26.5.3 Organic psychoses 6482 Curtis McKnight and

26.5.3 Organic psychoses 6482 Curtis McKnight and Jason Caplan

SECTION 26  Psychiatric and drug-related disorders 6482 26.5.3  Organic psychoses Curtis McKnight and Jason Caplan ESSENTIALS A psychosis is a syndrome characterized by delusions and hallu- cinations. Organic psychoses refer to those psychoses attributed to identifiable brain diseases and are thereby distinguished from pri- mary psychoses such as schizophrenia. Almost any condition that affects the brain can cause an organic psychosis. Delirium and de- mentia are the most common, although there are many other causes including other neurodegenerative diseases, autoimmune disorders, multiple sclerosis, endocrinopathies, metabolic disorders, and infec- tions. Making the diagnosis of an organic psychosis requires a high index of suspicion and appropriate investigation. The treatment is usually that of the primary disease when that is possible, while the symptoms of psychosis can be managed using antipsychotic drugs. Introduction The term ‘organic psychosis’ describes syndromes of psychotic symp- toms directly attributed to an identifiable pathophysiological cause. Differentiation of these disorders and the ‘primary’ or ‘functional’ psychoses (which includes schizophrenia and psychotic symptoms due to mood disorders) presumes that these latter diagnoses are not ‘organic’ in nature. However, as we gain a greater understanding of the anatomic and physiologic substrate of so-​called mental illness, it is likely that the term ‘organic psychosis’ will become less meaningful and have to be replaced by another such as ‘secondary psychosis’. Neurodegenerative diseases Dementia In DSM-​5, the dementias are subsumed under the designation of major neurocognitive disorder (MND), though the term dementia will likely remain in widespread use and have a role in the names of various existing subtypes. These disorders include a multitude of pathologies (Box 26.5.3.1), with Alzheimer’s disease being the most common. Anyone presenting with new onset psychosis late in life must be considered as having organic psychosis for a length of time until or unless a classic syndromal MND reveals itself. In some cases, high premorbid cognitive functioning and a large cognitive re- serve along with asymmetric brain pathology make dementia dif- ficult to identify in a patient presenting with psychosis. Psychosis due to a dementia presenting after age 65 is most likely to be due to Alzheimer’s disease simply because this is the most common form of dementia in this age group. For patients younger than 65 years of age, frontotemporal dementia (FTD) is as common as Alzheimer’s disease. FTD is a collection of pathologies that are clinically divis- ible into three types: behavioural variant frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia, and non-​ fluent variant primary progressive aphasia, although the autopsy histopathologies for these three subtypes do not correlate well with their phenotypes. The most common of these is bvFTD. By some es- timates, 50% of patients with bvFTD are initially misdiagnosed with a primary psychiatric illness. Parkinson’s disease Parkinson’s disease is characterized by a resting tremor, rigidity and bradykinesia related to formation of Lewy bodies with resulting destruction of dopaminergic neurons in the substantia nigra. Current treatment is directed at improving dopamine transmission and function in the remaining neurons. Dementia is common in Parkinson’s disease although typically presents later in the course. Early psychotic symptoms in Parkinson’s disease (absent dopamine medications and prior to MND) are unusual and may cast doubt on the veracity of the diagnosis. Often psychotic symptoms in Parkinson’s disease are comorbid with depression or visual acuity changes, so psychotic depression or Charles Bonnet syndrome can be included in the differential. Finally, the current mainstay of treat- ment for Parkinson’s disease includes dopamine enhancers, which have a well-​known proclivity for causing psychosis. As such, evalu- ation and (if possible) reduction of these medications is a recom- mended first step in treatment. If dopamine medication reduction is not possible, pimavanserin, a newly developed specific agent for the treatment of psychosis in Parkinson’s disease that functions as a selective serotonin inverse agonist, may have benefit. If these meas- ures prove unsuccessful, cautious attempts to treat psychosis with low doses of neuroleptics that have low affinity for the D2 receptor (i.e. clozapine) may be undertaken. Epilepsy