Functional Neurological Disorder New Subtypes and Shared Mechanisms - CLINICALKEY - DR Rivas

Review
Functional neurological disorder: new subtypes and shared

mechanisms
Mark Hallett, Selma Aybek, Barbara A Dworetzky, Lara McWhirter, Jeffrey P Staab, Jon Stone
Functional neurological disorder is common in neurological practice. A new approach to the positive diagnosis of this Lancet Neurol 2022
disorder focuses on recognisable patterns of genuinely experienced symptoms and signs that show variability within Published Online
the same task and between different tasks over time. Psychological stressors are common risk factors for functional April 14, 2022
https://doi.org/10.1016/
neurological disorder, but are often absent. Four entities—functional seizures, functional movement disorders,
S1474-4422(21)00422-1
persistent perceptual postural dizziness, and functional cognitive disorder—show similarities in aetiology and
See Online/Comment
pathophysiology and are variants of a disorder at the interface between neurology and psychiatry. All four entities have https://doi.org/10.1016/
distinctive features and can be diagnosed with the support of clinical neurophysiological studies and other biomarkers. S1474-4422(22)00095-3
The pathophysiology of functional neurological disorder includes overactivity of the limbic system, the development of Human Motor Control Section,
an internal symptom model as part of a predictive coding framework, and dysfunction of brain networks that gives National Institute of
Neurological Disorders and
movement the sense of voluntariness. Evidence supports tailored multidisciplinary treatment that can involve physical
Stroke, National Institutes of
and psychological therapy approaches. Health, Bethesda, MD, USA
(Prof M Hallett MD);
Introduction this Review due to space constraints. Functional disorders Psychosomatic Medicine Unit,
Neurology Department, Bern
The term functional neurological disorder conveys a have been defined in other medical specialties (eg, irritable
University Hospital Inselspital,
condition in which the primary pathophysiological bowel syndrome in gastroenterology, fibromyalgia in Bern, Switzerland (S Aybek MD);
processes are alterations in functioning of brain networks rheumatology, and painful bladder syndrome in urology). Department of Neurology,
rather than abnormalities of brain structures. Although Comorbidity of functional disorders with each other, Brigham and Women’s
Hospital, Harvard Medical
long recognised, this disorder was largely neglected in including functional neurological disorder, is common,
School, Boston, MA, USA
medical teaching and by health-care workers from the which suggests either shared risk factors or a tendency for (Prof B A Dworetzky MD); Centre
mid to late 20th century, and was given various diagnostic one disorder to lead to others over time. The relationship for Clinical Brain Sciences,
labels including conversion, psychogenic, and dissociative of other functional disorders to functional neurological University of Edinburgh,
Edinburgh, UK
disorders. Psychiatric diagnostic criteria are outlined in disorder is uncertain, except for some shared predisposing
(L McWhirter PhD,
the fifth edition (text revision) of the Diagnostic and and precipitating factors that we discuss in this Review. Prof J Stone PhD); Department
Statistical Manual of Mental Disorders, in which functional We include evidence from neuroimaging, neurophysio of Psychiatry and Psychology,
neurological disorder is referred to as functional logical, and genetic studies, and consider new concepts and Department of
Otorhinolaryngology – Head
neurological symptom disorder (conversion disorder). of voluntary motor and sensory control to explain the and Neck Surgery, Mayo Clinic,
Diagnostic criteria have also been established in unique alterations in neurological functioning that Rochester, MN, USA
partnership by neurologists, psychiatrists, and other identify functional neurological disorder as a bona fide (Prof J P Staab MD)
health-care professionals.1,2–4 In this Review, we define the condition. Finally, we discuss improved diagnostic Correspondence to:
term functional neurological disorder to denote clinical techniques, potential biomarkers, and emerging evidence Dr Mark Hallett, Human Motor
Control Section, National
syndromes consisting of symptoms and signs of for improved treatments based on a better understanding
Institute of Neurological
genuinely experienced alterations in motor, sensory, or of mechanisms. Disorders and Stroke, National
cognitive performance, which are distressing or Institutes of Health, Bethesda,
impairing, and manifest one or more patterns of deficits Epidemiology MD 20892, USA
[email protected]
that are consistent predominantly with dysfunction of the Functional neurological disorder has been reported in
nervous system, and show variability in performance people aged 4–94 years.5,6 There is a striking female
within the same task and between different tasks. preponderance (60–80%), although the gender gap is
This Review covers the most common presentations of narrower in early and late life.7,8 Functional movement
functional neurological disorder, namely functional disorders have a lower female predominance than
seizures (also called dissociative or psychogenic non- functional seizures, which might be due to interactions
epileptic seizures) and functional movement dis orders, of age and trauma history with sex. The mean age of
including paresis. Chronic dizziness and cognitive onset of functional movement disorders is in the late 30s7
dysfunction (as part of a functional disorder) have occupied versus functional seizures in the late 20s.8
an uncertain place in relation to functional neurological Global and historical data suggest that functional
disorder, and we also cover them in this Review. We discuss neurological disorder has a similar prevalence (cases per
possible shared mechanisms and distinguishing processes population) across geographical regions9 and eras,10
of these four entities, and note that individuals with although reported data are of poor quality due to inherent
functional neurological disorder often have more than one limitations in available sources and study designs.
subtype, or alternate from one to another over time. Other Moreover, the spectrum and nature of symptoms reported
frequent manifestations are somatosensory or visual by individuals with functional neurological disorder (eg,
symptoms and speech disorders, which we exclude from seizures and paralysis) are similar in Brazil, Europe, India,
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Review
2 Examples of precipitating factors 3 Comorbidities

