PRINCIPLES OF DIFFERENTIAL DIAGNOSIS

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.^5–7

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.^9–14 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

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

PRINCIPLES OF NEUROPSYCHIATRIC EVALUATION

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.

COGNITIVE-BEHAVIORAL NEUROANATOMY

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

Figure 73-1 Cortical anatomy and functional subtypes (areas) in relationship to Brodmann’s map of the human brain. The boundaries are not intended to be precise. Much of this information is based on experimental evidence obtained from laboratory animals and needs to be confirmed in the human brain. AA, Auditory association cortex; ag, angular gyrus; A1, primary auditory cortex; B, Broca’s area; cg, cingulate cortex; f, fusiform gyrus; FEF, frontal eye fields; ins, insula; ipl, inferior parietal lobule; it, inferior temporal gyrus; MA, motor association cortex; mpo, medial parieto-occipital area; mt, middle temporal gyrus; M1, primary motor area; of, orbitofrontal region; pc, prefrontal cortex; ph, parahippocampal region; po, parolfactory area; ps, peristriate cortex; rs, retrosplenial area; SA, somatosensory association cortex; sg, supramarginal gyrus; spl, superior parietal lobule; st, superior temporal gyrus; S1, primary somatosensory area; tp, temporopolar cortex; VA, visual association cortex; V1, primary visual cortex; W, Wernicke’s area.

(From Mesulam MM: Behavioral neuroanatomy. Large scale networks, association cortex, frontal syndromes, the limbic system and hemisphere specializations. In Mesulam MM, editor: Principles of behavioral and cognitive neurology, New York, 2000, Oxford University Press, p 13.)

Figure 73-2 Coronal section through the basal forebrain of a 25-year-old human brain stained for myelin. The substantia innominata (si) and the amygdaloid complex (a) are located on the surface of the brain. c, Head of the caudate nucleus; cg, cingulate gyrus; g, globus pallidus; i, insula.

(From Mesulam MM: Behavioral neuroanatomy. Large scale networks, association cortex, frontal syndromes, the limbic system and hemisphere specializations. In Mesulam MM, editor: Principles of behavioral and cognitive neurology, New York, 2000, Oxford University Press, p 4.)

Frontal-Subcortical Networks

Five frontal-subcortical circuits subserve cognition, behavior, and movement. Disruption of these networks at the cortical or subcortical level can be associated with similar neuropsychiatric symptoms. Each of these circuits shares the same components (Figure 73-3): frontal cortex; striatum (caudate, putamen, ventral striatum); globus pallidus and substantia nigra; and thalamus (which then projects back to frontal cortex).^6,7 There are also integrative connections to and from other subcortical and distant cortical regions related to each circuit. Neurotransmitters (e.g., dopamine [DA], glutamate, gamma-aminobutyric acid [GABA], acetylcholine, norepinephrine, and serotonin) are involved in various aspects of neural transmission and modulation through the circuits. The frontal-subcortical networks are named according to their site of origin or function. Somatic motor function is subserved by the motor circuit that originates in the supplementary motor area. Oculomotor function is governed by the oculomotor circuit that originates in the frontal eye fields. Three of the five circuits are most intimately involved in cognitive and behavioral changes: the dorsolateral prefrontal, the orbitofrontal, and the anterior cingulate circuits. The dorsolateral prefrontal circuit governs executive function, including the ability to plan and maintain attention, problem solve, learn, retrieve remote memories, sequence the temporal order of events, shift cognitive and behavioral sets, and generate motor program.²⁶ Executive dysfunction is a principle component of subcortical dementias. Deficits identified in subcortical dementias include slowed information processing, memory retrieval deficits, mood and behavioral changes, gait disturbance, dysarthria, and other motor impairments. Vascular dementias, Parkinson’s disease, and Huntington’s disease are a few of the conditions that affect this circuit.

Figure 73-3 General structure of frontal subcortical circuits.

The orbitofrontal circuit connects frontal monitoring to the limbic system. This circuit governs appropriate responses to social cues, empathy, social judgment, and interpersonal sensitivity. Dysfunction in this circuit can lead to disinhibition, irritability, aggressive outbursts, and inappropriate social responses. Conditions that exhibit impairment in this circuit include Alzheimer’s disease, which affects the cortical portion of the circuit, and Huntington’s disease, which involves subcortical pathology.

The anterior cingulate circuit is involved in motivated behavior. Lesions in this circuit result in apathy, abulia, and akinetic mutism. There also is a reported decrease in the ability to understand new thoughts and to participate in the creative thought process.^8,27 Some conditions that may affect this circuit include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, head trauma, brain tumors, cerebral infarcts, and obstructive hydrocephalus.

