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 (FTD) describes a group of neurodegenerative disorders that are characterized by the clinical syndrome of progressive dysfunction in executive functioning, behaviors, and language.

 FTD is thought to be the third most common type of dementia after Alzheimer disease (AD) and dementia with Lewy bodies.FTD is also a common type of early-onset dementia (occurring among individuals 65 years or younger).

FTD was noted in 1892 by Arnold Pick, MD, when he described an individual who presented with aphasia, temporal lobar atrophy, and presenile dementia.

 In 1911 the association between Pick bodies and FTD was described by Alois Alzheimer, MD, PhD, who named the disorder “Pick’s disease.” The term Pick’s disease became synonymous with FTD, referring to both the clinical syndrome and the pathological diagnosis. Currently, “Pick’s disease” is used only to describe the pathological diagnosis. In 1982, M. Marsel Mesulam, MD, identified the language subtype of FTD: primary progressive aphasia (PPA).

Available evidence indicates that FTD is the second most common cause of dementia among individuals 65 years or younger.

 The prevalence of FTD among individuals with early-onset dementia is between 3% and 26%. The population prevalence of FTD varies between 1 to 26 per 100,000.

 These numbers probably underestimate the true prevalence, as the disorder is often missed or misdiagnosed.

FTD has 2 main subtypes, based on their predominating presentations: the behavioral variant of FTD (bvFTD), and the language variant, ie, PPA.

 Based on the localizations and underlying cerebral dysfunction, the language variant can be further subdivided into the nonfluent variant of PPA (nfvPPA) and the semantic variant of PPA (svPPA). Male predominance has been noted in the bvFTD and svPPA variants and female predominance in the nfvPPA variant. 

 details the diagnostic criteria of FTD’s 3 variants.

A third variant of PPA has been described as logopenic PPA (lvPPA),in which individuals exhibit specific impairment with confrontation naming or word-finding difficulties and impaired sentence repetition.

 Neuroimaging studies among these individuals demonstrate predominant left posterior perisylvian or parietal atrophy/hypoperfusion/hypometabolism. Definite histopathologic evidence or the presence of a known pathogenic mutation allow for a definite diagnosis of FTD. 

Evidence indicates that approximately 12.5% of individuals with bvFTD have concomitant motor neuron disease.

 In addition, 27.3% of individuals have features of minor motor system dysfunction, including occasional fasciculations and mild muscle wasting or weakness. As the disease evolves, the clinical presentation of the 3 variants overlap with each other and with syndromes of atypical parkinsonism, including progressive supranuclear palsy (PSP) and corticobasal degeneration syndrome (CBS).

Compared with AD, patients with FTD tend to have a shorter duration of survival from diagnosis and more rapid decline of cognition and function.

 The average survival time with FTD depends on the subtype; the average survival time is approximately 3 years for bvFTD and motor neuron disease and 12 years for with svPPA.

Current evidence indicates that FTD is a highly heritable disorder, with familial FTD accounting for approximately one-third to half of cases.

 Most cases of familial FTD present as the bvFTD variant. A family history of dementia is found in 25% to 50% of FTD cases, and about 10% have a clear autosomal-dominant inheritance.

 Mutations in the microtubule-associated protein tau (τ), progranulin, and chromosome 9 open reading frame 72 expansion are the most common causes of familial FTD. These mutations result in the variable clinical presentations of FTD.

The major variants of FTD are classified based on their respective protein-based inclusions and underlying molecular pathologies.

 The current neuropathological classification allows most cases of FTD to be placed into 1 of 3 broad molecular subgroups: frontotemporal lobar degeneration (FTLD)-τ subtype; the FTLD-TDP subtype associated with TDP-43; or FET protein accumulation.

 The FTLD-τ variant accounts for approximately 40% of all FTD cases. Approximately half the postmortem cases of FTD have abnormal deposition of transactive response DNA-binding protein 43 (TDP-43).

FTD may be misdiagnosed as other psychiatric disorders, including schizophrenia, bipolar disorder, depression, or obsessive-compulsive disorder.

 The bvFTD variant is most likely to be misdiagnosed as another psychiatric disorder; FTD may be misdiagnosed as AD or another type of dementia. 

 describes the differentiating clinical features of the dementias.

