Rigidity in Parkinson's disease: evidence from biomechanical and neurophysiological measures.

Although rigidity is a cardinal motor sign in patients with Parkinson's disease (PD), the instrumental measurement of this clinical phenomenon is largely lacking, and its pathophysiological underpinning remains still unclear. Further advances in the field would require innovative methodological approaches able to measure parkinsonian rigidity objectively, discriminate the different biomechanical sources of muscle tone (neural or visco-elastic components), and finally clarify the contribution to 'objective rigidity' exerted by neurophysiological responses, which have previously been associated with this clinical sign (i.e. the long-latency stretch-induced reflex). Twenty patients with PD (67.3 ± 6.9 years) and 25 age- and sex-matched controls (66.9 ± 7.4 years) were recruited. Rigidity was measured clinically and through a robotic device. Participants underwent robot-assisted wrist extensions at seven different angular velocities randomly applied, when ON therapy. For each value of angular velocity, several biomechanical (i.e. elastic, viscous and neural components) and neurophysiological measures (i.e. short and long-latency reflex and shortening reaction) were synchronously assessed and correlated with the clinical score of rigidity (i.e. Unified Parkinson's Disease Rating Scale-part III, subitems for the upper limb). The biomechanical investigation allowed us to measure 'objective rigidity' in PD and estimate the neuronal source of this phenomenon. In patients, 'objective rigidity' progressively increased along with the rise of angular velocities during robot-assisted wrist extensions. The neurophysiological examination disclosed increased long-latency reflexes, but not short-latency reflexes nor shortening reaction, in PD compared with control subjects. Long-latency reflexes progressively increased according to angular velocities only in patients with PD. Lastly, specific biomechanical and neurophysiological abnormalities correlated with the clinical score of rigidity. 'Objective rigidity' in PD correlates with velocity-dependent abnormal neuronal activity. The observations overall (i.e. the velocity-dependent feature of biomechanical and neurophysiological measures of objective rigidity) would point to a putative subcortical network responsible for 'objective rigidity' in PD, which requires further investigation.

New Sensor and Wearable Technologies to Aid in the Diagnosis and Treatment Monitoring of Parkinson's Disease.

Parkinson's disease (PD) is a degenerative disorder of the brain characterized by the impairment of the nigrostriatal system. This impairment leads to specific motor manifestations (i.e., bradykinesia, tremor, and rigidity) that are assessed through clinical examination, scales, and patient-reported outcomes. New sensor-based and wearable technologies are progressively revolutionizing PD care by objectively measuring these manifestations and improving PD diagnosis and treatment monitoring. However, their use is still limited in clinical practice, perhaps because of the absence of external validation and standards for their continuous use at home. In the near future, these systems will progressively complement traditional tools and revolutionize the way we diagnose and monitor patients with PD.

Using wearables to assess bradykinesia and rigidity in patients with Parkinson's disease: a focused, narrative review of the literature.

The potential of using wearable technologies for the objective assessment of motor symptoms in Parkinson's disease (PD) has gained prominence recently. Nonetheless, compared to tremor and gait impairment, less emphasis has been placed on the quantification of bradykinesia and rigidity. This review aimed to consolidate the existing research on objective measurement of bradykinesia and rigidity in PD through the use of wearables, focusing on the continuous monitoring of these two symptoms in free-living environments. A search of PubMed was conducted through a combination of keyword and MeSH searches. We also searched the IEEE, Google Scholar, Embase, and Scopus databases to ensure thorough results and to minimize the chances of missing relevant studies. Papers published after the year 2000 with sample sizes greater than five were included. Studies were assessed for quality and information was extracted regarding the devices used and their location on the body, the setting and duration of the study, the "gold standard" used as a reference for validation, the metrics used, and the results of each paper. Thirty-one and eight studies met the search criteria and evaluated bradykinesia and rigidity, respectively. Several studies reported strong associations between wearable-based measures and the gold-standard references for bradykinesia, and, to a lesser extent, rigidity. Only a few, pilot studies investigated the measurement of bradykinesia and rigidity in the home and free-living settings. While the current results are promising for the future of wearables, additional work is needed on their validation and adaptation in ecological, free-living settings. Doing so has the potential to improve the assessment and treatment of motor fluctuations and symptoms of PD more generally through real-time objective monitoring of bradykinesia and rigidity.

