Recent advances in understanding the neurobiology of pediatric functional neurological disorder

Figures & data

Table 1. Common positive (rule-in) neurological signs found on physical examination in children with functional motor and sensory Symptoms^a.

Neurological symptom	Neurological sign that the neurologist may use to support a diagnosis of FND
Across symptoms	Symptoms are more marked when the child attends to them and less marked when the child’s attention is directed elsewhere Symptoms are variable across contexts (e.g. a child presenting with visual loss can use her mobile phone but cannot see the text that she needs to read in the classroom; a child’s gait difficulty is present when she walks forward but not when she turns around; tremor in a limb is less when the child is distracted by the neurologist)
Gait difficulty	A swaying gait or apparent loss of balance with a narrow-base gait Each foot is lifted off the ground as if requiring great effort and put back down as if requiring great effort The child walks with bent knees (which requires more strength than normal walking) An uncoordinated gait where the patient sways, lurches, and appears to find it difficult to balance but does not fall (astasia abasia)
Weakness (generalized or partial)	Discordance between strength or functional ability of the child’s affected body part on formal examination and during routine tasks (e.g. moving around on the hospital bed) Limb weakness not conforming to an anatomical distribution (e.g. arm and leg weakness on opposite sides of the body)
Tremor	Variable distribution or frequency of the child’s tremor when examined at different times The child’s tremor changes with contralateral body movements (entrainment)
Sensory symptoms (pain excluded)	Sensory symptoms not conforming to a dermatomal distribution Hemisensory loss with a sharp midline distribution
Visual loss	Tunnel vision Preserved response to a ‘menace reflex’ (the rapid approach of an object)

© Shekeeb Mohammad and Kasia Kozlowska 2022, reproduced with permission.

^aFor a more comprehensive list of rule-in signs in children and adolescents, see Kozlowska and Mohammad (2022) [30].

Table 2. Clinically useful neurological signs for diagnosis of functional seizures.

Seizure likely functional	Sensitivity	Specificity
Long duration (>2 min)	65%	93%
Eyes closed	34%–88%	74%–100%
Eyes clenched/shut tightly	33%	100%
Eyelid flutter	50%	100%
Fluctuating course	69%	96%
Side-to-side movements	25%–63%	96%–100%
Ictal crying/weeping	13%–14%	100%
Memory of seizure	63%	96%

© Stoyan Popkirov 2023. Reproduced with permission from Stoyan Popkirov. The table was compiled from a range of resources [34–39].

Figure 1. Circles metaphor of the stress-system model for functional somatic symptoms (including FND).

The overlap between the different components of the stress system – the HPA axis, autonomic nervous system, immune-inflammatory system, and brain stress systems – is presented by the overlap between the circles. The circadian clock is placed within the top circle because the master clock is found in the hypothalamus, a small region located in the base of the brain. The motor system, which includes central and peripheral components, is represented by the pink ball. The placement of the pink ball in the overlap between the brain stress systems and autonomic system reflects that activation of these systems can be accompanied by changes in motor function. The pain system, which also includes central and peripheral components, is represented by the spiky oval. The placement of pain in the overlap between the brain stress systems and immune-inflammatory system reflects that activation of these systems maintains chronic complex pain. (Reproduced with permission. © Kasia Kozlowska 2013).

Figure 2. Common signs and symptoms associated with increased arousal © Kasia Kozlowska 2019, reproduced with permission.

Table 3. Functional somatic symptoms caused by hyperventilation and the associated low PCO2 and respiratory alkalosis.

Location of the neurophysiological changes/symptoms experienced	Mechanism
In the body proper
Arms, legs, and face Pins and needles Twitchy muscles, or even spasms in the hands or feet (carpopedal spasms)	Activation of sensory and skeletomotor nerves
Chest Hyperventilation-induced chest pain.	Vasoconstriction of arteries supplying blood and oxygen to the heart results in decreased blood flow and delivery of oxygen
Whole body (energy regulation in the body as a whole) Fatigue	Sustained increases in respiratory rate over time – which increase the body’s demand for energy – contribute to symptoms of fatigue
In the brain
Phase 1 of the biphasic hyperventilation response Excitation of the cortex Difficulty in thinking clearly (impaired prefrontal cortex function) Children and adolescents prone to functional seizures – temporary dysregulation of neural networks – are at increased risk of triggering a functional seizure [82]	Hyperventilation initially causes cortical excitation (phase 1); that is, it increases brain arousal and neuron excitability [87–90] The prefrontal cortex is particularly sensitive to cortical arousal [45]
Phase 2 of the biphasic hyperventilation response Some degree of cerebral hypoxia Symptoms of cerebral hypoxia include the following [91]: dizziness changes in vision (ranging from changes in color to complete blackout) decreasing levels of consciousness (to loss of consciousness) loss of muscle tone (potentially culminating in falling)	If hyperventilation continues beyond the short term (proceeds to phase 2), it causes (to an extent that varies from individual to individual) vasoconstriction of arteries supplying blood and oxygen to the brain, resulting in decreased blood flow and delivery of oxygen, and in some degree of cerebral hypoxia [92–94] The prefrontal cortex is particularly sensitive to hypoxia

© Kasia Kozlowska 2022. Reproduced with permission.

