Deep brain stimulation of symptom-specific networks in Parkinson's disease.

Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson's disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the four symptom domains. Tremor improvements were associated with stimulation of tracts connected to primary motor cortex and cerebellum. In contrast, axial symptoms are associated with stimulation of tracts connected to the supplementary motor cortex and brainstem. Bradykinesia and rigidity improvements are associated with the stimulation of tracts connected to the supplementary motor and premotor cortices, respectively. We introduce an algorithm that uses these symptom-response tracts to suggest optimal stimulation parameters for DBS based on individual patient's symptom profiles. Application of the algorithm illustrates that our symptom-tract library may bear potential in personalizing stimulation treatment based on the symptoms that are most burdensome in an individual patient.

Spinal cord stimulation for the symptomatic treatment of rigidity and painful spasm in a case of stiff person syndrome.

BACKGROUND: Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by rigidity and painful spasm primarily affecting the truncal and paraspinal musculature due to autoimmune-mediated neuronal hyperexcitability. Spinal cord stimulation (SCS) is an approved therapy for managing painful neuropathic conditions, including diabetic peripheral neuropathy and refractory angina pectoris. We describe the novel use of SCS for the treatment of spasm and rigidity in a 49-year-old man with seropositive stiff person syndrome (SPS). The patient was treated with intravenous immunoglobulin (IVIG) and oral medications over a 13-month period with minimal improvement, prompting consideration of SCS. To our knowledge, this is the first report of the successful use of SCS in SPS with the demonstration of multifaceted clinical improvement. METHODS: Following a successful temporary SCS trial, permanent implantation was performed. Spasm/stiffness (Distribution of Stiffness Index; Heightened Sensitivity Scale; Penn Spasm Frequency Scale, PSFS), disability (Oswestry Disability Index, ODI; Pain Disability Index, PDI), depression (Patient Health Questionnaire-9, PHQ-9), sleep (Pittsburgh Sleep Quality Index, PSQI), fatigue (Fatigue Severity Scale, FSS), pain (Numerical Pain Rating Scale, NPRS), quality of life (EuroQoL 5 Dimension 5 Level, EQ-5D-5L), and medication usage were assessed at baseline, 6-month, and 10-month postimplantation. RESULTS: ODI, PHQ-9, FSS, NPRS, PSQI, and EQ-5D-5L scores showed a notable change from baseline and surpassed the defined minimal clinically important difference (MCID) at 6-month and 10-month follow-up. Oral medication dosages were reduced. CONCLUSIONS: The novel use of SCS therapy in seropositive SPS resulted in functional improvement and attenuation of symptoms. We present possible mechanisms by which SCS may produce clinical response in patients with SPS and aim to demonstrate proof-of-concept for a future comprehensive pilot study evaluating SCS-mediated response in SPS.

Tone Reduction and Physical Therapy: Strengthening Partners in Treatment of Children with Spastic Cerebral Palsy.

The aim of this paper is to provide a clinically applicable overview of different tone reducing modalities and how these can interact with or augment concurrent physical therapy (PT). Botulinum toxin (BoNT), oral tone-regulating medication, intrathecal baclofen (ITB), and selective dorsal rhizotomy are discussed within a physiotherapeutic context and in view of current scientific evidence. We propose clinical reasoning strategies to identify treatment goals as well as the appropriate and corresponding treatment interventions. Instrumented measurement of spasticity, standardized clinical assessment, and 3D clinical motion analysis are scientifically sound tools to help select the appropriate treatment and, when needed, to selectively target or spare individual muscles. In addition, particular attention is given to strength training as a necessary tool to tackle muscle weakness associated with specific modalities of tone reduction. More research is needed to methodologically assess the long-term effectiveness of such individualized tone treatment, optimize parameters such as medication dosage, and gain more insight into the kind of PT techniques that are essential in conjunction with tone reduction.

Washout of chronic therapeutic deep brain stimulation increases cortical phase-amplitude coupling.

Invasive human brain recordings have shown that acute therapeutic deep brain stimulation (DBS) reduces cortical synchronization, measured by coupling of beta phase to gamma amplitude. Here we show by noninvasive scalp electroencephalography that withdrawal of chronic DBS elevates phase-amplitude coupling, in proportion to the worsening of contralateral rigidity.

Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease.

OBJECTIVE: To investigate whether functional sweet spots of deep brain stimulation (DBS) in the subthalamic nucleus (STN) can predict motor improvement in Parkinson disease (PD) patients. METHODS: Stimulation effects of 449 DBS settings in 21 PD patients were clinically and quantitatively assessed through standardized monopolar reviews and mapped into standard space. A sweet spot for best motor outcome was determined using voxelwise and nonparametric permutation statistics. Two independent cohorts were used to investigate whether stimulation overlap with the sweet spot could predict acute motor outcome (10 patients, 163 settings) and long-term overall Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) improvement (63 patients). RESULTS: Significant clusters for suppression of rigidity and akinesia, as well as for overall motor improvement, resided around the dorsolateral border of the STN. Overlap of the volume of tissue activated with the sweet spot for overall motor improvement explained R2 = 37% of the variance in acute motor improvement, more than triple what was explained by overlap with the STN (R2 = 9%) and its sensorimotor subpart (R2 = 10%). In the second independent cohort, sweet spot overlap explained R2 = 20% of the variance in long-term UPDRS-III improvement, which was equivalent to the variance explained by overlap with the STN (R2 = 21%) and sensorimotor STN (R2 = 19%). INTERPRETATION: This study is the first to predict clinical improvement of parkinsonian motor symptoms across cohorts based on local DBS effects only. The new approach revealed a distinct sweet spot for STN DBS in PD. Stimulation overlap with the sweet spot can predict short- and long-term motor outcome and may be used to guide DBS programming. ANN NEUROL 2019;86:527-538.

Anti-glutamic acid decarboxylase (GAD) positive cerebellar Ataxia with transitioning to progressive encephalomyelitis with rigidity and myoclonus (PERM), responsive to immunotherapy: A case report and review of literature.

We present a case of a 65-year-old African American male, immunosuppressed on Tacrolimus, who initially presented with cerebellar ataxia and rapidly developed Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) with positive anti-glutamic acid decarboxylase (GAD65) antibodies, no underlying malignancy, and normal neuroimaging. PERM is a rare spectrum of Stiff Person Syndrome (SPS), which is strongly associated with anti-GAD antibodies and characterized by flare-ups and remissions of encephalopathy, myelopathy and rigidity with myoclonus. PERM is diagnosed clinically and has been successfully treated with both Intravenous Immunoglobulin (IVIg) and plasmapheresis. Our patient was successfully treated with IVIg. On day 14 after starting IVIg treatment, his neurological symptoms started to improve and ultimately returned to baseline.

The long-term efficacy of STN vs GPi deep brain stimulation for Parkinson disease: A meta-analysis.

OBJECTIVE: This meta-analysis assessed the long-term efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) for Parkinson disease (PD). METHODS: PubMed, Cochrane Library, and Clinical Trials databases were searched. Outcomes were unified Parkinson disease rating scale section (UPDRS) III off-medication score, Parkinson's disease questionnaire: 39 activities of daily living (PDQ-39 ADL) score, and levodopa-equivalent dosage after DBS. RESULTS: During the off-medication state, pooled weighted mean difference (WMD) of UPDRS III score was .69 (95% confidence interval [CI] = -1.77 to 3.16, P = .58). In subgroup analysis, WMD of UPDRS III off-medication scores from baseline to 2 years and 3 years post-DBS were -.61 (95% CI = -2.97 to 1.75, P = .61) and 2.59 (95% CI = -2.30 to 7.47, P = .30). Pooled WMD of changes in tremor, rigidity, and gait scores were 1.12 (95% CI = -0.05 to 2.28, P = .06), 1.22 (95% CI = -0.51 to 2.94, P = .17) and .37 (95% CI = -0.13 to 0.87, P = .15), respectively. After DBS, pooled WMD of PDQ-39 ADL and LED were -3.36 (95% CI = -6.36 to -0.36, P = .03) and 194.89 (95% CI = 113.16 to 276.63, P < .001). CONCLUSIONS: STN-DBS and GPi-DBS improve motor function and activities of daily living for PD. Differences in the long-term efficacy for PD on motor symptoms were not observed.

[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.

Thymoma-associated Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) with Myasthenia Gravis.