Vastly Different Exercise Programs Similarly Improve Parkinsonian Symptoms: A Randomized Clinical Trial.

OBJECTIVES: To directly compare the effects of agility exergaming (EXE) and stationary cycling (CYC) exercise training on Parkinson's disease (PD) patients' mobility and clinical symptoms. DESIGN: Randomized clinical trial. SETTING: Outpatient physiotherapy clinic in a hospital. PARTICIPANTS: Seventy-four stage 2-3, nondemented PD patients were included in this study. INTERVENTION: The groups were as follows: EXE (n = 25), CYC (n = 25), and a wait-listed control group (CON; n = 24). The EXE and CYC groups exercised 5×/week for 5 weeks, matched at 80% of the age-predicted maximal heart rate. MAIN OUTCOMES: The primary outcome was the Movement Disorders Society Unified Parkinson's Disease Rating Scale (UPDRS-II) score. Secondary outcomes were Parkinson's Disease Quastionnaire-39 (PDQ-39), the Beck Depression Inventory (BDI), the Schwab and England Activities of Daily Living (SE-ADL) scale, Euro-Quality of Life-5 Dimensions (EQ-5D) questionnaire, the Berg Balance Scale (BBS), the Balance Evaluation Systems Test (BESTest), the Tinetti Assessment Tool (TAT), the Dynamic Gait Index, the 6-min walk test (6MWT), and standing posturography. RESULTS: After treatment, UPDRS-II scores improved (mean change: EXE, -4.5 points; CYC, -3.2 points). The results for the other outcomes (EXE and CYC, respectively) were: PDQ, 13 and 17%; BDI, -2.5 and -2.1 points; 6MWT, 129.6 and 141.6 m; and EQ-5D, 12 and 9% (all p < 0.05, but there was no difference between groups). EXE vs. CYC resulted in improved SE-ADL (8.4 and 4.0 points, effect size [ES]: 0.12), BBS (8.8 and 4.2 points, ES: 0.44), and 2 measures of posturography (ES: 0.11 and 0.21) (p < 0.05). BESTtest, TAT, the Dynamic Gait Index, and 4 out of 6 posturography measures did not change (p > 0.05). CONCLUSION: Two highly different exercise programs resulted in similar improvement of most motor and clinical symptoms in PD patients.

Fact-finding survey on diagnostic procedures and therapeutic interventions for parkinsonism accompanying dementia with Lewy bodies.

BACKGROUND: We performed a questionnaire survey of medical doctors engaged in the management of dementia to identify the actual status of treatment for dementia with Lewy bodies (DLB) in Japan. METHODS: Among participating medical doctors, we selected neurologists (Group N) and psychiatrists (Group P) because these physicians are usually involved in the management of DLB patients. The two groups were compared based on their diagnosis and treatment of DLB and in particular, parkinsonism. RESULTS: Neurological examinations and biomarker tests were less frequently performed by Group P than Group N. Antipsychotics and other psychotropics excluding anti-dementia drugs were significantly more frequently administered by Group P than Group N. The proportion of physicians who selected L-dopa as a first-line therapy for parkinsonism was significantly higher in Group N than in Group P. Despite these between-group differences, the following findings were common to the two groups: there was a discrepancy between the symptom that patients expressed the greatest desire to treat, and the awareness of physicians regarding the treatment of these symptoms; the initial agent was L-dopa; and physicians exercised caution against the occurrence of hallucinations, delusions, and other adverse drug reactions. CONCLUSIONS: The results of the present survey offer valuable insight for the formulation of future DLB therapeutic strategies.

Muscular MRI-based algorithm to differentiate inherited myopathies presenting with spinal rigidity.

