Crude exogenous organic damage of the most varying kind can produce acute psychotic clinical pictures of a basically uniform kind.

Karl Bonhoeffer, 1909¹

The number of medical diseases that can present with psychotic symptoms (ie, delusions, hallucinations) is legion. A thorough differential diagnosis of possible medical and toxic causes of psychosis is necessary to avoid the mistaken attribution of psychosis to a psychiatric disorder. One organizing principle separates etiology into primary psychiatric and secondary categories, the latter includes delirium (toxic psychosis), dementia, medical illnesses, and substances (Figure) This terminology avoids the term “organic,” which implies a mind-body dichotomy that is no longer tenable.² Psychosis can be attributable to a combination of factors, and all possible causes must be systematically examined, hence the lack of a hierarchical organization in this nosology.

Figure

In this article, I focus on secondary psychosis due to a medical illness or substances and not on the cognitive disorders of delirium and dementia. It is important, however, to be aware that both are commonly associated with psychosis. Psychosis is a frequent ancillary symptom of delirium that can overshadow its cardinal cognitive features.^3,4 It is therefore critical to routinely consider the possibility of a delirium in any patient with psychosis. Dementias are also frequently accompanied by neuropsychiatric problems, including psychosis.⁵ Psychosis is present in about 40% of patients with Alzheimer disease, the most common form of dementia.⁶ Most patients with Lewy body dementia experience psychosis as well. Hallucinations, usually visual, are the most frequent psychotic symptom; they occur in 78% of patients, followed by misidentifications in 56% and delusions in 25%.^7,8

Approach to diagnosis

Karl Bonhoeffer, one of the fathers of “organic psychiatry,” recognized 100 years ago that the psychiatric clinical picture produced by a medical condition was rather uniform and unspecific, regardless of etiology.⁹ Unfortunately, there is also no easy way to differentiate primary from secondary psychoses on the basis of psychopathology alone.^10,11 While certain symptoms suggest a medical-toxic etiology (eg, visual hallucinations, lack of Schneider first rank symptoms), there are no pathognomonic signs or symptoms that unequivocally point clinicians either way.¹ To complicate matters, some acute, primary psychiatric presentations can include confusion and perplexity, seemingly implicating a toxic psychosis.¹² Instead, clinicians have to rely on typicality (with regard to age at onset, symptoms, treatment response, and course) as well as temporality and biological plausibility to judge whether a medical condition is causally related to psychosis.

A primary psychotic disorder, such as schizophrenia, is a diagnosis of exclusion, and all patients with new-onset psychosis need a medical workup that excludes medical-toxic causes of psychosis. The overall clinical and epidemiological situation is of utmost importance in narrowing the initially rather broad differential diagnosis of psychosis to keep the workup manageable and to determine the degree of urgency. For example, any new-onset psychosis in a hospitalized, elderly patient following hip surgery is most likely a toxic psychosis (delirium); an antisocial patient with polysubstance dependence who presents at the emergency department is likely suffering from a drug-induced psychosis.¹³

Some medical diagnoses are difficult to make. Clinicians may be unfamiliar with a disease that is rare per se (many genetic disorders fall into this category) or rare in the clinician’s practice (eg, cerebral malaria in the United States). Clinicians might also not recognize a common disease if it presents in an atypical manner (eg, HIV infection presenting with psychosis). Table 1 provides examples of diagnostic mistakes.

Table 1

Primary or secondary psychosis? Diagnostic mistakes

The medical workup

A thorough history and physical examination with emphasis on the neurological and cognitive parts are the cornerstones for the initial approach to psychosis. To detect fluctuations in mental status typical for a toxic psychosis, repeated visits with bedside testing of cognition may be necessary. The extent of the laboratory workup to complement the history and physical examination is a matter of debate, and there is no agreed-on workup.¹⁴ For test selection, test characteristics (sensitivity and specificity) as well as the prevalence of the disease are key considerations.¹⁵ If a disease is unlikely (low prior probability), a positive test result is probably a false positive, which argues against indiscriminate screening.

Among the tests selected for screening, the most sensitive test needs to be ordered because a negative test result removes the disease from the clinician’s differential diagnosis list. For example, the rapid plasma reagin (RPR) is not the most sensitive test for neurosyphilis, and a negative result could be a false negative; if one were to truly want to rule out neurosyphilis, a treponemal-specific test would be needed.¹⁶ Further complicating test selection is the unavailability of sensitive and specific tests for many diseases.

If there is a strong clinical suspicion for a disease, its diagnosis must be actively pursued with repeated tests (eg, serial electroencephalograms [EEGs] for epilepsy). Finally, a positive finding on an examination or a positive laboratory test result alone (eg, a urine drug test positive for cannabis) does not establish causality. This point is perhaps most relevant with regard to incidental findings on a sensitive neuroimaging modality, such as a brain MRI.

One possible medical workup is outlined in Table 2. The suggested laboratory battery is a compromise between broad-based screening (eg, erythrocyte sedimentation rate for inflammatory conditions) and exclusion of some specific conditions that are treatable if diagnosed (eg, HIV infection, syphilis, thyroid disease, vitamin B12 deficiency). If there is clinical concern for a delirium, EEGs, arterial blood gases, or lumbar punctures become more important.

Table 2

Suggested medical workup for secondary psychosis

Of note, there is no consensus regarding the need for routine brain imaging in first-episode psychosis.

CT or MRI may be reserved for patients with an atypical clinical presentation, neurological findings, or an unusual/treatment-refractory course. A normal baseline CT or MRI scan, however, is reassuring and can help patients and families accept that medical and neurological causes of illness have been excluded.

