Caregivers' burden and deep brain stimulation for Parkinson disease: A systematic review of qualitative studies.

BACKGROUND AND PURPOSE: The impact of subthalamic nucleus deep brain stimulation (STN-DBS) on caregivers' burden is understudied. We perform a systematic review and meta-synthesis aggregating qualitative studies involving partners of people with Parkinson disease (PwP) to explore their experiences and unmet needs. METHODS: A systematic review for retrieving qualitative studies included six databases: MEDLINE, Embase, CINAHL, Cochrane, PsycInfo, and Scopus. Inclusion criteria were as follows: (i) studies on the experience of caregivers of PwP in the context of STN-DBS, (ii) English peer-reviewed articles, and (iii) qualitative or mixed methods studies reporting caregivers' quotations. After the appraisal of included studies, we performed meta-synthesis of qualitative findings. Descriptive themes and conceptual elements related to PwP partners' experiences and unmet needs were generated. RESULTS: A total of 1108 articles were screened, and nine articles were included. Three categories were identified: (i) dealing with Parkinson disease (PD) every day (the starting situation characterized by the impact of PD on ordinary life; the limitations to partners' socialization; partners' efforts in stepping aside for love and care activities), (ii) facing life changes with STN-DBS (the feeling of being unprepared for changes; the fear and concern due to loved ones' behavioral changes; struggling to find an explanation for those changes), and (iii) rebuilding the role of caregiver and partner after STN-DBS. CONCLUSIONS: This meta-synthesis elucidates concerns, challenges, and unmet needs of partners of PwP who underwent STN-DBS. It is important to provide them with information, education, and adequate support to face these challenges. Professionals need to involve partners in the care and decision process, because STN-DBS-related outcomes do not depend solely on the well-being of PwP but also on the well-being of individuals surrounding them.

Interplay between speech and gait variables in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation: A long-term instrumental assessment.

OBJECTIVE: To evaluate correlations between speech and gait parameters in the long term and under different medication and subthalamic nucleus deep brain stimulation (STN-DBS) conditions in a cohort of advanced Parkinson's disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Axial symptoms were evaluated using a standardized clinical-instrumental approach. Speech and gait were assessed by perceptual and acoustic analyses and by the instrumented Timed Up and Go (iTUG) test, respectively. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. RESULTS: Twenty-five PD patients with a 5-year median follow-up after surgery (range 3-7 years) were included (18 males; disease duration at surgery: 10.44 [SD 4.62] years; age at surgery: 58.40 [SD 5.73] years). In the off-stimulation/off-medication and on-stimulation/on-medication conditions, patients who spoke louder had also the greater acceleration of the trunk during gait; whereas in the on-stimulation/on-medication condition only, patients with the poorer voice quality were also the worst to perform the sit to stand and gait phases of the iTUG. Conversely, patients with the higher speech rate performed well in the turning and walking phases of the iTUG. CONCLUSIONS: This study underlines the presence of different correlations between treatment effects of speech and gait parameters in PD patients treated with bilateral STN-DBS. This may allow us to better understand the common pathophysiological basis of these alterations and to develop a more specific and tailored rehabilitation approach for axial signs after surgery.

Parkinson's disease patients' needs during the COVID-19 pandemic in a red zone: A framework analysis of open-ended survey questions.

BACKGROUND AND PURPOSE: During the first phase of the COVID-19 pandemic, a lockdown was imposed in Italy. The aim of this study was to investigate the perceptions, feelings and unmet needs of Parkinson's disease (PD) patients who experienced the 2-month lockdown in a "red zone" in the northern part of Italy during the COVID-19 outbreak. METHODS: The study had a descriptive design that used a cross-sectional online survey which included open-ended questions to elicit responses on the participant's feelings concerning their risk of contracting coronavirus, how their physical activity had changed, and their personal needs, dictated by their condition, which were not met in this pandemic period as compared to previous periods. Demographic data were analysed using descriptive frequencies, while the open-ended questions were analysed using thematic framework analysis. RESULTS: The study included 103 participants (63 men/40 women [61.17 vs. 38.83%]). Framework analysis led to the identification of four main themes: (i) fearing the risk of contracting coronavirus; (ii) reduction of physical activity; (iii) perception of the risk of not being able to access outpatient clinics or support services; and (iv) negative experiences of the important reduction in socialization. The perceptions of unmet needs appeared to be greater than the actual experience, particularly for the reduction in physical activity and the interruption of contacts with the neurologist and other specialists. CONCLUSIONS: This study highlights how perceptions and actual experience shape the meaning of living with PD during the pandemic. Worth noting is the divergence between perceptions and real impact in some aspects of the COVID-19 outbreak.