Given the high risk for misdiagnosis, suspected cases of FTD should be carefully evaluated. A thorough history from the individual and a reliable collateral source that tracks the progression of behavioral and cognitive symptoms are essential. A focused physical examination that identifies parkinsonian and/or upper motor neuron signs will assist in the diagnosis. Laboratory testing (including complete metabolic panel, complete blood count, thyroid function tests, liver function tests, vitamin B12 levels, and urine drug screen) should be done to rule out reversible causes of cognitive and behavioral impairments. Among atypical cases, toxicology for heavy metals, inflammatory biomarkers for autoimmune and paraneoplastic syndromes, and testing for infectious etiologies including syphilis and HIV should be considered.

Neuroimaging studies including magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), and single photon emission computed tomography (SPECT) scans can also assist in diagnosing FTD. 

describes the neuroimaging findings in FTD.

 Cerebrospinal fluid (CSF) assessment will help rule out AD when the patient has low β-amyloid concentrations and high τ protein concentration. Neuropsychological testing will help rule out other causes of cognitive and functional changes. 

 provides neuropsychological profiles of various types of dementias.

 Among individuals with a family history of dementia, movement disorders, and/or psychotic disorders, genetic counseling and a search for genes that cause FTD are both recommended.

Currently there are no US Food and Drug Administration (FDA) approved disease-modifying drugs for the treatment of FTD.

 found a total of 9 randomized, controlled, double-blinded clinical trials that evaluated various drugs for the treatment of FTD.

 These included 2 trials of the selective serotonin reuptake inhibitor paroxetine, 1 trial of trazodone, 2 trials of stimulants (methylphenidate and dextroamphetamine), 1 trial of the acetylcholinesterase inhibitor galantamine, 2 trials of the N-methyl-d-aspartate (NMDA) antagonist memantine, and 1 trial of the neuropeptide oxytocin. The investigators concluded that SSRIs, trazodone, and the amphetamines may be effective in reducing some behavioral symptoms. None of these medications, however, improved cognition among individuals with FTD. Available data also indicated that these medications were well tolerated.

The evidence for the use of antipsychotics for the treatment of behavioral symptoms in FTD comes mainly from case reports and uncontrolled studies.

 In addition, the use of antipsychotics can worsen the risk of extrapyramidal adverse effects, to which individuals with FTD are especially vulnerable. Furthermore, the boxed warning for the risk for death with the use of antipsychotics among individuals with dementia holds true also for individuals with FTD. For the treatment of behavioral symptoms in FTD, the evidence for the use of anticonvulsants—including valproic acid, topiramate, and carbamazepine—is limited to case reports. Evidence indicates that individuals with FTD and parkinsonism often do not respond to dopaminergic drugs, including levodopa/carbidopa, although some case reports indicate some benefits with these agents. 

Trials of τ aggregation inhibitors, τ acetylation inhibitors, anti-τ active vaccine, anti-τ monoclonal antibodies, anti-human sortilin monoclonal antibody, microtubule-stabilizing drugs, and progranulin expression activators have been completed or are currently in various phases of trials.

 Unfortunately, available results indicate that none of these drugs have yet been found to be beneficial.

Available evidence indicates that nonpharmacological management techniques are helpful among individuals with FTD.

 These interventions include environmental approaches that assist individuals who struggle to accurately interpret, understand, and react to their environment. In addition, behavioral modification techniques and providing familiar activities appear to reduce different types of behaviors. Evidence indicates that educational services and coping strategies that are focused on problem-solving are effective in managing behavioral symptoms and reduce caregiver burden. The development of individualized regimens incorporating environmental and behavioral strategies have been proven to be highly beneficial in assisting individuals with FTD. The family caregivers who use these strategies become more competent in managing patients’ challenging behaviors. Speech therapy has been 

to be beneficial among individuals with PPA.

The clinical syndrome of FTD is characterized by executive dysfunction, behavioral disturbances, and language impairment. FTD is often misdiagnosed or underdiagnosed due to the heterogeneity of its clinical presentation and the overlap of its clinical symptoms with those of other common neuropsychiatric disorders. Although there are no FDA-approved medications for the treating FTD, some agents have shown modest efficacy in improving behavioral but not cognitive symptoms. Nonpharmacological techniques can be beneficial in managing behavioral symptoms. Many newer therapies are currently under trial, although their benefits are not yet certain.

is chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Cleveland, OH; and professor of medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH. 

is executive vice president, Diamond Healthcare, Richmond, VA. 

is with the Behavioral Advisory Group, Strongsville, OH. The authors report no conflicts of interest concerning the subject matter of this article.