Psychosis can be an ictal, post-​ictal, and interictal phenomenon in patients with seizure disorders. As an ictal manifestation, psychosis has been most reported in complex partial seizures (since a general- ized seizure would mask any ictal psychosis), usually of the temporal lobe (with only approximately 30% of these patients presenting with seizure focus outside of this region). As one might expect of an ictal presentation, psychotic symptoms in these cases are limited to the duration of the seizure itself. Postictal psychosis occurs in 10% of patients undergoing video-​ EEG monitoring. A window ranging from hours to days between the cessation of seizure activity and the onset of psychotic symptoms is described. The mean duration of post-​ictal psychoses is about 70 hours, and the extinction of these symptoms is accelerated by use of relatively low dose neuroleptic medication. Box 26.5.3.1  Subtypes of major neurocognitive disorder Alzheimer’s disease Vascular disease Frontotemporal lobar degeneration Lewy body disease Traumatic brain injury Substance/​medication use HIV infection Prion disease Parkinson disease Huntington disease Due to another medical condition (e.g. multiple sclerosis) Combined or multiple aetiologies

26.5.3  Organic psychoses 6483 One analysis of the available evidence estimates a 6–​12 times greater likelihood of psychosis in people with epilepsy than in the general population. Paranoia and hallucinations are especially prominent findings in chronic interictal psychosis. The average age of onset of chronic psychotic symptoms in patients with epilepsy (30 years) is later than in those without epilepsy. Autoimmune disorders The common factor in autoimmune disorders is a misdirected im- mune response that results in damage to endogenous tissue. When the targeted tissue lies with the central nervous system, clinical pres- entation is likely to include neuropsychiatric symptoms, and when that tissue lies within the limbic circuit, clinical presentation is likely to include symptoms of psychosis (Table 26.5.3.1). Autoimmune encephalitis Autoimmune encephalitis is a group of disorders that present with neurological and psychiatric presentations prompted by antibodies directed against a broad group of neural proteins. Initially referred to as paraneoplastic limbic encephalitis (since it was believed that the presence of cancer proteins prompted production of the culpable antibodies which subsequently cross-​reacted with nervous system targets), the name was shortened to limbic encephalitis when a series of cases were described in the absence of any cancer. The name was later updated to autoimmune encephalitis in light of several cases in which the neural injury occurred outside of the limbic circuit. Nonetheless, a previously undetected cancer remains a concern in newly diagnosed cases of autoimmune encephalitis. Autoantibodies implicated in autoimmune encephalitis can be broadly divided into two types: those directed against cell mem- brane targets and those directed against intracellular targets (Table 26.5.3.2). Of these two groups, antibodies directed against cell mem- brane targets have been most frequently associated with psychosis while the intracellular group more typically present with cognitive decline, lethargy, and disorientation. While the paraneoplastic association is no longer a diagnostic ne- cessity, cancer remains the most frequent underlying cause. Thus, the profile of individuals most at risk for these disorders mirrors those at risk for cancer. Some antibodies have been associated with specific malignancies (Table 26.5.3.3). Of particular diagnostic significance are cancers that typically present in younger individuals, since these presentations may be more easily mistaken for ‘first break’ schizo- phrenia because they manifest in the second or third decade of life. The clinical presentation of a young man with lethargy and confusion in the presence of anti-​Ma2 antibodies raises the possibility of testicular cancer. Similarly, a young woman presenting with symptoms of psych- osis and anxiety in the presence of anti-​NMDA-​receptor antibodies suggests ovarian teratoma. Definitive diagnosis requires specific testing of serum and cerebrospinal fluid (CSF) for these autoantibodies since neuroimaging and routine CSF studies can be non​specific. The EEG may be abnormal with a characteristic pattern described as ‘extreme delta brush’ with baseline rhythmic δ-activity at 1–​3 Hz with rapid β-activity of 20–​30 Hz superimposed on the crest of each δ-wave. The finding is relatively specific to the anti-NMDA-receptor antibody