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Neuropsychiatric Principles and Differential Diagnosis
Key Points
Background
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Behavioral Neurology and Neuropsychiatry is a medical specialty that cares for patients with problems that cross traditional boundaries between neurology and psychiatry.
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Neuropsychiatric symptoms and cognitive deficits can be correlated with altered function in anatomical regions and in cerebral networks.
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A firm understanding of the main cerebral structures and networks that mediate emotions, behavior, and cognition is the foundation of a useful neuropsychiatric approach.
History
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A thorough neuropsychiatric assessment includes taking a detailed longitudinal clinical history to identify signs and symptoms that yield clues about the neuroanatomical localization and pathophysiology of the neuropsychiatric dysfunction.
Clinical and Research Challenges
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A variety of neurological diseases can produce psychiatric symptoms as part of the illness or secondary to its treatments.
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The differential diagnosis of neuropsychiatric presentations is broad, and may include rare conditions that clinicians will encounter infrequently during their careers. Each condition may carry unique implications for prognosis, treatment, and long-term management.
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Acquiring knowledge of multiple diseases with psychiatric and neurological manifestations is a major clinical challenge in behavioral neurology and neuropsychiatry.
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Integrating neurosciences into clinical practice and developing neuroimaging biomarkers for neuropsychiatric disorders is a key research challenge.
Practical Pointers
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Atypical age of onset, acute course, cognitive impairment, catatonia, and progressive clinical deterioration with seizures, alterations in level of consciousness, or abnormalities on elemental neurological exam are indicators that a behavioral syndrome could be secondary to a neurological, neuropsychiatric, or general medical process.
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The decision to obtain investigational studies should be based upon the differential diagnosis, factoring in pre-test probabilities of the suspected diseases.
General Principles of Neuropsychiatry
Behavioral Neurology and Neuropsychiatry is a medical subspecialty committed to understanding the link between neuroscience and behavior, and providing care to persons with conditions (e.g., Tourette disorder, frontotemporal dementia, functional neurological symptom disorder) that cross the traditional, and often arbitrary, division between psychiatry and neurology. Behavioral neurology and neuropsychiatry have historically separate, but parallel traditions. They were recently integrated into a single subspecialty with standardized fellowship training requirements and board certification. It requires competence beyond the scope of general psychiatry and neurology. However, a basic understanding of neuropsychiatric principles and differential diagnosis should be an integral part of modern general psychiatric training.
The neuropsychiatric approach is based on the understanding that emotional and cognitive processes arise from complex electro-chemical physiological interactions within the brain's neuronal networks. Emotions and behavior occur as a result of the interplay of genetics, epigenetics, development, environment, and social influences on those neuronal networks. Abnormalities in specific networks have been documented in many major psychiatric syndromes, such as major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). In addition, pathophysiological models have been developed for some neuropsychiatric disorders that intrinsically combine psychiatric and neurological aspects, including behavioral variant frontotemporal dementia (bvFTD) and narcolepsy. Although psychiatric syndromes are sometimes referred to as being functional, due to absence of currently identified diagnostic pathology correlates, they are rooted in neurobiology. The term functional should be understood as referring to dynamic alterations in neurocircuitry, and not as the opposite of “organic”, a concept that will hopefully disappear from the medical vocabulary.
Specific neuropsychiatric symptoms can be correlated with altered function in distinct neuronal networks. Any disease, toxin, or drug that adversely impacts the function of a particular region can lead to changes in behavior that are mediated by the corresponding neural networks. For example, the Klűver-Bucy syndrome (with placidity, apathy, visual and auditory agnosia, hyperorality, and hypersexuality) is secondary to medial temporal-amygdalar lesions resulting from any of multiple conditions, including herpes encephalitis, traumatic brain injury (TBI), FTD, and advanced Alzheimer's disease (AD). Psychiatric symptoms (including psychosis, mania, depression, obsession/compulsion, and anxiety) can occur as a result of neurological diseases, including, but not limited to, stroke, multiple sclerosis, Parkinson's disease, and Huntington's disease. These symptoms can be indistinguishable from the idiopathic form. Consequently, a wide array of medical and neurological conditions must be considered in the differential diagnosis of any person with behavioral and emotional symptoms.
