Functional neurological disorder is a feminist issue.

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need.

A Critical Investigation of Cerebellar Associative Learning in Isolated Dystonia.

BACKGROUND: Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered. OBJECTIVE: To systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex. METHODS: Original neurophysiological data from all published studies (until 2019) were shared and compared to an age- and sex-matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model. RESULTS: Isolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT-TOR1A, DYT-THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies. CONCLUSIONS: The similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair.

Pyruvate dehydrogenase complex (PDC) deficiency caused by mutations in the X-linked PDHA1 gene has a broad clinical presentation, and the pattern of X-chromosome inactivation has been proposed as a major factor contributing to its variable expressivity in heterozygous females. Here, we report the first set of monozygotic twin females with PDC deficiency, caused by a novel, de novo heterozygous missense mutation in exon 11 of PDHA1 (NM_000284.3: c.1100A>T). Both twins presented in infancy with a similar clinical phenotype including developmental delay, episodes of hypotonia or encephalopathy, epilepsy, and slowly progressive motor impairment due to pyramidal, extrapyramidal, and cerebellar involvement. However, they exhibited clear differences in disease severity that correlated well with residual PDC activities (approximately 60% and 20% of mean control values, respectively) and levels of immunoreactive E1α subunit in cultured skin fibroblasts. To address whether the observed clinical and biochemical differences could be explained by the pattern of X-chromosome inactivation, we undertook an androgen receptor assay in peripheral blood. In the less severely affected twin, a significant bias in the relative activity of the two X chromosomes with a ratio of approximately 75:25 was detected, while the ratio was close to 50:50 in the other twin. Although it may be difficult to extrapolate these results to other tissues, our observation provides further support to the hypothesis that the pattern of X-chromosome inactivation may influence the phenotypic expression of the same mutation in heterozygous females and broadens the clinical and genetic spectrum of PDC deficiency.

Clinical commentary on "Paroxysmal kinesigenic dyskinesia-like phenotype in multiple sclerosis" and "Secondary paroxysmal dyskinesia in multiple sclerosis: Clinical-radiological features and treatment. Case report of seven patients".

This clinical commentary discusses the phenomenology and treatment of paroxysmal dyskinesia in patients with multiple sclerosis. It calls for a consensus on the definition as well as for larger studies to better understand this unusual clinical association.

Task-specific dystonia: pathophysiology and management.

Task-specific dystonia is a form of isolated focal dystonia with the peculiarity of being displayed only during performance of a specific skilled motor task. This distinctive feature makes task-specific dystonia a particularly mysterious and fascinating neurological condition. In this review, we cover phenomenology and its increasingly broad-spectrum risk factors for the disease, critically review pathophysiological theories and evaluate current therapeutic options. We conclude by highlighting the unique features of task-specific dystonia within the wider concept of dystonia. We emphasise the central contribution of environmental risk factors, and propose a model by which these triggers may impact on the motor control of skilled movement. By viewing task-specific dystonia through this new lens which considers the disorder a modifiable disorder of motor control, we are optimistic that research will yield novel therapeutic avenues for this highly motivated group of patients.

Transcranial magnetic stimulation follow-up study in early Parkinson's disease: A decline in compensation with disease progression?

BACKGROUND: A number of neurophysiological abnormalities have been described in patients with Parkinson's disease, but very few longitudinal studies of how these change with disease progression have been reported. We describe measures of motor cortex inhibition and plasticity at 6 and 12 mo in 12 patients that we previously reported at initial diagnosis. Given the well-known interindividual variation in these measures, we were particularly concerned with the within-subject changes over time. METHODS: Patients were assessed clinically, and transcranial magnetic stimulation (TMS) was used to measure motor cortical excitability, inhibition (short interval intracortical inhibition, cortical silent period), and plasticity (response to excitatory paired associative stimulation protocol) in both hemispheres. All measurements were performed 6 mo and 12 mo after the baseline experiments. RESULTS: Asymmetry in clinical motor symptoms was reflected in asymmetry of plasticity and inhibition. In the group as a whole, little change was seen in any of the parameters over 12 mo. However, analysis of within-individual data showed clear correlations between changes in clinical asymmetry and asymmetry of response to paired associative stimulation protocol and cortical silent period. CONCLUSIONS: Longitudinal changes in cortical silent period and response to paired associative stimulation protocol in Parkinson's disease reflect dynamic effects on motor cortex that are related to progression of motor signs. They are useful objective markers of early disease progression that could be used to detect effects of disease-modifying therapies. The decline in heightened plasticity that was present at disease onset may reflect failure of compensatory mechanisms that maintained function in the preclinical state.