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Frontotemporal dementia: latest evidence and clinical implications

2. Bang J, Spina S, Miller BL. Frontotemporal dementia. 

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Pharmacological treatments for frontotemporal dementias: a systematic review of randomized controlled trials

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Treatment of primary progressive aphasia.

Often misdiagnosed as other psychiatric disorders, FTD is the third most common type of dementia and the second most common among patients 65 years or younger. How to spot the signs.

Easy To Miss, Hard to Treat: Notes on Frontotemporal Dementia

 by Stanciu discussing cannabis use in pregnancy

 makes several useful and highly salient points. With a more complete understanding of the published literature further important patterns in the data emerge. They aid our understanding of the pathobiology of 

cannabis exposure and thereby powerfully inform the community on the most appropriate manner in which to regulate cannabis and cannabinoids from an improved evidence base.

It is well known that cannabis use has been liberalized across the United States as a result of well-financed and orchestrated campaigns.

 Stanciu is correct that most epidemiological studies point towards harmful associations, that cannabis use in pregnancy is becoming more common, that it is widely recommended in pregnancy by cannabis dispensaries, and that increased rates of low birth weight, premature and stillbirths, and increased neonatal intensive care admission are well recognized associations. It is correct that all 4 longitudinal studies of children born after prenatal cannabis exposure (PCE) show increased adverse neurodevelopmental outcomes including impaired executive function, visuomotor processing deficits, heightened startle responses, impulse control, heightened susceptibility to addiction in later life, emotional behaviors, and motor defects.

 Well-documented impacts on the glutamatergic, GABAergic and dopaminergic signaling in the brain are of concern as they represents major neurotransmitters in the central nervous system [CNS]. Well-established links between cannabis use and schizophrenia, bipolar disorder, anxiety, depression, and suicidal ideation are also correctly described. It is true that ACOG have made both historical and recent recommendations against its use in pregnancy, and these recommendations are relevant to practice in all medical specialties.

Conceptual and epidemiological extensions

While it is correct to observe that there is no described phenotype following PCE, it is also important to note that many of these neurodevelopmental deficits have been noted to overlap the ADHD and autism spectrum disorders. This is likely epidemiologically highly significant for the US, where autistic spectrum disorders have been shown to be growing exponentially.

 Cannabis use across the US was shown to be independently associated with autism rates across both time and space, to be dose-related

, and, based on conservative projections, has been predicted to be at least 60% higher in cannabis-legal states than in states where cannabis was illegal by 2030.

 found an increased incidence of microcephaly (R.R. = 12.80, 95%C.I. 4.13-36.17)

 and the CDC have twice reported elevated rates of anencephalus (adjusted O.R. 1.7, C.I. 0.9-3.4) and (posterior O.R. 1.9 (C.I. 1.1, 3.2).

 This sets up a clear spectrum of severity from mild neurodevelopmental impairment, to microcephaly, to anencephalus and then fetal death. In the context of dose-response relationships and strong geotemporospatial associations issues of causality necessarily arise.

Stanciu’s observation that preclinical studies in experimental animals are important to understand the likely effects of PCE in individuals, not least due to the problem of the frequent exposure to multiple substances clinically, is also correct. This issue was studied in detail long ago in the 1960s and 1970s, and succinctly summarized by Graham’s telling observation: “oedema, phocomelia, omphalocoele, spina bifida, exencephaly, multiple malformations including myelocoele. This is a formidable list.”

However, a reasonable question might be: “Why don’t we see such a broad teratological spectrum clinically?”

Stanciu’s remark that there are “no overt birth defects” is an oft-repeated myth and is in error, as well as obviously being at odds with several preclinical studies, especially in the most predictive species for human teratology (ie, hamsters and white rabbits).

A recent paper from the Centers for Disease Control (CDC) noted that 4 defects, anencephalus, gastroschisis, diaphragmatic hernia and esophageal atresia were more common following PCE.

 The American Academy of Pediatrics (AAP) and the American Heart Association (AHA) issued a joint position statement that both ventricular septal defect (VSD) and Ebsteins anomaly were also elevated by PCE.