A strong neuroanatomical conceptual framework is important for lesion localization, which allows for the development of a rational differential diagnosis and plan for investigation. The objective of this chapter is to provide an integrative approach towards the differential diagnosis and treatment of psychiatric symptoms arising as a result of, or in association with, neurological and general medical conditions.
Cognitive-Behavioral Neuroanatomy
The neuropsychiatric approach is based on an understanding of functional brain anatomy, which is described in more detail in Chapter 72 . A few key points will be reviewed.
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. Processing of sensory information occurs as information moves from primary sensory areas to adjacent unimodal association areas ( Figure 74-1 ). The complexity of processing increases as information is then transmitted to heteromodal association areas that receive input from more than one sensory modality. Further cortical processing occurs in paralimbic areas (orbitofrontal cortex, insula, temporal pole, parahippocampal cortex, and cingulate cortex), in which cognitive, emotional, and visceral inputs merge. The paralimbic structures connect to limbic structures (hippocampus, amygdala, substantia innominata, prepiriform olfactory cortex, and septal area) ( Figure 74-2 ), which are intimately involved with emotion, memory, and motivation, as well as autonomic and endocrine functions. 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. Inter-connections among transmodal areas allow integration of distributed perceptual processing systems, such as perceptual recognition of events becoming experiences and words taking on meaning.
The functional organization of neuronal networks has been investigated by a variety of methods including axonal tracings in monkeys, task-based functional magnetic resonance imaging (fMRI), resting state fMRI intrinsic connectivity, and structural co-variance. Cortical areas have been shown to have specialization, lateralized functions, and connections with more than one network.
Cortical Networks
At least five distributed networks govern various aspects of cognitive functions : (1) the left temporo-perisylvian language network (which includes transmodal regions or “epicenters” in Broca's and Wernicke's areas); (2) the fronto-parietal spatial attention network (which is based on transmodal regions in the frontal eye fields, cingulate cortex, and posterior parietal area); (3) the limbic/paralimbic network for explicit memory and motivational salience (which is located in the hippocampal-entorhinal region and amygdala); (4) the prefrontal executive function and working memory network (which is based on transmodal regions in the lateral prefrontal cortex and possibly the inferior parietal cortices); and, (5) the inferotemporal face and object recognition network (which is based on temporopolar and midtemporal cortices).
Lesions of transmodal cortical areas result in global impairments (such as hemi-neglect, anosognosia, amnesia, and multi-modal anomia). Disconnection of transmodal regions from a specific unimodal input results in selective perceptual impairments (e.g., category-specific anomias, prosopagnosia, pure word deafness, and pure word blindness).
The emergence of new neuroimaging technologies, such as resting state fMRI intrinsic connectivity and MRI structural co-variance, has facilitated the study of networks in vivo. Three intrinsic connectivity functional networks are particularly relevant to the understanding of emotions and behaviors: (1) the default mode network (DMN), which includes areas along the anterior and posterior mid-line (posterior cingulate, precuneus, medial prefrontal areas, anterior cingulate cortex), lateral parietal, prefrontal cortex (PFC), and medial temporal lobe, and is linked to self-referential thinking ; (2) the salience network, which is anchored in the fronto-insular cortex, dorsal anterior cingulate cortex (also referred to as middle cingulate cortex), has strong connections with subcortical and limbic structures, and is linked to reactions to external stimuli ; and (3) the executive function networks, which involve the dorsolateral prefrontal cortex and parietal neocortex, which are areas involved in working memory/sustained attention, response selection, and response inhibition.
Interestingly, the characteristic pathology of neurodegenerative diseases seems to evolve along explicit networks. For example, there is evidence showing predominant initial dysfunction in the salience network in bvFTD, as opposed to the development of pathology in the DMN in AD ( Figure 74-3 ). The relative preservation of the salience network could explain the retained emotional warmth, sensitivity, and connectedness seen in AD, as opposed to the loss of empathy and social isolation secondary to bvFTD.