Loss of sensory attenuation in patients with functional (psychogenic) movement disorders.

Functional movement disorders require attention to manifest yet patients report the abnormal movement to be out of their control. In this study we explore the phenomenon of sensory attenuation, a measure of the sense of agency for movement, in this group of patients by using a force matching task. Fourteen patients and 14 healthy control subjects were presented with forces varying from 1 to 3 N on the index finger of their left hand. Participants were required to match these forces; either by pressing directly on their own finger or by operating a robot that pressed on their finger. As expected, we found that healthy control subjects consistently overestimated the force required when pressing directly on their own finger than when operating a robot. However, patients did not, indicating a significant loss of sensory attenuation in this group of patients. These data are important because they demonstrate that a fundamental component of normal voluntary movement is impaired in patients with functional movement disorders. The loss of sensory attenuation has been correlated with the loss of sense of agency, and may help to explain why patients report that they do not experience the abnormal movement as voluntary.

Motor 'surround inhibition' is not correlated with activity in surround muscles.

Surround inhibition (SI) is a neural process that has been extensively investigated in the sensory system and has been recently probed in the motor system. Muscle-specific modulation of corticospinal excitability at the onset of an isolated finger movement has been assumed to reflect the presence of SI in the motor system. This study attempted to characterise this phenomenon in a large cohort of normal volunteers and investigate its relationship with muscle activity in the hand. Corticospinal excitability of the pathways projecting to three hand muscles [first dorsal interosseus (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM)] and electromyographic (EMG) activity of the same muscles were assessed in 31 healthy volunteers during an isolated index finger movement. In the agonist FDI muscle both corticospinal excitability and EMG activity were found to be increased at the onset of the movement (P < 0.001 and P < 0.001, respectively). On the contrary, in the surround ADM, there was dissociation between the corticospinal excitability (decreased: P < 0.001) and EMG activity (increased: P < 0.001). Cross-correlation analysis of the EMG activity showed that neuronal signals driving the agonist and surround muscles are not synchronised when SI is present. The results suggest a distinctive origin of the neuronal signals driving the agonist and surround muscles. In addition, they indicate that cortical output might be simultaneously modulated by voluntary and non-voluntary activity, generated in cortical and subcortical structures, respectively.

Normal motor adaptation in cervical dystonia: a fundamental cerebellar computation is intact.

The potential role of the cerebellum in the pathophysiology of dystonia has become a focus of recent research. However, direct evidence for a cerebellar contribution in humans with dystonia is difficult to obtain. We examined motor adaptation, a test of cerebellar function, in 20 subjects with primary cervical dystonia and an equal number of aged matched controls. Adaptation to both visuomotor (distorting visual feedback by 30°) and forcefield (applying a velocity-dependent force) conditions were tested. Our hypothesis was that cerebellar abnormalities observed in dystonia research would translate into deficits of cerebellar adaptation. We also examined the relationship between adaptation and dystonic head tremor as many primary tremor models implicate the cerebellothalamocortical network which is specifically tested by this motor paradigm. Rates of adaptation (learning) in cervical dystonia were identical to healthy controls in both visuomotor and forcefield tasks. Furthermore, the ability to adapt was not clearly related to clinical features of dystonic head tremor. We have shown that a key motor control function of the cerebellum is intact in the most common form of primary dystonia. These results have important implications for current anatomical models of the pathophysiology of dystonia. It is important to attempt to progress from general statements that implicate the cerebellum to a more specific evidence-based model. The role of the cerebellum in this enigmatic disease perhaps remains to be proven.

Secondary and primary dystonia: pathophysiological differences.

Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.

Levodopa-Induced Dyskinesias are Frequent and Impact Quality of Life in Parkinson's Disease: A 5-Year Follow-Up Study.