Psychological Pathophysiological Other functional disorders
Subtype Pathophysio- Psychophysio- • Anxiety or panic • Emotional • Other neurological and • Irritable bowel • Persistent fatigue
logical logical • PTSD instability medical conditions • Chronic pain • Overactive bladder
• Depression
Movement Limb injury Panic attack
disorder Drug side Dissociation
effects Depression
Seizures Syncope or PTSD
epilepsy Anxiety Top-down prediction
Cognitive Brain injury error
Dizziness Vestibular 4 Perpetuating factors
pathology • Diagnostic uncertainty (from doctor or
Functional neurological patient)
disorder • Misdiagnosis as another condition
• Poor communication
1 Predisposing factors • Lack of treatment
• Functional Disorders—eg pain syndromes, • Unnecessary investigations, treatment,
Impaired integration of
irritable bowel or surgery
bottom up sensory input
• Neurological and other medical conditions—eg • Sedative or opiate medication
migraine, epilepsy, Parkinson’s prodrome • Obstacles to recovery
• Psychological disorders/stress • Avoidance
• Anxiety/depression • Low motivation for change
• Stressful live events
• Childhood adversity
• Genetic risk factors
Partial or no recovery 5 Treatment
• Sometimes NO vulnerability
Explanation of disorder
6 Outcome Physical, occupational, or speech therapy
Psychological therapy
Healthy re-adaptation Recovery Treatment of comorbidities
Figure 1: Pathophysiological and psychophysiological events that might trigger functional neurological disorder
The aetiology of functional neurological disorder depends on predisposing, precipitating, and perpetuating factors that affect the neural mechanisms of the disorder.
The dotted line indicates that in most individuals the presence of these factors does not lead to functional neurological disorder. PTSD=post-traumatic stress disorder.
North America, and South Korea. Functional neurological more common in women, and women are more likely to
disorder is the second most common reason for a new present to health services generally.21 Risk factors in
outpatient neurological consultation.11 Population studies children can include family dysfunction, bullying,
suggest a prevalence of 50–100 cases in 100 000,12–14 which perceived peer pressure, and (in some cases) abuse.22
would correspond to up to 300 000 people in the USA, for Functional neurological disorder frequently coexists with
example. Levels of disability,11 caregiver burden, and depression, anxiety, post-traumatic stress disorder, and
adverse effects on quality of life15 are comparable with cluster B personality traits.23,24 Other functional somatic
those seen in other neurological conditions. Health-care disorders, including chronic pain and irritable bowel
costs for inpatient treatment of adults with functional syndrome are also common, which suggests common
neurological disorder in the USA exceed US$1 billion risk factors or mechanisms.25–27 Fatigue and pain have
annually.16 Access to diagnosis and treatment is been shown to have more effect on quality of life than the
problematic,17 because there are too few health-care symptoms of functional neurological disorder at a group
workers who have knowledge about the disorder.18 level.28,15 Psychiatric comorbidities are not unique to
Furthermore, the experience of the diagnosis is often functional neurological disorder, and are common in
stigmatising. Physicians often wrongly equate functional structural neurological disorders and other types of
neurological disorder with feigning (ie, malingering).18 functional disorders.
Predisposition to functional neurological disorder
Predisposition, precipitants, perpetuants, probably includes genetic factors. In a study of 18 single
and outcomes nucleotide polymorphisms from 14 candidate genes
Functional neurological disorder is multifactorial in among 69 patients with functional movement disorder,29
origin (figure 1). Risk factors for the disorder in adults the 703G→T polymorphism of the TPH2 gene significantly
include exposure to psychological stressors and a history predicted clinical manifestations and alterations in
of childhood adversity, particularly neglect, with odds neurocircuitry. Compared with GG homozygotes, carriers
ratios averaging about 3–4.19 However, in many published of a T allele (including both GT heterozygotes and
studies, such events were not recorded in over 50% of TT homozygotes) were younger at symptom onset,
people. The reported female preponderance in functional showed a greater interactive effect with childhood trauma
neurological disorder might be partly attributable to the in predicting symptom severity, and had less connectivity
higher exposure of females to childhood adversity,20 between the right amygdala and middle frontal gyrus.
although other disorders (eg, multiple sclerosis) are also Epigenetic processes, such as methylation, could underlie
2 www.thelancet.com/neurology Published online April 14, 2022 https://doi.org/10.1016/S1474-4422(21)00422-1

Review
associations between genes, physiological reactivity, and No one sign is pathognomonic of functional seizures.
environmental exposures (including childhood adversity). Studies have highlighted an overlap between preictal
For example, individuals with functional neurological panic-like symptoms or signs and functional seizures,52 in
disorder might have less resilient responses to stress, as which dissociation might occur in response to autonomic
indicated by decreased 24-h heart rate variability, than arousal and be perpetuated by classic and operant
healthy individuals of the same age and sex.30 A pilot study conditioning. In qualitative conversation analysis of
of 15 patients with functional neurological disorder found seizure descriptions, functional seizures were distin
increased methylation of the gene encoding the oxytocin guished from epilepsy with high sensitivity and
receptor (OXTR), which plays a role in regulating specificity.48 A machine learning algorithm processing
responsivity to stress.31 clusters of responses to questionnaires from patients and
Many clinicians associate functional neurological observers showed promise in distinguishing epilepsy
disorder exclusively with psychiatric morbidity, but from syncope, but this algorithm is not yet ready for
observations beginning in the 19th century already found diagnosing individual patients.54
that structural illnesses and injuries can also predispose The gold standard for diagnosis of functional seizures
to or precipitate functional neurological disorder. For is use of video EEG (vEEG) recordings to assess the See Online for video
example, epilepsy can predate functional seizures,32 and patient’s typical episodes.55 Some patients will have
migraine can trigger functional limb weakness.26 Physical events during an outpatient EEG. Most (81%) patients
injury, acute illness, and drug side-effects appear to who need long-term EEG monitoring will have events
precipitate functional neurological disorder by causing within 2 days.56 Signs that have high sensitivity or
novel nociceptive or unexpected sensory experiences.26 specificity for functional seizures are long duration of
Some neurological disorders are more likely than others events, fluctuating asynchronous limb or side-to-side
to trigger comorbid functional neurological disorder.26
For example, Parkinson’s disease is more likely to be a Established diagnostic features New diagnostic features*
precipitant of functional neurological disorder than
Functional seizures
Alzheimer’s disease,33 perhaps due to specific effects on
Seizures Eyes closed; prolonged attacks; Suggestive seizure induction;48 qualitative
motor-linked networks. hyperventilation; awareness conversation analysis;49 use of smartphone
Clinicians often fear making diagnostic errors in during generalised shaking; ictal or video;50 wrist-worn accelerometers;51 post-ictal
patients who present with functional neurological post-ictal weeping plasma proteins52
disorder, but its misdiagnosis in neurological clinics is Functional movement disorder
no more common than an incorrect diagnosis of other Tremor Tremor entrainment or cessation “Whack-a-mole” sign: holding down a
neurological and psychiatric disorders.34 In fact, missing to externally cued rhythm; tremulous body part induces tremor in
variability of frequency and another body part;40 coherence between
the diagnosis of functional neurological disorder could
amplitude of tremors antagonist muscles measured with standard
be a more frequent occurrence than making an erroneous coherence or wavelets41
diagnosis of functional neurological disorder.35,36 Dystonia Fixed inverted or plantar flexed Dystonia of the face: downward lip pulling,
The prognosis of functional neurological disorder is ankle; fixed clenched fist orbicularis oculi spasm, platysma spasm;42
usually poorer than most clinicians expect. In a systematic sustained facial movement to evoke a
spasm;42 functional hemifacial spasm lacks the
review of 24 studies of functional motor disorders, “other Babinski sign” (ie, raising of eyebrow
corresponding to a total of 2069 patients, 40% of patients on affected side)
were unchanged (ie, they stayed the same) or had worse Gait and balance Variability of gait performance; Classification of gait types into seven types:
functional motor symptoms after a mean of 7 years, and gait performance shows excellent ataxic, spastic, weak gait, antalgic,
balance; “walking-on-ice” gait, parkinsonian, hemiparetic, and dystonic;43
only 20% of patients went into remission.37 The frequency
dragging monoplegic gait, or “huffing and puffing” sign: huffing, grunting,
of remission of functional seizures (40–50%) is on average knee-buckling gait grimacing, and breath holding after small
higher than that for other subtypes of functional neuro amounts of exercise;40 posturographic
logical disorder, but considerable variability exists between improvement with distraction (guessing
numbers written on back or cognitive task)44
studies.37 Mortality is also higher in patients with
Jerks or myoclonus Truncal jerking, especially with Increased startle;45 event related
functional seizures compared with those without facial movement†; positive desynchronisation using back averaging44
functional seizures (eg, 2–3 fold increase), although the Bereitschaftspotential before
reasons for this greater mortality are unclear.38 movement using back averaging
Limb weakness and Hoover’s sign; hip abductor sign; Absence of amplitude suppression of median
Functional seizures generic motor
dysfunction
drift without pronation nerve somatosensory evoked potential;44
decreased prepulse inhibition of the blink
Individuals with functional seizures, which are also reflex by stimulation of the index finger;46
known as psychogenic non-epileptic seizures or absence of contingent negative variation in
dissociative seizures, have episodes that resemble reaction time task47
epilepsy or syncope. Making an accurate diagnosis can *Described in the past 10 years. †The diagnosis of functional jerks can be difficult, but 104 (58%) of 179 patients with
be a challenge because signs are transient and complete truncal myoclonus had functional neurological disorder in one series.53
histories might only be available from witnesses,
Table: Positive diagnostic features and biomarkers of functional seizures and functional movement disorder
meaning that the diagnosis is usually delayed (table).39–53

