March 18, 2006
Medical Conditions With Psychiatric Manifestations
By O'Brien, Rebecca Flynn; Kifuji, Kayoko; Summergrad, Paul
This article reviews medical disorders that may be mistaken for a primary psychiatric disturbance because of prominent and commonly associated psychiatric or behavioral manifestations. Although the main focus of treatment in such cases is on the underlying medical condition, symptomatic treatment for the psychiatric or behavioral manifestations should not be overlooked or even considered secondary; it should occur parallel to medical management. Several factors make the accurate diagnosis of psychiatric disorders due to medical conditions challenging. First, recognition of psychiatric illness in the general medical setting irrespective of cause is generally low. Second, adolescents who present with emotional or behavioral symptoms may not have symptoms that rise to the level of full psychiatric disorders (so-called "subsyndromal" presentations). Third, adult patients with known psychiatric illnesses have a higher rate of major medical disorders than those without a psychiatric diagnosis. Fourth, some psychiatric diagnostic criteria include physical symptoms (eg, fatigue or loss of energy in major depression, or tachycardia in panic disorder). Fifth, adolescents with behavioral and cognitive disorders may have difficulty in clearly describing their symptoms, whether they are somatic or psychiatric. Sixth, given the stigma often associated with mental illness even among professionals, once an adolescent is believed to have a psychiatric illness, somatic symptoms might be downplayed or ignored. Finally, physicians unfamiliar with psychiatric conditions may make psychiatric diagnoses purely by exclusion, by focusing on "ruling-out" medical conditions.
Box 1. Underlying disorders that cause delirium
To avoid these pitfalls, the evaluation of adolescents whose behavioral symptoms may be secondary to medical disorders should proceed with a consistent and thoughtful approach. This approach should: (1) focus on cognitive symptoms (eg, hopelessness or sense of doom) more than on somatic symptoms (eg, fatigue, tachycardia), with symptom complexes that suggest major depression or panic disorder; (2) identify the details of any personal or family history of psychiatric illness and response to treatment, even if the phenotype in prior generations is different than the current presentation; (3) include a meticulous neurologic examination with appropriate emphasis on a full cognitive and psychiatric mental status exam as part of the physical examination, (4) search carefully and repetitively at the adolescent who does not respond to standard care, with special attention to symptoms that may have been overlooked or deemphasized during prior examinations; (5) recognize that psychiatric diagnoses are made by the presence of specific symptoms and not merely by the exclusion of medical conditions, and that problems in the two domains often co-exist; and (6) include consultation with a psychiatrist who has experience in caring for adolescents in medical settings.
The 2000 version of the Diagnostic and Statistical Manual (DSM IV - TR [text revision]) eliminated the distinction between "organic" and "non-organic" conditions because most psychiatric disorders ultimately have a biologic basis. To diagnose a mental disorder due to a general medical condition three criteria must be met: (1) evidence from the history, physical examination, or laboratory findings shows that the disturbance is the direct physiologic consequence of such a condition, (2) the disturbance is not better accounted for by another mental disorder, and (3) the disturbance does not occur exclusively during the course of delirium. Clues that a medical condition may be causing the psychiatric disorder include an abrupt onset with no or minimal recognized precipitants, a temporal association between onset, exacerbation and remission of psychiatric symptoms with the course of the medical condition, and the presence of atypical features, such as severe weight loss in the setting of mild depressive symptoms .
Delirium is a disturbance of consciousness, attention, cognition, and perception-not explained by an underlying dementia-that is a consequence of an illness or its treatment. By definition, it is a medical condition presenting with psychiatric or behavioral manifestations, the hallmarks of which are a decreased attention span and a waxing and waning type of confusion. Box 1 lists the various types of disturbances that can result in delirium  as well as the specific multiplicity of causes within a given type of problem. All of these conditions must be considered when evaluating an adolescent with delirium, and these same conditions should be considered with other psychiatric presentations as well. Because delirium tends to present as an acute, neuropsychiatrie emergency, the reader is referred to the article by Edelsohn and Gomez in this volume that addresses psychiatric emergencies.
The medical differential diagnoses of major psychiatric presentations are summarized in Box 2 . Just as it is important to consider the diagnosis of depression when an adolescent is fatigued, or of anxiety when the presenting symptom is chest pain (see article elsewhere in this volume by Brookman and Sood), so too must an underlying medical or surgical condition be considered with a variety of psychiatric symptoms. Although adolescents with a variety of medical conditions and chronic illnesses are at increased risk of developing adjustment problems and internalizing symptoms of depression and anxiety, this article focuses on conditions in which psychiatric or behavioral manifestations may appear as primary symptoms but not be recognized as a component of the underlying problem. Of greatest concern are conditions in which the underlying physiologic aberration is not recognized, with the psychiatric symptoms being the sole focus of attention. Just as is true of delirium, the lack of recognition of the underlying condition will preclude optimal treatment, even though the psychiatric treatment might be appropriate for the symptoms. The remainder of this article addresses the various medical diagnoses in relation to their psychiatric and behavioral manifestations in a systems-based approach but does not address the nonpsychiatric details of diagnosis or treatment of medical conditions that are the focus of other volumes in this series.