We report a case of a 72-year-old woman who initially presented with symptoms of bulbar myasthenia and was positive for anti-acetylcholine receptor antibodies. She subsequently developed painful muscle spasms, myoclonus, and stiffness. Thymoma was detected, and both anti-glycine receptor and anti-glutamic acid decarboxylase antibodies were found. She was diagnosed with thymoma-associated progressive encephalomyelitis with rigidity and myoclonus (PERM). She experienced marked improvement after thymectomy followed by plasma exchange and intravenous immunoglobulin and prednisolone. This case suggests that thymectomy followed by sufficient immunosuppression may be useful in the treatment of thymoma-associated PERM. Myasthenia gravis may develop in thymoma-associated PERM patients.

Rigid shoulder taping with physiotherapy in patients with subacromial pain syndrome: A randomized controlled trial.

OBJECTIVE: To assess the effectiveness of individualized physiotherapy in combination with rigid taping compared with individualized physiotherapy alone in patients with subacromial pain syndrome. DESIGN: A prospective randomized trial with concealed allocation. PATIENTS: A total of 140 patients between 18 and 65 years of age from primary physiotherapy settings. METHODS: The intervention group received individualized physiotherapy and shoulder taping. The control group received individualized physiotherapy only. Primary outcomes were: pain intensit (numerical rating scale) and functioning (Simple Shoulder Test). Secondary outcomes were: global perceived effect and patient-specific complaints. Data were collected at baseline, and at 4, 12 and 26 weeks' follow-up. RESULTS: During the 6-month follow-up period multilevel analysis showed a significant difference between groups favouring the control group on pain intensity (p = 0.02), but not on functioning. Regarding secondary outcomes, a significant difference between groups was found favouring the intervention group for global perceived effect (p = 0.02), but not for patient-specific complaints. CONCLUSION: Rigid shoulder taping, as used in this study, cannot be recommended for improving physiotherapy outcomes in people with subacromial pain syndrome.

Redefining progressive encephalomyelitis with rigidity and myoclonus after the discovery of antibodies to glycine receptors.

PURPOSE OF REVIEW: This review highlights the recent discovery of antibodies to glycine receptor (GlyR-Ab) and discusses the relationship between these antibodies and neurological disorders. RECENT FINDINGS: Since the initial description in 2008 of antibodies to glycine receptors (GlyR-Abs) in a patient with progressive encephalomyelitis with rigidity and myoclonus (PERM), these antibodies have been found in PERM and in some patients with a variety of stiff person spectrum (SPS) or related disorders. Patients with GlyR-Abs often improve with aggressive immunotherapy, and antibody titres correlate with disease severity. Around 25% of patients have another autoimmune condition and 10-20% have an underlying malignancy. GlyR-Abs bind to extracellular determinants, are mainly Immunoglobulin G1 subclass and induce GlyR internalization in Human embryonic kidney 293 cells, suggesting pathogenicity. The spectrum of neurological disease associated with GlyR-Abs has not been fully characterized, and lower titres may not be syndrome specific, but GlyR-Abs, like antibodies to other neuronal cell-surface antigens, define immunotherapy-responsive disease and are likely to be pathogenic. This distinguishes them from the glutamic acid decarboxylase antibodies that can also be found at high titres in patients with classical stiff person syndrome which is more often chronic and relatively resistant to immunological treatments. SUMMARY: Irrespective of the clinical features, GlyR-Abs are helpful in the diagnosis of patients who very often have a subacute, progressive and life-threatening disorder which shows a favourable response to immunotherapy.

Forma focal y de larga evolución del síndrome de la persona rígida / Focal gradual-onset variant of stiff-person syndrome

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Changes in intracortical inhibition and clinical symptoms after STN-DBS in Parkinson's disease.