Review
head movements, pelvic thrusting, ictal eye closure, ictal Paresis and paralysis merit inclusion among mani
crying, post-ictal memory recall,55 and peri-ictal festations of functional movement disorders because they
responsiveness57 (video 1) The results of vEEG require commonly overlap with hyperkinetic movements and
interpretation by a skilled assessor because the vEEG can share similar pathophysiological alterations of higher
be normal in some types of focal epilepsy (eg, hypermotor control of brain networks involved in voluntary move
frontal lobe seizures). In addition, interictal non- ment. In functional movement disorders, disruptions of
epileptiform abnormalities that are seen on vEEG in voluntary movement contrast with preserved habitual or
people with functional seizures are commonly mis reflexive movements of the same body part, which is
interpreted by non-experts as epilepsy.58 helpful, for example, in distinguishing functional
A drawback of vEEG monitoring is that equivocal or movement disorders from isolated dystonia. Other
uneventful monitoring can lead to an indeterminate common features of functional movement disorders
diagnosis. Also, in some settings, patients might not have included sudden onset of symptoms (in 71% of patients),
access to specialised monitoring units. In these cases, a high rates of comorbidity with anxiety (52%),
diagnosis can be made using the criteria established by fatigue (45%), and pain (42%).27 Sudden onset of limb
the International League Against Epilepsy, for a less-than- weakness weakness is a common stroke mimic, after
certain diagnosis.1 Video-only recordings interpreted by migraine and epilepsy. In a single-centre, retrospective
experts, including videos captured using a smartphone,49 study of 1165 people who were admitted for acute stroke-
have shown acceptable reliability compared with vEEG.59 like presentations, 98 (8%) had functional neurological
Ambulatory EEG can also be useful when routine EEG is disorder, 163 (14%) had other medical conditions, and
equivocal or when medication withdrawal is not needed.60 904 (78%) had stroke.14
In a prospective study, suggestive seizure induction Diagnosis of functional movement disorders rests on
(using non-deceptive and consented procedures) avoided key elements of clinical history and characteristic signs
the need for long-lasting and expensive vEEG in 8 (21%) during examination (table). Although emphasis has been
of 39 patients with functional seizures, and decreased placed on examination, historical features can provide
indeterminate testing in 5 (13%) of 38 patients.47 guidance for differential diagnosis. In a single-centre,
Research on biomarkers to differentiate epileptic retrospective study of 874 patients with hyperkinetic
seizures from functional seizures is ongoing, but these movement disorders, a model, which used an algorithm
new biomarkers are currently less reliable for diagnosis of historical features, had a discriminative ability of 91%
than patient history, risk factors, and ictal data. Prolactin to classify functional movement disorder.66 The features
and lactate concentrations in blood can be elevated after that were more common included abrupt onset of
epileptic seizures, but a sample needs to be obtained symptoms, fluctuations of symptom severity during the
within 1–2 h of the event. These concentrations can be day, a waxing and waning longitudinal course, pain or
within the normal range after focal seizures, and fatigue, and positive psychiatric features. In a single-
sometimes can be abnormal after functional seizures, so centre, retrospective study of 99 patients with functional
their use is not recommended.61 A diagnostic accuracy dystonia, an algorithm of similar historical features had
study of four plasma proteins sampled within 24 h of a good specificity (89%) and sensitivity (92%) against other
seizure in 137 patients showed promising results for types of dystonia.67
distinguishing functional seizures from epileptic A patient’s movement patterns can be diagnostic
seizures.51 Wrist-worn accelero meters50 and surface (table).63 Variability in patterns of movement can be
electromyography both indepen
62
dently dis tinguished detected by comparing movements initiated with the
convulsive epileptic seizures from functional seizures patient’s full attention, movements performed under
with moderate sensitivity and specificity. Neuro distraction, habitual movements (eg, shifting position in
psychological assessment does not distinguish functional a chair), and movements induced by tendon reflexes.
seizures from epilepsy but can be helpful with other Various tests might show these differences, such as the
aspects, such as highlighting areas of poor cognitive Hoover’s sign or the hip abductor sign of functional leg
functioning.55 weakness, and the entrainment test for tremor.63
Techniques of suggestibility and deception, such as the
Functional movement disorders use of deceptive placebo, counter the principles of a
Functional movement disorders can manifest with any patient’s autonomy, unless undertaken after informed
type of abnormal movement.63 Most case series have consent, and add little information to well gathered
found that tremor is the most frequent abnormal histories and non-deceptive examinations.
movement (video 2), followed by dystonia,25 myoclonus,44 Clinical neurophysiological tests can aid diagnosis of
and gait disorders.42 Less common syndromes are functional movement disorders,68 and are often specific to
parkinsonism,33 tics,64 stereotypy,65 facial movements such the movement disorder type.63,43 New methods might
as hemifacial spasms,41 and chorea. In a multicentre prove to be useful if validated (table). Functional neuro
study of 410 patients with functional movement disorders, imaging and structural neuroimaging studies have
188 (46%) had a mixture of movement disorder types.27 identified group differences between patients with