BACKGROUND: Levodopa-induced dyskinesias (LID) are frequent in Parkinson's disease (PD). OBJECTIVE: To analyze the change in the frequency of LID over time, identify LID related factors, and characterize how LID impact on patients' quality of life (QoL). PATIENTS AND METHODS: PD patients from the 5-year follow-up COPPADIS cohort were included. LID were defined as a non-zero score in the item "Time spent with dyskinesia" of the Unified Parkinson's Disease Rating Scale-part IV (UPDRS-IV). The UPDRS-IV was applied at baseline (V0) and annually for 5 years. The 39-item Parkinson's disease Questionnaire Summary Index (PQ-39SI) was used to asses QoL. RESULTS: The frequency of LID at V0 in 672 PD patients (62.4 ± 8.9 years old; 60.1% males) with a mean disease duration of 5.5 ± 4.3 years was 18.9% (127/672) and increased progressively to 42.6% (185/434) at 5-year follow-up (V5). The frequency of disabling LID, painful LID, and morning dystonia increased from 6.9%, 3.3%, and 10.6% at V0 to 17.3%, 5.5%, and 24% at V5, respectively. Significant independent factors associated with LID (P < 0.05) were a longer disease duration and time under levodopa treatment, a higher dose of levodopa, a lower weight and dose of dopamine agonist, pain severity and the presence of motor fluctuations. LID at V0 (ß = 0.073; P = 0.027; R2 = 0.62) and to develop disabling LID at V5 (ß = 0.088; P = 0.009; R2 = 0.73) were independently associated with a higher score on the PDQ-39SI. CONCLUSION: LID are frequent in PD patients. A higher dose of levodopa and lower weight were factors associated to LID. LID significantly impact QoL.

Neurobiology of functional (psychogenic) movement disorders.

PURPOSE OF REVIEW: This review explores recent developments in understanding the neurobiological mechanism of functional (psychogenic) movement disorders (FMDs). This is particularly relevant given the resurgence of academic and clinical interest in patients with functional neurological symptoms and the clear shift in diagnostic and treatment approaches away from a pure psychological model of functional symptoms. RECENT FINDINGS: Recent research findings implicate three key processes in the neurobiology of FMD (and by extension other functional neurological symptoms): abnormal attentional focus, abnormal beliefs and expectations, and abnormalities in sense of agency. These three processes have been combined in recent neurobiological models of FMD in which abnormal predictions related to movement are triggered by self-focused attention, and the resulting movement is generated without the normal sense of agency that accompanies voluntary movement. SUMMARY: New understanding of the neurobiology of FMD forms an important part of reappraising the way that patients with FMD (and other functional disorders) are characterized and treated. It also provides a testable framework for further exploring the pathophysiology of these common causes of ill health.

Tremor in inflammatory neuropathies.

BACKGROUND: Tremor is known to occur in patients with neuropathies although its reported prevalence varies widely. Tremor has been shown to cause disability in children with Charcot-Marie-Tooth disease but no data exit about the disability caused by tremor in inflammatory neuropathies. Little is known about the response of neuropathic tremor to treatment and why it selectively occurs in some people and not others. METHODS: This case control study investigates the presence and severity of tremor in 43 consecutively recruited patients with inflammatory neuropathies at the National Hospital for Neurology and Neurosurgery, London. Clinical assessment, including Fahn-Tolosa-Marin Scale for tremor, sensory scores, power scores and Overall Neuropathy Limitations Scale, were recorded. Results of nerve conduction studies were retrieved and assessed. Nine patients' tremors were recorded with accelerometry. RESULTS: Tremor was most common in IgM paraproteinaemic neuropathies, as previously reported, but also occurred in 58% of those with chronic inflammatory demyelinating polyradiculoneuropathy and 56% of those with multifocal motor neuropathy with conduction block. We describe, for the first time, tremor in the majority of patients with multifocal motor neuropathy with conduction block. Tremor in all of these patients seems generally refractory to treatment except in a small number of cases where tremor improves with treatment of the underlying neuropathy. We provide evidence that tremor may add to disability in patients with inflammatory neuropathy. Mean tremor frequency was 6 Hz and did not vary with weight loading. We demonstrate for the first time that although tremor severity correlates with F wave latency, it is not sufficient to distinguish those with, from those without, tremor. CONCLUSION: Tremor in inflammatory neuropathies is common, adds to disability and yet does not often respond to treatment of the underlying neuropathy. When present, tremor severity is associated with F wave latency.

