Lazzaro di Biase

Low‐frequency deep brain stimulation for Parkinson's disease: Great expectation or false hope?

The long‐term efficacy of subthalamic deep brain stimulation for Parkinsons disease is not always retained, and many patients lose the improvement achieved during the “second honeymoon” following surgery. Deep brain stimulation is a versatile tool, as stimulation parameters may undergo a fine‐tuning depending on clinical needs. Among them, frequency is the parameter that leads to more complex scenarios because there is no generalizable relationship between its modulation and the overall clinical response, which also depends on the specific considered sign. High‐frequency stimulation (>100 Hz) has shown to be effective in improving most parkinsonian signs, particularly the levodopa‐responsive ones. However, its effect on axial signs (such as balance, gait, speech, or swallowing) may not be sustained, minimal, or even detrimental. For these reasons, several studies have explored the effectiveness of low‐frequency stimulation (generally 60 or 80 Hz). Methods, results, and especially interpretations of these studies are quite variable. Although the use of low‐frequency stimulation certainly opens new avenues in the field of deep brain stimulation, after having gathered all the available evidence in patients with subthalamic implants, our conclusion is that it might be clinically useful mainly when it lessens the detrimental effects of high‐frequency stimulation.

Tremor stability index: a new tool for differential diagnosis in tremor syndromes.

Misdiagnosis among tremor syndromes is common, and can impact on both clinical care and research. To date no validated neurophysiological technique is available that has proven to have good classification performance, and the diagnostic gold standard is the clinical evaluation made by a movement disorders expert. We present a robust new neurophysiological measure, the tremor stability index, which can discriminate Parkinson’s disease tremor and essential tremor with high diagnostic accuracy. The tremor stability index is derived from kinematic measurements of tremulous activity. It was assessed in a test cohort comprising 16 rest tremor recordings in tremor-dominant Parkinson’s disease and 20 postural tremor recordings in essential tremor, and validated on a second, independent cohort comprising a further 50 tremulous Parkinson’s disease and essential tremor recordings. Clinical diagnosis was used as gold standard. One hundred seconds of tremor recording were selected for analysis in each patient. The classification accuracy of the new index was assessed by binary logistic regression and by receiver operating characteristic analysis. The diagnostic performance was examined by calculating the sensitivity, specificity, accuracy, likelihood ratio positive, likelihood ratio negative, area under the receiver operating characteristic curve, and by cross-validation. Tremor stability index with a cut-off of 1.05 gave good classification performance for Parkinson’s disease tremor and essential tremor, in both test and validation datasets. Tremor stability index maximum sensitivity, specificity and accuracy were 95%, 95% and 92%, respectively. Receiver operating characteristic analysis showed an area under the curve of 0.916 (95% confidence interval 0.797–1.000) for the test dataset and a value of 0.855 (95% confidence interval 0.754–0.957) for the validation dataset. Classification accuracy proved independent of recording device and posture. The tremor stability index can aid in the differential diagnosis of the two most common tremor types. It has a high diagnostic accuracy, can be derived from short, cheap, widely available and non-invasive tremor recordings, and is independent of operator or postural context in its interpretation.

Alpha and beta EEG power reflects L-dopa acute administration in parkinsonian patients

Aim: To evaluate the effect of an acute L-dopa administration on eye-closed resting state electroencephalographic (EEG) activity of cognitively preserved Parkinsonian patients. Methods: We examined 24 right-handed patients diagnosed as uncomplicated probable Parkinson’s disease (PD). Each patient underwent Unified Parkinson’s Disease Rating Scale (UPDRS)-part-III evaluation before and 60 min after an oral load of L-dopa-methyl-ester/carbidopa 250/25 mg. Resting condition eyes-closed EEG data were recorded both pre- and post L-dopa load. Absolute EEG power values were calculated at each scalp derivation for Delta, Theta, Alpha and Beta frequency bands. UPDRS scores (both global and subscale scores) and EEG data (power values of different frequency bands for each scalp derivation) were submitted to a statistical analysis to compare Pre and Post L-Dopa conditions. Finally, a correlation analysis was carried out between EEG spectral content and UPDRS scores. Results: Considering EEG power spectral analysis, no statistically significant differences arose on Delta and Theta bands after L-dopa intake. Conversely, Alpha and Beta rhythms significantly increased on centro-parietal scalp derivations, as a function of L-dopa administration. Correlation analysis indicated a significant negative correlation between Beta power increase on centro-parietal areas and UPDRS subscores (Rigidity of arms and Bradykinesia). A minor significant negative correlation was also found between Alpha band increase and resting tremor. Conclusions: Assuming that a significant change in EEG power spectrum after L-dopa intake may be related to dopaminergic mechanisms, our findings are consistent with the hypothesis that dopaminergic defective networks are implicated in cortical oscillatory abnormalities at rest in non-demented PD patients.