Cortical networks underlie the ability to empathize with another person's psychological and physical circumstances. A system of human mirror neurons is hypothesized to be involved in comprehending the intentions and actions of others, potentially providing the basis for observational learning. The parietofrontal mirror system (which includes the parietal lobe, the premotor cortex, and the caudal part of the inferior frontal gyrus) is involved in recognition of voluntary behavior. The limbic mirror system, formed by the insula and the anterior medial frontal cortex, is linked to the recognition of affective behavior. Of note, these mirror neurons do not represent self-standing neuronal networks, but rather a mechanism intrinsic to motor and limbic-related areas. Dysfunction of this system may underlie deficits in theory of mind, and has been proposed as an explanation for the social deficits of autism spectrum disorders.
Frontal-Subcortical Networks
As detailed in Chapter 72 , five frontal-subcortical circuits subserve cognition, behavior, and movement. Disruption of these networks at either the cortical or subcortical level can cause similar neuropsychiatric symptoms. Each of these circuits shares the same components: frontal cortex, striatum, globus pallidus, and thalamus, which then project back to frontal cortex. There are also integrative connections to and from other subcortical and distant cortical regions related to each circuit. Neurotransmitters (e.g., dopamine, glutamate, gamma-aminobutyric acid [GABA], acetylcholine, norepinephrine [noradrenaline], serotonin) are involved in various aspects of neural transmission and modulation through these circuits.
Three of the five circuits are more crucially involved in cognition and behavior: the dorsolateral prefrontal, the lateral orbitofrontal, and the anterior cingulate circuits. The dorsolateral prefrontal circuit, also known as the dorsal cognitive circuit, governs executive functions (such as 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 a motor program). Dysfunction in this network is the source of the profound executive impairments observed in subcortical dementias. The lateral orbitofrontal circuit, also known as the ventral cognitive circuit, connects frontal monitoring systems to the limbic structures. This circuit governs appropriate responses to social cues, value determination, empathy, social judgment, and interpersonal sensitivity. Dysfunction in this circuit can lead to disinhibition, irritability, aggressive outbursts, and inappropriate social responses. The anterior cingulate circuit, also known as the affective circuit, is involved in motivated behavior, conflict monitoring, and potentially other complex behaviors, such as creative thought processes. Lesions in this circuit may result in apathy (or akinetic mutism in its most severe form). Both the lateral OFC and ACC circuits can demonstrate atrophy in bvFTD, which correlates with variable degrees of disinihibition and apathy.
Of note, all the cerebral cortex shares similar features of organization, each area having neighboring, short, long, commissural (cross-hemispheric), and subcortical (striatal, thalamic, pontine) connection fibers. It is important to have some knowledge of the major long association white matter tracts connecting cortical areas involved in behavior, such as the cingulum bundle and uncinate fasciculus. Lesions in these pathways can result in slowed cognitive processing and behavioral issues, such as apathy, that may occur in individuals with multiple sclerosis and subcortical strokes.
Finally, it is important to note that the cerebellum, especially the posterior lobe and posterior vermis, has been postulated to have a role in modulating executive functions, spatial cognition, language (e.g., prosody), emotion, and behavior. Damage to this area may result in a cerebellar cognitive-affective syndrome.
Neuropsychiatric Evaluation
A number of important principles must be taken into account when evaluating patients with behavioral disturbances. A few clinical key points are summarized in Box 74-1 .
Box 74-1
Clinical Pearls of the Neuropsychiatric Evaluation
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A normal neurological examination does not exclude neurological conditions. Lesions in the limbic, paralimbic, and prefrontal regions may cause cognitive-behavioral changes in the absence of elemental neurological abnormalities.
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Normal routine laboratory testing, brain imaging, electroencephalography, and cerebrospinal fluid are supportive of primary psychiatric disorders, but do not necessarily exclude all neurological diseases.
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New neurological complaints or behavioral changes in a person with a pre-existing psychiatric history should not be automatically assumed to be of psychiatric origin.
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The possibility of iatrogenic conditions must be taken into account. Medication side effects can complicate the clinical history and examination (e.g., hallucinations induced by dopamine agonists in Parkinson's disease). Medication side effects can also be harbingers of underlying pathology (e.g., marked parkinsonism after exposure to D 2 blocking agents can be a feature of Lewy Body Dementia before this condition has been clinically characterized).
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Treatment of psychiatric and neurological behavioral disturbances share common principles. A response to therapy does not constitute absolute evidence of a primary psychiatric disorder.