Review
Panel 1: Diagnostic criteria for persistent postural perceptual dizziness and functional cognitive disorder
These criteria for persistent postural perceptual dizziness were • Symptoms are not better accounted for by another disease
established by the Bárány Society in 2017.2 Criteria for or disorder
functional cognitive disorder have been proposed.4
Functional cognitive disorder
Persistent postural perceptual dizziness • One or more symptoms or signs of impaired cognitive
• One or more symptoms of dizziness, unsteadiness, or non- function
spinning vertigo on most days for at least 3 months • Clinical evidence of internal inconsistency
• Symptoms last for prolonged (hours-long) periods of • The ability to perform a task well in a particular cognitive
time but may wax and wane in severity domain at specific times, but with significantly impaired
• Symptoms or signs need not be present continuously ability shown in the same domain, particularly when the
throughout the entire day task is the focus of attention
• Persistent symptoms occur without a specific stimulus, • Not simply fluctuation over time
but are exacerbated by three factors: upright posture, • Consider red flags* for other cognitive disorders, which
active or passive motion without regard to direction or may present with features of inconsistency or
position, and exposure to moving visual stimuli or fluctuation
complex visual patterns • Symptoms or signs that are not better explained by another
• The disorder is triggered by events that cause vertigo, medical or psychiatric disorder, although comorbid
unsteadiness, dizziness, or problems with balance, including disorders can occur
acute, episodic, or chronic vestibular syndromes, other • Symptoms or signs that cause clinically significant distress
neurological or medical illnesses, and psychological distress or impairment in social, occupational, or other important
• When triggered by an acute or episodic event, symptoms areas of functioning, or that warrant medical evaluation
settle into a long-lasting, waxing and waning pattern that
*Red flags include: (1) inconsistency between cognitive domains (eg, impaired single word
persists as the event resolves; they may occur vs sentence comprehension in semantic dementia), difficulties relating to visual compre-
intermittently at first, and then consolidate into a hension (eg, posterior cortical atrophy) that can produce effects similar to internal incon-
sistency (eg, the reverse size effect), effects of apathy or low mood, intact implicit memory
persistent course
with defective conscious memory (eg, Korsakoff syndrome); and (2) variability over time
• When triggered by a chronic event, symptoms may can occur in other disorders such as Lewy body dementia, delirium, and obstructive sleep
develop slowly at first and worsen gradually apnoea.
• Symptoms cause significant distress or functional

impairment
functional movement disorders and comparison groups studies were 53, 55, and 59, with a two-to-one female
(ie, healthy individuals), but these differences cannot be predominance. Illnesses precipitating persistent postural
used diagnostically for individual patients.4 perceptual dizziness in the patients documented in these
studies included structural vestibular conditions, such as
Persistent postural perceptual dizziness benign paroxysmal positional vertigo and unilateral
The Bárány Society (The International Society for peripheral vestibulopathies (23–25% of patients);
Neuro-otology) defined the functional vestibular vestibular migraine (11–20%); panic disorders (15%) and
disorder of persistent postural perceptual dizziness for generalised anxiety disorders (15%); mild traumatic
the International Classification of Vestibular Disorders brain injuries (3–15%); stroke (2%); dysautonomia (1–7%);
(panel 1).2,4 Key symptoms of persistent postural and other medical conditions (3–6%).69
perceptual dizziness are chronic dizziness, unsteadi Investigations of patients with persistent postural
ness, and swaying or rocking (non-spinning) vertigo, perceptual dizziness and the four clinical entities that
which are exacerbated by the patient’s own movements preceded it suggest that neuroticism could predispose
and exposure to visually complex or motion-rich to the condition. High levels of body vigilance
environments (panel 2). The symptoms and syndromes (ie, conscious attention to internal cues) at the time of
of phobic postural vertigo, space motion discomfort, precipitating events (eg, illnesses) might initiate
visual vertigo, and chronic subjective dizziness, going persistent postural perceptual dizziness, leading to
back more than 150 years, preceded and informed the functional shifts in stance and gait (eg, stiffened postural
diagnostic criteria of persistent postural perceptual control, widened base of support, shorter stride length).69
dizziness.2 Patients with persistent postural perceptual dizziness
Studies from hospital-based neurology clinics found also overly rely on visual inputs versus vestibular and
the prevalence of persistent postural perceptual somatosensory inputs (ie, they have visual dependence),
dizziness to be 20% among all patients with vestibular making them susceptible to degradation of dynamic
symptoms, rising to 40% in a dedicated dizziness visual acuity when exposed to moving visual stimuli.69
centre.69 The median values for patient age in these Perceptual and reflexive responses can dissociate, with

Review
Panel 2: Case studies of functional neurological disorder

A patient with persistent postural perceptual dizziness A patient with functional cognitive disorder
A 24-year-old woman presented with a history of persistent A 63-year-old woman presented to a neurology clinic with
dizziness for the previous 2 years. She had an initial presentation symptoms of memory loss. She was concerned that she could
of continuous spinning vertigo, nausea, and pyrexia and could have Alzheimer’s disease, like her mother. The patient had first
hardly get out of bed for a week. The patient was diagnosed with realised that something might be wrong about 3 months
vestibular neuronitis and given an expectation that she would previously, when she was at the bank machine and had forgotten
recover over a period of days to weeks. During her recovery, the her PIN code, which had never happened before. The patient
complaint of spinning vertigo changed to a non-specific feeling reported that she lost focus during conversations and sometimes
of dizziness that the patient found hard to describe. The feeling could not remember things that her husband insisted he had
was no longer a spinning sensation but a feeling as if she was already told her. She began to use lists, notes, and reminders on
swaying or in motion, which was present mainly on standing and her mobile phone, feeling sure that she would miss an
walking. Every now and then, the patient also felt as if she was appointment if she did not do these things.
floating and people seemed far away, which she found The patient reported that, every day, she would walk into a room
frightening. The patient described sensitivity to objects moving and forget what she was there for. Although she had never got
in her environment when she was still. It was difficult for her to lost when out of the house, the patient started to worry that this
use a computer or be in busy environments, such as might happen. Her husband said that only he would drive the car,
supermarkets. The patient often thought about the possibility of and they should only go out together. After letting a saucepan
falling; she had fallen once but felt that she had experienced boil dry one evening, the patient stopped cooking and started to
some so-called near misses at times. Embarrassment at the buy microwave meals so it would not happen again. She had
thought of falling outside made her anxious, and she avoided trouble getting to sleep and would lie awake for hours worrying
busy places and going outside as much as possible. Over a about the things she had to do the next day, and about how her
12-month period, the patient reported that the dizziness had family would manage as her dementia got worse.
started to take over her life. She developed symptoms of fatigue
and poor concentration and had periods off work. She was The patient performed well on bedside cognitive testing, but she
desperate for an answer to what was causing the dizziness, and did not feel reassured by this result and believed something was
wondered why no one could tell her what was wrong and how to wrong with her memory. The diagnosis of functional cognitive
get better. Findings on neurological examination, including disorder was explained. The patient did not have a major
vestibular testing, were normal. depressive or anxiety disorder but had developed poor
confidence in her memory, and she had developed abnormal
During Romberg's test, the patient reported a marked sense of
attentional focus on memory lapses. Education (such as about
sway, but no objective increase in sway was reported. Clinical
the frequency of normal memory lapses in the general
assessment led to a diagnosis of persistent postural perceptual
population), encouragement to rely on her memory more, and
dizziness, according to Bárány Society criteria.2 The initial
an altered focus on times that her memory was working very well
triggering event was probable vestibular neuronitis with
began to persuade the patient about the diagnosis. The patient
comorbidities of anxiety and dissociative symptoms. Treatment
also became more able to control her anxiety about her memory.
with a detailed explanation, vestibular habituation exercises, and
She stopped using notes and lists, and despite making some
cognitive behavioural therapy directed specifically towards the
mistakes with shopping, the patient reported not nearly as many
dizziness gradually improved the patient’s symptoms over a
mistakes as expected. Although the patient still has concerns
6-month period, such that they were only intermittent. The
about getting dementia in the future, she has started seeing her
patient was able to resume social and work activities.
friends again, and has stopped planning for the worst scenario.
thresholds for conscious detection of rotary stimuli symptoms with clear evidence of internal inconsistency,
reduced by more than half, whereas vestibular–ocular not better explained by another disorder, and causing
reflex responses remain unchanged.70 Spatial navigation distress or impairment, or warranting medical evaluation
and internal representations of the body in space can be (panel 1).4 Similar to other functional neurological
impaired.71 disorders, internal inconsistency refers to differences
between occupational functioning and observed
Functional cognitive disorder performance during interview, and variable patterns
Cognitive symptoms have traditionally been excluded within cognitive tests. Analysis of the patient’s behaviour
from definitions of functional neurological disorder, but and language during a consultation helps to discriminate
research from the past 5 years has highlighted positively functional cognitive disorder from neurodegenerative
identifiable symptoms and signs of the condition. disorders. Patients with functional cognitive symptoms
Consortium diagnostic criteria, published in 2020, defined typically give detailed and specific descriptions of
functional cognitive disorder as a condition of cognitive episodes of memory failure, are more likely to attend a