Vestibular Hypofunction in ARSACS Syndrome: A Possible Pitfall in the Differential Diagnosis of Recessive Cerebellar and Afferent Ataxias.

Objectives: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset ataxia characterized by cerebellar dysfunction, spasticity, and sensory-motor polyneuropathy due to variations in the SACS gene (13q11). To date, no studies have instrumentally assessed vestibular function in this condition. Methods: We report a 36-year-old woman with diagnosis of ARSACS syndrome due to homozygous mutation (c.12232 C>T, p.Arg4078Ter) in the SACS gene. Neurologic examination showed spastic-ataxic gait, dysarthric speech, 4-limb ataxia, and spastic hypertonia with lower limb hyperreflexia. Results: A vestibular instrumental evaluation including bedside oculomotor testing found gaze-evoked and rebound nystagmus on horizontal and vertical gaze, saccadic movements within normality ranges, saccadic pursuit, and slightly impaired visually enhanced vestibulo-ocular reflex (VVOR). A near-normal VOR suppression (VORS) was recorded. Neither head shakings, skull vibrations, nor supine positionings could evoke nystagmus. Finally, the video-head impulse test detected a symmetrical VOR impairment for all the semicircular canals (SCs), mostly involving the horizontal SCs, with corrective saccades in all planes. Discussion: Vestibular hypofunction may be found in ARSACS syndrome and may represent a possible pitfall in the differential diagnosis of recessive cerebellar and afferent ataxias. In this setting, ARSACS syndrome should be considered in the differential diagnosis of CANVAS.

Safety of thrombolysis in stroke mimics: results from a multicenter cohort study.

BACKGROUND AND PURPOSE: Intravenous thrombolysis for acute ischemic stroke is beneficial within 4.5 hours of symptom onset, but the effect rapidly decreases over time, necessitating quick diagnostic in-hospital work-up. Initial time strain occasionally results in treatment of patients with an alternate diagnosis (stroke mimics). We investigated whether intravenous thrombolysis is safe in these patients. METHODS: In this multicenter observational cohort study containing 5581 consecutive patients treated with intravenous thrombolysis, we determined the frequency and the clinical characteristics of stroke mimics. For safety, we compared the symptomatic intracranial hemorrhage (European Cooperative Acute Stroke Study II [ECASS-II] definition) rate of stroke mimics with ischemic strokes. RESULTS: One hundred stroke mimics were identified, resulting in a frequency of 1.8% (95% confidence interval, 1.5-2.2). Patients with a stroke mimic were younger, more often female, and had fewer risk factors except smoking and previous stroke or transient ischemic attack. The symptomatic intracranial hemorrhage rate in stroke mimics was 1.0% (95% confidence interval, 0.0-5.0) compared with 7.9% (95% confidence interval, 7.2-8.7) in ischemic strokes. CONCLUSIONS: In experienced stroke centers, among patients treated with intravenous thrombolysis, only a few had a final diagnosis other than stroke. The complication rate in these stroke mimics was low.

A study on the correlations between acoustic speech variables and bradykinesia in advanced Parkinson's disease.

Background: Very few studies have assessed the presence of a possible correlation between speech variables and limb bradykinesia in patients with Parkinson's disease (PD). The objective of this study was to find correlations between different speech variables and upper extremity bradykinesia under different medication conditions in advanced PD patients. Methods: Retrospective data were collected from a cohort of advanced PD patients before and after an acute levodopa challenge. Each patient was assessed with a perceptual-acoustic analysis of speech, which included several quantitative parameters [i.e., maximum phonation time (MPT) and intensity (dB)]; the Unified Parkinson's Disease Rating Scale (UPDRS) (total scores, subscores, and items); and a timed test (a tapping test for 20 s) to quantify upper extremity bradykinesia. Pearson's correlation coefficient was applied to find correlations between the different speech variables and the tapping rate. Results: A total of 53 PD patients [men: 34; disease duration: 10.66 (SD 4.37) years; age at PD onset: 49.81 years (SD 6.12)] were included. Levodopa intake increased the MPT of sustained phonation (p < 0.01), but it reduced the speech rate (p = 0.05). In the defined-OFF condition, MPT of sustained phonation positively correlated with both bilateral mean (p = 0.044, r-value:0.299) and left (p = 0.033, r-value:0.314) tapping. In the defined-ON condition, the MPT correlated positively with bilateral mean tapping (p = 0.003), left tapping (p = 0.003), and right tapping (p = 0.008). Conclusion: This study confirms the presence of correlations between speech acoustic variables and upper extremity bradykinesia in advanced PD patients. These findings suggest common pathophysiological mechanisms.