Central nervous system
Traumatic brain injury
Traumatic brain injury (TBI) includes the primary focal or diffuse brain injury due to direct impact, causing shearing and stretching, as well as secondary indirect injuries. TBI is associated with several neuropsychiatrie disturbances that can range from subtle deficits to severe disturbances including cognitive deficits, mood and anxiety disorders, psychosis, and behavioral problems . More than 50% of individuals with TBI develop psychiatric sequelae . Although a variety of terms have been applied to the neuropsychiatrie symptoms occurring after TBI, Rao uses the term "behavior dyscontrol disorder" to describe post-TBI somatic, mood, cognitive, and behavior symptoms. The minor variant, post-concussive syndrome refers to a cluster of signs and symptoms sometimes occurring after minor TBI, often not accompanied by loss of consciousness. Most will recover within 3 to 6 months, although 15% may persist longer than a year.
Box 2. General medical considerations in various child and adolescent psychiatric diagnoses
Box 2. General medical considerations in various child and adolescent psychiatric diagnoses
Box 2. General medical considerations in various child and adolescent psychiatric diagnoses
Mood disturbances include depression and anxiety . Cognitive impairments include problems with attention, memory, concentration, and executive functions. Symptoms are related to the area of the brain injured: (1) disinhibition occurs with orbital-frontal injury, (2) executive function problems are seen with dorsal convexity of the frontal lobe injuries, and (3) emotional lability and memory problems are related to temporal lobe injury. Common behavioral elements include irritability, anger and rage, and behavioral problems of impulsivity, aggression, and hyperactivity along with cognitive deficits and can be challenging to treat . The management of psychiatric disorders of TBI needs to be interdisciplinary and include empirical trials of pharmacotherapy, behavioral therapy, and caregiver and family education and support .
Several types of epilepsy can present with psychiatric features. Partial seizures, both simple and complex (associated with disturbance in consciousness), usually have paroxysmal onset and symptoms depend on their origin of location; for example, those arising from the temporal lobe may cause hallucinations or panic attacks. Simple partial seizures may present with motor signs, somatosensory or visual, tactile, auditory, or gustatory hallucinations, autonomie symptoms or signs, or with symptoms including "deja-vu," anxiety, depression, euphoria, involuntary laughing or crying, or delusions. In complex partial seizures, the adolescent may appear confused. Behaviors during a complex partial seizure may range from automatisms, such as lip smacking, fumbling with clothing or sheets, to looking around or walking aimlessly, to more complex behavior ranges, such as dis\robing or dancing; the behavior pattern in complex partial seizures is neither directed nor purposeful, however. Rarely the patient can be violent, although usually this occurs during attempts to restrain the patient .
Mesial temporal lobe epilepsy secondary to mesial temporal sclerosis, or scarring in the hippocampus, can be intractable to medication treatment, with a typical course being partial complex seizures in childhood that initially responds to medication but then returns in adolescence. More than 90% of patients have an aura, often a rising epigastric sensation, followed by motor arrest, staring, and automatisms. Diagnosis of mesial temporal lobe epilepsy is made by anterior temporal slowing and epileptiform discharges on EEG, and hippocampal atrophy on high-resolution MRI. Seizures can be eliminated surgically in 80% to 90% of patients .
Frontal lobe epilepsy is a poorly understood but distinct seizure type characterized by brief, stereotypical, nocturnal seizures with the explosive onset of screaming, agitation, stiffening, kicking, bicycling of the legs, or incontinence. Adolescents may be misdiagnosed as having a sleep disturbance or a primary psychiatric disorder. Interictal EEGs are often normal, and diagnosis often requires long-term video EEG monitoring .
Behavioral and psychiatric problems are commonly seen in adolescents with epilepsy and include attention-deficit hyperactivity disorder (ADHD) (-40%), depression (~30%), anxiety (~25%), and oppositional defiant or conduct disorder (~35%) . Depending on when the symptoms occur relative to seizure activity, psychosis associated with epilepsy is classified as ictal, postictal or interictal and is most common in temporal lobe epilepsy. Ictal psychosis is generally associated with partial complex status epilepticus. In postictal psychosis, there typically is a nonpsychotic period of hours to days immediately after a seizure, followed by psychotic symptoms including delusions, hallucinations, or catatonia and affective symptoms (manic or depressive) that usually resolve within a few days. Chronic interictal psychosis is rare in adolescence, typically occurring more than 10 years after the onset of seizures. It is sometimes referred to as schizophrenia- like psychoses of epilepsy (SLPE) and may be only partially responsive to anti-psychotic agents. Psychosis may also be a side effect of some antiepileptic drugs [10,11].
