.

Psychotic symptoms. Psychotic symptoms are less common but do occur in Huntington disease. It is essential to rule out alternative comorbid medical conditions that may have precipitated psychotic symptoms. There are no evidence-based guidelines for managing psychosis in Huntington disease, but atypical antipsychotics are typically utilized.

Cognitive dysfunction. Cognitive decline is a core feature of Huntington disease. The predominant early pattern is a dysexecutive syndrome secondary to degeneration of front striatal circuits with a relative sparing of memory (13). Anosognosia is common, often affecting safety and creating conflicts with family and caregivers. There are no approved medications to help with cognitive decline in Huntington disease.

Behavioral disturbance. Irritability, low frustration tolerance, and disinhibition can often lead to verbal or physical aggression and behavioral disturbances in patients with Huntington disease.

Behavioral interventions are the most important for these symptoms (de-escalation, distraction, strategies to avoid conflict, caregiver education). Pharmacologically, SSRIs have been shown to reduce irritability and aggression. If severe, atypical antipsychotics or mood stabilizers may have a role.

Tourette syndrome. Tourette syndrome is a neuropsychiatric condition characterized by motor and phonic tics with onset in childhood or adolescence. It is associated with obsessive-compulsive disorder, attention deficit hyperactivity disorder, depression, anxiety, and behavioral disturbances and requires thoughtful behavioral and pharmacologic management of both motor and nonmotor manifestations.

Mood and anxiety disorders. Depression and anxiety occur in about 30% of patients with Tourette syndrome. Risk of suicide is also increased, with some studies showing four-fold risk of suicide attempt and death (35). Patients should be screened for these disorders. Treatment is similar to that of depression and anxiety in patients without Tourette syndrome.

Obsessive-compulsive disorder. The lifetime prevalence of obsessive-compulsive disorder in patients with Tourette syndrome is about 30% to 50% (35). Patients with Tourette syndrome are more likely to have compulsions and are less likely to have obsessions like fear of contamination and negative thoughts, compared to patients with obsessive-compulsive disorder without Tourette syndrome. Given the prevalence, patients should be screened and treated.

Treatment typically includes exposure and prevention therapy. If symptoms remain impairing, high-dose SSRIs are utilized, followed by adding an atypical antipsychotic or switching to a TCA if response is suboptimal.

Attention deficit hyperactivity disorder. The prevalence of ADHD in patients with Tourette syndrome is about 50% to 60% (35). Patients with Tourette syndrome should be screened and treated. Untreated ADHD can have a negative effect on function and quality of life. It can also increase the risk of disruptive behaviors.

Treatment options are similar to those for patients with ADHD without Tourette syndrome. There are medications such as alpha-2 adrenergic agonists that may help with both tics and ADHD symptoms. Although stimulants were previously thought to worsen tics, more recent evidence suggests this is less likely. Picking out the appropriate medication involves a thorough discussion of potential side effects and close monitoring to ensure no worsening of motor symptoms.

Behavioral disturbance. Anger, irritability, temper outbursts, and aggression are common in patients with Tourette syndrome and can lead to self-injurious behaviors. Oppositional defiant disorder and conduct disorder may be comorbid. Management includes behavioral and environmental interventions and management of comorbidities.

Neurocognitive disorders

Cognitive decline presents with a variety of neuropsychiatric symptoms and can involve a range of severity. Mild neurocognitive disorder, also known as mild cognitive impairment, represents an acquired decline in cognition beyond normal aging, but functional ability and independence in daily activities are preserved. Major neurocognitive disorder, also known as dementia, also refers to cognitive decline but is severe enough to interfere with independence in everyday activities due to the cognitive issues. The underlying etiology leading to cognitive decline can include Alzheimer disease, frontotemporal degeneration, Lewy body disease, Parkinson disease, Huntington disease, prion disease, traumatic brain injury, and other medical conditions. When assessing cognitive complaints, it’s first important to assess whether delirium or cognitive changes secondary to a mood disorder are playing a role. Delirium is defined as a disturbance in attention with acute onset and fluctuating course accompanied by cognitive disturbance that develops over hours to days and represents a change from baseline. It is often secondary to toxic, metabolic, or infectious etiologies and is conceptualized as acute brain failure (20). Presumably, delirium would be reversible with addressing the underlying insult, but not always fully back to baseline. Refer to Table 2 and the associated discussion on distinguishing cognitive complaints in depression and Alzheimer disease.