Figure 3. Sustained beta activation following hyperventilation in children with functional seizures.

The graph shows the expected increase in power across all frequency bands with hyperventilation (hyperventilation increases cortical arousal) in children with FS aged 10–14 years. It also shows the sustained activation in the high-frequency beta band on cessation of hyperventilation that is seen in children with FS (but not in children with epilepsy or in healthy controls). © Marvin Braun, 2021. Reproduced with permission from [84].

Figure 4. Visual representation of the changes in connectivity in the resting state and during a functional seizure.

The visual representation shows the change in functional connectivity – in this case the loss of functional connectivity – when functional connectivity during the functional seizures was compared with functional connectivity in the background period. Lines that are colored from orange to blue mark decreases in connectivity, with dark blue representing most decreased and orange/yellow representing least decreased. Overall, the representation shows that the most important decrease of connectivity affects the relationship between the anterior insular (demarcated as OF) and parietal cortices (demarcated as PA’ in patient 1 [frame A] and PI‘ in patient 2 [frame B]). (For a more comprehensive legend see Madec and colleagues (2020) [114]). Reproduced from [114] with permission from John Wiley and Sons.

Table 4. Most common comorbid mental health diagnoses in the Danish health register study of children with functional seizures.

Type of psychiatric disorder (ICD 8 or ICD 10)	Prevalent psychiatric diagnosis (%) (present before the diagnosis of functional seizures)	Incident psychiatric diagnosis (%) (emerging in the two years after diagnosis of functional seizures)
Adjustment disorders (including PTSD and adjustment and attachment disorders)	17.5%	12.5%
Somatic symptom and related disorders (excluding functional seizures)	12.5%	9.1%
Neurodevelopmental disorders (ADHD, ASD, ODD/CD, tics/Tourette)	11.5%	6.5%
Emotional disorders (anxiety, bipolar disorder, depression, OCD)	9.9%	9.9%
Intellectual disabilities	6.8%
Psychotic disorders	Not reported	7.4%

ASD, autism spectrum disorders; CD, conduct disorder; OCD, obsessive compulsive disorder; ICD, International Classification of Diseases; ODD, oppositional defiant disorder; PTSD, posttraumatic stress disorder.

Figure 5. Visual representation linking adverse life experiences, stress system activation, and epigenetic/plasticity processes that increase vulnerability for FND. © Kasia Kozlowska 2021, reproduced with permission.

Figure 6. Conceptual model of developmental trajectories of early life stress leading to increased vulnerability to functional neurological disorder (FND) and other disparate health outcomes (including other comorbid functional conditions [e.g. chronic complex pain], comorbid mental health disorders, and concurrent physical health disorders). The model identifies the many different biological, psychological, and social factors that interact with adverse childhood experiences (ACEs) across development to alter allostatic processes and reduce adaptability to stress. Changed allostatic processes found in children with FND (discussed in this review) include the following: activation of autonomic nervous system, brain arousal systems, or immune system; dysregulation of HPA axis or sleep and circadian system; and, in the context of childhood abuse, epigenetic programming of genes modulating neuron development and brain network connectivity. The individual effects of ACEs on the organism depend on the specific genetic background and fetal programming (hit-1), the timing, duration, intensity, and type of ACEs (hit-2), and other later-life challenges, such as additional stressors, coping strategies, support availability, lifestyle, and aging (hit-3). Interactions among these factors explain inter-individual variations both in resilience and vulnerability to altered biopsychological functioning and in lifelong health outcomes.

GC-signaling: glucocorticoid signaling.hit: set of factors compromising/shaping development at particular time in life cycle.HPA axis: hypothalamic-pituitary-adrenal axis.LC/ANS activity: locus coeruleus/autonomic nervous system activity (the brain and body regions that mediate arousal).miRNA: micro ribonucleic acid, RNA molecules that play a role in post-transcriptional gene regulation and that are thought to have a role in complex multifactorial illnesses [170].OXS: oxidative stress.The visual representation was developed by Agorastos Agorastos and modified from [47] under the terms of its CC BY 4.0 License.

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