Recent Advances in the Treatment of Genetic Forms of Parkinson's Disease: Hype or Hope?

Parkinson's disease (PD) is a multifarious neurodegenerative disease. Its pathology is characterized by a prominent early death of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies with aggregated α-synuclein. Although the α-synuclein pathological aggregation and propagation, induced by several factors, is considered one of the most relevant hypotheses, PD pathogenesis is still a matter of debate. Indeed, environmental factors and genetic predisposition play an important role in PD. Mutations associated with a high risk for PD, usually called monogenic PD, underlie 5% to 10% of all PD cases. However, this percentage tends to increase over time because of the continuous identification of new genes associated with PD. The identification of genetic variants that can cause or increase the risk of PD has also given researchers the possibility to explore new personalized therapies. In this narrative review, we discuss the recent advances in the treatment of genetic forms of PD, focusing on different pathophysiologic aspects and ongoing clinical trials.

Longitudinal Neuropsychological Assessment of Symptomatic Edema after Subthalamic Nucleus Deep Brain Stimulation Surgery: A Case Series Study.

Severe non-infectious or non-haemorrhagic brain edema surrounding the electrode represents a rare complication of subthalamic nucleus deep brain stimulation (STN-DBS) surgery. The aim of this study is to report three patients with advanced Parkinson's Disease (PD) who developed symptomatic brain edema after STN-DBS surgery treated with intravenous steroids with a specific profile of reversible cognitive alterations. Patients were both assessed with a comprehensive neuropsychological battery including attention, memory, visuo-spatial and executive tasks. They were also briefly assessed for emotional and behavioural alterations, and for possible limitations in the activities of daily living. Normative data for an Italian population were available for all neuropsychological tests. The patients were firstly assessed before the surgery (baseline) as soon as they became symptomatic for the post-surgery edema and a few more times in follow-up up to ten months. In all patients we observed the resolution of cognitive deficits within six months after surgery with the corresponding reabsorption of edema at brain CT scans. The appearance of post-DBS edema is a fairly frequent and clinically benign event. However, in some rare cases it can be very marked and lead to important clinical-albeit transient-disturbances. These events can compromise, at least from a psychological point of view, the delicate path of patients who undergo DBS and can prolong the post-operative hospital stay. In this setting it could be helpful to perform a brain CT scan in 2-3 days with the aim of detecting the early appearance of edema and treating it before it can constitute a relevant clinical problem.

Long-term effects of subthalamic nucleus deep brain stimulation on speech in Parkinson's disease.

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson's Disease (PD). However, the effects of STN-DBS on speech are still debated, particularly in the long-term follow-up. The objective of this study was to evaluate the long-term effects of bilateral STN-DBS on speech in a cohort of advanced PD patients treated with bilateral STN-DBS. Each patient was assessed before surgery through a neurological evaluation and a perceptual-acoustic analysis of speech and re-assessed in the long-term in different stimulation and drug conditions. The primary outcome was the percentage change of speech intelligibility obtained by comparing the postoperative on-stimulation/off-medication condition with the preoperative off-medication condition. Twenty-five PD patients treated with bilateral STN-DBS with a 5-year follow-up were included. In the long-term, speech intelligibility stayed at the same level as preoperative values when compared with preoperative values. STN-DBS induced a significant acute improvement of speech intelligibility (p < 0.005) in the postoperative assessment when compared to the on-stimulation/off-medication and off-stimulation/off-medication conditions. These results highlight that STN-DBS may handle speech intelligibility even in the long-term.

Speech, Gait, and Vestibular Function in Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome.