The review of 17 years of birth defects from Hawaii found 21 defects to be elevated after PCE and featured prominently cardiovascular defects (atrial septal defect (ASD), VSD, hypoplastic left heart syndrome, tetralogy of Fallot (ToF) and pulmonary valve atresia or stenosis), chromosomal defects such as Downs syndrome, body wall defects such as gastroschisis, limb defects including syndactyly and upper limb reduction defects, facial, bowel and genitourinary system defects with calculated rate ratios ranging from 5.26 (C.I. 1.08-15.46) to 39.98 (C.I. 9.03-122.29).

 of congenital anomalies across the period of its cannabis legalization program from 2000 to 2013 and 2000 to 2014 and reported 87,772 and 64,463 major defects respectively (which are obviously contradictory).

 Based on 4830 and 4026 major anomalies in the year 2000 this represents a case excess of 20,152 (29.80%) or 11,753 anomalies (22.30%) respectively. During this period the use of tobacco and alcohol was declining and other drug use was not rising. Only cannabis use rose. Importantly, models quartic in time indicated a non-linear response of total birth defects to rising cannabinoid exposure. Estimated exposure to several cannabinoids including cannabinol, THC, and tetrahydrocannabivarin was shown to be positively associated with major defect rates and to be robust to adjustment for other drug use. CNS defects (microcephalus, neural tube defects), cardiovascular defects (ASD, VSD, patent ductus arteriosus (PDA)), total chromosomal anomalies including Downs syndrome, musculoskeletal, respiratory and genitourinary anomalies all rose dramatically. 

Defects described as being cannabis-related (by the Hawaiian, CDC, AAP and AHA investigators) rose more quickly than cannabis-unrelated defects (P<0.003). As fetal cardiac tissue and the central great vessels have high numbers of cannabinoid receptors from early in fetal life it is easy to understand why this pattern might emerge. Since ASD, VSD and PDA are the most common cardiovascular congenital anomalies it is understandable that total cardiovascular anomalies increased in Colorado.

recent review of total congenital anomalies in Canada

 showed that they were 3 times more common in the northern territories which consume more cannabis, and that these effects were robust to adjustment for other drug exposure and for socioeconomic variables.

 Total cardiovascular defects, Downs syndrome and gastroschisis were noted prominently in this series. Neural tube defects including anencephalus and spinal bifida and meningomyelocoele were falling across Canada from 1991 to 2007, although it was not clear whether the decline was due to dietary folate supplementation or increased antenatal early termination of pregnancy for anomalies (ETOPFA).

 Notwithstanding this it was recently shown that within each of 3 periods (the pre-folate period, the transitional period and the post-folate period) neural tube defects across Canada were becoming more common.

An Australian dataset found greatly elevated relative rates of cardiovascular (PDA, ASD, VSD, ToF, transposition of great vessels), body wall (gastroschisis, exomphalos, diaphragmatic hernia), chromosomal (Downs syndrome, Turners syndrome, Edwards Syndrome (trisomy 18)), genitourinary, hydrocephalus, neural tube defects, and bowel defects with borderline results for anencephalus (ETOPFA data unavailable) in a high cannabis use area in Northern New South Wales compared to Queensland state-wide data.

Transposition of the great vessels was previously linked with paternal cannabis exposure.

The presence of Downs syndrome on the list of cannabis-associated anomalies in Hawaii, Colorado, Canada and Australia is important as it necessarily implies megabase-scale genetic damage.

 Since cannabis interferes with tubulin metabolism and thus the separation of the chromosomes which occurs in mitotic anaphase it is easy to see how PCE-induced chromosomal mis-segregation errors might occur.

 Studies of PCE in rodents show that cannabis induces major alterations of gene expression widely with 8% alteration in DNA sperm methylation patterns, changes which are transmissible to subsequent F1 generations.

Stanciu’s comment about a so-called “cannabis phenotype” is provocative. It is true that a “fetal cannabis syndrome” (FCS) has not been described in the way that a “fetal alcohol syndrome” (FAS) has. Fetal alcohol syndrome of course is a very diverse and pleomorphic group of clinical presentations and a wide spectrum of presentations is described. Importantly the fetal alcohol has been described as being mediated by the cannabinoid type 1 receptor (CB1R’s) and is mediated epigenetically.