In adults, left middle cerebral artery infarction has been associated with an increased rate of major depression, even when controlling for degree of disability. There is much less known about the psychiatric complications of stroke in adolescents . In a study comparing 29 patients 5 to 19 years old who had a stroke to those with congenital clubfoot or scoliosis, post-stroke psychiatric disorder occurred in 59%, compared with only 14% of the control group. The most common diagnoses were ADHD, anxiety, and mood disorders .
Multiple sclerosis and acute disseminated encephalomyelitis in childhood
Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) are autoimmune neurologic disorders accompanied by demyelination on MRI scan. ADEM usually presents acutely after a viral infection or vaccination and is typically a monophasic illness with associated systemic symptoms, presenting with encephalopathy, fever, seizures, motor or cranial nerve abnormalities, although psychosis is rarely a major feature . In contrast to ADEM, MS is characterized as a relapsing-remitting disease. Depression, anxiety, and cognitive changes can be seen . Sluder and colleagues  published a comprehensive review of MS in children and adolescents in a recent volume in this series.
Difficulty falling asleep and nighttime awakenings are associated with major depressive disorder and anxiety disorders. Early morning awakening associated with major depression may be associated with anxiety and mood disturbances that are worse in the morning and improve over the course of the day. Primary sleep disorders including obstructive sleep apnea syndrome (commonly due to obesity in adolescents), narcolepsy, parasomnias, and delayed sleep phase syndrome can present with attentional problems. These need to be differentiated from sleep disorders that accompany medical conditions such as sleep-related asthma, gastroesophageal reflux, neurologic disorders such as sleep related epilepsy, and cluster headaches . Kleine-Levin is a rare syndrome that presents in adolescents, more commonly in males, characterized by episodes of excessive somnolence, overeating, and abnormal behavior, thought to be due to hypothalamic dysfunction. During attacks, affected adolescents display irritability, depression, difficulty concentrating, incoherent speech, apathy, lethargy, delusions, hallucinations, and amnesia. Diagnosis can be delayed and can be confused with other sleep disorders, hypothalamic tumors, encephalitis, or psychiatric diagnoses such as affective disorder .
Central nervous system tumors
Behavioral changes, including change in personality, lethargy, depression, or irritability can be seen in half of adolescents with brain tumors . The clinical presentation of brain tumors depends on their location. Cerebral hemispheric tumors often produce headaches, seizures, or focal neurologic deficits. Supratentorial midline tumors present with symptoms related to compression or infiltration of structures. Infratentorial rumors of the cerebellum produce gait abnormalities, ataxia, and signs of increased intracranial pressure. Increased intracranial pressure, with prominent vomiting, is characteristic of ependymomas that arise in the floor of the fourth ventricle. Tumors most likely to be associated with behavioral disturbances, including presentations that can mimic anorexia nervosa are those around the hypothalamus and optic chiasm, such as craniopharyngioma .
Endocrine and metabolic disorders
Common clinical symptoms due to hypothyroidism relevant to the focus of this article include fatigue, drop in school performance, impaired memory, slowed mental processing, and depression . Hypothyroidism may rarely present as psychosis, ataxia, seizures or coma . The term myxedema madness refers to the cognitive and psychotic symptoms, such as paranoid delusions and auditory hallucinations, seen before the availability of effective treatment . Affective symptoms in the context of somatic symptoms of hypothyroidism (slow growth, short stature, pubertal delay, cold intolerance, bradycardia, periorbital edema, constipation, dry skin, galactorrhea and amenorrhea) should prompt a thyroid evaluation.
Common symptoms of hyperthyroidism include nervousness, hyperactivity, restlessness, palpitations, emotional lability, sleep disorder, weight loss, or fatigue-all of which may suggest anxiety (both generalized anxiety and panic disorder), attentional, or mood disorder. Behavioral abnormalities including declining school performance, emotional instability, and anxiety may dominate the clinical picture. In other patients, cardiovascular signs are more prominent, and attention may be focused on a cardiac murmur or decreased exercise tolerance. In juvenile thyrotoxicosis, 60% to 70% have fatigability and objective muscle weakness; myopathy, including periodic paralysis, may be the most prominent symptom . If hyperthyroidism is due to Graves disease, a search for other autoimmune diseases should be conducted, not only because adolescents can have more than one autoimmune condition but also because conditions such as systemic lupus erythematosus can be associated with psychiatric symptoms.
Hyperadrenalism (Cushing syndrome)
Rare in adolescents, adrenal hyperactivity may result in major depression as an early manifestation; mania, anxiety, and cognitive dysfunction are less common . The depression seen in Cushing syndrome may be intermittent and associated with greater irritability than is usually seen with major depression . In contrast to adults, in whom more than half present with depression, only about one-fifth of adolescents present with mental or behavioral problems . Hypercortisolemic children have been reported to exhibit obsessive-compulsive behavior. After treatment of hypercortisolism, symptoms of anxiety or irritability may persist, and school performance  and cognitive ability may decline . Mood disorders, both depression and mania, are common side effects of exogenous administration of corticosteroids, especially at higher doses. Treatment can include reduction or change in medication, as well as short-term use of atypical antipsychotic or mood-stabilizing agents.
