Diagnostic Considerations
Disorders to be considered in the differential diagnosis of schizophrenia include the following:
-
Other psychiatric illnesses
-
Anatomic lesions
-
Metabolic illnesses
-
Endocrine disorders
-
Infectious illnesses
-
Miscellaneous disorders
-
Vitamin deficiency
Other psychiatric illnesses
Schizophrenia and bipolar affective disorder (manic-depressive illness) may be difficult to distinguish from each other. Patients with manic-depressive illness predominantly have disturbances in their affect or mood. Psychotic symptoms may be prominent during a mania or depression.
In classic manic-depressive illness, the psychotic symptoms are congruent with mania or depression, and the person has periods of euthymia (normal mood) with no psychotic symptoms between the episodes. However, some patients have periods of psychotic symptoms in the absence of depression or mania. In these cases, schizoaffective disorder is diagnosed.
In delusional disorder, the person has a variety of paranoid beliefs, but these beliefs are not bizarre and are not accompanied by any other symptoms of schizophrenia. For example, a person who is functioning well at work but becomes unreasonably convinced that his or her spouse is having an affair has a delusional disorder rather than schizophrenia.
Schizotypal personality disorder is characterized by a pervasive pattern of discomfort in close relationships with others, along with the presence of odd thoughts and behaviors. The oddness in this disorder is not as extreme as that observed in schizophrenia.
In schizoid personality disorder, the person has difficulty and lack of interest in forming close relationships with others and prefers solitary activities. No other symptoms of schizophrenia are present.
In paranoid personality disorder, the person is distrustful and suspicious of others. No actual delusions or other symptoms of schizophrenia are present.
Substance abuse is discussed below.
Anatomic lesions
In rare cases, brain tumors may be confused with a psychotic illness. Because brain tumors are potentially lethal but treatable, it is important to consider brain imaging studies for every person with a new onset of a psychotic illness or, perhaps, a marked change in symptoms.
Subdural hematomas can manifest as changes in mental status. Intracranial bleeding should be considered in patients who report head trauma or who, for whatever reason, are not able to provide a clear history. Brain imaging may be appropriate in these cases.
Idiopathic calcification of the basal ganglia is a rare disorder that tends to present as psychosis in patients who become symptomatic early in adulthood; those presenting later in life typically present with dementia and a motor system disorder. Schizophrenialike symptoms may precede the onset of intellectual deterioration and extrapyramidal motor disturbances. [75]
Metabolic illnesses
Wilson disease, also known as hepatolenticular degeneration, is a disorder of the metabolism of copper.
It is an autosomal recessive illness. The first psychiatric symptoms are often vague changes in behavior during adolescence. It is primarily a liver disease.
Laboratory findings include increased urinary levels of copper and low serum levels of copper and ceruloplasmin. Kayser-Fleischer rings (copper deposits around the cornea) can sometimes be seen. The diagnosis is usually confirmed by finding increased hepatic copper at biopsy.
Porphyrias are disorders of heme biosynthesis. Acute intermittent porphyria can present with psychiatric symptoms. Patients may have a family history of psychosis. The psychiatric symptoms may be associated with electrolyte changes, peripheral neuropathy, and episodic severe abdominal pain. Abnormally high levels of porphyrins in a 24-hour urine collection confirm the diagnosis.
Patients with hypoxemia or electrolyte disturbances may present with confusion and psychotic symptoms. Hypoglycemia or hyperglycemia can produce confusion and irritability and may be mistaken for psychosis.
Delirium from whatever cause (eg, metabolic or endocrine disorders) is an important condition to consider, especially in the elderly or hospitalized patient. The clinical hallmarks are decreased attention span and a waxing-and-waning type of confusion.
Endocrine disorders
Severe hypothyroidism or hyperthyroidism can be associated with psychotic symptoms. Hypothyroidism is usually associated with depression, which if severe may be accompanied by psychotic symptoms. A hyperthyroid person is typically depressed, anxious, and irritable.
Both adrenocortical insufficiency (Addison disease) and hypercortisolism (Cushing syndrome) may result in mental status changes. Both disorders also produce physical signs and symptoms that can suggest the diagnosis. In addition, most patients with Cushing syndrome will have a history of long-term steroid therapy for a medical illness.
Hypoparathyroidism or hyperparathyroidism can on occasion be associated with vague mental status changes. These are related to abnormalities in serum calcium concentrations.
Infectious illnesses
Many infectious illnesses, such as influenza, Lyme disease, hepatitis C, and any of the encephalitides (particularly those caused by the herpesviruses), can cause mental status changes such as depression, anxiety, irritability, or psychosis. Elderly people with pneumonias or urinary tract infections may become confused or frankly psychotic.
