73: Neuropsychiatric Dysfunction

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CHAPTER 73 Neuropsychiatric Dysfunction


Emotional and cognitive processes are based on brain structure and physiology. Abnormal behavior can be attributable to the complex interplay of social influences, physical environment, and neural physiology. Psychosis, mania, depression, disinhibition, obsessive-compulsive disorder (OCD), and anxiety can all occur as a result of neurological disease and be indistinguishable from the idiopathic forms.1,2 Neurological conditions must be considered in the differential diagnosis of any person with psychiatric symptoms.

Neuropsychiatric dysfunction can be correlated with altered function in anatomical regions. Any disease, toxin, drug, or process that affects a particular region can be expected to show changes in behavior that are mediated by the circuits within that region. The limbic system and the frontal-subcortical circuits are the ones most commonly involved in neuropsychiatric dysfunction. Understanding this neuroanatomical conceptual framework can guide lesion localization and creation of a differential diagnosis. For example, the Kluver-Bucy syndrome3 (manifest by placidity, apathy, visual and auditory agnosia, hyperorality, and hypersexuality) involves injury to bilateral medial temporal-amygdalar regions. Common causes of this syndrome include herpes encephalitis,4 traumatic brain injury, frontotemporal dementias, and late-onset or severe Alzheimer’s disease. Brain trauma, ischemic disease, demyelination, abscesses, and tumors, as well as degenerative dementias, can also result in behavioral disinhibition. Damage to any portion of the circuit (between the orbital frontal cortex, ventral caudate, anterior globus pallidus, or medial dorsal thalamus) can result in disinhibition.57

Mood disorders, paranoia, disinhibition, and apathy derive from dysfunction in the limbic system and basal ganglia, structures that are phylogenetically more primitive.8 Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies suggest that similar regions of abnormality are involved in acquired forms of depression, mania, OCD, and psychosis, as compared with primary psychiatric presentations.914 Table 73-1 summarizes neuropsychiatric symptoms and their anatomical correlates. Additionally, the developmental phase during which a neurological illness occurs has an impact on the frequency with which some neuropsychiatric syndromes occur. In addition, adults with posttraumatic brain injury tend to have a higher rate of depression and anxiety. In contrast, difficulties secondary to posttraumatic brain injury in children often involve deficits in attention, hyperactivity, irritability, aggressivity, and oppositional behavior.15 When temporal lobe epilepsy or Huntington’s disease begins in adolescence, a higher incidence of psychosis is noted than when these conditions develop later in life.2,16 Early onset of multiple sclerosis and stroke is also associated with a higher incidence of depression.17

Table 73-1 Neuropsychiatric Symptoms and Corresponding Neuroanatomy

Depression Frontal lobes, left anterior frontal cortex, anterior cingulate gyrus, subgenu of the corpus callosum, basal ganglia, and left caudate
Mania Inferomedial and ventromedial frontal cortex, right inferomedial frontal cortex, anterior cingulate, caudate nucleus, thalamus, and temporal-thalamic projections
Apathy Anterior cingulate gyrus, nucleus accumbens, globus pallidus, and thalamus
Obsessive-compulsive disorder Orbital or medial frontal cortex, caudate nucleus, and globus pallidus
Disinhibition Orbitofrontal cortex, hypothalamus, and septum
Paraphilia Medial temporal cortex, hypothalamus, septum, and rostral brainstem
Hallucinations Unimodal association cortex, orbitofrontal cortex, paralimbic cortex, limbic cortex, striatum, thalamus, and midbrain
Delusions Orbitofrontal cortex, amygdala, striatum, and thalamus
Psychosis Frontal lobes and left temporal cortex

Patients with Alzheimer’s disease, Huntington’s disease, and frontotemporal dementias can develop multiple co-existing symptoms (e.g., irritability, agitation, apathy, depression, delusions, or psychosis) (Table 73-2). Once present, these symptoms tend to persist or recur, but little research data are available on response rates to specific treatments. The complex relationship between behavioral changes and a caregiver’s ability to cope also plays a role in illness management and in nursing home placement.18,19 Behavioral disturbances in patients with neurological illness have been related to the severity of caregiver distress.20

Table 73-2 Neurological Disorders and Associated Prominent Behavioral Features

Neurological Disorder Associated Behavioral Disturbances
Alzheimer’s disease Depression, irritability, anxiety, apathy, delusions, paranoia, and psychosis
Lewy body dementia Fluctuating confusion, hallucinations, delusions, depression, and rapid eye movement (REM) sleep behavior disorder (RBD)
Vascular dementia Depression, apathy, and psychosis
Parkinson’s disease Depression, anxiety, drug-associated hallucinations and psychosis, and RBD
Frontotemporal dementia Early impaired judgment, disinhibition, apathy, depression, delusions, and psychosis
Progressive supranuclear palsy Disinhibition and apathy
Traumatic brain injury Depression, disinhibition, apathy, and irritability; psychosis uncommon
Huntington’s disease Depression, irritability, delusions, mania, apathy, obsessive-compulsive disorder, and psychosis
Corticobasalganglionic degeneration Depression, irritability, RBD, and alien-hand syndrome
Epilepsy Depression and psychosis
Human immunodeficiency virus infection Apathy, depression, mania, and psychosis
Multiple sclerosis Depression, irritability, anxiety, euphoria, and psychosis
Amyotrophic lateral sclerosis Depression, disinhibition, apathy, and impaired judgment


A number of important principles must be taken into account when evaluating and treating a patient with behavioral disturbances (Table 73-3).

