Medical Conditions with N e u ro p s y c h i a t r i c Manifestations Margaret L. Isaac,
MD
a,
*, Eric B. Larson,
MD, MPH
b
KEYWORDS Cognitive impairment Mood disorders Neuropsychiatric symptoms Dementia Autoimmune/inflammatory disease Central nervous system (CNS) Peripheral nervous system KEY POINTS Many medical conditions can have neuropsychiatric manifestations and a high index of suspicion is necessary, particularly in patients with other unexplained systemic symptoms and signs. These neuropsychiatric symptoms are nonspecific so additional information (eg, detailed history and physical examination, laboratory and imaging studies) may be needed to determine whether medical disease is the true cause. The most commonly implicated pathophysiologic categories that produce neuropsychiatric symptoms and signs include infectious, autoimmune, endocrinologic, metabolic, and neoplastic diseases. Involvement of subspecialty colleagues can be important when these conditions are suspected. Treatment of these disorders usually includes symptom-directed therapies, and also therapies directed at treating the underlying systemic condition. These therapies are widely variable depending on the specific disease process.
INTRODUCTION
Many medical conditions have neurologic and psychiatric symptoms, and early identification of the underlying cause can be critical in directing further management (Table 1). Medical conditions known to cause neuropsychiatric symptoms can also be varied in presentation, making diagnosis challenging. The number of medical conditions that potentially cause neurologic and psychiatric symptoms is extensive. This
Financial Disclosures: None. a Medicine, Harborview Medical Center, University of Washington School of Medicine, 325 9th Avenue, Box 359892, Seattle, WA 98104, USA; b Medicine, Group Health Research Institute, University of Washington School of Medicine, Seattle, WA, USA * Corresponding author. E-mail address: [email protected] Med Clin N Am 98 (2014) 1193–1208 http://dx.doi.org/10.1016/j.mcna.2014.06.012 medical.theclinics.com 0025-7125/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
1194
Isaac & Larson
Table 1 Medical conditions with neuropsychiatric manifestations System
Disease
Infectious
HIV/AIDS Opportunistic infections/malignancies Syphilis Lyme disease Prion disease
Rheumatologic/autoimmune
Systemic lupus erythematosus Sarcoidosis Vasculitides Multiple sclerosis
Endocrinologic
Hypothyroidism/hyperthyroidism Hypoparathyroidism/hyperparathyroidism Cushing syndrome Adrenal insufficiency
Metabolic
Vitamin deficiencies Thiamine (vitamin B1) Vitamin B12 Micronutrient abnormalities Hypocalcemia/hypercalcemia Acute hepatic porphyrias Wilson disease Amyloidosis Hepatic encephalopathy Uremia
Neoplastic
Paraneoplastic syndromes CNS tumors (primary and metastatic) Carcinomatous meningitis
Hematologic
Sickle cell disease (cerebrovascular disease)
Heritable/genetic
Huntington disease Lysosomal storage diseases
Abbreviations: AIDS, acquired immunodeficiency syndrome; CNS, central nervous system; HIV, human immunodeficiency virus.
article highlights several broad categories of medical diseases (infectious, autoimmune, endocrinologic, metabolic, and neoplastic), with a focus on pragmatic considerations in evaluation, diagnosis, and management in the primary care setting. The focus of this article is on common medical conditions with neuropsychiatric manifestations, as well as specific diseases that have a characteristic neuropsychiatric presentation requiring early detection and evaluation. INFECTIOUS Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) disease can cause neuropsychiatric manifestations as a result of primary HIV disease, opportunistic infections and malignancies, medication side effects, and the psychosocial consequences and stigma associated with HIV infection. Common neuropsychiatric disorders that are associated or comorbid with HIV disease include minor cognitive impairment and dementia1; delirium; peripheral nervous system disorders such as polyneuropathy; and psychiatric syndromes such as bipolar affective disorder, major depression, schizophrenia, and substance abuse.2 Cognitive impairment in the setting of HIV infection can be caused by
Neuropsychiatric Manifestations
encephalopathy attributed to the virus; central nervous system (CNS) lymphoma; and primary CNS infections such as progressive multifocal leukoencephalopathy (PML), cryptococcal meningitis, toxoplasmosis, and cytomegalovirus (CMV) encephalitis. HIV-associated neurocognitive disorders (HAND), can be classified as asymptomatic neurocognitive impairment, mild neurocognitive disorder, or HIV-associated dementia, with HIV-associated dementia being the most severe, characterized by profound abnormalities in neuropsychological testing and significant impairment in a patient’s ability to perform activities of daily living.3 Some degree of neurocognitive impairment has been found to be present in between a quarter and half of all patients infected with HIV in one large study,4 although other studies have found the rate of cognitive impairment in patients with early stage HIV and high viral loads to be similar to that in HIV-negative individuals.5 HAND is characterized by the triad of memory impairment, mood (depressive) symptoms, and movement disorders such as ataxia, tremor, weakness, and bradykinesia.6 Screening for HAND in patients infected with HIV includes neuropsychological testing, and is a diagnosis of exclusion made after alternate causes have been ruled out. Treatment includes antiretroviral (ARV) medications, medications intended to manage symptoms, such as stimulants