 The suggestion that alcohol can work epigenetically via CB1Rs but cannabinoids cannot defies the bounds of credulity. Moreover, as noted above, there is as yet no objective marker of gestational cannabinoid exposure. Once such a biomarker has been derived (say epigenetically and / or glycomically

) then an objective measure will exist to allow genotype-epigenotype-phenotype correlative studies to be performed so that we can usefully investigate if a fetal cannabis syndrome phenotype spectrum might exist. However, if researchers do not believe it might exist then it is clear that one will not be described. It is our view that once an objective biomarker is established it will only be a matter of time before a diverse and highly variable FCS is also defined and enters the clinical diagnostic compendium.

CDC publish 5-year averaged birth defect data for many states as part of the National Birth Defects Prevention Network (NBDPN) annual reports which can be combined with Substance Abuse and Mental Health Services Administration (SAMHSA) state and substate data to examine nationwide drug-related trends. ETOPFA rates are taken from historical time series.

 charts Downs syndrome rates corrected for estimated ETOPFA rates against cannabis exposure. Both rates are elevated (shown as pink and purple) in Colorado, Oregon, Washington, Alaska, Maine and Massachusetts. 

 shows the relationship of Downs syndrome to cigarette use for this year which is very different.

 also shows the Downs syndrome rates by cannabis use quintile for both the raw Downs syndrome rates (

). One notes not only a rising trend with cannabis use, but also an abrupt jump from the fourth to the fifth quintile.

This jump is seen when many defects are analyzed in this manner. A list of defects would include, but would not be limited to: atrial septal defect, atrioventricular septal defect, cleft lip and / or palate (all forms combined), trisomy 21 (Downs syndrome), Turners syndrome and ventricular septal defect.

 lists the prevalence ratio of 62 congenital anomalies tracked by the National Birth Defect Prevention Network (NBDPN) in quintile 5 versus lower quintiles and notes that 44 of them are significantly elevated in the highest quintile of cannabis using states.

It should be noted in passing that most of these studies suffer from several major common limitations. Many of the defects described are disorders for which ETOPFA is commonly practiced and frequently recommended to pregnant patients. ETOPFA data was generally not available to investigators. It is beyond question that were such data included the findings would be of greater magnitude and of even greater concern. Secondly many studies rely on self-report which is subject to recall-bias and may be misled. Patients who use cannabis early in pregnancy but stop after they are informed of their pregnant status might answer “no” to questions of PCE, but in fact their fetus is exposed prenatally due to the prolonged terminal half-life of excretion of cannabinoids from body fat stores. Hence a reliable biomarker is required to properly define the denominator in these studies, but it is not thought to exist at present. It could however easily be derived from epigenomic and/or glycomic studies.

Thirdly there are major analytical limitations of the described series. Advanced analytical methods that allow data analysis simultaneously across both space and time exist and are called geospatial or spatiotemporal techniques. The CDC has demonstrated ability to track congenital anomalies by county. Application of geospatial techniques to county data is therefore possible and would be well assisted by the provision of cannabis-exposure data from the SAMHSA 395 substate areas. Methods which allow the investigation of apparently causal relationships, including inverse probability weighting and the calculation of E-values to quantify unmeasured confounding have similarly not been deployed in this field.

These deficits in the literature represent major gaps in our knowledge which may readily be addressed by the application of available techniques to currently extant data and thus vastly augment the evidence base for well-informed policy formulation. Our group is presently addressing this major knowledge gap with a series of papers on these and related subjects utilizing geospatiotemporal regression, the formal techniques of causal inference, and multiple imputation of chained equations to complete CDC data for various congential anomalies and heritable childhood cancers where such data is missing or withheld for specific ethnic minorities.

Extensive presently unpublished analyses from our group extend the United States analyses presented in preliminary and embryonic form in 

 using geotemporospatial and causal inference techniques with strongly confirmatory results for both state-based spatiotemporal association and in several cases causal links.

