Christian Blahak

Association of gait and balance disorders with age-related white matter changes The LADIS Study

Objective: In the Leukoaraiosis and Disability (LADIS) Study, 11 European centers are evaluating the role of age-related white matter changes (ARWMC) as an independent determinant of the transition to disability in the elderly (65 to 84 years). We aimed at determining the influence of ARWMC on different objective measures of gait and balance. Methods: Six hundred thirty-nine nondisabled individuals were prospectively enrolled and are being followed-up for 3 years. Subjects are graded in three standardized categories of ARWMC (mild, moderate, and severe) according to central MRI reading. Quantitative tests of gait and balance include the Short Physical Performance Battery (SPPB; range: 0 [poor] to 12 [normal]), a timed 8-m walk, and a timed single leg stance test. Results: In cross-sectional analysis, deficiencies in gait and balance performance were correlated with the severity of ARWMC (SPPB: 10.2 ± 2.1 in the mild, 9.9 ± 2.0 in the moderate, 8.9 ± 2.6 in the severe group; p < 0.001). Walking speed correlated with the severity of ARWMC (1.24 ± 0.28 m/second in the mild, 1.18 ± 0.32 m/second in the moderate, and 1.09 ± 0.31 m/second in the severe group; p < 0.001). Balance was best in individuals with mild ARWMC (single leg stance time: 18.9 ± 10.8 seconds) compared with moderate and severe ARWMC (16.4 ± 10.8 and 13.6 ± 11.2 seconds) (p < 0.001). Physically inactive individuals had a higher risk of a pathologic SPPB score (moderate vs mild ARWMC: odds ratio 1.60, 95% CI 1.02 to 2.52; severe vs mild ARWMC: odds ratio 1.75, 95% CI 1.09 to 2.80). Conclusions: Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise. Physical activity might have the potential to reduce the risk of limitations in mobility.

Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross sectional results from the LADIS study

Background: Global age related white matter changes (ARWMC) are associated with progressive gait disturbances and falls, hypothesised to result from interruptions of cortico-subcortical circuits controlling balance, posture and locomotion. Methods: The location of ARWMC in a large cohort of elderly non-disabled individuals with reported falls was analysed, using the cross sectional data of the Leukoaraiosis and Disability (LADIS) study. Detailed anatomical distributions of ARWMC assessed by MRI studies were analysed with respect to falls and balance performance. Results: The severity of global ARWMC was significantly associated with a history of falls in the year prior to study inclusion (22.2% in the mild, 31.6% in the moderate and 37.3% in the severe ARWMC group according to the Fazekas scale; p = 0.002). Analysing the anatomical distribution of ARWMC, using the semiquantitative Scheltens scale, in multivariate analysis, periventricular (p = 0.006) and frontal deep (p = 0.033) ARWMC were independently associated with falls. Furthermore, logistic regression identified frontal deep (p = 0.003) ARWMC, but not basal ganglia and infratentorial hyperintensities, as significantly associated with balance disturbances. Conclusion: The association of frontal and periventricular ARWMC with falls supports the hypothesis that interruption of frontal subcortical motor circuits lead to balance disturbances and hence to an increased risk for falls in ARWMC.

GPi-DBS may induce a hypokinetic gait disorder with freezing of gait in patients with dystonia

Objectives: Stimulation-induced hypokinetic gait disorders with freezing of gait (FOG) have been reported only recently as adverse effects of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with dystonia. The aim of this work was to determine the frequency and the nature of this GPi-DBS–induced phenomenon. Methods: We retrospectively screened our database of patients with dystonia who underwent DBS. Patients with focal, segmental, or generalized dystonia of primary or tardive origin and no gait disorder due to lower limb dystonia before DBS, bilateral pallidal stimulation, and a follow-up for more than 6 months were included. Reports of adverse events were analyzed, and gait abnormalities were scored by comparing preoperative and postoperative video recordings using Movement Disorder Society–sponsored revision of the Unified Parkinsons Disease Rating Scale (MDS-UPDRS) items 3.10 (gait) and 3.11 (FOG). To assess the role of GPi-DBS in gait abnormalities, DBS was paused for 24 hours. Gait and FOG were assessed 30 minutes, 2 hours, and 24 hours after restarting DBS. Finally, a standardized adjustment algorithm was performed trying to eliminate the gait disorder. Results: Of a collective of 71 patients with dystonia, 6 presented with a new gait disorder (8.5%; 2 men, 4 women, mean age 61.3 years [48–69 years], 2 craniocervical, 1 DYT-1 segmental, 1 truncal, 2 tardive dystonia). GPi-DBS improved Burke-Fahn-Marsden Dystonia Rating Scale motor score by 54% and disability score by 52%. MDS-UPDRS item 3.10 worsened from 0.5 (±0.8) to 2.0 (±0.9) and item 3.11 from 0 to 2.5 (±0.5). The gait disorder displayed shuffling steps and difficulties with gait initiation and turning. Increasing voltages improved dystonia but triggered FOG, sometimes worsening over a period of a few hours. It vanished within minutes after ceasing DBS. Electrode misplacement was ruled out. In all but one patient, no optimal configuration was found despite extensive testing of settings (monopolar, bipolar, pulse width 60–210 μs, frequency 60–180 Hz). Nevertheless, a compromise between optimal stimulation for dystonia and eliciting FOG was achieved in each case. Conclusions: A hypokinetic gait disorder with FOG can be a complication of GPi-DBS.