Review
consultation alone than are patients with with functional neurological disorder than with other
neurodegenerative disorders, and are more concerned neurological conditions that have symptoms such as
about their symptoms than other people around them pain or fatigue, or for conditions with psychiatric
(panel 2).72,73 Performance validity tests within cognitive symptoms such as depression or anxiety.77 The
batteries might not be as helpful as previously thought voluntary–automatic dissociation seen in patients with
for diagnosing functional cognitive disorders. Tests functional neurological disorder also exists during
applied on their own are often positive in conditions specific circumstances in other neurological conditions,
such as epilepsy and mild cognitive impairment.74 such as stroke and Parkinson’s disease (eg, automatic
Functional cognitive disorder accounts for symptoms but impaired voluntary smiling in opercular syndrome81).
in a proportion of patients with subjective cognitive Feigning is often divided into factitious disorder
decline or mild cognitive impairment who do not go on (wilfully simulating symptoms for medical care) or
to develop dementia. A meta-analysis of 12 003 patients malingering (simulating symptoms for other gain). Both
attending memory clinics found that 2832 (24%) subtypes of feigning require evidence of conscious
received descriptive diagnoses consistent with functional deception and action for identification.82 Evidence of
cognitive disorder.75 feigning primarily involves a major discrepancy between
Functional cognitive disorder can also coexist with reported and observed activity (ie, what the person says
structural and metabolic causes of cognitive decline. they can do vs what they are seen to do), such as someone
The relation can be comorbid, with both disorders claiming they cannot walk who is seen walking their
contributing to disability or change over time, with dog. However, discrepancies between reported
anxiety-related prodromal functional symptoms symptoms and observed daily activity, or variability in
predating onset of dementia. In some cases, a disease performance, that the patient reports usually do not
biomarker such as amyloid β detected by an amyloid provide evidence of feigning. For example, someone
PET scan could prove to be a false-positive finding, with might say that their leg is always weak to some extent,
the patient never progressing to degenerative illness. and be in a wheelchair at an appointment, but might
Abnormal metacognition (ie, awareness and under also state that at other times their leg weakness improves
standing of one’s own thought processes) is a prominent enough to allow them to walk the dog.
feature in people with functional cognitive disorder.76 An expanding range of evidence supports functional
Individuals with functional cognitive disorder describe neurological disorder as a genuinely experienced
cognitive failures (eg, walking into a room and not disorder. The observable manifestations of functional
knowing why they are there) experienced by healthy neurological disorder, aetiological risk factors, and
people in everyday life.77 They might perceive themselves coexistence with other medical and psychiatric
as having a severe impairment despite good performance conditions are similar around the world and throughout
on cognitive tests or in occupational settings. Some history, allowing for cultural differences in attributions
patients consider that they had an above average of illness. Neurophysiological studies, including
memory in the past, although it remains unclear those looking at event-related potentials and sensory
whether this inclination is a risk factor or consequence attenuation,83,84 and functional neuroimaging studies85–88
of the functional neurological disorder. have identified differences between functional neuro
Various subtypes of functional cognitive disorder have logical disorder and feigning. Differential positive treat
been proposed,75 including isolated cognitive symptoms, ment responses obtained from randomised controlled
illness anxiety about dementia, cognitive symptoms in trials of therapeutic interventions designed specifically
mixed functional neurological disorder,78 and dissociative for patients with functional neurological disorder89,90 are
amnesia. A subtype of cognitive symptoms caused by hard to explain if such studies were contaminated by the
anxiety or depressive disorders has been suggested, but inclusion of individuals feigning illness.
anxiety and depression could also be viewed as
comorbidities that exacerbate cognitive symptoms.79 Pathophysiology
The fundamental pathophysiology of functional
Distinguishing functional neurological disorder seizures, functional movement disorders, persistent
from feigning perceptual postural dizziness, and functional cognitive
Unfortunately, patients with functional neurological disorder can be considered in a similar way—as a
disorder are frequently suspected of feigning symptoms dysfunction of sensory processing, motor or thought
by clinicians,80 and this scepticism has led to substantial output, or both. Functional movement disorders,
stigma surrounding this condition.18 Suspicion about functional seizures, and functional cognitive disorder
feigning arises because functional neurological disorder have prominent output abnormalities, whereas
is a disorder of voluntary movement, in which persistent postural perceptual dizziness has both
performance changes with attention, and symptoms and sensory and motor dysfunction. Our understanding of
disability might be variable. Currently, no data are the model is best explained in terms of movement, so
available to suggest that feigning is more of a concern we will describe it that way.