OBJECTIVES: Inherited myopathies are major causes of muscle atrophy and are often characterized by rigid spine syndrome, a clinical feature designating patients with early spinal contractures. We aim to present a decision algorithm based on muscular whole body magnetic resonance imaging (mWB-MRI) as a unique tool to orientate the diagnosis of each inherited myopathy long before the genetically confirmed diagnosis. METHODS: This multicentre retrospective study enrolled 79 patients from referral centres in France, Brazil and Chile. The patients underwent 1.5-T or 3-T mWB-MRI. The protocol comprised STIR and T1 sequences in axial and coronal planes, from head to toe. All images were analyzed manually by multiple raters. Fatty muscle replacement was evaluated on mWB-MRI using both the Mercuri scale and statistical comparison based on the percentage of affected muscle. RESULTS: Between February 2005 and December 2015, 76 patients with genetically confirmed inherited myopathy were included. They were affected by Pompe disease or harbored mutations in RYR1, Collagen VI, LMNA, SEPN1, LAMA2 and MYH7 genes. Each myopathy had a specific pattern of affected muscles recognizable on mWB-MRI. This allowed us to create a novel decision algorithm for patients with rigid spine syndrome by segregating these signs. This algorithm was validated by five external evaluators on a cohort of seven patients with a diagnostic accuracy of 94.3% compared with the genetic diagnosis. CONCLUSION: We provide a novel decision algorithm based on muscle fat replacement graded on mWB-MRI that allows diagnosis and differentiation of inherited myopathies presenting with spinal rigidity. KEY POINTS: • Inherited myopathies are rare, diagnosis is challenging and genetic tests require specialized centres and often take years. • Inherited myopathies are often characterized by spinal rigidity. • Whole body magnetic resonance imaging is a unique tool to orientate the diagnosis of each inherited myopathy presenting with spinal rigidity. • Each inherited myopathy in this study has a specific pattern of affected muscles that orientate diagnosis. • A novel MRI-based algorithm, usable by every radiologist, can help the early diagnosis of these myopathies.

A case report of rigidity and recurrent lower limb myoclonus: progressive encephalomyelitis rigidity and myoclonus syndrome, a chameleon.

BACKGROUND: Progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome is a rare neurological condition. Its clinical characteristics include axial and limb muscle rigidity, myoclonus, painful spasms and hyperekplexia. Diagnosis of this disease can be very challenging and optimal long-term treatment is unclear. CASE PRESENTATION: We report a case of a 62 year old patient admitted for repetitive myoclonus and rigidity in the lower limbs progressing since 10 years, associated with a fluctuating encephalopathy requiring stays in Intensive Care Unit. Multiple diagnostics and treatment were proposed, unsuccessfully, before the diagnosis of PERM syndrome was established. In association with the clinical presentation, a strong positive result for GAD (glutamic acid decarboxylase) antibodies lead to the diagnosis of PERM syndrome. CONCLUSIONS: PERM syndrome is a rare disease and its diagnosis is not easy. Once the diagnosis is established, the correct treatment should follow and could be lifesaving, regardless of a delayed diagnosis. Maintenance of long-term oral corticotherapy is suggested to prevent relapses.

[From stiff man syndrome to stiff person spectrum disorders]. / Vom Stiff-man-Syndrom zu den Stiff-person-Spektrum-Erkrankungen.

The identification of new variants of the stiff man syndrome (SMS) and of new, probably pathogenic neuronal autoantibodies has led to the concept of stiff man (or person) spectrum disorders (SPSD). This is an expanding group of rare chronic autoimmune inflammatory diseases of the central nervous system (CNS) that have in common the main symptoms of fluctuating rigidity and spasms with pronounced stimulus sensitivity. These core symptoms are mandatory and can be accompanied by a wide variety of other neurological signs. The SPSDs are associated with autoantibodies directed against neuronal proteins that attenuate excitability. Neither clinical phenotypes nor the course of SPSD correlate closely with the antibody status. The treatment of these diseases aims at maintaining mobility and is pragmatically oriented to the degree of impediment and comprises antispastic, anticonvulsant and immunomodulating or immunosuppressive medication strategies.

Parkinsonian syndromes presenting with circadian rhythm sleep disorder- advanced sleep-phase type.