The infectious illnesses of particular interest are the following:
-
Neurosyphilis
-
HIV infection
-
Cerebral abscess
-
Chronic Lyme disease
-
Creutzfeldt-Jakob disease (CJD)
Neurosyphilis
Neurosyphilis can be divided into the following 3 categories:
-
Meningovascular syphilis
-
Tabes dorsalis
-
General paresis
Patients with general paresis may present with behavioral changes, psychosis or dementia. The diagnosis can be suggested by a history of exposure, personality changes, and pupillary changes (Argyll Robertson pupil).
The Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are nontreponemal tests that use antigens to detect antibodies to Treponema pallidum. Because antibodies decline during the disease, these tests have a high false-negative rate. If neurosyphilis is strongly suspected, more specific treponemal tests, such as the fluorescent-treponemal antibody absorption test (FTA-ABS), can be useful.
HIV infection
HIV penetrates the blood-brain barrier early in the course of the infection and thus can cause a number of mental status changes, particularly dementia or other neuropsychological impairment. In addition, patients infected with HIV are at risk for opportunistic infections, such as neurosyphilis, toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, cytomegalovirus encephalopathy, and tuberculous meningitis, all of which can lead to mental status changes.
Persons infected with HIV are also at risk for primary central nervous system lymphoma. Many medications used to treat HIV may cause mental status changes. Finally, persons infected with HIV are at risk for nutritional deficiencies that also contribute to mental status changes.
Cerebral abscess
Patients with cerebral abscesses rarely have psychotic symptoms, but brain imaging should be considered to rule out this treatable possibility. Immunosuppressed persons and people living in or traveling in underdeveloped countries are particularly at risk.
Lyme disease
A few patients with chronic Lyme disease may have problems of fatigue and difficulty thinking. There is much controversy about this diagnosis.
Creutzfeldt-Jakob disease
Prions cause the rare CJD, one of the transmissible spongiform encephalopathies. The disease usually occurs in people older than 50 years and is marked by rapid deterioration, dementia, abnormal electroencephalographic complexes, and myoclonic jerks.
A variant of this illness, vCJD, is the human form of bovine spongiform encephalopathy (so-called mad cow disease). Fewer than 200 cases of vCJD have occurred worldwide, and as of 2003, only 2 cases had occurred in the United States. Unlike CJD, vCJD seems to affect people aged 20-40 years. It begins with behavioral changes. In several cases, the patient was diagnosed with schizophrenia before the diagnosis of vCJD was made.
Miscellaneous disorders
Multiple sclerosis is notoriously difficult to diagnose in its early stages. The physical symptoms may be overlooked, and psychological symptoms may occasionally be an early feature.
Huntington disease is a neurodegenerative disorder marked by neuronal loss throughout the brain, especially in the striatum. This is an autosomal dominant disorder, the gene for which has been located on chromosome 4. A family history is essential to making the diagnosis.
The occurrence of choreoathetoid movements well before exposure to antipsychotic agents is suggestive of Huntington disease. About three-fourths of patients with Huntington disease initially present with psychiatric symptoms.
Alzheimer disease, the most common cause of dementia, is marked by loss of memory and personality, other cognitive, and mood changes in elderly persons. As the illness progresses the person may develop psychotic symptoms.
Dementia with Lewy bodies is the second most common type of dementia. Patients present with fluctuating mental status and prominent psychiatric symptoms, including depression and visual hallucinations. These patients are reported to do poorly when treated with antipsychotic drugs.
Lipid storage disorders include metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, and ceroid lipofuscinosis. These illnesses usually occur in childhood but may occasionally come to medical attention during adolescence. Patients may present with psychiatric symptoms such as cognitive deterioration and changes in personality. Patients may be diagnosed with schizophrenia until the neurologic symptoms of these illnesses become more prominent. [76]
Encephalitis related to paraneoplastic or autoimmune disorders can be confused with schizophrenia.
Of the several paraneoplastic neurologic syndromes, one of them, limbic encephalitis, an inflammation of the limbic system, is particularly likely to be misdiagnosed as schizophrenia. People with this disorder can experience emotional or personality changes, memory problems, hallucinations, odd motor movements, or sleep disturbances. Acuteness of onset, seizures, and EEG and MRI changes differentiate this syndrome from schizophrenia. The syndrome often develops before any evidence of malignancy and is caused by antibodies to tumor cells that cross-react with antigens within the brain.