In broad overview the patterns which emerge from these major population-based studies of cannabis-related human teratology indicate several findings that are remarkable for their consistency across series originating from Hawaii, Colorado, Canada, and Australia and for their exact and precise concordance with very worrying data in experimental animals. Prominent amongst affected organ systems includes the CNS, CVS and chromosomal disorders. Body wall and limb defects also likely follow the endovascular cannabinoid receptor distribution pattern, and this is consistent with current understandings related to the pathogenesis of gastroschisis and limb embryogenesis which are both thought to be primarily vasculocentric. Similarly, in the genitourinary and gastrointestinal systems, peripheral cannabinoid receptors are widely distributed and appear from as early as 12 weeks of fetal life. Dose-response effects are seen in many of the above analyses which is one of the major criteria of Hill’s causal algorithm. The sequence of severity of CNS defects (neurodevelopmental impairments/autism-microcephaly-anencephaly-foetal death) also implies a gradation of phenotypic effects of PCE.

The PCE literature has widespread limitations including its reliance on self-report data, the general non-availability of ETOPFA data, the lack of reliable biomarkers to define exposure, and the pointed absence of state-of-the-art analytical techniques including high-resolution geotemporospatial analysis and the formal techniques of causal inference assessment.

Given these limitations the concordance with preclinical and mechanistic data and the positive and highly consistent associations that have been demonstrated in several jurisdictions are particularly concerning. They carry far-reaching genotoxic and intergenerational implications and argue powerfully against cannabis legalization.

is practice principal at Southcity Family Medical Centre and Professor of Medicine at University of Western Australia and Edith Cowan University

is Professor of Addiction Medicine within the Division of Psychiatry at The University of Western Australia and the Faculty of Health Sciences at the Edith Cowan University

Neither author has any conflicts of interest to declare.

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https://www.opensocietyfoundations.org/what-we-do/themes/justice-reform-and-the-rule-of-law

. Published 2020. Accessed October 3rd, 2020, 2020.

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17.Reece A. S., Hulse G.K. Cannabis Consumption Patterns Parallel the East-West Gradient in Canadian Neural Tube Defect Incidence: An Ecological Study. 

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Cannabis use during pregnancy is associated with a host of negative outcomes.

Cannabis in Pregnancy – Rejoinder, Exposition and Cautionary Tales

In 1959 I had finished my last term at school and had 3 months of freedom before going off to university. So what did I do? Nothing dramatic. I cycled 3 miles from my home to Rubery Hill Hospital, formerly the Birmingham City Asylum (this is Birmingham, England, not Birmingham, Alabama), to ask if I could work there as a volunteer.

I was not accepted. The union representative said it would “undermine their negotiating position,” and so I left. But I did notice 1 thing while I was waiting there: the hospital was exceptionally clean. I now know the bloody story behind the cleanliness. Its main character was still present, just down the road, only a mile or 2 from my house.

Thomas Chivers Graves was born in 1883 in Cambridgeshire. He was the grandson of Stephen Chivers, the founder of the famous 

, but his family was not close enough to the successful fruit entrepreneurs, so Thomas grew up indigent. If his family had been wealthier, he would probably have had nothing to do with psychiatry, as he only went into the profession late.

 (FRCS) in 1914, expecting to become a surgeon. But after the war he concluded he did not have the financial resources to become a surgeon, changed over to psychiatry, quickly qualified, and became medical superintendent of Rubery Hill and Hollymoor Hospitals in Birmingham. In retrospect he did not change; he retained the thinking of a surgeon.

He developed the idea, together with Henry Cotton, a psychiatrist from Trenton, New Jersey, that mental illness was a reaction to illness elsewhere in the body, now encapsulated in the words “auto-toxicity” and “

.” Cotton had trained in Europe and also at Johns Hopkins Hospital, where he was a pupil of Adolf Meyer, who was the dominant figure in American psychiatry in the early years of the 20th century.

Cotton was nothing if not bold. He started by removing patients’ teeth as an obvious cause of focal sepsis, but if this failed to cure the psychiatric disorder, he removed tonsils, testicles, ovaries, appendices, gall bladders, spleens, and colons. Thomas Chivers, essentially a surgeon manqué, embraced Cotton’s theory with equal enthusiasm, and as he was an excellent politician, he attracted long-term interest in the subject in the United Kingdom. But Cotton was lionized in the United States, too. In June 1922 the 

"At the State Hospital at Trenton, N.J., under the brilliant leadership of the medical director, Dr Henry A. Cotton, there is on foot the most searching, aggressive, and profound scientific investigation that has yet been made of the whole field of mental and nervous disorders... there is hope, high hope... for the future.”