Table 73-3 Principles of Neuropsychiatric Evaluation

The medical evaluation of affective illness and psychotic disorders must be individualized based on the patient’s family history, social environment, habits, risk factors, age, gender, clinical history, and examination findings. A careful review of the patient’s medical history and a general physical examination, as well as a neurological examination, should be performed to assess for possible neurological and medical causes. The most basic evaluation should include vital signs (blood pressure, pulse, respiratory rate, and temperature) and a laboratory evaluation that minimally includes a complete blood cell count, electrolyte panel, serum glucose, blood urea nitrogen, creatinine, calcium, serum total protein, albumin, liver function assessment, thyroid function assessment, and additional laboratory testing as clinically indicated. Consideration should be given to checking the patient’s oxygen saturation on room air (especially in the elderly) . Neurological abnormalities suggested by the clinical history or identified on examination, especially those attributable to the central nervous system (CNS), should prompt further evaluation for neurological and medical causes of psychiatric illness. A clear consensus is not available as to when neuroimaging is indicated as a part of the evaluation of new-onset depression in patients without focal neurological complaints and a normal neurological examination. This must be individualized based on clinical judgment. Treatment-resistant depression should prompt reassessment of the diagnosis and evaluation to rule out secondary causes of depressive illness. A careful history to rule out a primary sleep disorder, such as sleep apnea, should be considered in the evaluation of refractory depressive symptoms.23 When new-onset psychosis occurs in the absence of identifiable infectious/inflammatory, metabolic, toxic, or other causes, magnetic resonance imaging (MRI) of the brain should be incorporated into the evaluation. Approximately 5% to 10% of such patients have findings on brain MRI that identify potential neurological contributions (particularly in those age 65 and older). The MRI will help exclude lesions (such as demyelination, ischemic disease, neoplasm, congenital structural abnormalities, or evidence of metabolic storage diseases) in limbic, paralimbic, and frontal regions that may not be associated with neurological abnormalities on elemental examination.24 An electroencephalogram (EEG) should be considered to evaluate for complex partial seizures, if there is a history of intermittent, discreet, or abrupt episodes of psychiatric dysfunction (usually confusion, spells of lost time, or psychotic symptoms), stereotypy of hallucinations, automatisms (e.g., lip smacking or repetitive movements) associated with episodes of psychiatric dysfunction (or confusion), or a suspicion of encephalopathy (or delirium). Sensitivity of the EEG for detection of seizure activity is highest when the patient has experienced the specific symptoms while undergoing the study. Selected cases may require 24-hour or longer EEG monitoring to capture a clinical event to clarify whether a seizure disorder is present.


The cerebral cortex can be subdivided into five major functional subtypes: primary sensory-motor, unimodal association, heteromodal association, paralimbic, and limbic. The primary sensory areas are the point of entry for sensory information into the cortical circuitry. The primary motor cortex conveys complex motor programs to motor neurons in the brainstem and the spinal cord. Processing of sensory information occurs as information moves from primary sensory areas to adjacent unimodal association areas (Figure 73-1). The unimodal and heteromodal cortices are involved in perceptual processing and motor planning. The complexity of processing increases as information is then transmitted to heteromodal association areas that receive input from more than one sensory modality. Examples of heteromodal association cortices include the prefrontal cortex, the posterior parietal cortex, parts of the lateral temporal cortex, and portions of the parahippocampal gyrus. These cortical regions have a six-layered architecture. Further cortical processing occurs in areas designated as paralimbic. These regions demonstrate a gradual transition of cortical architecture from the six layered to the more primitive and simplified allocortex of limbic structures. The paralimbic regions consist of orbitofrontal cortex, insula, temporal pole, parahippocampal cortex, and cingulate cortex. Cognitive, emotional, and visceral inputs merge in this region. The limbic subdivision is composed of the hippocampus, amygdala, substantia innominata, prepiriform olfactory cortex, and septal area (Figure 73-2). These structures are to a great extent reciprocally interconnected with the hypothalamus. The limbic region is intimately involved with regulation of emotion, memory, and motivation, as well as autonomic and endocrine function. The highest level of cognitive processing occurs in regions referred to as transmodal areas. These areas are composed of heteromodal, paralimbic, and limbic regions that are collectively linked, in parallel, to other transmodal regions. Interconnections amongst transmodal areas (such as Wernicke’s area, the posterior parietal cortex, and the hippocampal-enterorhinal complex) allow integration of distributed perceptual processing systems that results in perceptual recognition (such as scenes and events becoming experiences and words taking on meaning).8