Adrenocortical insufficiency is often associated with psychiatric symptoms, most commonly depression. In addition to the somatic symptoms of depression (weakness, fatigue, poor appetite, and weight loss), irritability, anhedonia, psychosis, delirium, and coma may occur. Adrenal insufficiency also may be mistaken for anorexia nervosa, but patients with eating disorders do not have hyperpigmentation (associated with elevated ACTH) nor hyponatremic hyperkalemia characteristic of adrenal failure [23,28].
Pheochromocytomas are rare catecholamine-secreting tumors that may mimic panic attacks with paroxysmal episodes of anxiety. Clues to a pheochromocytoma include associated symptoms of headaches, palpitations, diaphoresis, elevated blood pressure, and lack of phobic symptoms that might suggest panic disorder .
Parathyroid disorders and disorders of calcium metabolism
Overactivity of the parathyroid gland results in elevated parathyroid hormone levels causing hypercalcemia. Symptoms associated with moderately elevated blood calcium levels include depression, decrea\sed concentration, paranoia, and memory problems. Higher levels of calcium can be associated with confusion and delirium. The differential diagnosis of hypercalcemia also includes paraneoplastic syndromes, hyperparathyroidism in association with multiple endocrine neoplasias, thyrotoxicosis, hypophosphatemia, hypervitaminosis A, Vitamin D excess, excessive exogenous calcium administration, thiazides, lithium, prolonged immobilization, granulomatous diseases such as tuberculosis or sarcoidosis [23,28,29].
Reduced parathyroid activity and lowered parathyroid hormone levels results in hypocalcemia, which can be associated with depression, irritability, and anxiety. Hypomagnesemia, itself a cause of weakness, fatigue, and decreased cognitive ability, can cause hypoparathyroidism and is often associated with alcohol abuse and poor diet .
Diabetes in adolescents is associated with a threefold increased risk of psychiatric disorders, as high as 33% , primarily major depression (28%)  and anxiety disorder (18%) . Psychiatric illness is often associated with poor metabolic control, especially in adolescents with recurrent diabetic ketoacidosis. Type I diabetes is associated with eating disorders ; a recent cross sectional study found a nearly fivefold increased mortality rate for adolescents with comorbid anorexia nervosa and diabetes as compared with anorexia alone, and almost 16 fold higher compared with those with diabetes alone . Hyperglycemia, either as diabetic ketoacidosis or hyperosmolar nonketotic syndrome, can cause mental status changes from lethargy and drowsiness to delirium and coma. With hypoglycemia, autonomie symptoms often arise suddenly and include anxiety, palpitations, tremulousness, diaphoresis, and pallor. Symptoms appearing more gradually include easy fatigability, lightheadedness and depersonalization, and even delirium .
In addition to those conditions described in the endocrine disorders section earlier, electrolyte disturbances can present with a variety of symptoms that affect mental status. see Table 1 for a summary of the symptoms related to deficiency and excess of various electrolytes.
Encephalopathy represents a constellation of neuropsychiatrie symptoms including a progressive loss of memory and cognitive ability, subtle personality changes, inability to concentrate, lethargy, and progressive loss of consciousness. With renal failure, symptoms depend on its cause and whether renal failure occurs acutely or insidiously. Delirium may develop, often with visual hallucinations, and in some, asterixis and dysarthria; with progression, stupor, coma, and death may ensue . Adolescents on dialysis have high rates of depression.
Copper (Wilson disease)
Wilson disease is an autosomal recessive disorder of hepatic copper metabolism. Clinical findings associated with tissue copper accumulation include liver disease, Kayser-Fleisher corneal rings, and neuropsychiatrie manifestations that often present initially in adolescence. One third of adolescents present with psychiatric disturbances such as reduced school performance, depression, labile mood, or frank psychosis. A progressive movement disorder of dysarthria, dysphagia, apraxia, and tremor-rigidity syndrome can develop . Wilson disease should be considered in adolescents who have elevated liver enzymes, tremors, dysarthria, dysphagia, movement disorders (including micrographia making handwriting illegible), mood disorders, Coombs negative anemia, cirrhosis, or liver failure. Diagnosis is most often made clinically by presence of pathognomonic Kayser-Fleisher rings by slit lamp examination and low levels of serum ceruloplasmin. Early diagnosis is essential before permanent CNS damage has occurred. Treatment is lifelong, with various chelating agents such as penicillamine or trientene [36,37].
Electrolyte disturbances causing psychiatric manifestations
The porphyrias are a group of metabolic disorders caused by enzyme defects in the biosynthetic pathways of heme production and may be inherited or acquired. The major clinical manifestations are cutaneous photosensitivity and neurologic dysfunction, most commonly presenting as abdominal pain, usually categorized into acute or chronic forms. The combination of recurrent abdominal pain (most likely due to an autonomie neuropathy in the gut) and episodic psychiatric symptoms should prompt consideration of porphyria. Neuropsychiatrie symptoms may accompany the acute attacks, often precipitated by various medications, fasting, alcohol, or hormonal changes of the menstrual cycle and include anxiety, depression, disorientation, hallucinations, and frank paranoia. Numerous medications can precipitate abdominal pain in adolescents with porphyria (http://www.porphyriafoundation.com/) [37a]. Peripheral neuropathy, sensory losses over the trunk, cranial neuropathy, seizures, or coma may develop. Urine porphobilinogen is increased (causing purple urine) in most acute porphyric attacks that manifest with neuropsychiatrie abnormalities .