Alzheimer disease. Alzheimer disease is the most common cause of dementia, accounting for approximately 60% to 80% of cases (21). Most cases are characterized by a progressive memory impairment that impairs the learning and retention of new information. Neuropsychiatric symptoms are prominent, especially with disease progression, and can include apathy, depression, anxiety, irritability, behavioral disturbance, and psychosis.

Mood and anxiety disorders. Depression, anxiety, and apathy have a prevalence of up to 50% in Alzheimer disease and increase caregivers’ burden (38). Untreated symptoms can also lead to increased agitation and behavioral disturbance. Treatment includes first ensuring the typical medications directed for Alzheimer disease (eg, acetylcholinesterase inhibitors) have been tried, as there is some evidence of benefit for managing neuropsychiatric symptoms too. Otherwise, treatment is similar to that of depression and anxiety in patients without Alzheimer disease and includes lifestyle modifications, psychotherapy, and pharmacologic options. Careful dosing and slow titration are preferred for the geriatric population to minimize side effects. Benzodiazepines, TCAs, and agents with high anticholinergic burden are avoided to minimize the risk of falls and worsening confusion.

Psychotic symptoms. Delusions and hallucinations are also common in Alzheimer disease and can affect about a third of patients (38). The presence of these symptoms is associated with increased levels of abnormally phosphorylated tau proteins and neurofibrillary tangles. Nonpharmacologic interventions are preferred in managing these symptoms. Cholinesterase inhibitors may also have a small role and are helpful in some patients. However, if the symptoms are uncontrolled and presenting significant distress and safety concerns, atypical antipsychotics can be trialed at low doses, ideally for a limited duration. Antipsychotics carry a black-box warning for increased risk of death in patients with dementia-related psychosis, and this should be discussed with the patient and caregivers.

Cognitive dysfunction. Episodic memory impairment is a prominent feature of Alzheimer disease, though other domains are also affected. Additionally, there are variants of Alzheimer disease that preferentially involve executive function, language, or visual processing. Although there is no cure, treatment includes cholinesterase inhibitors and memantine. Newer disease-modifying treatments targeting amyloid plaques are available in select cases of mild cognitive impairment and mild Alzheimer disease. Therapies targeting tau protein tangles are under development to slow and possibly reverse the neurodegenerative process.

Behavioral disturbance. Agitation and irritability increase with disease severity and contribute significantly to caregiver burnout. First-line management includes nonpharmacologic interventions such as redirection, minimizing environmental stressors, and caregiver education. It’s important to identify modifiable causes of increased agitation, such as pain, constipation, and other medical illnesses that may be contributing. SSRIs at low doses may help reduce agitation, though evidence is limited. Again, antipsychotics have a black box warning for increased risk of death, but second-generation antipsychotics can be utilized when symptoms are severe and cause significant distress or safety concerns. Additionally, managing sleep disturbance can often be helpful and can involve sleep hygiene and cognitive behavioral therapy for insomnia, along with pharmacologic interventions if needed.

Frontotemporal lobar degeneration. Frontotemporal dementia most commonly presents with personality changes, disinhibition, and language issues and is characterized by degeneration of the frontal and temporal lobes. The most common variant of frontotemporal lobar degeneration is behavioral variant frontoemporal dementia (bvFTD) and involves deficits in executive function, social cognition, and relatively less severe issues with episodic memory compared to Alzheimer disease. Primary progressive aphasia variants involve progressive deficits in grammar and speech output (nonfluent variant) as well as semantic knowledge and naming (semantic variant). A third variant of primary progressive aphasia, logopenic primary progressive aphasia, is a precursor of Alzheimer disease. Additionally, frontotemporal lobar degeneration can present with a motor neuron disease, amyotrophic lateral sclerosis, in which case C9orf72 expansion is the most common genetic cause. Motor neuron disease can precede or follow the onset of neurobehavioral symptoms, and different family members can have one or the other disorder. Neuropsychiatric symptoms are prominent in these disorders.

Mood and anxiety disorders. Apathy is a hallmark feature of bvFTD with varying estimates across studies, but it affects at least half of patients. Depression and anxiety can be present but are less common, affecting about a third of patients early in the disease course, and could represent prodromal illness (17). Treatment is similar to that of patients without frontotemporal lobar degeneration, except for the need to pay attention to differentiating apathy from depression first (see Table 1).

