Cardinal motor features of Parkinson’s disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal ...denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD.
ABSTRACT
Background
Progress in genetics – particularly the advent of next‐generation sequencing (NGS) – has enabled an unparalleled gene discovery and revealed unmatched complexity of ...genotype–phenotype correlations in movement disorders. Among other things, it has emerged that mutations in one and the same gene can cause multiple, often markedly different phenotypes. Consequently, movement disorder specialists have increasingly experienced challenges in clinicogenetic correlations.
Objectives
To deconstruct biological phenomena and mechanistic bases of phenotypic heterogeneity in monogenic movement disorders and neurodegenerative diseases. To discuss the evolving role of movement disorder specialists in reshaping disease phenotypes in the NGS era.
Methods
This scoping review details phenomena contributing to phenotypic heterogeneity and their underlying mechanisms.
Results
Three phenomena contribute to phenotypic heterogeneity, namely incomplete penetrance, variable expressivity and pleiotropy. Their underlying mechanisms, which are often shared across phenomena and non‐mutually exclusive, are not fully elucidated. They involve genetic factors (ie, different mutation types, dynamic mutations, somatic mosaicism, intragenic intra‐ and inter‐allelic interactions, modifiers and epistatic genes, mitochondrial heteroplasmy), epigenetic factors (ie, genomic imprinting, X‐chromosome inactivation, modulation of genetic and chromosomal defects), and environmental factors.
Conclusion
Movement disorders is unique in its reliance on clinical judgment to accurately define disease phenotypes. This has been reaffirmed by the NGS revolution, which provides ever‐growing sequencing data and fuels challenges in variant pathogenicity assertions for such clinically heterogeneous disorders. Deep phenotyping, with characterization and continual updating of “core” phenotypes, and comprehension of determinants of genotype–phenotype complex relationships are crucial for clinicogenetic correlations and have implications for the diagnosis, treatment and counseling.
Pathological forward trunk flexion is a disabling and drug-refractory motor complication of Parkinson's disease (PD) leading to imbalance, pain, and fall-related injuries. Since it might be ...reversible, early and multidisciplinary management is emphasised. The primary aim was to compare the effects of a four-week trunk-specific rehabilitation program on the severity of the forward trunk flexion. The secondary aim was to compare the training effects on the motor impairments, dynamic and static balance, pain, falls, and quality of life.
37 patients with PD (H&Y ≤ 4) and forward trunk flexion were randomized in the experimental (n = 19) or control group (n = 18). The former consisted of active self-correction exercises with visual and proprioceptive feedback, passive and active trunk stabilization exercises and functional tasks. The latter consisted of joint mobilization, muscle strengthening and stretching, gait and balance exercises. Protocols lasted 4 weeks (60 min/day, 5 days/week). Before, after, and at 1-month follow-up, a blinded examiner evaluated patients using primary and secondary outcomes. The primary outcome was the forward trunk flexion severity (degree). Secondary outcomes were the UPDRS III, dynamic and static balance, pain falls, and quality of life assessment.
The experimental group reported a significantly greater reduction in forward trunk flexion than the control group from T0 to both T1 (p = 0.003) and T2 (p = 0.004). The improvements in dynamic and static balance were significantly greater for the experimental group than the control group from T0 to T2 (p = 0.017 and 0.004, respectively). Comparable effects were reported on the other outcomes. Pre-treatment forward trunk flexion values were highly correlated to post-treatment trunk deviation changes.
The four-week trunk-specific rehabilitation training decreased the forward trunk flexion severity and increased postural control in patients with PD. NCT03741959.
•Forward trunk flexion is a disabling and drug-refractory motor complication.•Promoting an early and multidisciplinary management is essential.•Specific trunk rehabilitation decreases forward trunk flexion posture.
Camptocormia is a disabling complication of Parkinson's disease (PD), but its pathophysiology is poorly elucidated. Depending on the fulcrum of forward trunk flexion, two subtypes have been defined, ...upper (UCC) and lower camptocormia, the former being much more frequent. The aim of the study was to explore possible pathophysiological mechanisms of PD-related UCC.
Ten PD patients with UCC (UCC-PD) and ten PD patients without camptocormia (NoUCC-PD) underwent simultaneous electromyography (EMG) of thoracic paraspinal (TPS), obliquus externus abdominis (OEA), rectus abdominis (RA), and iliopsoas (IP) muscles during relaxed standing (both groups) and trunk realignment (UCC-PD group). Quantitative EMG and magnetic resonance imaging (MRI) of TPS muscles were also performed.