Thiamine deficiency (vitamin B1, beri-beri)
Thiamine deficiency can be seen with severe malnutrition or malabsorption such as occurs with prolonged parenteral nutrition, after gastric bypass surgery, malignancies, anorexia nervosa, or hyperemesis gravidarum. The full classic triad of ocular abnormalities, mental status changes, and ataxia are not always present, and thiamine deficiency is often underdiagnosed; in a review of pdiatrie cases, 42% were diagnosed post mortem. Mental status changes (confusion, somnolence, stupor, or coma) represented the most frequent symptom in 82%, ocular signs (ophthalmoplegia, nystagmus, or ptosis) in 68%, and ataxia in 21 %. MRI abnormalities include increased T2-weighted images and contrast enhancement of basal ganglia, medial thalami, mamillary bodies, or peri-aqueductal gray matter .
Niacin deficiency (nicotinic acid, vitamin 83, pellagra)
Niacin deficiency is uncommon in industrialized countries but has been associated with gastrointestinal disorders and medications (isoniazid, anticonvulsants, pyrazinamide, 6-mercaptopurine, 5- fluorouracil, azathioprine, and antituberculars). Symptoms of pellagra include diarrhea, dementia, and dermatitis that typically begins with erythema and progresses to vesicles and bullae in sun- exposed areas . Psychiatric symptoms progress from irritability, depression, anxiety, and insomnia to hallucinations, delusions, and dementia.
Vitamin B12 (cobalamin) deficiency
Vitamin B12 deficiency can cause a spectrum of neuropsychiatric disease including paresthesias, peripheral neuopathy, corticospinal and dorsal tract disease, irritability, personality change, depression, psychosis, mild memory impairment, or dementia. Risk factors in adolescent patients include dietary restriction such as strict vegans, malabsorption from Crohn's disease, celiac disease, pernicious anemia, gastric or ileal surgery, and prolonged use of H2 receptor or proton pump inhibitors and metformin. Diagnosis can be made by a low-serum vitamin Bi2 level and elevated methylmalonic acid and homocysteine. Contrary to prevailing medical practice, recent studies support the use of oral vitamin B12 supplementation .
Mitral valve prolapse
Recent research has not confirmed a previously assumed association between mitral valve prolapse (MVP) and anxiety . In a case-control study of children and adolescents with anxiety disorder, none of the 52 subjects with anxiety disorder had MVP, compared with one of 51 controls .
Because palpitations that are associated with dizziness, near syncope, or syncope are more likely to be associated with a cardiac arrhythmia than otherwise asymptomatic palpitations, they deserve further evaluation . Palpitations without evidence of compromised circulation to the brain are more likely to be related to anxiety disorder or panic attacks. A total of 15% to 30% of patients with palpitations have panic disorder. Other noncardiac causes of palpitations include stimulant drugs and medications, alcohol, caffeine, tobacco, beta-agonists, anemia, electrolyte imbalance, fever, hyperthyroidism, hypoglycemia, hypovolemia, pheochromocytoma, vasovagal syndrome, and pulmonary disease.
Given the high prevalence of anxiety and panic disorders and the frequency with which they go undetected, a screening question to detect panic attacks in general medical settings has been proposed by Ballenger : "Have you experienced brief periods, for seconds or minutes, of an overwhelming panic or terror that was accompanied by racing heart beats, shortness of breath or dizziness?" Given the high frequency of panic disorder, especially in emergency settings, it may be valuable for clinicians to ask about family or personal history of anxiety disorders and also to ask specifically about fears of "going crazy" or needing to flee to a safe place in an attempt to distinguish between panic disorder and cardiac diagnoses. Although anxiety may cause palpitations, clinicians must avoid prematurely attributing palpitations to anxiety. Lessmeier and colleagues  found that two-thirds of a group of patients with paroxysmal supraventricular tachycardia (PSVT) also met criteria for panic disorder. However, for more than half of these patients their physicians had diagnosed only panic, anxiety, or stress before the identification of PSVT, and this was twice as likely to occur in young women.
The relationship between asthma and psychiatric issues has been explored frequently. Psychiatric conditions that can mimic asthma include anxiety disorders, panic attacks, hyperventilation, and somatoform disorders such as psychogenic upper airway obstruction that has been variously labeled "factitiousasthma,""vocal cord dysfunction," and "emotional laryngeal wheezing" . Conversely, asthma may be associated with comorbid psychiatric disorders, especially anxiety and depression [48,49]. Direct exacerbation of asthma symptoms from panic and anxiety may occur through hyperventilation. Those with anxiety or panic may overuse as-needed asthma medications, have more frequent hospitalizations with longer length of stay, and more use of corticosteroids, independent of objective pulmonary findings [50,51]. Stressful life events increase the risk of new asthma attacks both acutely and up to 7 weeks after . Coexistent depression and severe asthma increases the risk for fatal status asthmaticus .