Familial psychogenic movement disorders.

BACKGROUND: Psychogenic (or functional) movement disorders (PMDs) are considered sporadic. Despite the growing literature describing the clinical features and the natural history of sporadic cases with PMDs, their occurrence in familial clusters is not reported. METHODS: We identified 10 patients from 5 families affected by PMDs. In this report, we describe the clinical characteristics along with videos and long-term follow-up of these patients. RESULTS: Clinical clues from the history and signs suggesting a functional origin of the symptoms in these patients with familial PMD were similar to those identified in sporadic cases. The phenomenology of the PMD was similar in the affected members of the same family. CONCLUSIONS: We wish to highlight that a positive family history does not necessarily imply an organic disorder. When a positive family history for a condition is reported by a patient with PMD, examination of these further affected members may be needed and may identify further family members suffering from PMDs. A positive family history of PMDs may be an additional risk factor for developing PMDs. © 2013 Movement Disorder Society.

Failure of explicit movement control in patients with functional motor symptoms.

Functional neurological symptoms are one of the most common conditions observed in neurological practice, but understanding of their underlying neurobiology is poor. Historic psychological models, based on the concept of conversion of emotional trauma into physical symptoms, have not been implemented neurobiologically, and are not generally supported by epidemiological studies. In contrast, there are robust clinical procedures that positively distinguish between organic and functional motor signs that rely primarily on distracting attention away from movement or accessing it covertly. We aimed to investigate the neurobiological principles underpinning these techniques and implications for understanding functional symptoms. We assessed 11 patients with functional motor symptoms and 11 healthy controls in three experimental set-ups, where voluntary movements were made either with full explicit control or could additionally be influenced automatically by factors of which participants were much less aware (one-back reaching, visuomotor transformation, and precued reaction time with variable predictive value of the precue). Patients specifically failed in those tasks where preplanning of movement could occur and under conditions of increasing certainty regarding the movement to be performed. However, they implicitly learned to adapt to a visuomotor transformation as well as healthy controls. We propose that when the movement to be performed can be preplanned or is highly predicted, patients with functional motor symptoms shift to an explicit attentive mode of processing that impairs kinematics of movement control, but movement becomes normal when such processes cannot be employed (e.g., during unexpected movement or implicit motor adaptation).

Functional movement disorders are not uncommon in the elderly.

BACKGROUND: Functional movement disorders (FMDs) are thought to be rare in the elderly. Clinical characteristics of the elderly people who develop FMDs are rarely reported. The objective of this study was to highlight the clinical characteristics of FMD in the elderly and compared these with a cohort of patients with a younger age of onset. METHODS: The authors performed a retrospective review of the clinical records of patients with FMD who were seen at their center in the last 5 years and had consented to be included in research studies. Patients fulfilling currently accepted diagnostic criteria for FMD as documented, clinically established, or probable were included. RESULTS: Of 151 patients with FMD who were identified and had sufficient information, 21.0% (n=33) had an onset after age 60 years (elderly group). The mean age of onset of FMD was 63.5 years (standard deviation, 5.2 years) in the elderly group and 35.5 years (standard deviation, 12.6 years) in the younger group. Tremor was the most common movement disorder in both groups (elderly group, 33.3%; younger group: 38.9%). Fixed dystonia was not observed in any patient who had an FMD onset after age 60 years. Gait abnormalities were significantly more common in the elderly group (69.7%) than in younger patients (23.5%; P<0.001). Associated psychogenic nonepileptic seizures tended to be more common in elderly patients (18.2%) compared with younger patients (13%; P=0.06). CONCLUSIONS: Contrary to common perceptions, FMDs are not uncommon in the elderly, and 1 in 5 patients in the current cohort, onset of FMD occurred after age 60 years. Gait abnormalities and psychogenic nonepileptic seizures may be more common in older patients.