Directional local field potentials: A tool to optimize deep brain stimulation.

Background: Although recently introduced directional DBS leads provide control of the stimulation field, programing is time‐consuming.

Dyskinesias during levodopa–carbidopa intestinal gel (LCIG) infusion: Management inclinical practice

The continuous levodopaecarbidopa intestinal gel (LCIG) infusion is a valid alternative for motor control in advanced Parkinsons disease (PD). It has been demonstrated to improve motor fluctuation with a global increase in ON-time, generally without the outbreak of troublesome hyperkinesias [1]. However both peakdose and biphasic dyskinesias are observed in patients undergoing LCIG treatment. Here is reported our experience with a PD patient, whose LCIG treatment was challenged by the outbreak of peculiar dyskinesiasfollowingthe PEG-J-tube bedtime flushing. A 73 yearsold woman was affected by advanced PD with motor fluctuations. Because of her extreme susceptibility to develop dyskinesias even with very small doses of levodopa (otherwise defined as “brittle response” [2]), the maximum acceptable oral treatment was of 475 mg fractionated in 9 small doses a day. APEG-J was inserted and LCIG therapy was started in order to obtain a lower and more stable therapeutic regimen. A significant reduction of the OFFperiods and of the dyskinesias were obtained through a LCIG titration of the morning dose to1.5 ml (30 mg of levodopa), of the continuous dose to 1.0 ml (20 mg) per hour per 16 h a day (total dose of 350mg) and of the extra-doses to 1.0 ml (20mg). Nevertheless, at the end of the daily treatment, the mandatory operation of flushing the PEG-J-tube after pump disconnection [3] resulted in stereotypical violent peak-dose choreo-dystonic hyperkinesias that required patient protections to prevent disastrous falls. The tube cleaning led to the immediate delivery of the 3 ml (60 mg) of levodopa-gel contained in the device. Unfortunately the patient was highly sensitive to levodopa; so much that extra-doses have to be set at 1 ml (20mg) per dose. LCIG pump turning off may result in biphasic dyskinesias due to the incipient discontinuation of the levodopa effect; in this case the simple interruption of the infusion did not lead to any dyskinesia contrary to what was observed after bedtime tube cleaning. In fact through the flushing the patient received extra 60 mg of levodopa gel, that is three times the dose needed to overcome OFF-period, resulting in violent peak-dose dyskinesias. Levodopa gel is contained in a reservoir bag inside a hard plastic cassette. A used reservoir bag was cleaned out from residual gel through a solution of diluted ethyl alcohol delivered through a syringe connected to the cassette tube, and later rinsed with room temperature tap water. Then, the cassette was connected to the tube and the water was administered at usual maintenance dose (1 ml/h), so that it could slowly push the column of levodopa gel contained in the tube. After 3 h, water completely replaced the gel in the tube, and cleaning operations could be easily performed without the risk of delivering a high bolus of levodopa