Bidirectional neuroendocrine pathways linking cognitive and emotional centers in the brain with the enteric nervous system are called the "brain-gut axis" . The effect of the stress response on the gastrointestinal system is now recognized as the activation of vagal and sacral parasympathetic efferents that can inhibit gastric secretion and motility, inhibit small intestinal motility, enhance large bowel transit, deplete mucin and mucosal blood flow, and increase susceptibility to inflammation and stress ulcration, likely through corticotrophinreleasing hormone . These factors do not result in primary psychiatric manifestations but are important to recognize in their management, applying a biopsychosocial model.
Inflammatory bowel diseases
Although physicians tend to believe that psychosocial factors affect the clinical exacerbations but do not cause inflammatory bowel diseases (IBD) , more than half of the patients with IBD believe that stress or personality is a major contributor to the development of their disease, and more than 90% think that stress influences disease activity [57,58]. Ringel and Drossman  recently summarized human studies in IBD and psychosocial aspects, noting that: (1) epidemiologic and clinical data have historically indicated an association between various psychosocial stressors and illness exacerbation, (2) data relating life events to IBD exacerbation are inconsistent and conflicting, (3) data linking life events and daily stressors with physiologic effects (eg, pain and diarrhea) are supported, (4) the major stressors identified in life events research are not unique and include illness and death in the family, divorce or separation, interpersonal conflict, or other major loss, and (5) the data on effects of psychotherapeutic intervention with the illness or disease activity are insufficient and require additional research with careful design and careful choice of assessment instruments.
Irritable bowel syndrome
Irritable bowel syndrome (IBS) is the most common gastrointestinal condition seen in clinical practice  and is the most common functional gastrointestinal disorder. Evidence suggests that there is altered colonie wall sensitivity and motility in these patients, resulting in exaggerated motor reactivity to various stimuli, including meals, psychological stress, and balloon distention of the rectosigmoid colon. The resulting symptoms are pain and altered transit time resulting in constipation, diarrhea, or both. The commonly observed phenomenon of "entrainment" with the menstrual cycle, which results in a worsening of symptoms around the time of menses, can easily result in the incorrect diagnosis of dysmenorrhea or endometriosis for these women .
A total of 50% to 90% of patients who seek treatment for IBS have a lifetime history of, or currently have, one or more psychiatric conditions including: social phobia (14% to 30%), dysthymia (55% to 60%), posttraumatic stress disorder (15% to 30%), depression (6% to 37%), generalized anxiety disorder (15% to 20%), personality disorder (10% to 20%), panic disorder (6% to 25%), and somatization disorder (30% to 45%) [62-64], and 40% to 60% of patients have some form of anxiety, depression, or panic disorder . Severe stressors account for more than 90% of the variance of IBS symptoms. The symptoms of IBS do not likely induce psychiatric disease because such features predate or occur simultaneously with the onset of bowel symptoms in 65% to 85% of patients . The prevalence of anxiety and mood disorders, particularly panic disorder, in patients attending gastroenterology clinics with functional bowel disorders (50% to 60%) is approximately twice that of IBD [67,68].
Peptic ulcer disease
Psychologic stress causing increased gastric acid excretion was suggested by early studies to have a role in peptic ulcer formation. Psychological factors affecting clinical expression of symptoms may do so by reducing immune responses and thus increasing vulnerability to H. Pylori infection . A study that included patients with peptic ulcer and IBD of recent onset showed that 16% of patients had definite psychiatric disorders and 32% had mild psychiatric disorders [7O]. Peptic ulcer disease is associated with anxiety or depression , neuroticism , and personality traits of social withdrawal, suspiciousness, hostility, and dependency in a group of patients [73,74].
Syndenham chorea (SC) is a neuropsychiatrie disorder seen in 15% of patients with acute rheumatic fever. The disorder begins with psychiatric signs such as emotional lability, hyperactivity, separation anxiety, and obsessions and compulsions followed over the next several weeks by chorea and hypotonia . Behavioral symptoms often arise abruptly with obsessive-compulsive symptoms arising shortly before the movement disorder. The disease is characterized by chorea with other motor symptoms, including facial grimacing, hypotonia, and loss of fine motor control and gait disturbance. Half of acute SC cases appear to spontaneously recover within 2 to 6 months; however, mild or moderate chorea may persist for more than 2 years in half of SC cases . Corticosteroids may help symptoms to resolve .