BRAIN DISORDERS, ANATOMY, AND THEIR ASSOCIATION WITH PSYCHOSIS

A wide variety of neurological conditions, medications, and toxic exposures can be associated with psychosis. No consensus is available in the literature regarding precise localization of various psychotic syndromes. Schizophrenia has been associated with frontal lobe dysfunction and with abnormal regulation of subcortical DA²⁸ and glutamate systems.²⁹ Functional imaging studies in patients with schizophrenia show decreased cerebral blood flow (CBF) in the dorsolateral prefrontal cortex during specific cognitive tasks.^30,31 Patients with schizophrenia (who have prominent negative symptoms) display reduced glucose utilization in the frontal lobes.³² Functional imaging studies suggest that disruption in distributed functional circuits (e.g., related to the dorsolateral prefrontal cortex, the orbitofrontal cortex, the medial frontal cortex, the anterior cingulate gyrus, the thalamus, the temporal lobe subregions, and the cerebellum)³³ is important in the development of schizophrenia. Several conditions (such as Huntington’s disease, Parkinson’s disease, frontotemporal degenerations, and stroke) are commonly associated with frontal and subcortical dysfunction. Psychosis can also be associated with these conditions. Dorsolateral and medial frontal hypoperfusion on functional imaging has also been demonstrated in a subset of Alzheimer’s disease patients with delusions.¹¹

BRAIN DISORDERS, ANATOMY, AND THEIR ASSOCIATION WITH DEPRESSION

Studies suggest that anterior temporal paralimbic and orbitofrontal regions are involved in the mediation of primary and acquired depression. Functional imaging studies of unmedicated patients with familial depression reveal increased CBF and glucose metabolism in the amygdala, orbital cortex, and medial thalamus, and decreased CBF and glucose metabolism in the dorsomedial/dorsal anterolateral prefrontal cortex and the anterior cingulate cortex.³⁴ Damage to the prefrontal cortex from stroke, tumor, or striatum from degenerative diseases (such as Parkinson’s and Huntington’s), is associated with depression.^34,35 Functional imaging studies of subcortical disorders, such as these, reveal hypometabolism in paralimbic regions (e.g., the anterior temporal cortex and anterior cingulate) that are correlated with the depression seen in these patients.^36,37 Depression in patients with Parkinson’s disease, Huntington’s disease, and epilepsy has been correlated with reduced metabolic activity in the orbitofrontal cortex and the caudate nucleus.^38,39

Mayberg³⁶ proposed that primary depression was due to dysfunction in a network that included two known pathways: the orbitofrontal–basal ganglia–thalamic circuit and the basotemporal limbic circuit that links the orbitofrontal cortex and the anterior temporal cortex by the uncinate fasciculus. Portions of this are illustrated in Figure 73-4.

Figure 73-4 Frontal lobe dysfunction in secondary depression (midline sagittal human brain). Frontal lobe = red; parietal lobe = dark blue; occipital lobe = green; temporal lobe = light blue; limbic cortex = orange. Thick black lines approximate a cortical–basal ganglia–thalamic–cortical loop (circuit) to the orbital frontal cortex.

(Redrawn from Mayberg HS: Frontal lobe dysfunction in secondary depression, J Neuropsychiatry Clin Neurosci 6[4]:428-442, 1994.)

CLINICAL SYMPTOMS AND SIGNS SUGGESTING NEUROLOGICAL DISEASE

Many neurological conditions have associated psychiatric symptoms. Psychiatrists and neurologists need to be intimately acquainted with features of the clinical history and the examination that indicate the need for further investigation. Table 73-4 outlines some key historical features that raise the suspicion of an underlying neurological condition. Table 73-5 reviews some key areas of the review of systems that can be helpful when assessing for neurological and medical causes of psychiatric symptoms. Table 72-1 reviews abnormalities in the elemental neurological examination associated with diseases that can exhibit significant neuropsychiatric features.

Table 73-4 Historical Features Suggesting Neurological Disease in Patients with Psychiatric Symptoms

Table 73-5 Review of Systems with Possible Neuropsychiatric Relevance and Related Neurological Conditions

PSYCHIATRIC MANIFESTATIONS OF NEUROLOGICAL DISEASE

Virtually any process that affects the neuroanatomical circuits described previously can result in behavioral changes and psychiatric symptoms at some point in the natural history of a condition. Psychiatric symptoms may be striking and precede (by years) any neurological manifestation. Table 73-6 lists conditions that can be associated with psychosis or depression. More detailed information regarding the evaluation, natural history, pathology, and specific treatment recommendations for these conditions is beyond the scope of this chapter.

Table 73-6 Selected Neurological and Systemic Causes of Depression and Psychosis

CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; MDMA, 3,4-methylenedioxymethamphetamine.

TREATMENT PRINCIPLES

Each condition has subtleties associated with its prognosis, treatment, and management that should be carefully re-viewed before proceeding with a treatment plan. In general, patients with an underlying neurological condition tend to be more susceptible to the adverse reactions of psychotropic medications, particularly extrapyramidal and cognitive side effects. These adverse reactions tend to be minimized with initiation of medications at low doses and gentle titration of doses. When clinically indicated, atypical neuroleptics are often preferred (due to fewer adverse side effects) over conventional antipsychotics. Electroconvulsive therapy (ECT) can also be useful as an option for treatment of refractory mood disorders or in circumstances wherein medications cannot be tolerated. Individual and family supportive psychotherapy is often helpful. Other options to consider for treatment of refractory depression (or other behavioral disorders such as OCD) include vagal nerve stimulation,^40–43 transcranial magnetic stimulation,⁴⁴ deep brain stimulation,⁴⁵ and stereotactic ablative surgery.^46–49

CONCLUSIONS

With the advancements in neuroscience, and our new understanding of the substrates of cognition and emotional behavior, the traditional boundaries between neurology and psychiatry have become obsolete. The future of psychiatric and neurological care, training, and research will inevitably require effective collaboration between both disciplines.^50,51