Quantitative Analysis of Bradykinesia and Rigidity in Parkinson’s Disease

Background In the last decades, several studies showed that wearable sensors, used for assessing Parkinson’s disease (PD) motor symptoms and recording their fluctuations, could provide a quantitative and reliable tool for patient’s motor performance monitoring. Objective The aim of this study is to make a step forward the capability of quantitatively describing PD motor symptoms. The specific aims are: identify the most sensible place where to locate sensors to monitor PD bradykinesia and rigidity, and identify objective indexes able to discriminate PD OFF/ON motor status, and PD patients from healthy subjects (HSs). Methods Fourteen PD patients (H&Y stage 1–2.5), and 13 age-matched HSs, were enrolled. Five magneto-inertial wearable sensors, placed on index finger, thumb, metacarpus, wrist, and arm, were used as motion tracking systems. Sensors were placed on the most affected arm of PD patients, and on dominant hand of HS. Three UPDRS part III tasks were evaluated: rigidity (task 22), finger tapping (task 23), and prono-supination movements of the hands (task 25). A movement disorders expert rated the three tasks according to the UPDRS part III scoring system. In order to describe each task, different kinematic indexes from sensors were extracted and analyzed. Results Four kinematic indexes were extracted: fatigability; total time; total power; smoothness. The last three well-described PD OFF/ON motor status, during finger-tapping task, with an index finger sensor. During prono-supination task, wrist sensor was able to differentiate PD OFF/ON motor condition. Smoothness index, used as a rigidity descriptor, provided a good discrimination of the PD OFF/ON motor status. Total power index, showed the best accuracy for PD vs healthy discrimination, with any sensor location among index finger, thumb, metacarpus, and wrist. Conclusion The present study shows that, in order to better describe the kinematic features of Parkinsonian movements, wearable sensors should be placed on a distal location on upper limb, on index finger or wrist. The proposed indexes demonstrated a good correlation with clinical scores, thus providing a quantitative tool for research purposes in future studies in this field.

Oscillatory Activities in Neurological Disorders of Elderly: Biomarkers to Target for Neuromodulation

Non-invasive brain stimulation (NIBS) has been under investigation as adjunct treatment of various neurological disorders with variable success. One challenge is the limited knowledge on what would be effective neuronal targets for an intervention, combined with limited knowledge on the neuronal mechanisms of NIBS. Motivated on the one hand by recent evidence that oscillatory activities in neural systems play a role in orchestrating brain functions and dysfunctions, in particular those of neurological disorders specific of elderly patients, and on the other hand that NIBS techniques may be used to interact with these brain oscillations in a controlled way, we here explore the potential of modulating brain oscillations as an effective strategy for clinical NIBS interventions. We first review the evidence for abnormal oscillatory profiles to be associated with a range of neurological disorders of elderly (e.g., Parkinson’s disease (PD), Alzheimer’s disease (AD), stroke, epilepsy), and for these signals of abnormal network activity to normalize with treatment, and/or to be predictive of disease progression or recovery. We then ask the question to what extent existing NIBS protocols have been tailored to interact with these oscillations and possibly associated dysfunctions. Our review shows that, despite evidence for both reliable neurophysiological markers of specific oscillatory dis-functionalities in neurological disorders and NIBS protocols potentially able to interact with them, there are few applications of NIBS aiming to explore clinical outcomes of this interaction. Our review article aims to point out oscillatory markers of neurological, which are also suitable targets for modification by NIBS, in order to facilitate in future studies the matching of technical application to clinical targets.

Reply to: Comments on recent viewpoint article by Lazzaro di Biase and Alfonso Fasano titled "Low-frequency deep brain stimulation for Parkinson's disease: Great expectation or false hope?"

We read with great interest the viewpoint article by Lazzaro di Biase and Alfonso Fasano, which provides a nice summary on the effect of low-frequency stimulation (LFS) when compared with high-frequency stimulation (HFS) on PD symptoms. We appreciate their comments on our randomized, double-blind, prospective, crossover study on the effect of LFS versus HFS on dysphagia, freezing of gait (FOG), and other axial symptoms as summarized in part in their Fig. 1. We agree that “HFS was clearly associated with a significant worsening of axial functions when compared with no stimulation” based on our study conducted in medicated state and the other papers cited, and a meta-analysis study as well showing that the worsening of axial symptoms was found two years after STN DBS during medication on state. Although “there was no statistically significant difference when comparing LFS with no stimulation” in our study, their interpretation “that DBS does not improve swallowing per se” needs to be balanced with the fact that we had limited statistical power, as our study was designed to test the effect of LFS versus HFS, not LFS versus DBS Off. We did find a significant beneficial effect of LFS on axial and total motor scores when compared with the DBS Off state, besides the beneficial effect of LFS compared to HFS on swallowing function and FOG in our study patients. Another important unresolved issue that the authors raised is the correlation of total electric energy delivered (TEED) with clinical efficacy. The adjustment of TEED will bring another variable of “voltage” instead of just “frequency” change. The reduction in the total TEED by “decreased frequency without increasing the voltage” in our study is less likely to have caused the favorable changes observed with LFS, as frequency seems to be a more important variable than total TEED to produce clinical difference. In addition, we evaluated the effect of LFS on FOG with and without adjusting the TEED in a double-blind crossover study and reached the same conclusion on the beneficial effect of LFS on FOG and axial symptoms regardless of the TEED adjustment status (unpublished data). Overall, we agree that LFS should be recommended in STN DBS patients with refractory axial symptoms (particularly FOG) at HFS, as long as tremor does not worsen significantly with LFS because about 15% of the patients had to switch back to HFS for that reason. Whether LFS DBS simply addresses the detrimental effect of HFS DBS or it has beneficial effect by itself requires further studies.