and antipsychotics,7 and supportive care (including psychiatric care and attention to functional needs with rehabilitation services). PML, a demyelinating disease that affects the CNS, is caused by the opportunistic reactivation of polyomavirus (JC virus) infection. PML occurs in immunosuppressed patients, and, before the advent of ARV therapy, affected up to 5% of patients with advanced HIV disease.8 The disease is far less prevalent since the broader use of ARVs. PML has historically been thought of as a disease of the white matter (specifically affecting oligodendrocytes and astrocytes) but it can also affect structures such as the cortical gray matter, thalamus, and basal ganglia.9 It rarely affects the spinal cord.10 Classic symptoms include weakness, sensory changes, cognitive dysfunction, ataxia, visual symptoms such as hemianopsia and diplopia, aphasia, and seizures.9 Definitive diagnosis can be made by brain biopsy, but can also be made by using polymerase chain reaction to show the presence of JC virus in the cerebrospinal fluid (CSF) and by the characteristic demyelinating lesions seen on neuroimaging. The prognosis for patients with PML is poor, with a median survival in patients affected by HIV of 1.8 years in the post-ARV era. Prognosis is improved in patients with higher CD4 counts.11 Treatment is focused on optimizing ARV therapies and although several specific treatment agents have been studied, there are no largescale, robust data to support the use of these agents, and there is no treatment currently available that is designed to treat JC virus specifically.12,13 Cryptococcal meningitis is a protozoan infection that affects immunocompromised patients, including patients with advanced HIV/acquired immunodeficiency syndrome. Symptoms typically present insidiously and subacutely, with headaches, mental status changes, lethargy, and memory loss developing over a period of weeks. Diagnosis is made using lumbar puncture, which highlights the importance of a high index of suspicion in susceptible patients given that the diagnosis cannot be made from serology alone. Patients with cryptococcal meningitis classically have a markedly high opening pressure. CSF examination can be significant for low glucose and high protein levels, and cell counts are typically low when the infection is HIV associated. Cryptococcal meningitis is treated with antifungals including amphotericin B, flucytosine, and fluconazole, and is fatal if untreated.13 Toxoplasmosis gondii is a protozoan disease that is usually a manifestation of reactivation of latent cysts in immunosuppressed patients (typically patients with HIV with CD4 counts
MD
a,
*, Eric B. Larson,
MD, MPH
b
KEYWORDS Cognitive impairment Mood disorders Neuropsychiatric symptoms Dementia Autoimmune/inflammatory disease Central nervous system (CNS) Peripheral nervous system KEY POINTS Many medical conditions can have neuropsychiatric manifestations and a high index of suspicion is necessary, particularly in patients with other unexplained systemic symptoms and signs. These neuropsychiatric symptoms are nonspecific so additional information (eg, detailed history and physical examination, laboratory and imaging studies) may be needed to determine whether medical disease is the true cause. The most commonly implicated pathophysiologic categories that produce neuropsychiatric symptoms and signs include infectious, autoimmune, endocrinologic, metabolic, and neoplastic diseases. Involvement of subspecialty colleagues can be important when these conditions are suspected. Treatment of these disorders usually includes symptom-directed therapies, and also therapies directed at treating the underlying systemic condition. These therapies are widely variable depending on the specific disease process.
INTRODUCTION
Many medical conditions have neurologic and psychiatric symptoms, and early identification of the underlying cause can be critical in directing further management (Table 1). Medical conditions known to cause neuropsychiatric symptoms can also be varied in presentation, making diagnosis challenging. The number of medical conditions that potentially cause neurologic and psychiatric symptoms is extensive. This
Financial Disclosures: None. a Medicine, Harborview Medical Center, University of Washington School of Medicine, 325 9th Avenue, Box 359892, Seattle, WA 98104, USA; b Medicine, Group Health Research Institute, University of Washington School of Medicine, Seattle, WA, USA * Corresponding author. E-mail address: [email protected] Med Clin N Am 98 (2014) 1193–1208 http://dx.doi.org/10.1016/j.mcna.2014.06.012 medical.theclinics.com 0025-7125/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
1194
Isaac & Larson
Table 1 Medical conditions with neuropsychiatric manifestations System
Disease
Infectious
HIV/AIDS Opportunistic infections/malignancies Syphilis Lyme disease Prion disease
Rheumatologic/autoimmune
Systemic lupus erythematosus Sarcoidosis Vasculitides Multiple sclerosis
Endocrinologic
Hypothyroidism/hyperthyroidism Hypoparathyroidism/hyperparathyroidism Cushing syndrome Adrenal insufficiency
Metabolic
Vitamin deficiencies Thiamine (vitamin B1) Vitamin B12 Micronutrient abnormalities Hypocalcemia/hypercalcemia Acute hepatic porphyrias Wilson disease Amyloidosis Hepatic encephalopathy Uremia
Neoplastic
Paraneoplastic syndromes CNS tumors (primary and metastatic) Carcinomatous meningitis
Hematologic
Sickle cell disease (cerebrovascular disease)
Heritable/genetic
Huntington disease Lysosomal storage diseases
Abbreviations: AIDS, acquired immunodeficiency syndrome; CNS, central nervous system; HIV, human immunodeficiency virus.