Review
Active inference Prediction error

Intention Symptom model
Predictive coding
Feedforward signals
DLPFC abnormal
connectivity
Movement planning
Emotion
Hyperactivity in amygdala
and limbic-motor system
Interoception
SMA abnormal
connectivity
Movement Impaired
generation interoceptive
Attention accuracy (both
Reduced sensory reduced and
attenuation increased)
Multimodal
Integration
Hypoactivity basal
ganglia. Normal M1
Exteroception
Movement Abnormal sense of

agency rTPJ
abnormal activity
Feedback signal
Novel sensory
experience e.g. injury,
illness
Figure 2: Neural mechanisms of functional neurological disorder

This scheme relates to functional movement disorder, but its principles are applicable to all functional neurological disorder entities. Movements are generated
by the motor cortex after planning and preparation in the SMA. Planning and preparation of movement produce feedforward signals to be compared with
feedback from interoceptive and external signals after action. If the signals do not match, movement will not be appreciated as voluntary. The brain has a model
of the body and world that adds predictive coding to this multimodal integration. Feedback signals that do not match predictive coding create prediction error,
which modifies the model so that predictive coding matches subsequent feedback. In functional neurological disorder, it is hypothesised that prediction error is
not accurately updated, perpetuating dysfunction. The green arrow shows that there are multiple general influences on motor generation, including emotion and
attention. DLPFC=dorsolateral prefrontal cortex. SMA=supplementary motor area. M1=primary motor area. rTPJ=right temporoparietal junction.
A key element of functional neurological disorder is functional somatic symptoms in general.91,92 Many studies
partial loss of voluntary control over the body. Patients converge to a mechanism of abnormal sense of agency,
report feeling that they are not in control of their abnormal with neuroimaging studies pointing to abnormal
movements. This symptom can be understood in the activation of the right temporoparietal junction.63,43 An
frame of predictive coding models about how the brain uncontrolled pilot study noted clinical improvement after
generates the sense that the individual is the agent of what non-invasive stimulation of the right temporoparietal
happens in their body, particularly when generating junction in seven patients with functional seizures.93
movements (figure 2). When a movement is planned, a In functional neurological disorder, evidence points to
motor command is sent to the motor cortex, which will an overweighting of the feedforward message under the
execute the movement. In parallel, a feedforward signal influence of previous expectations, attention, and emotion
goes to the so-called agency network (an important hub is (figure 2). A cognitive bias (ie, the tendency to jump to
the right temporoparietal junction). Once the movement conclusions) found in patients with functional neurological
is executed, feedback information goes to the agency disorder supports this hypothesis. Patients tend to favour
network and a comparison between feedforward and their past expectation of an outcome over objective data
feedback data occurs. When there is a good match in this regarding the future outcome.94 An electrophysiological
comparison, the sense of agency arises.63 A similar model experiment provided evidence for slow sensory
has been developed to explain functional seizures and information processing in patients with functional

Review
Panel 3: Diagnostic and treatment pitfalls in functional neurological disorder

Diagnostic pitfalls • Encourage early and active goal-directed rehabilitation and
Common reasons for a wrong diagnosis engage family and friends with that process
• Jumping to conclusions based on a patient's psychological • Refer the patient for appropriate therapies
history or psychological stress (eg, physiotherapy, psychotherapy, speech-language
• Failure to consider an additional medical or neurological cause therapy, or occupational therapy)
• Not basing diagnosis on the presence of positive diagnostic • Treat comorbidities (eg, depression, anxiety disorders
signs (ie, features typical of functional neurological [including post-traumatic stress disorder], or sleep
disorder) disorders), and refer to psychiatry if necessary
• Diagnosis based on “bizarre” presentation alone • Review medication regimens; opiates, benzodiazepines, and
• Reliance on usual (ie, laboratory testing with results in the other sedatives can worsen symptoms of functional
normal range) investigations neurological disorder
• Connect with, and train, other professionals to prevent the
Common reasons for missing a diagnosis patient undergoing unnecessary and potentially harmful
• Absence of psychological risk factors or stress in the patient investigations or treatments
• Failure of the clinician to consider functional neurological The clinician should not
disorder in the presence of other medical or neurological • Make a diagnosis of functional neurological disorder on the
conditions basis of normal radiological or laboratory diagnostics
• Insufficient knowledge of the clinician of positive features of • Frame the patient's diagnosis as a medical mystery
functional neurological disorder • Highlight risk factors (eg, stress, psychological) when
• Patient is a male old adult (the disorder is commonly discussing possible causes
overdiagnosed in young women and underdiagnosed in • Provide written information or signpost to online
older men) information without also providing treatment or referring
• Placing too much importance on incidental imaging the patient for further treatment
findings (eg, white matter lesions) • Encourage unrealistic expectations; improvement is a
Treatment pitfalls gradual active process, and many patients do not improve
The clinician should • Neglect to treat comorbid psychiatric disorders
• Explain the diagnosis to the patient on the basis of positive • Withdraw medications suddenly or without explaining the
clinical features of functional neurological disorder reason
• When possible, show the patient positive clinical signs • Assume that any new symptoms are attributable to
supporting the diagnosis and explain signs to the patient's functional neurological disorder; the disorder could be
family and friends comorbid with or precede other neurological disorders; new
• Check and consolidate the patient’s understanding of the signs should be assessed on their own merits
diagnosis, consider copying correspondence to patients and Some common areas in which errors occur in the diagnosis and treatment of functional
signpost patients to online information and support neurological disorder.34,103–105
organisations (eg, neurosymptoms.org, fndhope.org,
fndaction.org.uk)
neurological disorder, suggesting a reduced attention emotional tasks,98 increased concentrations of cortisol, and
allocation to objective body signals,95 which could explain variability in heart rate99 all point to abnormal stress
the shift towards an overemphasised feedforward signal. reactivity and regulation of emotion.98 These abnormalities
In patients with chronic functional dystonia, increased can be important precipitating and perpetuating factors.
pain tolerance has been found, despite a normal pain Findings in functional seizures and persistent postural
threshold, indicating a dissociation between the perceptual dizziness, although less extensively studied,
discriminative and affective components of pain.96 It can suggest similar abnormalities in agency and emotional
be postulated that attention also plays a role in filtering the networks that have been seen in functional neurological
feedback signal during multimodal integration, including disorder. Functional neuroimaging studies in people with
emotional salience. Abnormal increased attention to the functional seizures highlight increased connectivity
symptom also explains why explicit or deliberate between the insular, motor, and parietal areas.100 Small
movements (eg, lifting the leg during examination) are studies of ictal SPECT in patients with functional seizures
harder to execute than implicit or automatic movements, highlighted abnormalities of agency and limbic networks.101
because a different motor programme is involved.63,97 Changes in persistent postural perceptual dizziness are
Increased activity in the limbic system seen on more nuanced. Activity and connectivity in vestibular
neuroimaging (ie, functional MRI) during motor and cortical areas, including the posterior insula and parietal