sub- type of autoimmune receptor encephalitis. Treatment of autoimmune encephalitis requires the identification and removal of any inciting lesion (i.e. a cancer) and modulation of the immune system. If an autoimmune encephalitis is suspected, Table 26.5.3.1  Some of the major neural structures of the limbic circuit Cortex Orbitofrontal cortex Piriform cortex Limbic lobe Hippocampus Entorhinal cortex Fornix Subcortex Amygdalae Nucleus accumbens Septal nuclei Diencephalon Hypothalamus Mammillary bodies Anterior thalamic nuclei Table 26.5.3.2  Autoantibodies implicated in autoimmune encephalitis Intracellular Anti-​amphiphysin Anti-​Hu Anti-​Ma2 Anti-​CV2/​Anti-​CRMP5 Anti-​Ri Anti-​Yo Anti-​Tr Cell membrane Anti-​NMDA-​receptor Anti-​VGKC Anti-​LGI1 Anti-​CASPR2 Anti-​AMPA Anti-​GABAB Table 26.5.3.3  Cancer/​antibody associations in autoimmune encephalitis Anti-​amphiphysin Small cell lung cancer (SCLC) Breast cancer Anti-​Hu SCLC Non-​small cell lung cancer Colon adenocarcinoma Prostate cancer Rhabdosarcoma Neuroblastoma Thymoma Anti-​Ma2 Testicular cancer Non-​small cell lung cancer Breast cancer Anti-​CV2/​CRMP5 Thymoma SCLC Breast cancer Anti-​Ri SCLC Ovarian teratoma Breast cancer Endobronchial carcinoid Anti-​NMDA-​receptor Ovarian teratoma Anti-​VGKC Prostate cancer Thymoma Adapted from: Foster AR, Caplan JP. (2009). Paraneoplastic limbic encephalitis. Psychosomatics, 50(2):108−113. Copyright © 2011, with permission from Elsevier.

SECTION 26  Psychiatric and drug-related disorders 6484 serum and CSF should be sent for antibody studies while the patient is screened for any underlying neoplasm. If a cancer is found, it should be treated aggressively as in some cases, excision of an underlying cancer has proved curative. A variety of immunomodulation tech- niques are recommended including administration of intravenous steroids, plasmapheresis, and use of intravenous immunoglobulin. If these approaches are unsuccessful, some have recommended pro- ceeding to pulsed doses of cyclophosphamide or rituximab. There is no evidence favouring one psychotropic agent over another in managing specific manifestations of psychosis. Steroid-​responsive encephalopathy associated with thyroiditis (SREAT) SREAT has replaced the previously favoured eponymous designa- tion Hashimoto’s encephalopathy. First described by Lord Brain and colleagues in 1966, the syndrome presents with a variety of symp- toms, which include frank psychosis in 30% of patients. There are thyroglobulin and/​or thyroperoxidase antibodies on testing. While the first reported case was diagnosed with Hashimoto’s thyroiditis, subsequent studies have not found an association between SREAT and thyroid function (Box 26.5.3.2). The current leading hypothesis is that the elevated thyroid antibodies serve as a marker of increased autoimmunity and perhaps an as-​yet unidentified specific auto- immune process. As the name suggests, the treatment for SREAT is administration of corticosteroids, with plasmapheresis and intra- venous immunoglobulin considered second-​line interventions. Again, there is no good evidence favouring one psychotropic agent over another in managing specific manifestations of psychosis. Multiple sclerosis (MS) Multiple sclerosis is a demyelinating disease that can present with a variety of neurologic, somatic, and psychiatric symptoms depending on the distribution of the demyelinating lesions. While disturbances of mood are described, studies of the prevalence of psychosis in MS vary from as few as 0% of patients to as many as 17%. Studies, comparing MS patients with psychotic symptoms to those without, have found increased lesion volume and greater concentration of lesions in the periventricular white matter and temporal regions. Immunomodulation to treat the MS is also ef- fective for the psychosis, though adjunctive use of a neuroleptic may also be beneficial. Systemic lupus erythematosus (SLE) The autoimmune manifestations of SLE affect several organ systems including the kidneys, joints, skin, and central nervous system (CNS) with estimates of 14–​75% of patients experiencing neurological and psychiatric symptoms including psychosis; the majority have these symptoms either before diagnosis or within the following year. More than 100 specific autoantibodies have been reported in SLE and of those, the anti-​RP antibody is the most extensively studied. While anti-​RP testing does not discriminate between patients with or without psychotic symptoms, psychotic symptoms have been asso- ciated with higher titres. Endocrinopathies Thyroid Thyroid hormones have well-​known roles in the