(1) Background: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is characterized by late-onset cerebellar ataxia, bilateral vestibulopathy, and sensory neuronopathy mostly due to biallelic RFC1 expansion. (2) Objectives: The aim of this case series is to describe vestibular, gait, and speech alterations in CANVAS via a systematic approach. (3) Methods: All patients (n = 5) underwent a standardized clinical-instrumental examination, including the perceptual and acoustic analysis of speech, instrumental gait, and balance analysis (posturographic data were acquired using a force plate [Kistler, Winterthur, Switzerland] while 3D gait analysis, inclusive of surface electromyography, was acquired using a motion capture system [SMART DX, BTS Bioengineering, Milan, Italy], a wireless electromyograph [FreeEMG, BTS Bioengineering, Milan, Italy]), and vestibular assessment with video-oculography. (4) Results: Five patients were included in the analysis: three females (patients A, B, C) and two males (patients D and E) with a mean age at evaluation of 62 years (SD ± 15.16, range 36-74). The mean age of symptoms' onset was 55.6 years (SD ± 15.04, range 30-68), and patients were clinically and instrumentally evaluated with a mean disease duration of 6.4 years (SD ± 0.54, range 6-7). Video-Frenzel examination documented spontaneous downbeat nystagmus enhanced on bilateral gaze in all patients, except for one presenting with slight downbeat nystagmus in the supine position. All patients exhibited different degrees of symmetrically reduced VOR gain for allsix semicircular canals on the video-head impulse test and an unexpectedly normal ("false negative") VOR suppression, consistent with combined cerebellar dysfunction and bilateral vestibular loss. Posturographic indices were outside their age-matched normative ranges in all patients, while 3D gait analysis highlighted a reduction in ankle dorsiflexion (limited forward rotation of the tibia over the stance foot during the stance phase of gait and fatigue of the dorsiflexor muscles) and variable out-of-phase activity of plantar flexors during the swing phase. Finally, perceptual-acoustic evaluation of speech showed ataxic dysarthria in three patients. Dysdiadochokinesis, rhythm instability, and irregularity were observed in the oral diadochokinesis task. (5) Conclusions: CANVAS is a recently discovered syndrome that is gaining more and more relevance within late-onset ataxias. In this paper, we aimed to contribute to a detailed description of its phenotype.

Quantitative dopamine transporter imaging assessment in Parkinson's disease patients carrying GBA gene mutations compared with idiopathic PD patients: A case-control study.

BACKGROUND: Genetic risk factors impact around 15% of Parkinson's disease (PD) patients and at least 23 variants have been identified including Glucocerebrosidase (GBA) gene variants. Using different clinical and instrumental qualitative-based data, various studies have been published on GBA-PD cohorts which suggested possible differences in dopaminergic nigrostriatal denervation pattern, particularly in caudate and putamen nuclei. METHODS: This retrospective study included two consecutive homogenous cohorts of GBA-PD and idiopathic (I-PD) patients. Each consecutive GBA-PD patient has been matched with a 1:1 pairing method with a consecutive I-PD subject according to age, age at disease onset, sex, Hoehn & Yahr (H&Y) staging scale and comorbidity level (CCI). Semiquantitative volumetric data by the DaTQUANTTM software integrated in the DaTSCAN exam performed at time of the diagnosis (SPECT imaging performed according to current guidelines of I-123 FPCIT SPECT imaging) were extrapolated. Bilateral specific binding ratios (SBR) at putamen and caudate levels were calculated, using the occipital lobes uptake. The Mann-Whitney test was performed to compare the two cohorts while the Spearman's test was used to find correlations between motor and volumetric data in each group. Bonferroni correction was used to account for multiple comparisons. RESULTS: Two cohorts of 25 patients each (GBA-PD and I-PD), were included. By comparing GBA-PD and I-PD patients, lower SBR values were found in the most affected anterior putamen and left caudate of the GBA-PD cohort. Furthermore, in the GBA-PD cohort the SBR of the most affected posterior putamen negatively correlated with the H&Y scale. However, none of these differences or correlations remained significant after Bonferroni correction for multiple comparisons. CONCLUSIONS: We observed differences in SBR values in GBA-PD patients compared with I-PD. However, these differences were no longer significant after Bonferroni multiple comparisons correction highlighting the need for larger, longitudinal studies.

Long-term effects of bilateral subthalamic nucleus deep brain stimulation on gait disorders in Parkinson's disease: a clinical-instrumental study.

