Differential Diagnosis of Psychotic Symptoms: Medical “Mimics”: Page 2 of 2
Differential Diagnosis of Psychotic Symptoms: Medical “Mimics”: Page 2 of 2
Seizures. The link between seizures, particularly temporal lobe epilepsy, and psychosis is well established.49 Epidemiological studies have shown a higher rate of schizophrenia in patients with epilepsy and vice versa.50 Psychosis in the setting of seizures can occur during the ictal, postictal, and interictal phases. Ictal psychosis can occur in complex partial or absence status epilepticus. Postictal psychosis emerges close to the seizure and can last several days or weeks, rarely morphing into a chronic psychosis.51,52 Interictal psychosis typically emerges after a decade of poorly treated or poorly responsive epilepsy and is characterized by intense dysphoric affect in addition to psychosis.53 Earlier development of interictal psychosis suggests individual vulnerability as opposed to epilepsy-related damage.54
Confusion, episodic violence, and catatonia are clinical symptoms that should raise suspicion for seizures. If a seizure or epilepsy is suspected, the diagnosis needs to be pursued appropriately. A normal, routine interictal EEG is insufficient to exclude epilepsy. Serial EEGs and optimal lead placement improve the chances of making a diagnosis of epilepsy.55 Frontal lobe seizures, in particular, can be very difficult to diagnose. A high index of suspicion based on history (abrupt onset and cessation of bizarre motor automatisms and vocalizations but little if any postictal confusion) combined with EEG monitoring and alternative electrode placement (eg, pharyngeal leads) can succeed in making this diagnosis.
Space-occupying lesions. Primary or secondary brain tumors can cause psychosis as their first manifestation and should be considered in elderly patients, particularly if there is a persistent headache or other neurological signs, including seizures. However, in the case of “silent” indolent-growing tumors, such as frontal meningiomas, neurological examination findings are often normal.56 Tumor histology is not as important as rapidity of growth and location for the clinical presentation. Temporal lobe location is thought to increase the likelihood of psychosis, although it must be stressed that no lesion location in the brain reliably produces psychosis. Causal attribution of psychosis to incidental neuroimaging findings (eg, cysts or vascular malformations in the temporal lobes) is therefore often unclear. Conditions that increase intracranial pressure, such as normal pressure hydrocephalus, have been associated with psychosis as well.57
Strokes. Rarely, psychosis can be the presenting symptom of a stroke.58 In some cases, stroke-related seizure activity is responsible for the psychosis. The sudden onset of complex visual hallucinations should lead to consideration of 2 lesion-related conditions: peduncular hallucinosis caused by focal midbrain (peduncular) lesions and the Charles Bonnet syndrome following occipital infarction.59 However, in both conditions, causes other than a stroke are possible.
Head injury. A history of head injury is a risk factor for the development of a chronic psychotic syndrome that can be clinically indistinguishable from schizophrenia. Head injury–related psychosis is typically a mostly paranoid-hallucinatory syndrome that develops insidiously several years after injury.60 Patients experiencing psychosis can appear blunted and withdrawn, and it is critical not to ascribe apparent negative symptoms to brain damage but to consider active psychosis. The severity of head injury (as judged by the duration of loss of consciousness) and a family history of psychosis are 2 variables associated with the emergence of psychosis following head injury.61
Demyelinating diseases. Diseases that disrupt the integrity of white matter tracts in the brain can lead to psychosis, likely to be caused by the functional disconnectivity of critical brain regions.62 Demyelinating diseases would be expected to be associated with psychosis if (1) the disease affects the brain as opposed to the brain stem and spinal cord, and (2) the “right” brain regions are disconnected.
Multiple sclerosis, the most common demyelinating disease, is associated with psychosis more often than can be expected by chance, although the rate of psychosis is low.63-65 Inherited leukodystrophies, such as metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD), on the other hand, are associated with a high prevalence of neuropsychiatric symptoms, including psychosis. MLD in particular is associated with a very high rate of psychosis, perhaps as high as 50%.66 MLD is an autosomal recessive disorder caused by a deficiency in the lysosomal enzyme, arylsulfatase A.
ALD is an X-linked disorder in which very-long-chain fatty acids accumulate because of defective peroxisomal oxidation. While inherited leukodystrophies are typically diagnosed in childhood because of their aggressive clinical course with systemic and neurological symptoms, adult-onset cases can present with a predominantly psychiatric picture. The diagnosis of a demyelinating disorder is suggested by abnormal findings on MRI scans. Clinical red flags for inherited leukodystrophies include progressive cognitive decline, other neurological findings (eg, seizures or a neuropathy), or other systemic findings (eg, adrenal insufficiency in patients with ALD).