The medical evaluation of cognitive-behavioral disorders must be individualized based on the patient's age, gender, family history, social environment, habits, culture of origin, risk factors, and examination findings. A detailed clinical history, including collateral information from family and caregivers, is of paramount importance for precisely determining the nature and time course of symptoms, thereby aiding the diagnosis. In new-onset presentations, a careful review of the patient's medical antecedents in addition to the performance of a general physical examination with vital signs, cognitive screening, and neurological examination are necessary to assess for neurological and general medical causes of unexplained behavioral changes. Consideration should be given to checking the patient's oxygen saturation on room air, especially in the elderly, as this can be an unrecognized cause of subacute delirium.
Although it is not possible to blindly recommend hematological and biochemical tests for all symptoms, in general a basic work-up should include a complete blood cell count, blood urea nitrogen, creatinine, electrolytes panel, serum glucose, calcium, total serum protein, liver function tests, and thyroid function assessment. Additional laboratory testing may be considered according to the clinical history and risk factors. Studies might include a toxicology panel, vitamin B 12 , folate, HIV serology, FTA-ABS, HCV serology, Lyme serology, ANA, ESR, CRP, cortisol, prolactin, testosterone, ceruloplasmin, heavy metal screen, ammonia, homocysteine, serum paraneoplastic panel, urine copper, urine porphobilinogen, fragile X testing, whole genome microarray, number of CAG repeats for Huntington's disease, C9ORF72 mutation, and other specialized rheumatologic, metabolic and genetic tests. Regarding substance-related disorders, clinicians need to be aware that some newer designer drugs, such as “bath salts,” might not be detected by current blood and urine tests.
Neuroimaging
With the increased availability of MRI, obtaining brain imaging has become a common practice in psychiatry. Considerable debate continues regarding the indications for use of this technology, both in medical and economical terms. Neurological symptoms gleaned during history-taking or findings on examination that suggest central nervous system (CNS) pathology should prompt further investigation. MRI is a safe method to help exclude lesions (demyelination, ischemic, neoplasm, congenital structural abnormalities) in limbic, paralimbic, and frontal regions that may not be associated with abnormalities on elemental neurological exam. It is also useful for detecting rare metabolic storage diseases than can present with a schizophrenia-like clinical picture (e.g., metachromatic leukodystrophy, Niemann-Pick type C; see Box 74-2 for complete list).
Box 74-2
Neuropsychiatric Differential Diagnosis of Emotional, Behavioral, and Cognitive Symptoms
| Category | Disease/Disorder |
|---|---|
| Traumatic | Traumatic brain injury and post-concussion syndrome |
| Subdural hematoma | |
| Chronic traumatic encephalopathy | |
| Infectious | HIV infection and HIV neurocognitive disorder |
| Opportunistic infections | |
| Neurosyphilis | |
| Viral infections/encephalitides (herpes simplex, CMV, EBV, others) | |
| Other infectious encephalitis (bacterial, fungal, parasites) | |
| CNS Whipple's disease | |
| CNS Lyme disease | |
| Prion diseases (e.g., Creutzfeldt-Jacob disease) | |
| Cerebral malaria | |
| Inflammatory/Autoimmune | Anti-NMDA encephalitis |
| Anti-LGI1 (anti voltage gated potassium channel—VGKC) encephalitis | |
| Limbic encephalitis (anti-GAD and others) | |
| Systemic lupus erythematous and lupus cerebritis | |
| Sjögren's syndrome | |
| Antiphospholipid syndrome | |
| Neurosarcoidosis | |
| Hashimoto's encephalopathy | |
| Sydenham's chorea | |
| Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) | |
| Neoplastic | Primary or secondary cerebral neoplasm |
| Systemic neoplasm | |
| Pancreatic cancer | |
| Paraneoplastic encephalitis (anti-NMDA, anti-Hu, anti-Ma, anti-CRMP5/CV2) | |
| Pheochromocytoma | |
| Carcinoid tumors | |
| Endocrine/Acquired | Hepatic encephalopathy |