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis usually begins with a headache and or fever, and is followed by agitation, odd behavior, and impaired memory. Symptoms that differ from those seen in schizophrenia include seizures, decreased level of consciousness, dyskinesias, and autonomic instability. A variety of other neurological symptoms may develop. EEG, MRI, and CSF may be abnormal.
About one half of women with anti-NMDAR encephalitis have an ovarian teratoma. The illness may remit after removal of the tumor. Other cases of anti-NMDAR encephalitis may be associated with a viral infection, particularly the herpes simplex virus. The syndrome is caused by antibodies reacting to a subunit of the NMDAR in the brain.
Patients with a seizure or ictal disorder, especially temporal lobe epilepsy, may occasionally display odd behavior before, during, or after a seizure. Aura and ictal symptoms can include hallucinations, disturbances of memory, or affective and cognitive changes. Ictal and postictal phenomena can include complex motor abnormalities.
Patients with systemic lupus erythematosus, typically young women, may present with psychiatric symptoms, such as psychosis or cognitive deficit, in association with unexplained fever or joint pain. The diagnosis can be suggested by the physical findings of malar flush and the laboratory findings of anemia, renal dysfunction, elevated erythrocyte sedimentation rate (ESR), and, most specifically, elevated antinuclear antibody (ANA) levels.
Presenting features of systemic vasculitides (eg, polyarteritis nodosa, Churg-Strauss syndrome, Wegener granulomatosis, and Behçet disease) may include personality changes. Other symptoms, such as weight loss and fever, usually occur. Magnetic resonance imaging (MRI) shows characteristic lesions of vasculitis.
Heavy metal toxicity may cause changes in personality, thinking, or mood. Occupational exposure is the usual source of heavy metal toxicity, but cases have also resulted from ingestion of herbal medications contaminated with heavy metals.
Many medications have been associated with mental status changes, especially the following:
-
Corticosteroids (psychosis, depression, or mania)
-
Levodopa (hallucinations or insomnia)
-
Antidepressants (mania)
-
Interferon alfa (depression)
-
Beta blockers, including those in eye drops (depression)
Substance abuse (eg, abuse of alcohol, cocaine, opiates, psychostimulants, or hallucinogens) not uncommonly leads to disturbed perceptions, thought, mood, and behavior. The anabolic steroids used by body builders and athletes can lead to psychotic symptoms. [77] Anticholinergic medications can lead to delirium, especially if abused.
Vitamin deficiency
A deficiency of vitamin B-1 (thiamine) can occur in people who rely on alcohol for calories or patients with advanced malignancies or malabsorption syndromes. Acute and severe thiamine depletion can lead to Wernicke encephalopathy, marked by oculomotor disturbances, ataxia, and confabulation. If this condition is left untreated, Korsakoff psychosis may develop. Wernicke encephalopathy is a common and underdiagnosed cause of chronic cognitive impairment in people with alcoholism. [78]
Deficiency of vitamin B-12, folate, or both may produce depression or dementia. Very rarely, these deficiencies may result in delusional thinking.
Differential Diagnoses
-
Brief Psychotic Disorder
-
Mental Disorders Secondary to General Medical Conditions
-
Schizophreniform Disorder
-
Cortical activation patterns during verbal working memory maintenance. Healthy controls (A), patients with schizophrenia (B), and significantly different activation between groups (subtraction of SZ-CO) (C) are shown. The time series plots in the middle column show activation associated with true memory maintenance (red lines) relative to the baseline activities (blue line). Bright parts in the middle of each plot represent 1-volume (1.5 s) after onset, and offset of the maintenance phase (4.5 secs). All p-values are corrected with false discovery rate of q< 0.005. Image courtesy of Kim J, Matthews NL, and Park S. An event-related fMRI study of phonological verbal working memory in schizophrenia. PLoS One. 2010; 5(8): e12068.
-
Cortical activation patterns during false memory trials. (A) False memory, baseline in controls (CO). (B) False memory, baseline in schizophrenia (SZ). (C) SZ – CO. All p-values are corrected with a false discovery rate of q< 0.005. The time course plots show false memory-related activities (yellow) and true memory-related activities (red) relative to the baseline (blue). Image courtesy of Kim J, Matthews NL, and Park S. An event-related fMRI study of phonological verbal working memory in schizophrenia. PLoS One. 2010; 5(8): e12068.
-
Magnetic resonance imaging showing differences in brain ventricle size in twins. The twin on the right has schizophrenia, whereas the twin on the left does not. Image courtesy of Dr. Daniel Weinberger, Clinical Brain Disorders Branch, National Institutes of Health.