Cotton was also supported by Adolf Meyer, as the focal sepsis theory fit in with Meyer’s psychobiological approach.

Cotton and Chivers presented their findings jointly at the Medico-Psychological Meeting in London (this was the equivalent of the Royal College of Psychiatrists Annual Congress today) in July 1923. Cotton was the more expansive presenter. He told the meeting that focal sepsis in the teeth, tonsils, and stomach were the cause of so-called functional illness, and that only an “aggressive response against infection” was needed. He was the gung-ho pioneer and had absolutely no doubts. He told the assembly:

"As a result of our decision we were finally convinced, in 1918, that chronic sepsis should be eliminated in this group of patients (ie, functional disorders, including schizophrenia). As a result of our decision we started to literally “clean up” our patients of all foci of chronic sepsis . . . and were able to increase our recoveries from 37% to 85% in the first year.)"

He finished by showing tables of proportions of sepsis in teeth, tonsils, stomach, and “vaccine-treated” patients (those injected with ad hoc streptococcal antigens). Graves was more circumspect in his paper, confining more of his discussion to sepsis in the jaw, with its tendency to chronicity. He modestly concluded that “long-continued infection with these organisms produced a varying degree of emotional reaction.”

Development and expansion of the auto-toxicity theory

Graves took this theory much further than Cotton. He was riding the wave of the English anti-psychoanalytic movement of the 1920s. He was a powerful figure in psychiatry, and he was showing, to all who wanted to listen, that psychiatry belonged within the fold of general medicine, not apart. This allowed Thomas Graves to realize his surgical ambitions. Not only dentists, but surgeons (particularly specializing in abdominal surgery), gynecologists and ENT surgeons, were all visitors to the new operating theater created at Rubery Hill Hospital, where the eradication of focal sepsis became the main focus of treatment.

This process was accompanied by much fanfare. The Mental Hospitals Committee of the Birmingham City Council was highly impressed by Graves, as was Sir Gilbert Barling, Vice Chancellor of Birmingham University, who helped him to set up a mental health research department at the University. But the main subject of the research was surgery. Tonsillectomies, complete dental extractions, appendectomies, and other similar operations became commonplace for depression and schizophrenia at the hospital in the late 1920s and 1930s. The hospital observed scrupulous hygiene in the hope that all extraneous bacteria could be removed. Such was his prestige that eventually he was appointed chief medical officer of all the mental hospitals controlled by the City Corporation in Birmingham. In 1940 he was elected president of the Royal Medico-Psychological Association and continued in his office for the next 4 years, longer than any other president.

as “Diphasic Vascular Variation in the Treatment of Mental Inefficiency Arising from a Common Somatic Cause,” is one of the most unintelligible papers ever published in the journal. By this time, he was almost completely isolated academically. He maintained that the main reason for “mental inefficiency” (ie illness) was “closed sepsis.” Diphasic vascular variation referred to the circulatory stimulus created by open sepsis, which allowed an increase in blood flow so that “the potential toxaemia and bacteriaemia are reduced to minor values and there is a rise in mental efficiency.”

 Where was the evidence for this therapeutic flushing of blood to relieve all mental suffering? None, there were only 2 references in this rambling shambles of a paper, both articles published by Graves himself.

After penicillin was first produced in 1945 it was reserved for military purposes. Graves was desperate to obtain supplies and when he failed he made his own penicillin cultures in the laboratory at Rubery Hill and injected them into patients. Consent was never discussed.

After the war Graves lost all influence but his focal sepsis theory was a highly respected element of psychiatric practice for over 20 years. Though he accumulated many devotees, he had several powerful critics, including David Henderson from Gartnavel Hospital, who pointed out that Graves largely relied on case reports to demonstrate the effectiveness of surgical interventions instead of any formal comparisons. Andrew Scull,

 who has written a comprehensive review of Graves and his influence, points out that the critics were not on the firmest of ground, as nobody could claim that infection should not be treated. So they could easily be dismissed as uncaring.

Thomas Graves continued to practice until 1950, and his influence persisted locally,which explains why the environment at Rubery Hill Hospital impressed me by its cleanliness 9 years later. He seemed to have taken no notice of the famous Northfield experiment carried out by Bion and Rickman on group psychotherapy at Rubery Hill and Hollymoor Hospitals (collectively called Northfield) during World War II.