Review
operculum, were decreased in individuals with persistent automatic movements can be used to retrain aberrant
postural perceptual dizziness compared with those motor function. In a randomised study in people with
without this condition, whereas connectivity between functional motor disorders, 29 patients received a specific
prefrontal and primary visual cortices was increased in new physical therapy intervention and 28 patients
proportion to symptom severity in individuals with this received a similar number of treatment sessions of
condition, an association modulated by anxiety and conventional physiotherapy (ie, treatment as usual).89 At
neuroticism.71 6 months, 21 (72%) patients in the new physiotherapy
Several studies have shown brain anatomical differences group rated their symptoms as improved compared with
(in grey matter and basal ganglia volumes) in patients 5 (18%) patients in the conventional physiotherapy group.
with functional neurological disorder.102 Machine-learning A physical therapy programme can be managed by
paradigms have categorised individuals with functional telemedicine and still be successful.110 In persistent
neurological disorder and healthy controls with good postural perceptual dizziness, studies of vestibular
accuracy, both with resting state functional and structural rehabilitation111 have reported reductions in patients’
neuroimaging.85 Correlation between structural changes sensitivity to motion and dizziness. Occupational therapy
and clinical data (ie, symptom severity, emotion, mood, can also have an important role, and consensus recom
dissociation, sex, and childhood trauma85) strongly mendations have been published.112 However, occupational
suggests a link between symptoms of functional therapy has generally been only research as part of
neurological disorder and anatomical differences, but multidisciplinary treatment.109
longitudinal studies are needed to address causality. Various forms of psychotherapy have been shown to
reduce morbidity in patients with functional seizures, but
Treatment none are effective across all aspects of this illness. A
Effective treatment for all types of functional neurological systematic review found eight randomised controlled
disorder begins by establishing a two-way communication trials and 11 case series with medium sized benefits from
between clinician and patient to improve understanding psychotherapy for physical symptoms, mental health,
and engage patients in their own treatment (panel 3).34,103–105 wellbeing, function, and resource use.113 In the past decade,
Neurologists have historically avoided taking responsibility several randomised controlled trials have shown benefit
for the treatment of people with functional neurological from cognitive behavioural therapy (CBT)-informed
disorder, although these clinicians are often the most psychotherapy over usual care for reduction of seizure
appropriate experts to engage patients in treatment.105 frequency over periods of up to 6 months.113 In the largest
Explaining the diagnosis with clarity using the principles randomised controlled trial, 368 patients with functional
of a diagnosis of inclusion is a key step in treatment.106 seizures received either CBT and standardised therapy or
Patients should be provided with information, although a standardised therapy alone.90 Both groups showed
randomised trial showed that being provided with online reductions in seizure frequency but no change in
information alone was insufficient to improve outcome.107 frequency of seizures was seen from adding CBT to
Individualised treatment for patients with functional standardised therapy. CBT did, however, lead to
neurological disorder has gained support over a purely improvement in eight of 13 secondary outcomes, such as
psychological therapeutic approach.34,108,109 A common general functioning, distress, somatic symptoms, and
theme of a multidisciplinary approach is that treatment is duration of seizure freedom.90 Other types of psychotherapy
based on the new, mechanistic understanding of (eg, mindfulness-based psychotherapy, psychodynamic
functional neurological disorder symptoms, and not just psychotherapy, and prolonged exposure therapy for
the individual’s aetiological risk factors. For example, individuals with concomitant post-traumatic stress
therapy for functional seizures now commonly focuses on disorder114,115) have shown promising outcomes for patients
the psychophysiological mechanism of the seizure events. with functional seizures in, mostly, small studies. Self-
Therapy for functional motor disorders builds on help treatments for stress reduction116 are safe and
differences between automatic and voluntary movement acceptable to patients with functional seizures, and they
that form the diagnosis and uses these differences in might be helpful for patients with scarce access to
physical therapy. Clinical experience suggests that treatment. Evidence for the use of psychotherapy for
treatment for coexisting conditions (eg, migraine, patients with functional movement disorders is scant,113
orthostatic intolerance, anxiety, or depression) is also and to our knowledge only one study on psychotherapy for
important. functional cognitive disorder has been published.117 In
Good evidence suggests that new approaches to patients with persistent postural perceptual dizziness,
physiotherapy, which are especially modified to the CBT enhanced the response to sertraline in a single-site,
condition, can be used for the treatment of functional randomised, parallel arm trial,118 and acceptance and
motor disorders.34 For example, someone with stroke commitment therapy produced significant benefits when
might be encouraged to focus on their affected limb combined with vestibular rehabilitation.119
during physiotherapy, whereas in functional motor Up to now, trials of psychopharmacological treatments
disorder, explicit use of distraction and preserved have been small and findings inconclusive for seizure and

Review
motor symptoms in functional neurological disorder,

although treatment of comorbidity is less controversial.120 Search strategy and selection criteria
For treatment of persistent postural perceptual dizziness, References included in this Review were identified by searches
eight uncontrolled trials (totalling more than 300 patients) of PubMed between Jan 1, 2016, to Nov 30, 2021, and from
found that selective serotonin reuptake inhibitors and the references of relevant articles. The following search terms
serotonin norepinephrine reuptake inhibitors reduced the were used: “functional neurological disorder”; “conversion
mean severity of persistent postural perceptual dizziness disorder”; “functional movement disorder”; “psychogenic
or previous syndromes of persistent dizziness by 50% in movement disorder”; “psychogenic”, “dissociative” or
6–12 weeks.69 For functional seizures, removing any “nonepileptic”, and “seizure”, “attack”, or “spell”; “persistent
antiseizure medications that are not treating common postural perceptual dizziness” and “functional cognitive
comorbidities (eg, anxiety, depression, or epilepsy) has disorder”. There were no language restrictions. The final
been shown to be helpful and safe.121 reference list was generated on the basis of relevance to the
Repetitive transcranial magnetic stimulation,122 including topics covered in this Review.
intermittent theta burst stimulation,123 has had mixed
results in functional motor disorders. A large placebo-
controlled trial of botulinum toxin therapy for tremulous The pathophysiology of functional neurological disorder
and jerky functional motor disorders showed no benefit, overlaps in all its variants (figure 2). In all functional
although both groups (botulinum toxin vs placebo) neurological disorder entities, the patient develops an
improved.124 Treatments such as hypnotherapy, therapeutic abnormal internal model of brain and body function. The
sedation, and intensive inpatient treatment could help model confirms and reinforces the abnormal function.
some patients.125 The underlying push towards the abnormal model comes
from a physical, cognitive, or emotional experience that
Conclusions and future directions cannot be subsumed into normal function. Functional
Since 1968, when DSM-II was published, functional neurological disorder is arguably what might be expected
neurological disorder has been considered to comprise to happen when predictive processing in the brain goes
conditions involving the voluntary motor and sensory awry.
nervous system. Functional seizures are paroxysmal Commonalities exist in the best therapeutic approaches
motor events, which is a strong reason to discuss them in for all these disorders. Physical therapy in functional
this Review alongside functional motor disorders.27 We motor disorders promotes automatic move ments over
also included in our Review two common functional abnormal overlearned impaired voluntary ones. In
neurological disorder subtypes involving dizziness and persistent postural perceptual dizziness, habituation
cognition, to explore their overlap with functional seizures exercises aim to desensitise a similarly aberrant sensory
and functional motor disorders (figure 1). We have not and motor system, in which there is an overlearned
included sensory disorders (eg, functional anaesthesia or abnormal attentional spotlight on the symptom of
blindness) or other motor disorders (eg, speech and dizziness. Similarly, psychotherapies, such as CBT for
swallowing disorders), which have their own diagnostic functional neurological disorder, aim to modify the various
features, but are based on similar principles to those we inputs that might contribute to the disorder, including
have discussed. interoception, attentional style, cognition, emotion, and
A striking feature of many functional disorders is that psychological comorbidities.
they are triggered by, and coexist with, recognised Clearly, there are important differences between these
pathophysiological events. Functional motor disorders diverse symptoms. Seizures are paroxysmal, whereas
and functional seizures are often triggered by injury or persistent postural perceptual dizziness and functional
other neurological disease. For persistent postural motor disorders are typically continuous and are arguably
perceptual dizziness, an initial, usually vestibular, event is as different as panic disorder and depression. As with
part of the definition. Functional cognitive disorder panic disorder and depression, functional motor disorders
commonly follows mild traumatic brain injury, after the and persistent postural perceptual dizziness often coexist,
point when natural recovery might have been expected to and treatment typically improves with the understanding
occur. Psychological factors (eg, adversity, personality of their overlap.
traits, or psychiatric disorder) might be relevant as The new principle of making a diagnosis of inclusion on
predisposing, precipitating, or perpetuating factors at all the basis of clinical signs relates to increased understanding
stages of functional neurological disorder (figure 1). of pathophysiology and treatment, and allows diagnosis in
However, contrary to previous conversion disorder models, people with other neurological conditions. Establishing
they are not a prerequisite. The strength of these triggering reliability in the positive diagnosis of persistent postural
pathophysiological events, which themselves often shape perceptual dizziness and functional cognitive disorder will
the symptom of the subsequent functional disorder, could be especially important when evaluating their relevance to
partly explain why there is such heterogeneity in the risk syndromes that are still to be clarified, such as the Havana
for functional neurological disorder. syndrome and long COVID. With increasing availibility of