Psychotic symptoms. Cases of frontotemporal dementia occurring with psychotic symptoms have been reported, though the exact prevalence is difficult to discern. Psychotic symptoms appear less prevalent than in Alzheimer disease, though they are likely more common in the TDP pathology subtypes (24). Treatment is conservative, and options are similar for patients with psychosis from other neurodegenerative disorders, except that an acetylcholinesterase inhibitor is not used and may even worsen neuropsychiatric symptoms.

Cognitive dysfunction. Executive dysfunction and language deficits are prominent in frontotemporal lobar degeneration, with relative preservation of episodic memory. There are no effective treatments available for cognitive deficits in frontotemporal lobar degeneration.

Behavioral disturbance. Disinhibition is common in bvFTD and can lead to significant distress and caregiver burden. Additionally, hyperorality, appetite changes, repetitive and compulsive behaviors are among the cardinal symptoms and are primarily managed through behavioral and environmental interventions. SSRIs can be helpful for obsessive-compulsive disorder-like behaviors.

Dementia with Lewy bodies. Dementia with Lewy bodies is another cause of neurodegenerative decline, accounting for up to 24% of dementia cases (37). It presents with attention, executive, and visuospatial deficits along with cognitive fluctuations, hallucinations, parkinsonism, and REM behavior sleep disorder. Clinically, the presentation can look similar to Parkinson disease dementia. However, in dementia with Lewy bodies, cognitive symptoms precede or occur within a year of motor symptoms. The neuropsychiatric manifestations and management are similar to those in Parkinson disease and Parkinson disease dementia; please refer to the Parkinson disease section for further details.

Vascular dementia. Post-stroke dementia and vascular dementia are common causes of cognitive decline secondary to ischemic or hemorrhagic strokes, and small and large vessel vascular disease. Additional etiologies of cognitive decline secondary to vascular pathology, such as cerebral amyloid angiopathy and CADASIL, should also be considered in the differential diagnosis for vascular dementia. Please refer to the stroke section for further details on cognitive decline associated with large and small vessel disease. It is also not uncommon to have multiple pathologies underlying dementia in a particular patient (eg, Alzheimer disease and vascular dementia).

Neuroimmunology

Multiple sclerosis. Neuropsychiatric symptoms of multiple sclerosis are widespread and debilitating and thought to result from diffuse inflammatory changes throughout the brain. These changes span beyond the psychological burden of living with a disabling chronic illness and can significantly impact quality of life if left unaddressed.

Mood and anxiety disorders. Major depressive disorder is the most common psychiatric condition seen in patients with multiple sclerosis, affecting up to half of patients in their lifetime. Suicide risk is increased. Anxiety is also common, affecting about a third of this population. Bipolar disorder is twice or more prevalent than in the general population and might have a genetic component, given the known familial clustering of bipolar disorder and multiple sclerosis (23).

Treatment is similar to that of depression and anxiety in patients without multiple sclerosis, though common comorbidities such as fatigue, pain, or concentration difficulties can be taken into consideration when choosing medications. For example, SNRIs can be useful with pain comorbidities, and bupropion can sometimes be helpful with comorbid fatigue, smoking cessation, and concentration difficulties.

Fatigue. Fatigue is one of the most common symptoms of multiple sclerosis, with a prevalence of 36.5% to 78% (25). It is characterized by a persistent lack of mental and physical energy that impairs daily functioning. It is thought to be related to the underlying disease mechanism. It can also be exacerbated by medications commonly used to treat pain, spasticity, and bladder issues. Secondary causes of fatigue, such as vitamin deficiencies, metabolic and endocrine abnormalities, mood disturbance, and sleep issues, should be evaluated and addressed.

Treatment options are limited and involve behavioral and pharmacologic strategies in addition to a careful review of contributing medications and secondary causes of fatigue. Physical and occupational therapy can be helpful, as well as temperature management and energy conservation techniques. Amantadine, wakefulness-promoting agents, stimulant medications, and bupropion are sometimes trialed off-label, though there is no strong evidence for these.