OBJECTIVES: To examine effects of subthalamic nucleus deep brain stimulation (STN-DBS) on intracortical inhibition in Parkinson's disease (PD) and the correlation between intracortical inhibition and clinical symptoms after alteration of STN-DBS status. METHODS: Nine PD patients treated by STN-DBS were compared with eight age-matched controls. Antiparkinsonian medication was withdrawn 12h before the study. Short-interval intracortical inhibition (SICI) with a 3-ms interval and silent period (SP) were examined using transcranial magnetic stimulation. SP duration, SICI and motor symptoms (rigidity and tremor) were evaluated with STN-DBS ON, and over 120 min during STN-DBS OFF. RESULTS: Even during STN-DBS, PD patients showed a shortened SP and reduced SICI relative to normal controls. SICI decreased further throughout STN-DBS OFF, resulting in facilitation rather than inhibition; SP shortened only after 120 min STN-DBS OFF. Both rigidity and tremor worsened throughout STN-DBS OFF, with a time course similar to SICI. CONCLUSION: Even during STN-DBS, both SICI and SP in PD patients remain impaired without medication. Changes in SICI, but not SP, show a time course similar to those of motor symptoms. SIGNIFICANCE: The dissimilarity of SICI and SP changes suggests differences in mediation of inhibitory mechanisms and/or superimposition of exaggerated intracortical facilitation on SICI.

Acupuncture for Erectile Dysfunction: A Systematic Review.

BACKGROUND: Acupuncture is increasingly used to treat patients with erectile dysfunction (ED), and our systematic review aimed to evaluate the current evidence for the efficacy and safety of acupuncture in treating ED. METHODS: An electronic search was conducted in eight databases to identify randomized controlled trials (RCTs) of acupuncture for treating erectile dysfunction that were published in English and Chinese. The Cochrane Risk of Bias tool was used to assess the risk of bias. RESULTS: Three RCTs with a total of 183 participants met the inclusion criteria. One trial showed the beneficial effects of acupuncture compared with sham acupuncture while the others did not. One trial suggested that acupuncture combined with psychological therapy was superior to psychological therapy alone. However, the overall methodological and reporting quality of the studies was low. The safety of acupuncture for ED was unclear because there were too few reports on this topic. CONCLUSION: The available evidence supporting that acupuncture alone improves ED was insufficient and the available studies failed to show the specific therapeutic effect of acupuncture. Future well-designed and rigorous RCTs with a large sample size are required. This trial is registered with CRD42014013575.

Placebo effects induced by auditory cues decrease parkinsonian rigidity in patients with subthalamic stimulation.

Placebo effects are the consequence of an interaction between an organism and its surroundings and may be influenced by cues from the environment. Our study was designed to analyze if conditioned auditory cues could trigger placebo effects and affect parkinsonian rigidity as measured by viscoelastic properties of skeletal muscles in patients treated with subthalamic stimulation. We found that after repeatedly associating with the effect of deep brain stimulation on rigidity, a common dial phone signal itself was able to reduce the mean values of viscoelastic stiffness in the placebo stage (368.8±50.4Nm(-1)) as compared to the stimulation-off conditions (383.7±61.2Nm(-1)) (q=4.18; p<0.05) in ten patients with Parkinson's disease. Thus, it appears that due to associative learning processes environmental cues can acquire the capacity to trigger placebo effects affecting the clinical status of the patients.

GAD Antibodies as Key Link Between Chronic Intestinal Pseudoobstruction, Autonomic Neuropathy, and Limb Stiffness in a Nondiabetic Patient: A CARE-Compliant Case Report and Review of the Literature.

Chronic intestinal pseudoobstruction (CIP) can be a severe burden and even a life-threatening disorder. Typically, several years of uncertainty are passing before diagnosis. We are reporting the case of a young woman with a decade of severe, progressive gastrointestinal dysmotility. Unusually, she had also developed an autonomic neuropathy, and a stiff limb syndrome.In addition to achalasia and CIP the young woman also developed neuropathic symptoms: orthostatic intolerance, urinary retention, a Horner syndrome, and lower limb stiffness. Careful interdisciplinary diagnostics excluded underlying infectious, rheumatoid, metabolic or tumorous diseases.The detection of GAD (glutamic acid decarboxylase) antibodies, however, seemed to link CIP, autonomic neuropathy, and limb stiffness and pointed at an autoimmune origin of our patient's complaints. This was supported by the positive effects of intravenous immunoglobulin. In response to this therapy the body weight had stabilized, orthostatic tolerance had improved, and limb stiffness was reversed.The case suggested that GAD antibodies should be considered in CIP also in nondiabetic patients. This may support earlier diagnosis and immunotherapy.