He must have known at some level, as he remained medical superintendent at both hospitals until 1948, but he regarded all psychotherapy as abhorrent. Scull comments that Graves never lost his enthusiasm for his focal sepsis theory and worked persistently on his theories until his death in 1964.

Are there lessons to learn now from this long-held error?

Psychiatry has long been under attack for being too divorced from general medicine, and many now exhort it to become a distant branch of neurology linked to neuroscience. The case of Thomas Chivers is a warning to all of these individuals, as well as a reminder that changes in practice cannot be based on untested theory. Many of Graves’ patients would have been better off if he had found his way back into the family jam business.

is emeritus professor of Community Psychiatry at Imperial College, London. He was editor of the 

3. Cotton H. The relation of chronic sepsis to so-called functional mental disorders. 

4. Graves TC. The relation of chronic sepsis to so-called functional mental disorders. 

5. Graves TC.Diphasicvascular variation in the treatment of mental inefficiency arising from a common somatic cause. 

6. Scull A. Focal sepsis and psychosis: the career of Thomas Chivers Graves (1883-1964). In: Freeman H, Berrios GE, eds. 

150 Years of British Psychiatry: Volume II, The Aftermath. 

In the early 20th century, British and American doctors looked for the causes of mental illnesses elsewhere in the body, with gruesome results.

The Doctors Who Cut Out Your Appendix to Fix Your Head

 are proud to deliver a publication that provides a voice to a wide range of perspectives and opinions, including my own. Nonetheless, there are some comments in this provocative commentary that seem to malign our profession, with inaccuracies. First, I do not agree with the thesis that “Psychiatrists have an inferiority complex.” Second, although the piece may have meant to be tongue-in-cheek, psychiatry is not a pseudo-science, but rather a young and exciting field of science with a mission of furthering our understanding of the brain/mind continuum with the goal of decreasing human suffering by understanding and providing evidence based treatments related to the brain. Third, psychiatry has established its place in the center of medicine, as ultimately the mind/body complex is an interconnected and interdependent system.

Every field of science is a “work in progress,” which does not negate the science that is known at a particular time. In physics, the general theory of relativity was believed as concluded dogma until Albert Einstein introduced us to special relativity. In psychiatry, a competent clinician will utilize many medical diagnostics to arrive at the most likely diagnosis that will inform a treatment. These include a thorough physical and history, vital signs, substances use, MRI and CT scans, EEGs, serum drug levels, and a range of lab tests to name just a few. Twenty years ago acute psychosis with delusions and hallucinations ultimately diagnosed today as NMDA-receptor autoimmune encephalitis would have been treated with antipsychotic medication, with a poor response. Today, we treat this rare etiology to acute psychosis with plasmapheresis, high dose steroids, and intravenous immunoglobulin with rapid improvement. The science of any specialty begins with fragments of information that over years, decades and centuries continue to evolve into a greater understanding.

“Dude,” the medical student said with an informal millennial drawl, “do you even like psychiatry?”

He stared at the books that line my office shelves. Mixed among the Freuds (both Sigmund and Anna), the Jaspers, and the textbooks are any number of works by Foucault, Laing, and Szasz. Between my 

. I have a number of books on philosophy, history, and scientology. This particular student finally picked up the nearly extinct first American edition of 

I, Pierre Rivière, having slaughtered my mother, my sister, and my brother…

“Dude, why?” he asked semi-innocently.

Psychiatry, at this moment anyway, remains blood-test and imaging-free. It offers the last frontier of semi-free thought to the thinking person who wishes to enter medicine. More in this opinion piece.

Neuropsychiatry

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Cannabis in Pregnancy – Rejoinder, Exposition and Cautionary Tales

The Doctors Who Cut Out Your Appendix to Fix Your Head

Is It Time to Do Away With Psychiatry?

4 Stages of Chronic Traumatic Encephalopathy

Anti-NMDA Receptor Encephalitis With Visual Hallucinations and Cognitive Impairment

Delirium, Encephalopathy, and COVID-19: An Update From the Field

New Research Finds Troubling Link Between COVID-19 and Neuropsychiatric Health

A Double Whammy: Psychosis and Huntington Disease

5 Diagnostic Tests for Autoimmune Encephalitis