Psychotic symptoms. The risk of psychosis in people with multiple sclerosis is elevated compared to the general population. People with multiple sclerosis may experience primary psychotic disorders or present with symptoms of psychosis at disease onset or relapse. Additionally, treatment of multiple sclerosis with steroids or interferons may also contribute to developing psychotic symptoms. It can be difficult to elucidate the etiology of psychosis at presentation. A key distinguishing feature of multiple sclerosis-associated psychosis from a primary psychotic disorder is a temporal relationship with disease activity. If psychosis is primarily evident during disease exacerbations, multiple sclerosis-related psychosis is more likely and would respond favorably to acute treatment of multiple sclerosis. Atypical features for primary psychosis could include age at presentation or type of hallucinations. For example, olfactory hallucinations may occur with temporal lobe pathology but are uncommon in primary psychotic disorders. Auditory hallucinations, on the other hand, are commonly seen in primary psychotic disorders. Periventricular white matter and temporal lobe demyelination have also been correlated with multiple sclerosis-related psychosis and would not be present in primary psychotic disorders, so imaging could be used as another data point.

Treatment, regardless of etiology, is important, given the negative impacts on medication adherence and disability when left untreated. Disease course over time often clarifies diagnosis, and longitudinal multidisciplinary management is recommended. Good control of underlying multiple sclerosis disease activity is imperative. New drugs for multiple sclerosis have made this much more successful. A variety of atypical antipsychotics are available as starting points for symptomatic psychosis management in this population.

Cognitive dysfunction. Cognitive impairment is seen in one to two thirds of patients with multiple sclerosis (03), significantly affecting quality of life, relationships, and employment status independently of physical disability. It is attributed to the lesions, atrophy, and white matter disruptions that cause network dysfunction. The deficits were traditionally thought to be primarily characterized by slowed information processing speed, though emerging evidence from patients on disease-modifying therapies suggests that verbal and visuospatial memory may be predominantly affected (33). Patient-reported measures, neuropsychological testing, and driving evaluations may be helpful in assessing impairments.

There are no medications approved for cognitive dysfunction in multiple sclerosis. Treatment revolves around cognitive therapies and managing contributing comorbidities (vascular risk factors, sleep disruption, polypharmacy, mood disorders) while maintaining a healthy lifestyle (diet, exercise, smoking cessation, social engagement).

Autoimmune encephalitis. Autoimmune encephalitis can present with a broad spectrum of neuropsychiatric manifestations, including acute psychosis, mood, behavior, and memory changes, in addition to progressive neurologic symptoms such as abnormal movements, seizures, and changes in consciousness. Anti-NMDAR encephalitis is the most common form to present with neuropsychiatric symptoms and is the focus of this article, though other forms, such as limbic encephalitis, can present with neuropsychiatric symptoms. For example, anti-LGI1 encephalitis often presents with memory loss, confusion, behavior changes, visual hallucinations, speech changes, and mood instability in addition to faciobrachial dystonic seizures. Please refer to the work by Dalmau and colleagues for further descriptions of common autoimmune encephalitis presentations (07).

It is estimated that 90% of cases of anti-NMDAR encephalitis can involve psychiatric symptoms, and a third of cases may present with primarily neuropsychiatric symptoms without other neurologic signs or symptoms (07). Neuropsychiatric symptoms most commonly include psychosis, delirium, catatonia, depression, anxiety, mania, agitation, and aggression. Diagnosis and distinguishing from a primary psychiatric disorder can be challenging. The acute or subacute onset and progression of psychiatric symptoms with no prior psychiatric history should prompt the consideration of autoimmune encephalitis in the differential diagnosis. Presence of a viral prodrome, language or short-term memory impairment, new-onset seizures, abnormal movements, autonomic dysfunction, or fluctuating levels of consciousness should further raise the suspicion. If there’s clinical suspicion of autoimmune encephalitis, MRI, EEG, and an LP are warranted to arrive at a diagnosis. Treatment involves targeting the underlying autoimmune process in addition to managing residual mood and cognitive symptoms during recovery. Neuropsychiatric sequelae may need long-term management.

Epilepsy

Neuropsychiatric symptoms for persons with epilepsy are common and have a bidirectional relationship with epilepsy itself (34). The symptoms can be categorized based on timing relative to the seizures. Pre-ictal, ictal, and post-ictal refer to before, during, and after a seizure, respectively. Inter-ictal refers to symptoms that have no clear temporal relationship to seizures.