regulation of mood, cognition, and behaviour. Thyroid hormone receptors (T3 triiodothyronine type) are highly concentrated in the limbic system. Thyroid hormones also modulate translation and action of sero- tonin, dopamine, and other neurotransmitters. Nonetheless, isolated psychosis is a rare presentation thyroid disease. In most cases there will be clinical evidence of thyroid deficiency or excess (fatigue, cold intolerance, weight gain in the former; heat intolerance, excessive sweating, weight loss, palpitations, and gastrointestinal upset in the latter). Useful investigations include thyroid-​stimulating hormone, free thyroxine level, free triiodothyronine, and levels of thyroid car- rier proteins. Treatment involves correction of the thyroid dysfunc- tion while neuroleptics are used to manage the psychotic symptoms. Steroids Psychosis is a well-​known effect of exogenous corticosteroid admin- istration. Disruption in the hypothalamic-​pituitary-​adrenal (HPA) axis leading to elevated endogenous glucocorticoids (especially cor- tisol) is equally likely to result in psychosis. Anabolic-​androgenic steroids have a variety of adverse psychiatric effects, although psych- osis as a single isolated presenting symptom is rare. Noradrenergic A pheochromocytoma is a catecholamine (mostly epinephrine) se- creting tumour most commonly associated with anxiety. In some cases, the agitation of severe anxiety can resemble psychosis. If psychosis presents in this fashion, it is usually accompanied by par- oxysmal tachycardia and hypertension. Parathyroid Though not specifically an endocrine disorder, Fahr syndrome (or idiopathic basal ganglia calcification) is linked with derangements of parathyroid hormone function (several other precipitating condi- tions are also recognized). Calcification of the basal ganglia is readily identifiable on neuroimaging. A host of other neurological and psy- chiatric symptoms including movement disorders and cognitive de- cline typically accompanies the symptoms of psychosis. Metabolic disorders The metabolic disorders are a diverse group of rare conditions that may present with psychosis. Initially termed inborn errors of metab- olism these are now more commonly referred to as congenital meta- bolic diseases, inherited metabolic diseases, or hereditary metabolic disorders. Most of these diseases are the result of single gene mu- tations that lead to a single enzymatic deficiency or dysfunction. There are hundreds of hereditary metabolic disorders and many re- main poorly characterized. They can be grouped by the metabolic process that is disrupted (Table 26.5.3.4) although many evade this Box 26.5.3.2  Thyroid function in cases of SREAT Hypothyroid c.20% Euthyroid or subclinical hypothyroid c.70% Hyperthyroid c.10%

26.5.3  Organic psychoses 6485 taxonomy. The chief clinical challenge is accurate and timely identi- fication of these rare conditions in order to direct appropriate treat- ment. Most cases of hereditary metabolic disorder are diagnosed in childhood or early adulthood. In a patient presenting with isolated first episode psychosis without an abnormal physical examination or investigation it is unlikely that the cause is an hereditary metabolic disorder. Atypical presentations with abnormal physical and laboratory findings should, however, in- crease suspicion of an hereditary metabolic disorder. A judicious ap- proach in such cases is to investigate in proportion to the atypicality of the psychosis (i.e. unusual variations in age and variety, chron- icity, or severity of symptoms). Many hereditary metabolic disorders can be treated, which usu- ally requires closely coordinated referral and multidisciplinary care. Often, when an individual with psychosis is subsequently found to have a hereditary metabolic disorder, treatment of that condition will result in improvement but not complete remission of psych- osis. Of the hereditary metabolic disorders, urea cycle disorders, remethylation disorders, and the porphyrias are generally the most acute, identifiable, and treatable. The urea cycle eliminates nitrogen by converting ammonia into urea. Several enzymatic deficiencies can result in a urea cycle dis- order. These may present at any age. The most common symptom cluster featuring psychosis features hallucinations accompanied by headaches and gastrointestinal symptoms. The treatment would in- clude timely specialist referral and dietary interventions such as pro- tein restriction. Valproic acid is contraindicated for these patients. Remethylation disorders result from defective remethylation of homocysteine to methionine