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection
The acronym PANDAS for pdiatrie autoimmune neuropsychiatrie disorders associated with streptococcal infection was suggested by Swedo and colleagues  who described 50 young subjects with a post-Group A streptococcal tic disorder and obsessive-compulsive disorder. Although this has been proposed to be a variant of SC, the absence of an associated carditis makes this unlikely [79,80]. Other poststreptococcal neuropsychiatrie manifestations have been described including ADHD, myoclonus, dystonia, dyskinesias, disseminated encephalomyelitis, and anorexia nervosa. This remains a controversial area and the reader is referred to Kurlan and Kaplan's article for a discussion of clinical considerations .
Psychiatric symptoms of Epstein-Barr virus (EBV) include prolonged fatigue, hypersomnia, and short-lived depressive disorders . A characteristic neuropsychiatric disorder of EBV infection is the "Alice-in-Wonderland" syndrome (AIWS) in which patients experience micropsia (objects appear smaller), macropsia (objects appear larger), metamorphopsia (objects, such as faces, appear distorted), teleopsia (objects appear far away), and depersonalization . In a case report of AIWS, MRI findings included transient T2 prolongation and swelling of the cerebral cortex, especially at the bilateral temporal lobes, bilateral cingulated gyrus, right upper frontal gyms, bilateral caudate nucleus, and bilateral putamen, whereas CT showed no abnormalities . The once hypothesized association between EBV (or human herpes virus) and "chronic fatigue syndrome" has not been found in epidemiologic studies.
Lyme disease (LD) is caused by infection with the spirochete Borrelia Burgdorferi and is transmitted through the bite of the deer tick (Ixodes scapularis). The clinical presentations of LD are summarized in Table 2 [84-97]. After acute, untreated infection, about 60% of patients may progress to later stage LD and develop chronic symptoms. A recent review cites a variety of psychiatric symptoms that have been associated with LD: "depression, mania, delirium, dementia, psychosis, obsessions or compulsions, panic attacks, catatonia, and personality change" . Many of the studies linking LD to psychiatric symptoms, however, relied on a single Lyme ELISA without confirmatory Western blot, and further controlled studies are needed .
The literature on neurocognitive abnormalities in young patients does not always specify age ranges, making it difficult to comment about the effects of LD on adolescents. Language, memory, learning, visuospatial, and constructional abilities appear to be spared in LD in pediatric patients. New-onset behavioral changes (eg, listlessness, irritability, malaise, and loss of interest) may adversely affect other abilities and learning problems may be seen in educational and vocational settings . In a study of 37 children with early disseminated LD, the most frequent self- reported symptoms included fatigue, listlessness (84%), headache (81%), and mood disturbances (70%), but psychometric testing showed no differences between cases and controls . Because those with early disseminated disease do not have long-term complications, neuropsychologic testing is not recommended in this group. However, further studies are needed to confirm chronic neurologic sequelae in adolescents with late LD presentations .
Meningoencephalitis is unlikely to present only with psychiatric symptoms, but these may predominate in highly localized infections. Acute bacterial and viral meningitis presents with fever, headache, stiff neck, and may be accompanied by change in level of consciousness (drowsiness, stupor, or coma), mood symptoms (irritability or depressed mood), anxiety, or psychosis. All o\f these symptoms are compatible with delirium, discussed earlier in this article. Encephalitis generally presents with disorientation, altered level of consciousness, and behavioral or speech disturbances. The extent and location of the involvement of the brain determine clinical findings, with rabies for example affecting the limbic system and causing delusions [10O]. Herpes simplex encephalitis is the most common focal encephalitis affecting frontal and temporal lobes, and diagnosis is suggested with symptoms of fever, headache, personality change, decreased level of consciousness, and focal neurologic signs such as hemiparesis, dysphasia, or focal seizures. Diagnosis may be difficult as many infections can mimic herpes simplex encephalitis [101,102]. Mania may be the only initial manifestation. Given the predilection of herpes virus to affect the temporal lobe, symptoms consistent with complex partial seizures (including olfactory and gustatory hallucinations) may occur [10O]. The diagnosis is made by polymerase chain reaction detection of herpes simplex virus DNA in the CSF . Chronic meningitis causative agents include Mycobacterium tuberculosis, Cryptococcus, and Coccidioides. Symptoms include neck stiffness, fever, headache, cognitive impairment, behavioral change, confusion, change in consciousness (drowsiness, stupor or coma), mood symptoms (irritability or depression), anxiety, and psychosis. CSF typically shows a lymphocytic pleocytosis with elevated protein, decreased glucose, and elevated opening pressure. Specific CSF antigen may be positive and helpful, as fungi and tuberculous bacilli may take weeks to grow in culture. Cryptococcus is most often seen in immunocompromised patients, often associated with human immunodeficiency virus (HIV) infection . As discussed previously, Lyme disease is also a cause of chronic meningitis.