Mood and anxiety disorders. The factors contributing to depression and anxiety in persons with epilepsy are multifactorial and may include peri-ictal discharges (eg, sensation of fear from seizure involving the amygdala), disruption in sleep, underlying etiology of the seizures (eg, traumatic brain injury), side effects of antiseizure medications, disability, loss of employment or ability to drive, and the effects of stigma. In a meta-analysis, persons with epilepsy were statistically more likely to have depression than people without epilepsy (13.7% vs. 9.3%; OR, 2.45) and also were more likely to have suicidal ideation (20.0% vs. 11.7%; OR, 2.25) (16). Similarly, anxiety disorders were more prevalent (8.4% vs. 5.7%; OR, 2.11). A more noticeable difference is seen with structured clinical interviewing (24.6% vs. 8.1%; OR, 2.43), indicating that intentional questioning uncovers more recognition of these issues. The specific anxiety disorders can be divided into generalized anxiety disorder (OR 2.34), specific phobia (OR 1.73), social phobia (OR 3.00), and agoraphobia (OR 2.17).

Psychotic symptoms. Psychotic disorders are more common in persons with epilepsy than in people without epilepsy (14.8% vs. 6.3%; OR, 3.98) (16). This risk is higher in patients with temporal lobe epilepsy, a family history of psychosis, earlier onset of epilepsy, hippocampal sclerosis or other brain lesions, and treatment resistance (34).

Ictal phenomena may present as hallucinations (perceptions that are not there) and in any sensory modality. For example, seizure activity in the occipital lobe may result in visual, parietal lobe somatosensory, temporal lobe auditory or olfactory, and insula gustatory hallucinations. Brief (30 seconds to 3 minutes) stereotyped hallucinations with associated confusion that sometimes evolve into more classic generalized seizures would all be clues of an ictal event. Psychotic symptoms that are interictal (without relationship to the seizures) and chronic may present like schizophrenia, but often lack the prodromal stage and negative symptoms that often accompany schizophrenia (31).

The differential for behavioral issues after a seizure includes post-ictal confusion, post-ictal psychosis, and forced normalization. Post-ictal confusion immediately follows a seizure, especially generalized ones, and usually resolves within minutes to hours. Logsdail and Toone defined post-ictal psychosis to have a “lucid interval” of up to 1 week before the onset of hallucinations and delusions that last a day to 3 months (but usually less than 1 week) (19). Post-ictal psychosis is more likely after a cluster of seizures and in patients with bilateral independent epileptiform discharges (15). Forced normalization (referring to the normalization of the EEG), while also occurring after a seizure ends, hints at the antagonistic relationship between psychiatric symptoms and seizures. That is, with the dramatic cessation of refractory seizures (from antiseizure medications or neurosurgery), psychotic (or mood) symptoms emerge in a way that may be expected if one were to abruptly discontinue ECT for the treatment of mood or psychotic disorders. A related term, "alternative psychosis" of epilepsy, is used when the “normalization” of the EEG is not available, but similarly manifests as “alternating” between seizures without psychosis and seizure-freedom with the emergence of psychosis.

The treatment of the underlying issue in post-ictal psychosis is to improve seizure control to minimize the chances of post-ictal psychosis recurrence. During post-ictal psychosis, atypical antipsychotics may be used but only temporarily, as the natural history of post-ictal psychosis is to resolve with time. Longer-term use of antipsychotics may be indicated in interictal psychosis, but caution would be advised on the use of clozapine, given that it lowers seizure threshold the most.

Antiseizure medication-related neuropsychiatric symptoms. Medications used to treat seizures can, in and of themselves, cause low mood, anxiety, or psychosis as an adverse effect. In fact, the U.S. FDA issued a class warning in 2008 regarding the increased risk of suicidal ideation, attempts, and completion with the use of antiseizure medications. However, this concern was based on a meta-analysis that pooled data from 11 antiseizure medications and was based on spontaneous reporting rather than systematic data collection (12). Furthermore, the risk of uncontrolled seizures likely outweighs the small increased risk of suicide if even present. It is still wise to screen for suicidal thoughts in all patients before and after starting an antiseizure medication, but this would not be a reason not to prescribe an antiseizure medication when it is needed.