The appropriate role of routine genetic screening in patients with psychosis is an area in flux. Currently, only the Clinical Practice Guidelines for the Treatment of Schizophrenia by the Canadian Psychiatric Association recommends testing for a genetic syndrome, the velocardiofacial syndrome, but only if it is clinically suspected.¹⁷

SECONDARY PSYCHOSIS—SPECIFIC CONDITIONS
Psychosis from a general medical condition

Endocrine diseases. Endocrine diseases are the prototype for systemic illnesses that affect the brain and lead to a wide variety of neuropsychiatric symptoms. Thyroid disease in the form of hyperthyroidism or hypothyroidism (myxedema madness) can be associated with psychosis.^18-20 Steroid-producing tumors, located in either the adrenal gland (Cushing disease) or other tissues (eg, ectopic Cushing syndrome from small-cell lung cancer) need to be considered, particularly in cases of refractory psychosis.^21,22 Insulinomas can present with an array of psychiatric symptoms, including confusion and bizarre behavior that can be falsely attributed to psychiatric illness.²³ A pheochromocytoma is yet another rare hormone-producing tumor that characteristically produces episodic anxiety states but can present with psychosis.²⁴

Metabolic diseases. Among the metabolic disorders, only acute intermittent porphyria (AIP) is sufficiently common to be routinely considered in patients with psychosis, particularly if abdominal complaints (colicky pain, severe constipation) and peripheral motor neuropathy are present.^25,26 AIP is an autosomal dominant disease of heme synthesis that results from defects in the enzyme porphobilinogen deaminase (PBGD). These defects could result in an accumulation of the porphyrin precursors, porphobilinogen (PBG) and aminolevulinic acid (ALA).²⁷ A diagnosis of AIP is therefore suggested by an excess of ALA and PBG in urine and a concomitant decrease in PBGD enzyme activity in erythrocytes. The course of AIP is episodic, and patients are well between episodes. Fasting, alcohol, and a host of porphyrogenic medications can trigger episodes.²⁸

Tay-Sachs disease (GM2 gangliosidosis type 1) and Niemann-Pick disease type C are rare storage disorders that have adult-onset variants. Psychosis is one of the possible symptoms.^29,30

Autoimmune. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease for which 2 CNS symptoms, psychosis and seizures, have long been recognized as diagnostic criteria by the American College of Rheumatology.³¹ Psychosis has been well documented to occur in a significant minority of patients as a result of the immune disease itself, unrelated to medical treatment.³² For example, in a cohort study of 520 consecutive SLE patients, Appenzeller and colleagues³³ found that 11% of patients with SLE had psychosis secondary to brain involvement. Moreover, psychosis correlated with markers of SLE disease activity. By contrast, psychosis as a result of corticosteroid treatment was diagnosed in only 5% of patients, and psychosis was thought to be from a primary psychiatric disorder in fewer than 1% of cases.

Other autoimmune disorders to be considered include Hashimoto encephalopathy and paraneoplastic syndromes. Hashimoto encephalopathy is associated with autoimmune thyroiditis and recurrent episodes of psychosis.³⁴ It is exquisitely corticosteroid-responsive, and prompt treatment leads to rapid recovery.³⁵ Paraneoplastic limbic encephalitis (PLE) can cause neuropsychiatric symptoms that are the result of autoantibodies directed toward neuronal intracellular or cell membrane antigens.³⁶

Although PLE is most commonly associated with small-cell lung cancer, many other tumors have been implicated. A young woman who presents with psychosis that progresses to seizures, autonomic instability, and unresponsiveness should have a workup for ovarian tumors because she might have encephalitis associated with N-methyl d-aspartate (NMDA) receptor antibodies.^37,38 Considering PLE in progressive or poorly responsive neuropsychiatric syndromes is critical so that a tumor search is initiated.

Infections. Immigrant populations or travelers can present with diseases associated with psychosis that would be considered uncommon in the United States (eg, cerebral malaria, toxoplasmosis, neurocysticercosis, sleeping sickness). In addition to the patient’s geographic locale and travel history, immune status can help identify likely infectious agents. HIV infection and neurosyphilis are treatable diseases that affect the brain. They can present with psychosis and should specifically be considered in all patients with psychosis.^39,40

In contrast to neurosyphilis, the link between chronic psychosis and another spirochetal disease, neuroborreliosis, is controversial, although it has been linked to acute psychosis in a case report.⁴¹ Be mindful that patients with encephalitis can inadvertently present to a psychiatric service if psychiatric symptoms dominate the clinical picture.⁴² Among the viral infections, herpes simplex encephalitis is the most urgent to consider because any delay in administering acyclovir worsens prognosis.⁴³

Narcolepsy. Narcolepsy is characterized by the tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations (ie, vivid auditory or visual illusions that occur when falling asleep).⁴⁴ However, the full tetrad is present in only 10% of patients. In some patients, prominent psychosis-like experiences occur throughout the day and overshadow other symptoms of narcolepsy that can lead to a mistaken diagnosis of schizophrenia.⁴⁵ In one small series of 69 patients in a state hospital, 7% of patients with a diagnosis of schizophrenia were found to have narcolepsy.⁴⁶ The treatment of narcolepsy with stimulants can further complicate the picture because psychosis can result from the medical treatment.⁴⁷ The diagnosis of narcolepsy requires a nocturnal sleep study followed by a multiple sleep latency test (MSLT) to identify reduced daytime sleep latency and sleep onset rapid eye movement (SOREM) periods. Human leukocyte antigen testing and cerebrospinal fluid levels of hypocretin-1 can further assist in making the correct diagnosis.⁴⁸