UCC-PD patients showed hyperactivity of TPS and OEA muscles in quiet stance. During voluntary trunk extension, hyperactivity of OEA muscles persisted, thus revealing a co-contraction of flexor and extensor trunk muscles. Motor unit potentials (MUP) of TPS muscles showed shorter duration (p = 0.005) and lower amplitude (p = 0.004) in UCC-PD than in NoUCC-PD patients. MRI did not detect significant between-group differences in the cross-sectional area and fat fraction of TPS muscles, although the latter was higher in the UCC-PD than in the NoUCC-PD group at all thoracic levels.
Our findings suggest that hyperactivity of OEA might sustain UCC in PD. Concurrent mild myopathic changes in TPS muscles in PD with UCC may be secondary to muscle disuse but nevertheless may contribute to abnormal trunk posture.
•Co-contraction of antagonistic trunk muscles exists in upper camptocormia.•Obliquus externus muscles play a crucial role in upper camptocormia.•Thoracic paraspinal muscles show subtle myopathic EMG changes in upper camptocormia.•Central and peripheral patomechanisms contribute to PD-related upper camptocormia.
Although restless legs syndrome (RLS) is a common neurological disorder, it remains poorly understood from both clinical and pathophysiological perspectives. RLS is classified among sleep-related ...movement disorders, namely, conditions characterized by simple, often stereotyped movements occurring during sleep. However, several clinical, neurophysiological and neuroimaging observations question this view. The aim of the present review is to summarize and query some of the current concepts (known knowns) and to identify open questions (known unknowns) on RLS pathophysiology. Based on several lines of evidence, we propose that RLS should be viewed as a disorder of sensorimotor interaction with a typical circadian pattern of occurrence, possibly arising from neurochemical dysfunction and abnormal excitability in different brain structures.
Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines ...in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with neuropathic pain (NP). We recruited a group of 32 type 2 DM patients who underwent serum cytokines (TNF-α, IL-2, IL-4, IL-6, and IL-10) dosage as well as electrodiagnostic and quantitative sensory testing (QST) assessment to explore damage to large and small nerve fibers. Raised serum levels of IL-6 and IL-10 correlated with markers of large nerve fiber sensory and motor axonal damage. Raised IL-10 serum level was associated with signs of motor nerve demyelination. No differences were found in pain characteristics and electrodiagnostic and QST markers of small nerve fiber function in relation to cytokines serum levels. IL-6 and IL-10 serum levels were associated with large nerve fiber damage but not to small fibers function or NP. IL-6 and IL-10 cytokines might play a role in the pathogenesis of nerve fiber damage or represent a compensatory or neuroprotective mechanism.
Background
The treatment of chronic pain is still unsatisfactory. Despite the availability of different drugs, most patients with chronic pain do not receive satisfactory pain relief or report side ...effects. Converging evidence implicates involvement of the immune system in the pathogenesis of different types of nociceptive and neuropathic chronic pain.
Design
At a workshop in Liverpool, UK (October 2012), experts presented evidence suggesting immunological involvement in chronic pain and recent data supporting the concept that the established immune‐modulating drug, polyvalent immunoglobulin G (IgG), either given intravenously (IVIg) or subcutaneously (SCIg), may reduce pain in some peripheral neuropathies and a range of other pain disorders. Workshop's attendees discussed the practicalities of using IVIg and SCIg in these disorders, including indications, cost‐effectiveness, and side effects.
Results
IgG may reduce pain in a range of nociceptive and neuropathic chronic pain conditions, including diabetes mellitus, Sjögren's syndrome, fibromyalgia, complex regional pain syndrome, post‐polio syndrome, and pain secondary to pathological autoantibodies.
Conclusions
IgG is a promising treatment in several chronic pain conditions. IgG is a relatively safe therapeutic strategy, with uncommon and mild side effects but high costs. Randomized, controlled trials and predictive tests are needed to better support the use of IgG for refractory chronic pain.
Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) is a rare painful peripheral neuropathic complication of diabetes mellitus. The clinical features of DLRPN include severe neuropathic pain, ...weakness, atrophy, and sensory loss in the lower limbs with asymmetrical distribution. Nerve ischemia due to inflammation and microvasculitis has been suggested as the pathophysiological mechanism for DLRPN. Analgesics and drugs for neuropathic pain often cannot achieve adequate pain control in DLRPN. Some reports suggest that intravenous immunoglobulin (IVIg) may reduce pain in DLRPN, but the mechanisms of this effect are unclear.
We report a patient with relapsing DLRPN who was followed up for 8 years and whose pain improved after IVIg on nine occasions. We measured serum cytokines before and after IVIg; serum tumor necrosis factor α was increased when the patient reported pain and normalized after IVIg in parallel with pain improvement.
Our data extend the notion that some types of pain, including peripheral neuropathic pain, may respond to IVIg and give some clue on the mechanism of this therapeutic effect. They are also consistent with the suggested role of the immune system in the pathophysiology of neuropathic pain and offer support to the hypothesis that cytokines may contribute to the pathogenesis of neuropathic pain.
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