Corrigendum: oscillatory activities in neurological disorders of elderly: biomarkers to target for neuromodulation

[This corrects the article on p. 189 in vol. 9, PMID: 28659788.].

Hepatitis C Virus–Related Hepatic Myelopathy After Treatment With Sofosbuvir and Ribavirin: A Case Report

Background: Hepatic myelopathy is a rare complication of advanced-phase liver dysfunction (1). The most common presentation is spastic paraparesis, which is associated with variable sensory deficits (2). Hepatic myelopathy is a progressive, disabling condition that may reverse if normal liver function is restoredfor example, after transplantation (Appendix Table) (2). Sofosbuvir is a novel nucleotide analogue that inhibits the NS5B polymerase of hepatitis C virus (HCV). Sofosbuvir produces a high rate of sustained virologic response when used to treat HCV infection (3). Appendix Table. Outcome of Reported Patients With Hepatic Myelopathy Objective: To report the course of hepatic myelopathy in a patient with HCV infection who was treated with sofosbuvir and ribavirin. Case Report: A 61-year-old man was diagnosed with genotype 2 HCV infection in 2004 and developed cirrhosis and liver failure 8 years later. In April 2013, he started having spells of hepatic encephalopathy that were managed with lactulose and protein restriction. In April 2014, after a 2-month episode of confusion, he developed a subacute shuffling gait that steadily progressed to spastic paraparesis. In May 2015, the patient required a wheelchair for mobility and was diagnosed with hepatic myelopathy. He had bilateral ankle clonus, Babinski sign, diffuse brisk reflexes, mild generalized bradykinesia, mild upper-limb rigidity, fine tremor of the hands during posture, and distal sensory deficit of the lower extremities. Magnetic resonance imaging in July 2013 and May 2015 showed moderate to severe brain atrophy with multifocal areas of remote infarctions and a normal thoracic and lumbosacral spine. In October 2014, blood tests showed an HCV viral load of 469 IU/mL, cryoglobulins, alanine aminotransferase level of 21 U/L, aspartate aminotransferase level of 39 U/L, low platelet count (79109 cells/L), high international normalized ratio (1.54), low albumin level (25 g/L), and high bilirubin level (59 mol/L [3.4 mg/dL]). Between October 2014 and January 2015, the patient was treated with sofosbuvir, 400 mg/d, plus ribavirin, 1000 mg/d, and achieved a sustained virologic response. In May 2015, blood tests showed no cryoglobulins, stability of other hepatic function tests, and a slightly elevated manganese level (393 nmol/L) (not previously measured). In June 2015, episodes of confusion dramatically decreased and dietary proteins were reintroduced. The patients gait slowly improved, and at the time of the last evaluation in October 2015 he was able to walk a few steps with a walker. The patients functionality and level of autonomy did not improve and kept fluctuating, particularly during rare and mild episodes of confusion. Discussion: Hepatic myelopathy is resistant to the treatments typically used for portosystemic encephalopathy. Liver transplantation is the only treatment recognized to be effective (Appendix Table), and transplantation within 18 months of the onset of hepatic myelopathy is associated with a better neurologic outcome (2). To our knowledge, this is the first report of stabilization of motor autonomy and improvement in hepatic myelopathy unrelated to liver transplantation, except for 1 patient with a transjugular intrahepatic portosystemic shunt who improved when the shunt occluded (4).