| Metabolic | Renal failure and uremia |
| Dialysis dementia | |
| Hypoglycemia | |
| Hypo/hyperthyroidism | |
| Hypo/hyperparathyroidism | |
| Addison's disease | |
| Cushing's disease | |
| Wernicke-Korsakoff encephalopathy (thiamine deficiency) | |
| Other vitamin deficiencies: vitamin B 12 , folate, niacin, vitamin C, vitamin E | |
| Gastric-bypass associated nutritional deficiencies | |
| Celiac disease | |
| Vascular | Cerebrovascular accidents (ischemic, hemorrhagic) |
| Vascular dementia | |
| CNS vasculitis | |
| Transient global amnesia | |
| Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) | |
| Peduncular hallucinosis | |
| Susac's syndrome | |
| Neurodegenerative | Alzheimer's disease |
| Frontotemporal dementia (behavioral variant, primary progressive aphasias) | |
| Lewy body dementia | |
| Progressive supranuclear palsy | |
| Corticobasal degeneration | |
| Multiple system atrophy (parkinsonian and cerebellar subtypes) | |
| Parkinson's disease | |
| Huntington's disease | |
| Idiopathic basal ganglia calcification (Fahr's disease) | |
| Demyelinating/Dysmyelinating | Multiple sclerosis |
| Acute disseminated encephalomyelitis | |
| Subacute sclerosing panencephalitis | |
| Adrenoleukodystrophy | |
| Metachromatic leukodystrophy | |
| Inherited metabolic | Wilson's disease |
| Hexosaminidase deficiencies (e.g., Tay-Sachs disease, late-onset GM 2 gangliosidosis) | |
| Niemann-Pick type C | |
| Adult neuronal ceroid lipofuscinosis (Kufs' disease) | |
| Neuroacanthocytosis/McLeod syndrome | |
| Acute intermittent porphyria | |
| Other inborn errors of metabolism (e.g., urea cycle defects, MTHFR deficiency, cerebrotendinous xanthomatosis) | |
| Mitochondrial disorders | |
| Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) | |
| Epilepsy | Ictal, inter-ictal, or post-ictal behavioral changes (e.g., post-ictal psychosis) |
| Changes post epilepsy surgery (e.g., forced normalization) | |
| Sleep | Obstructive sleep apnea |
| Narcolepsy | |
| Kleine-Levin syndrome | |
| REM sleep behavior disorder | |
| Medications/Drugs/Toxins | Any psychotropic medication |
| Serotonin syndrome | |
| Neuroleptic malignant syndrome | |
| Drugs of abuse | |
| Drug withdrawal syndromes (alcohol, barbiturates, benzodiazepines, opiates) | |
| Heavy metals (e.g., lead poisoning) | |
| Inhalants | |
| Chemotherapy, interferon-alpha, anti-malarial agents | |
| Other | Cerebral hypoxia |
| Normal pressure hydrocephalus | |
| Sagging brain syndrome | |
| Malignant catatonia | |
| Ionizing radiation exposure | |
| Post-radiotherapy cognitive deficits | |
| Decompression sickness |
At a minimum, the MRI scan should include T1 and T2/FLAIR sequences in axial and sagittal planes. When stroke or cerebral ischemia is suspected, diffusion-weighted sequences are indicated. Thin coronal cuts are helpful for close inspection of the temporal lobes in suspected cases of seizures or AD. Gradient echo or susceptibility-weighted sequences can be useful to identify remote bleeds, especially in cases of TBI. The use of contrast is recommended whenever there is a need to assess for conditions (inflammatory, autoimmune, neoplastic, traumatic and ischemic) that disrupt the blood–brain barrier. CT scanning still has some advantages in emergency settings given that it is more quickly obtained, and takes less time to complete, which is especially helpful with agitated or claustrophobic patients. CT is superior for visualizing bone and calcifications, but does not optimally visualize the posterior fossa.
Functional imaging methods include single-photon emission computed tomography (SPECT) and positron emission tomography (PET). These tests find their greatest clinical application in the differentiation of AD from FTD or from Lewy body dementia (LBD), and the localization of a seizure focus. PET ligands for amyloid have been developed recently to aid in the diagnosis of AD. Although adopted enthusiastically by some clinicians, based on limited evidence, PET and SPECT do not currently have clear clinical indications in general psychiatry outside of research settings. Details on the different neuroimaging modalities are reviewed in Chapter 75 .
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