article highlights several broad categories of medical diseases (infectious, autoimmune, endocrinologic, metabolic, and neoplastic), with a focus on pragmatic considerations in evaluation, diagnosis, and management in the primary care setting. The focus of this article is on common medical conditions with neuropsychiatric manifestations, as well as specific diseases that have a characteristic neuropsychiatric presentation requiring early detection and evaluation. INFECTIOUS Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) disease can cause neuropsychiatric manifestations as a result of primary HIV disease, opportunistic infections and malignancies, medication side effects, and the psychosocial consequences and stigma associated with HIV infection. Common neuropsychiatric disorders that are associated or comorbid with HIV disease include minor cognitive impairment and dementia1; delirium; peripheral nervous system disorders such as polyneuropathy; and psychiatric syndromes such as bipolar affective disorder, major depression, schizophrenia, and substance abuse.2 Cognitive impairment in the setting of HIV infection can be caused by
Neuropsychiatric Manifestations
encephalopathy attributed to the virus; central nervous system (CNS) lymphoma; and primary CNS infections such as progressive multifocal leukoencephalopathy (PML), cryptococcal meningitis, toxoplasmosis, and cytomegalovirus (CMV) encephalitis. HIV-associated neurocognitive disorders (HAND), can be classified as asymptomatic neurocognitive impairment, mild neurocognitive disorder, or HIV-associated dementia, with HIV-associated dementia being the most severe, characterized by profound abnormalities in neuropsychological testing and significant impairment in a patient’s ability to perform activities of daily living.3 Some degree of neurocognitive impairment has been found to be present in between a quarter and half of all patients infected with HIV in one large study,4 although other studies have found the rate of cognitive impairment in patients with early stage HIV and high viral loads to be similar to that in HIV-negative individuals.5 HAND is characterized by the triad of memory impairment, mood (depressive) symptoms, and movement disorders such as ataxia, tremor, weakness, and bradykinesia.6 Screening for HAND in patients infected with HIV includes neuropsychological testing, and is a diagnosis of exclusion made after alternate causes have been ruled out. Treatment includes antiretroviral (ARV) medications, medications intended to manage symptoms, such as stimulants and antipsychotics,7 and supportive care (including psychiatric care and attention to functional needs with rehabilitation services). PML, a demyelinating disease that affects the CNS, is caused by the opportunistic reactivation of polyomavirus (JC virus) infection. PML occurs in immunosuppressed patients, and, before the advent of ARV therapy, affected up to 5% of patients with advanced HIV disease.8 The disease is far less prevalent since the broader use of ARVs. PML has historically been thought of as a disease of the white matter (specifically affecting oligodendrocytes and astrocytes) but it can also affect structures such as the cortical gray matter, thalamus, and basal ganglia.9 It rarely affects the spinal cord.10 Classic symptoms include weakness, sensory changes, cognitive dysfunction, ataxia, visual symptoms such as hemianopsia and diplopia, aphasia, and seizures.9 Definitive diagnosis can be made by brain biopsy, but can also be made by using polymerase chain reaction to show the presence of JC virus in the cerebrospinal fluid (CSF) and by the characteristic demyelinating lesions seen on neuroimaging. The prognosis for patients with PML is poor, with a median survival in patients affected by HIV of 1.8 years in the post-ARV era. Prognosis is improved in patients with higher CD4 counts.11 Treatment is focused on optimizing ARV therapies and although several specific treatment agents have been studied, there are no largescale, robust data to support the use of these agents, and there is no treatment currently available that is designed to treat JC virus specifically.12,13 Cryptococcal meningitis is a protozoan infection that affects immunocompromised patients, including patients with advanced HIV/acquired immunodeficiency syndrome. Symptoms typically present insidiously and subacutely, with headaches, mental status changes, lethargy, and memory loss developing over a period of weeks. Diagnosis is made using lumbar puncture, which highlights the importance of a high index of suspicion in susceptible patients given that the diagnosis cannot be made from serology alone. Patients with cryptococcal meningitis classically have a markedly high opening pressure. CSF examination can be significant for low glucose and high protein levels, and cell counts are typically low when the infection is HIV associated. Cryptococcal meningitis is treated with antifungals including amphotericin B, flucytosine, and fluconazole, and is fatal if untreated.13 Toxoplasmosis gondii is a protozoan disease that is usually a manifestation of reactivation of latent cysts in immunosuppressed patients (typically patients with HIV with CD4 counts