BACKGROUND: Circadian rhythm sleep disorder-advanced sleep-phase type is a relatively uncommon disorder, mostly seen among the elderly population. Impaired circadian rhythms have been reported in neurodegenerative conditions; however, there are no reports of any circadian rhythm sleep disorder among patients with Parkinsonian syndromes. We report two patients who presented with this circadian rhythm disorder, and were then diagnosed with a Parkinsonian syndrome. The cases. A 65-year-old retired man presented with history of abrupt change in sleep schedules, sleeping around 6.30-7 p.m. and waking up around 3-4 a.m. for the last 2 months. On detailed examination, the patient was observed to have symmetrical bradykinesia and cogwheel rigidity of limbs. A diagnosis of multiple system atrophy was made, supported by MRI findings and evidence of autonomic dysfunction. Symptoms of change in sleep-wake cycles resolved over the next 1 year, while the patient was treated with dopaminergic therapy. A 47-year-old man, who was being evaluated for presurgical investigation for refractory temporal lobe epilepsy, presented with complaints suggestive of dysarthria, bradykinesia of limbs and frequent falls for 5 months. Simultaneously, he began to sleep around 7 p.m. and wake up at about 2-3 a.m. Examination revealed severe axial rigidity, restricted vertical gaze and bradykinesia of limbs. A diagnosis of progressive supranuclear palsy was made. CONCLUSION: This is the first report of Parkinson's plus syndromes presenting with a circadian rhythm sleep disorder-advanced sleep-phase type. More prospective assessment for circadian sleep disorders may introduce useful insights into similar associations.

Neonatal seizures-part 1: Not everything that jerks, stiffens and shakes is a fit.

The neonatal period is the most frequent time of life to have epileptic seizures. However, neonates can also exhibit unusual movements that are not epileptic seizures. Differentiating between epileptic and non-epileptic movements can be difficult. Many neonatal seizures exhibit few or no clinical features at all. This article is for the benefit of paediatric trainees and reviews the published evidence on which neonatal movements are likely to be epileptic seizures and which are not. We also discuss epileptic seizure classification.

Stiff Person Syndrome.

Stiff-person syndrome or Moersch-Woltmann is a very rare and disabling neurologic disorder characterized by muscle rigidity and episodic spasms involving axial and limb musculature. It is an autoimmune disorder resulting in a malfunction of aminobutyric acid mediated inhibitory networks in the central nervous system. We describe a patient of stiff person syndrome.

Clinical features in antiglycine receptor antibody-related disease: a case report and update literature review.

Background and objectives: Antiglycine receptor (anti-GlyR) antibody mediates multiple immune-related diseases. This study aimed to summarize the clinical features to enhance our understanding of anti-GlyR antibody-related disease. Methods: By collecting clinical information from admitted patients positive for glycine receptor (GlyR) antibody, the clinical characteristics of a new patient positive for GlyR antibody were reported in this study. To obtain additional information regarding anti-GlyR antibody-linked illness, clinical data and findings on both newly reported instances in this study and previously published cases were merged and analyzed. Results: A new case of anti-GlyR antibody-related progressive encephalomyelitis with rigidity and myoclonus (PERM) was identified in this study. A 20-year-old man with only positive cerebrospinal fluid anti-GlyR antibody had a good prognosis with first-line immunotherapy. The literature review indicated that the common clinical manifestations of anti-GlyR antibody-related disease included PERM or stiff-person syndrome (SPS) (n = 179, 50.1%), epileptic seizure (n = 94, 26.3%), and other neurological disorders (n = 84, 24.5%). Other neurological issues included demyelination, inflammation, cerebellar ataxia and movement disorders, encephalitis, acute psychosis, cognitive impairment or dementia, celiac disease, Parkinson's disease, neuropathic pain and allodynia, steroid-responsive deafness, hemiballism/tics, laryngeal dystonia, and generalized weakness included respiratory muscles. The group of PERM/SPS exhibited a better response to immunotherapy than others. Conclusions: The findings suggest the presence of multiple clinical phenotypes in anti-GlyR antibody-related disease. Common clinical phenotypes include PERM, SPS, epileptic seizure, and paraneoplastic disease. Patients with RERM/SPS respond well to immunotherapy.

Stiff Person Syndrome and GAD Antibody-Spectrum Disorders.