OBJECTIVE: To assess the long-term effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on gait in a cohort of advanced Parkinson's Disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. Each patient performed the instrumented Timed Up and Go test (iTUG). The instrumental evaluation of walking ability was carried out with a wearable inertial sensor containing a three-dimensional (3D) accelerometer, gyroscope, and magnetometer. This device could provide 3D linear acceleration, angular velocity, and magnetic field vector. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson Disease Rating Scale part III. RESULTS: Twenty-five PD patients with a 5-years median follow-up after surgery (range 3-7) were included (18 men; mean disease duration at surgery 10.44 ± 4.62 years; mean age at surgery 58.40 ± 5.73 years). Both stimulation and medication reduced the total duration of the iTUG and most of its different phases, suggesting a long-term beneficial effect on gait after surgery. However, comparing the two treatments, dopaminergic therapy had a more marked effect in all test phases. STN-DBS alone reduced total iTUG duration, sit-to-stand, and second turn phases duration, while it had a lower effect on stand-to-sit, first turn, forward walking, and walking backward phases duration. CONCLUSIONS: This study highlighted that in the long-term after surgery, STN-DBS may contribute to gait and postural control improvement when used together with dopamine replacement therapy, which still shows a substantial beneficial effect.

COVID-19 and Parkinsonism: A Critical Appraisal.

A few cases of parkinsonism linked to COVID-19 infection have been reported so far, raising the possibility of a post-viral parkinsonian syndrome. The objective of this review is to summarize the clinical, biological, and neuroimaging features of published cases describing COVID-19-related parkinsonism and to discuss the possible pathophysiological mechanisms. A comprehensive literature search was performed using NCBI's PubMed database and standardized search terms. Thirteen cases of COVID-19-related parkinsonism were included (7 males; mean age: 51 years ± 14.51, range 31-73). Patients were classified based on the possible mechanisms of post-COVID-19 parkinsonism: extensive inflammation or hypoxic brain injury within the context of encephalopathy (n = 5); unmasking of underlying still non-symptomatic Parkinson's Disease (PD) (n = 5), and structural and functional basal ganglia damage (n = 3). The various clinical scenarios show different outcomes and responses to dopaminergic treatment. Different mechanisms may play a role, including vascular damage, neuroinflammation, SARS-CoV-2 neuroinvasive potential, and the impact of SARS-CoV-2 on α-synuclein. Our results confirm that the appearance of parkinsonism during or immediately after COVID-19 infection represents a very rare event. Future long-term observational studies are needed to evaluate the possible role of SARS-CoV-2 infection as a trigger for the development of PD in the long term.

Adult-onset KMT2B-related dystonia.

KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal dominant neurological disorder characterized by varying combinations of generalized dystonia, psychomotor developmental delay, mild-to-moderate intellectual disability and short stature. Disease onset occurs typically before 10 years of age. We report the clinical and genetic findings of a series of subjects affected by adult-onset dystonia, hearing loss or intellectual disability carrying rare heterozygous KMT2B variants. Twelve cases from five unrelated families carrying four rare KMT2B missense variants predicted to impact protein function are described. Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature. Genome-wide DNA methylation profiling allowed to discriminate these adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients. These findings document the relevance of KMT2B variants as a potential genetic determinant of adult-onset dystonia and prompt to further characterize KMT2B carriers investigating non-dystonic features.

Freezing of Gait in Parkinson's Disease Patients Treated with Bilateral Subthalamic Nucleus Deep Brain Stimulation: A Long-Term Overview.

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson's Disease (PD). However, the effects of STN-DBS on freezing of gait (FOG) are still debated, particularly in the long-term follow-up (≥5-years). The main aim of the current study is to evaluate the long-term effects of STN-DBS on FOG. Twenty STN-DBS treated PD patients were included. Each patient was assessed before surgery through a detailed neurological evaluation, including FOG score, and revaluated in the long-term (median follow-up: 5-years) in different stimulation and drug conditions. In the long term follow-up, FOG score significantly worsened in the off-stimulation/off-medication condition compared with the pre-operative off-medication assessment (z = -1.930; p = 0.05) but not in the on-stimulation/off-medication (z = -0.357; p = 0.721). There was also a significant improvement of FOG at long-term assessment by comparing on-stimulation/off-medication and off-stimulation/off-medication conditions (z = -2.944; p = 0.003). These results highlight the possible beneficial long-term effects of STN-DBS on FOG.

Rapidly progressive amyotrophic lateral sclerosis in a young patient with hereditary neuropathy with liability to pressure palsies.

We describe the rare case of a young woman with hereditary neuropathy with liability to compression palsy (HNPP), who developed a rapidly progressive ALS. We suggest that underexpression of PMP22 protein in the nervous system might interfere with motor neuron function by impairing myelin formation and exposure of the axon to injury. Patients with ALS and evidence of demyelination should be screened for HNPP.