Basal ganglia disorders. Rare, inherited basal ganglia disorders associated with psychosis include Wilson disease, Huntington disease, and Fahr disease.67 Wilson disease is a disorder of copper metabolism that leads to copper deposits in the liver and the lenticular nucleus of the brain (hence the term “hepatolenticular” degeneration). Since early diagnosis and treatment can prevent irreversible end-organ damage, screening with 24-hour urinary copper and serum ceruloplasmin levels should be considered in psychotic patients, particularly if patients show evidence of liver abnormalities. Kayser-Fleischer rings of the cornea as detected by slitlamp examination are not always present in neuropsychiatric Wilson disease.68
The diagnosis of Huntington disease, an autosomal dominant disorder, is usually not difficult because most patients will have a family history. Psychosis can precede the motor symptoms of Huntington disease and delay its recognition.69,70 While Huntington disease will eventually declare itself clinically, a definite diagnosis can be made earlier with genetic testing.
Fahr disease is characterized by bilateral basal ganglia calcifications and neuropsychiatric symptoms, including psychosis.71 However, basal ganglia calcification can also be an incidental CT finding of unclear significance.
Hallucinations, particularly visual hallucinations, are a common problem associated with Parkinson disease.72 Their etiology is likely to be multifactorial and includes disease severity and dementia as well as treatment with levodopa.73
Nutritional deficiencies. Vitamin B12 deficiency is easily correctable and should be specifically excluded in all patients. Psychosis from vitamin B12 deficiency can predate anemia and the typical spinal symptoms.74,75 Thiamin deficiency is easily correctable as well; therefore, thiamin must be given in the appropriate setting (ie, alcoholism). Niacin deficiency (pellagra) is rare in the United States; symptoms include psychosis in addition to diarrhea, dermatitis, and stomatitis/glossitis.76
Psychosis due to substances
Many toxins, drugs, and medications can cause psychosis without a delirium, although the line between secondary psychosis caused by a substance and toxic psychosis can be difficult to draw. In addition, establishing a causal link between substances and psychosis is not always possible, and in many circumstances of illicit drug use in particular, the exact relationship between psychotic symptoms and the ingested drug requires long-term follow-up. In cases of cannabis use and a psychotic illness, an interaction between drug use and genetic predisposition to schizophrenia is likely.77
Inquiring about all drugs and medications taken (eg, over-the-counter, bought over the Internet, prescribed, nonprescribed, illicit) and an exposure history (occupation and hobbies such as gardening) can provide clues that guide further investigation. Many patients will not volunteer their use of “natural” herbal remedies because they do not appreciate the possibility of adverse reactions. An herbal preparation associated with psychosis is the now-banned ephedra that patients might take for weight loss.78 Patients who subscribe to weight lifting and body building might be taking anabolic steroids. While uncommon and most importantly idiosyncratic (as opposed to dose-related), psychosis is a possible complication of recreational anabolic steroid use.79
The detection of environmental toxin poisoning requires a high index of suspicion. Toxins to consider include carbon monoxide; organophosphates; and heavy metals, particularly arsenic, manganese, mercury, and thallium.80
In many clinical settings, alcohol, sedative-hypnotics, and illicit drugs will be common causes of psychosis. Alcohol and sedative-hypnotics can lead to psychosis during intoxication (rare), during withdrawal, or during a delirium tremens. In persons with long-term alcohol abuse, persistent psychosis in the form of alcoholic hallucinosis or pathological jealousy (Othello syndrome) can develop.81,82 Stimulant drugs (eg, cocaine, methamphetamine) and psychotomimetics (eg, lysergic acid diethylamide [LSD], hallucinogenic mushrooms, phencyclidine [PCP]) as well as cannabis are important drugs that can cause psychosis.
Table 3 lists some medications that have been associated with psychosis.
For a diagnosis of drug-induced psychosis, it is helpful to consider which drugs are prevalent in particular geographic areas and clinical subpopulations. For example, men who have sex with men from urban centers are at risk for using methamphetamine.83 College students might experiment with psychotomimetic party drugs or misuse stimulants obtained (legally and illegally) for the purpose of “cramming” before exams.84 Clinicians need to be cognizant of the drugs included in the urine drug screen because only drugs included in it can potentially be detected.
Ruling out secondary causes of psychosis is important because the causation of psychosis by a medical disorder or substance can dramatically change management and prognosis. Table 4 summarizes key clinical points to consider when evaluating a patient with new-onset psychosis of unknown etiology. Readers with further interest in secondary psychosis can consult 2 excellent books—The Schizophrenias. A Biological Approach to the Schizophrenia Spectrum Disorders and Secondary Schizophrenia—that cover this topic in more detail.
[Editor's Note: Originally presented as an independent educational activity under the direction of CME LLC, this article was published by Psychiatric Times (2010;27:56-61; click here for a pdf of the original article and author's financial disclosure). The ability to receive CME credits has expired. The article is presented here for your reference.]
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