Review
evidence-based treatment, the diagnosis of functional 13 Duncan R, Razvi S, Mulhern S. Newly presenting psychogenic
nonepileptic seizures: incidence, population characteristics, and
neurological disorder should be a process of looking for early outcome from a prospective audit of a first seizure clinic.
potentially reversible causes of disability and distress, Epilepsy Behav 2011; 20: 308–11.
regardless of whether an individual has abnormalities on 14 Gargalas S, Weeks R, Khan-Bourne N, et al. Incidence and outcome
conventional laboratory or radiological testing. of functional stroke mimics admitted to a hyperacute stroke unit.
J Neurol Neurosurg Psychiatry 2017; 88: 2–6.
Contributors 15 Jones B, Reuber M, Norman P. Correlates of health-related quality
All authors contributed equally to the literature selection, of life in adults with psychogenic nonepileptic seizures:
conceptualisation, writing, and revision of this Review. a systematic review. Epilepsia 2016; 57: 171–81.
16 Stephen CD, Fung V, Lungu CI, Espay AJ. Assessment of
Declaration of interests
emergency department and inpatient use and costs in adult and
JS reports royalties from UpToDate for articles on functional neurological pediatric functional neurological disorders. JAMA Neurol 2021;
disorder and runs a free self-help website for people with functional 78: 88–101.
neurological disorder. JS also carries out independent expert medicolegal 17 Hingray C, El-Hage W, Duncan R, et al. Access to diagnostic and
work including in relation to functional neurological disorder, and is on therapeutic facilities for psychogenic nonepileptic seizures:
the medical advisory board for FND Hope and FND Action. BAD receives an international survey by the ILAE PNES Task Force. Epilepsia
royalties from Oxford University Press on her book Psychogenic 2018; 59: 203–14.
Nonepileptic Seizures: Toward the Integration of Care. LM reports expert 18 MacDuffie KE, Grubbs L, Best T, et al. Stigma and functional
witness work in personal injury and negligence cases including functional neurological disorder: a research agenda targeting the clinical
neurological disorder. All other authors declare no competing interests. encounter. CNS Spectr 2020; published online Dec 3.
https://doi.org/10.1017/S1092852920002084.
Acknowledgments
19 Ludwig L, Pasman JA, Nicholson T, et al. Stressful life events and
MH is supported by the National Institute of Neurological Disorders and
maltreatment in conversion (functional neurological) disorder:
Stroke Intramural Program. BAD is supported by the Andrew J Trustey systematic review and meta-analysis of case-control studies.
Research Fund. JS is supported by a National Health Service Scotland Lancet Psychiatry 2018; 5: 307–20.
Research Career Fellowship. JPS is supported by a grant 20 Kletenik I, Holden SK, Sillau SH, et al. Gender disparity and abuse
(W81XWH1810760) from the US Army Medical Research and in functional movement disorders: a multi-center case-control
Development Command via the Congressionally Directed Medical study. J Neurol 2022; published online Jan 31. https://doi.
Research Program. SA is supported by a grant from the Swiss National org/10.1007/s00415-021-10943-6.
Science Foundation (PP00P3_176985). LM is supported by a Baillie Gifford 21 Hobbs FDR, Bankhead C, Mukhtar T, et al. Clinical workload in UK
Clinical Research Fellowship and the NHS Scotland Chief Scientist’s primary care: a retrospective analysis of 100 million consultations in
Office. We thank Stoyan Popkirov for the graphic concept in figure 1. England, 2007-14. Lancet 2016; 387: 2323–30.
22 Watson C, Sivaswamy L, Agarwal R, Du W, Agarwal R. Functional
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Functional Neurological Disorder New Subtypes and Shared Mechanisms - CLINICALKEY - DR Rivas

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Review

Functional neurological disorder: new subtypes and shared

www.thelancet.com/neurology Published online April 14, 2022 https://doi.org/10.1016/S1474-4422(21)00422-1 1

2 Examples of precipitating factors 3 Comorbidities

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4 www.thelancet.com/neurology Published online April 14, 2022 https://doi.org/10.1016/S1474-4422(21)00422-1

• Symptoms cause significant distress or functional

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Panel 2: Case studies of functional neurological disorder

6 www.thelancet.com/neurology Published online April 14, 2022 https://doi.org/10.1016/S1474-4422(21)00422-1

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Active inference Prediction error

Movement Abnormal sense of

Figure 2: Neural mechanisms of functional neurological disorder

8 www.thelancet.com/neurology Published online April 14, 2022 https://doi.org/10.1016/S1474-4422(21)00422-1

Panel 3: Diagnostic and treatment pitfalls in functional neurological disorder

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10 www.thelancet.com/neurology Published online April 14, 2022 https://doi.org/10.1016/S1474-4422(21)00422-1

motor symptoms in functional neurological disorder,

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14 www.thelancet.com/neurology Published online April 14, 2022 https://doi.org/10.1016/S1474-4422(21)00422-1

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