OBJECTIVE: Antibodies against glutamic acid decarboxylase (GAD), originally associated with stiff person syndrome (SPS), define the GAD antibody-spectrum disorders that also include cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and eye movement disorders, all of which are characterized by autoimmune neuronal excitability. This article elaborates on the diagnostic criteria for SPS and SPS spectrum disorders, highlights disease mimics and misdiagnoses, describes the electrophysiologic mechanisms and underlying autoimmunity of stiffness and spasms, and provides a step-by-step therapeutic scheme. LATEST DEVELOPMENTS: Very-high serum GAD antibody titers are diagnostic for GAD antibody-spectrum disorders and also predict the presence of GAD antibodies in the CSF, increased intrathecal synthesis, and reduced CSF γ-aminobutyric acid (GABA) levels. Low serum GAD antibody titers or the absence of antibodies generates diagnostic challenges that require careful distinction in patients with a variety of painful spasms and stiffness, including functional neurologic disorders. Antibodies against glycine receptors, first found in patients with PERM, are seen in 13% to 15% of patients with SPS, whereas amphiphysin and gephyrin antibodies, seen in 5% of patients with SPS spectrum disorders, predict a paraneoplastic association. GAD-IgG from different SPS spectrum disorders recognizes the same dominant GAD intracellular epitope and, although the pathogenicity is unclear, is an excellent diagnostic marker. The biological basis of muscle stiffness and spasms is related to autoimmune neuronal hyperexcitability caused by impaired reciprocal γ-aminobutyric acid-mediated (GABA-ergic) inhibition, which explains the therapeutic response to GABA-enhancing agents and immunotherapies. ESSENTIAL POINTS: It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses, considering that SPS is treatable if managed correctly from the outset to prevent disease progression. A step-by-step, combination therapy of GABA-enhancing medications along with immunotherapies ensures prolonged clinical benefits.

Novel mutation in GLRB in a large family with hereditary hyperekplexia.

Hereditary hyperekplexia (HH) is a disorder of the inhibitory glycinergic neurotransmitter system. Mutations in five genes have been reported to cause the disease. However, only single mutation in GLRB, the gene encoding beta-subunit of the glycine receptor, in a singleton patient with HH has been found to date. In this study, 13 patients with HH were identified through neurology and genetic clinics. Formal clinical examinations, linkage analysis, homozygosity mapping, in-mutation screening of GLRB and in silico functional analyses were carried out. A novel mutation in GLRB among nine patients was identified. This c.596 T>G perturbation results in the change of the highly conserved methionine at position 177 to arginine. Besides the classical HH phenotype, seven patients had esotropia and few of them had behavioral problems. This study presents a large family with HH as a result of homozygous mutation in GLRB and expands the clinical spectrum of HH to include eye misalignment disorder. Moreover, the report of these familial cases supports the previous evidence in a single patient of an autosomal recessive inheritance of HH because of defects in GLRB.

Stiff Person syndrome and other anti-GAD-associated neurologic disorders.

Antibodies directed against glutamic acid decarboxylase (GAD) are present in many patients with stiff person syndrome and increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia. The classic clinical features of stiff person syndrome include muscular stiffness with superimposed painful muscular spasms. Gait is often impaired. Other CNS disorders associated with GAD antibodies include progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and even epilepsy. Glutamic acid decarboxylase is the rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter. Presumably, antibodies directed against GAD impair GABA production, but the precise pathogenic mechanism of GAD-antibody-related neurologic disorders is uncertain. Many patients respond to treatment with immunomodulating therapy. Symptomatic treatment with agents that enhance GABA activity, such as benzodiazepines and baclofen, is also helpful for many patients.

A torque-based method demonstrates increased rigidity in Parkinson's disease during low-frequency stimulation.

Low-frequency oscillations in the basal ganglia are prominent in patients with Parkinson's disease off medication. Correlative and more recent interventional studies potentially implicate these rhythms in the pathophysiology of Parkinson's disease. However, effect sizes have generally been small and limited to bradykinesia. In this study, we investigate whether these effects extend to rigidity and are maintained in the on-medication state. We studied 24 sides in 12 patients on levodopa during bilateral stimulation of the STN at 5, 10, 20, 50, 130 Hz and in the off-stimulation state. Passive rigidity at the wrist was assessed clinically and with a torque-based mechanical device. Low-frequency stimulation at ≤20 Hz increased rigidity by 24 % overall (p = 0.035), whereas high-frequency stimulation (130 Hz) reduced rigidity by 18 % (p = 0.033). The effects of low-frequency stimulation (5, 10 and 20 Hz) were well correlated with each other for both flexion and extension (r = 0.725 ± SEM 0.016 and 0.568 ± 0.009, respectively). Clinical assessments were unable to show an effect of low-frequency stimulation but did show a significant effect at 130 Hz (p = 0.002). This study provides evidence consistent with a mechanistic link between oscillatory activity at low frequency and Parkinsonian rigidity and, in addition, validates a new method for rigidity quantification at the wrist.