Regarding the choice of antiseizure medications, probably the one most questioned is levetiracetam, given its frequency of use and known psychiatric side effects. Additional antiseizure medications that could result in psychiatric side effects include perampanel, phenobarbital, vigabatrin, topiramate, and zonisamide. If adverse effects are noted, one should consider whether the dosage can be reduced or the medication replaced with an alternative option. Notably, many antiseizure medications are also used by psychiatrists as “mood stabilizers,” so these medications may be options for persons with epilepsy prone to psychiatric symptoms. These include lamotrigine, valproic acid, carbamazepine, and oxcarbazepine. Some psychiatrists will also use gabapentin or pregabalin for anxiety management, although not first-line. Lacosamide is also thought to have a lower likelihood of psychiatric side effects, so it may be a good option.

Vascular neurology

Stroke. Neuropsychiatric symptoms are common and persistent after stroke. These can include changes in mood, personality, sleep, and cognition and are associated with poor outcomes, highlighting the importance of screening and treatment.

Mood and anxiety disorders. Depression and anxiety can affect a third of people after a stroke and often coexist. Fatigue, apathy, pseudobulbar affect, and emotional lability are also common. These can negatively affect patients’ ability to participate in necessary rehabilitation therapies, delay recovery of activities of daily living, and reduce overall social functioning. Treatment is similar to that of depression and anxiety in patients without stroke, though common comorbidities such as fatigue, pain, or sleeping difficulties can be taken into consideration when choosing medications.

Psychotic symptoms. Psychosis after stroke is relatively rare, affecting 4% to 5% of people (32). Isolated psychotic symptoms such as delusions or hallucinations are more common, though more pervasive thought disorders can also occur. There is often a delay of months before these symptoms develop. Strokes producing lesions in the right hemisphere tend to be involved. Visual hallucinations are particularly common with lesions involving the occipital lobes. It is important to rule out delirium and comorbid mood disorders with psychotic features in patients presenting with psychosis after stroke. No treatments are specific to post-stroke psychosis beyond the usual stroke secondary prevention strategies. Antipsychotics are utilized for symptom management.

Cognitive dysfunction. Vascular cognitive impairment is found in up to 50% of people after stroke and is associated with higher disability and greater institutionalization rates (36). Vascular dementia is caused by cerebrovascular disease that can occur with or without a history of symptomatic stroke. It may follow the classic “step-wise” decline with each symptomatic stroke, or there may be a slow, insidious decline from progressive accumulation of microvascular pathology. The cognitive domains that are most affected are memory, orientation, language, executive function, and attention. Treatments remain limited but often include cognitive rehabilitation, exercise, and management of mood, sleep, and preexisting neurodegenerative comorbidities.

Prognosis and complications

Neuropsychiatric symptoms are substantial factors determining quality of life for persons with neurologic disease. Compared to the general population, the risk of neuropsychiatric symptoms is increased in most neurologic conditions and requires proactive identification and management.

Biological basis

The pathophysiology of behavioral disturbances generally cannot be understood using a single lesion model. Certain brain-behavior relationships are understood, however, and involve functional brain systems with overlapping neuroanatomy. Disease or dysfunction in these systems results in signature psychopathology useful for eliciting different diagnostic considerations (Table 6).

Table 6. Example Brain-Behavior Associations

Differential diagnosis

Confusing conditions

The differential diagnosis for psychiatric symptoms in neurologic disease falls into five major diagnostic categories: normal (no clinical diagnosis), adjustment (overreaction to situation), secondary to another medical condition (physiologically caused by neurologic disease), substance- or medication-induced (intoxication, withdrawal, or side effect), and primary psychiatric disorder. Table 7 below provides a definition, diagnoses, and examples using a case of behavioral variant frontotemporal dementia. More specific differentials are discussed within each particular neurologic disorder topic above.

Table 7. Differential Diagnosis Examples for Psychiatric Symptoms in Neurologic Disease

Diagnostic workup

The diagnostic workup is dependent on the presentation and underlying neurologic differential diagnosis and is decided on a case-by-case basis. A more in-depth explanation can be found in other resources (04).

Management

Treatment of psychiatric and behavioral disturbances due to a neurologic condition begins with treating the underlying condition. When these disturbances persist, pharmacologic and nonpharmacologic treatments are similar to those for patients with primary psychiatric disorders, with close attention paid to the high occurrence of comorbid general medical conditions and the increased sensitivity to the side effects of somatic treatments. Further details are provided under each neurologic condition above. The importance of a collaborative spirit on a multidisciplinary team, which may include neurology, psychiatry, psychology, physiotherapy or rehabilitation, and social work, cannot be understated.