resulting in increased serum homo- cysteine levels and ineffective utilization of folate and vitamin B12. This is usually due to genetic polymorphisms resulting in dysfunc- tion of the enzyme methylenetetrahydrofolate reductase (MTHFR) or deficiencies of cobalamin metabolism. Laboratory testing is avail- able for the 40 or so polymorphisms identified in homocystinuria. Remethylation disorders may present at any age and psychosis (dis- organized behaviour, hallucinations) is generally accompanied by elevated serum homocysteine. Other associated signs are throm- bosis and neurologic deficits. Acute intermittent porphyria is an autosomal dominant disease with variable penetrance linked to deficiency of the porphobilinogen deaminase enzyme. If psychosis presents in the context of this dis- ease it is accompanied by recurrent unexplained pain, typically of the abdomen. Avoidance of the inciting trigger (which may include a broad variety of drugs) combined with carbohydrate infusion and hematin or heme arginate (United States or the United Kingdom, respectively) is the recommended course of treatment. Alcohol and tobacco use are to be strictly avoided. Wilson disease, Niemann-​Pick type C, and cerebrotendinous xanthomatosis are more chronic in progression with psychosis typic- ally presenting late. Wilson disease is an autosomal recessive disorder caused by a mutation in the Wilson disease protein (ATP7B) gene that causes pathologic copper accumulation in several organs, most notably the liver and brain. Most diagnoses are made in preadolescent children or young adults, although it may occur as late as the sev- enth decade. Psychosis is found in only a small percentage of cases; aggression or personality changes are more common. Unusually early onset psychosis should precipitate testing for Wilson disease. Since screening is relatively non​invasive and inexpensive, the clinical threshold for proceeding with testing should be low. Niemann-​Pick disease type C is a lysosomal storage disease re- sulting from mutations in either the NPC1 or NPC2 gene. Psychotic symptoms such as delusions and visual hallucinations may present in isolation for many years prior to onset of neurologic deficits. Of the hereditary metabolic disorders, this is most likely to be mis- diagnosed as a psychiatric disorder because of its rarity (1:150 000 people) and lack of obvious motor deficits until late stages. When present the commonest motor signs are ataxia, abnormal move- ments, and vertical supranuclear gaze palsy. These findings can be obscured by or misattributed to neuroleptic treatment. Testing is available but currently expensive and requires laboratory culture of the patient’s fibroblasts. Cerebrotendinous xanthomatosis is due to mutations of the gene GYP27A1. The enzyme deficiency from genetic mutation results in build-​up of cholesterol in various tissues including the brain. Individuals presenting with psychosis, ataxia, and juvenile cataracts warrant further testing for this condition. Infection Theoretically, any infection of the central nervous system may precipitate symptoms of psychosis depending on the structures damaged. Moreover, any systemic infection can cause psychotic symptoms in the setting of a delirium. Here we focus on infec- tious agents that have been directly associated with psychosis (Box 26.5.3.3). Of these, neurosyphilis remains an important preventable cause of psychosis. The rate of syphilis infection fell after the dis- covery of penicillin, but since the early 1990s the rates of spirochete Table 26.5.3.4  Hereditary metabolic disorders Carbohydrate metabolism Glycogen storage disease Amino acid metabolism Phenylketonuria, maple syrup urine disease, glutaric acidemia type 1 Urea cycle Carbamoyl phosphate synthetase I deficiency Organic acid metabolism Alcaptonuria, 2-​hydroxyglutaric acidurias Fatty acid oxidation and mitochondrial metabolism Medium-​chain acyl-​coenzyme A dehydrogenase deficiency Porphyrin metabolism Acute intermittent porphyria Purine or pyrimidine metabolism Lesch–​Nyhan syndrome Steroid metabolism Lipoid congenital adrenal hyperplasia, congenital adrenal hyperplasia Mitochondrial function Oculocraniosomatic neuromuscular disorder with ragged red fibres Peroxisomal function Cerebrohepatorenal syndrome Lysosomal storage Gaucher’s disease, Niemann-​Pick disease, Tay-​Sachs disease Dietary elements Wilson’s disease Methionine synthase, remethylation Elevated levels of homocysteine, folate or B12 deficiency Leukodystrophies Cerebrotendineous xanthomatosis Creatine deficiency Guanidinoacetate methyltransferase (GAMT) deficiency