Human immunodeficiency virus
High rates of social and emotional dysfunction and behavior problems have been observed in youth with HIV infection; these problems may be due to the disease process but may also be manifestations of environmental stresses encountered by these youth and their families . Emotional problems (withdrawal, depression, apathy, or anxiety) and attentional problems, and hyperactivity are common sequelae, and more rarely reported problems include psychotic symptoms in progressive encephalopathy and end- stage wasting syndrome with apathy and withdrawal symptoms . Psychiatric conditions, such as bipolar disorder, schizophrenia, depression, and anxiety, have been associated with both HIV- associated risk behavior and HIV infection . A study of HIV- infected children found that the most frequent psychiatric diagnoses were major depressive disorder (47%) and ADHD (29%). The appearance of psychiatric complication indicates severe HIV infection, and depressive disorders may be a clinical form of encephalopathy .
Perinatally infected patients have higher risk to be hospitali/ ed for psychiatric illnesses, such as depression and behavioral disorders than the incidence in the general pediatric population. Although syphilis must be considered in the differential diagnosis of neurologic disease in HIV-infected patients [106,107], neurosyphilis (which affects the frontal lobes and results in personality changes, development of poor judgment, irritability, and decreased care for self) is a late complication, rarely seen in adolescents.
Collagen vascular diseases and other vasculitides
Large vessel vasculitis is uncommon in adolescents. Takayasu giant cell arteritis occurs in young females, more commonly in Asians. Absent peripheral pulses, syncope and visual disturbance are classic symptoms. Medium-sized vessel arteritides including periarteritis nodosa, Kawasaki disease, Churge-Strauss syndrome, and Wegener granulomatosis can all present with stroke and encephalopathy .
Selected drugs taht alter mental status and muscle tone
Selected drugs taht alter mental status and muscle tone
Central nervous system involvement is commonly seen in systemic lupus erythromatosis (SLE) and mixed connective tissue disease, rarely in scleroderma and rheumatoid arthritis. Sjogren syndrome can complicated collagen vascular disorders and can have focal or diffuse CNS disease due to antineuronal antibodies, with symptoms of motor, sensory, language, movement disorders, encephalopathy, aseptic meningitis, and dementia. Behet disease can also present with CNS disease including encephalitis, meningoencephalitis, and neuropathy but will be accompanied by oral or genital ulcers and often ocular involvement .
SLE is a multisystem autoimmune disease that has a variable presentation and course. Whereas skin, musculoskeletal, and renal systems are the most commonly involved, neuropsychiatrie lupus (NP- SLE) occurs in up to 30% of adolescents at presentation and in up to 95% at some time during their illness. Headache is the most common symptom of NP-SLE and often is resistant to analgesics. Psychiatric manifestations include an acute confusional state (delirium) in 20% to 40%, anxiety disorder in 20% to 57%, mood disorder/depression in 28% to 57%, psychosis in 12% to 30%, and cognitive dysfunction in 28% to 57% . Psychiatric disorders in SLE are related to presence of antiribosomal P antibodies in serum. Distinguishing SLE- mediated psychosis from treatment effects with corticosteroids can be challenging. NP-SLE can occur at any time during the course of the disease and is likely caused by many factors, including autoantibody production, microvasculopathy, and pro-inflammatory cytokines [110,111]. Other features of NP-SLE include CNS involvement of aseptic meningitis, stroke, demyelinating syndromes, chorea, seizures, as well as peripheral nervous system syndromes. Diagnosis and management are summarized elsewhere [109-111].
Substance use and toxic ingestion
Whenever an adolescent presents with neuropsychiatrie disturbance, substance use and toxic ingestion must be considered. This is, however, beyond the scope of this article. Table 3 summarizes some of the drugs that may alter mental status ; Eicher and Avery  have recently published an excellent review of toxic encephalopathies.
A variety of medical conditions can present, or be associated, with psychiatric symptoms. At times, these may be so prominent that they can overshadow the underlying pathophysiologic process that accounts for them. Thus, it is equally important for mental health providers to be alert to the possibility that adolescents whom they are treating may have symptoms related to a treatable medical condition as it is for primary care providers to conduct a targeted history and physical examination with their adolescent patients exhibiting psychiatric symptoms. Using the biopsychosocial approach, these two domains are not considered separately or hierarchically, but as highly interactive. In some cases (eg, adrenal insufficiency), appropriate and continued treatment of the underlying condition results in resolution of the psychiatric symptoms. In others (eg, SLE), treatment of the underlying condition may alleviate but may also exacerbate psychiatric symptoms. Therefore, comprehensive treatment of adolescents with psychiatric symptoms due to a medical condition may require the professional services of primary care, mental health, and specialty care providers, but their services should follow the collaborative model espoused throughout the other articles in this volume.
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Rebecca Flynn O'Brien, MD(a,*), Kayoko Kifuji, MD, PhD(b), Paul Summergrad, MD(b)
a Tufts University School of Medicine, Division of General Pediatrics and Adolescent Medicine, The Floating Hospital for Children, Tufts-New England Medical Center, 750 Washington Street, Box 479, Boston, MA 02111, USA
b Tufts University School of Medicine, Department of Psychiatry, Tufts-New England Medical Center, 750 Washington Street, Box 1007 Boston, MA 02111, USA
* Corresponding author.
E-mail address: [email protected] (R.F. O'Brien).
Copyright Hanley & Belfus, Inc. Feb 2006