Physical Activity Prevents Progression for Cognitive Impairment and Vascular Dementia: Results From the LADIS (Leukoaraiosis and Disability) Study

Background and Purpose— We aimed to study if physical activity could interfere with progression for cognitive impairment and dementia in older people with white matter changes living independently. Methods— The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluates the impact of white matter changes on the transition of independent elderly subjects into disability. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and cognitive assessment with classification of cognitive impairment and dementia according to usual clinical criteria. Physical activity was recorded during the clinical interview. MRI was performed at entry and at the end of the study. Results— Six hundred thirty-nine subjects were included (74.1±5 years old, 55% women, 9.6±3.8 years of schooling, 64% physically active). At the end of follow-up, 90 patients had dementia (vascular dementia, 54; Alzheimer disease with vascular component, 34; frontotemporal dementia, 2), and 147 had cognitive impairment not dementia. Using Cox regression analysis, physical activity reduced the risk of cognitive impairment (dementia and not dementia: &bgr;=−0.45, P=0.002; hazard ratio, 0.64; 95% CI, 0.48–0.85), dementia (&bgr;=−0.49, P=0.043; hazard ratio, 0.61; 95% CI, 0.38–0.98), and vascular dementia (&bgr;=−0.86, P=0.008; hazard ratio, 0.42; 95% CI, 0.22–0.80), independent of age, education, white matter change severity, medial temporal atrophy, previous and incident stroke, and diabetes. Conclusions— Physical activity reduces the risk of cognitive impairment, mainly vascular dementia, in older people living independently.

Long-Term Clinical Outcome in Meige Syndrome Treated with Internal Pallidum Deep Brain Stimulation

Deep brain stimulation of the globus pallidus internus (GPi DBS) is effective in the treatment of primary segmental and generalized dystonia. Although limb, neck, or truncal dystonia are markedly improved, orofacial dystonia is ameliorated to a lesser extent. Nevertheless, several case reports and small cohort studies have described favorable short‐term results of GPi DBS in patients with severe Meige syndrome. Here, we extend this preliminary experience by reporting long‐term outcome in a multicenter case series, following 12 patients (6 women, 6 men) with Meige syndrome for up to 78 months after bilateral GPi DBS. We retrospectively assessed dystonia severity based on preoperative and postoperative video documentation. Mean age of patients at surgery was 64.5 ± 4.4 years, and mean disease duration 8.3 ± 4.4 years. Dystonia severity as assessed by the Burke–Fahn–Marsden Dystonia Rating Scale showed a mean improvement of 45% at short‐term follow‐up (4.4 ± 1.5 months; P < 0.001) and of 53% at long‐term follow‐up (38.8 ± 21.7 months; P < 0.001). Subscores for eyes were improved by 38% (P = 0.004) and 47% (P < 0.001), for mouth by 50% (P < 0.001) and 56% (P < 0.001), and for speech/swallowing by 44% (P = 0.058) and 64% (P = 0.004). Mean improvements were 25% (P = 0.006) and 38% (P < 0.001) on the Blepharospasm Movement Scale and 44% (P < 0.001) and 49% (P < 0.001) on the Abnormal Involuntary Movement Scale. This series, which is the first to demonstrate a long‐term follow‐up in a large number of patients, shows that GPi DBS is a safe and highly effective therapy for Meige syndrome. The benefit is preserved for up to 6 years.

Scaling of Movement Is Related to Pallidal γ Oscillations in Patients with Dystonia

Neuronal synchronization in the gamma (γ) band is considered important for information processing through functional integration of neuronal assemblies across different brain areas. Movement-related γ synchronization occurs in the human basal ganglia where it is centered at ∼70 Hz and more pronounced contralateral to the moved hand. However, its functional significance in motor performance is not yet well understood. Here, we assessed whether event-related γ synchronization (ERS) recorded from the globus pallidus internus in patients undergoing deep brain stimulation for medically intractable primary focal and segmental dystonia might code specific motor parameters. Pallidal local field potentials were recorded in 22 patients during performance of a choice-reaction-time task. Movement amplitude of the forearm pronation-supination movements was parametrically modulated with an angular degree of 30°, 60°, and 90°. Only patients with limbs not affected by dystonia were tested. A broad contralateral γ band (35–105 Hz) ERS occurred at movement onset with a maximum reached at peak velocity of the movement. The pallidal oscillatory γ activity correlated with movement parameters: the larger and faster the movement, the stronger was the synchronization in the γ band. In contrast, the event-related decrease in beta band activity was similar for all movements. Gamma band activity did not change with movement direction and did not occur during passive movements. The stepwise increase of γ activity with movement size and velocity suggests a role of neuronal synchronization in this frequency range in basal ganglia control of the scaling of ongoing movements.

Chronic Deep Brain Stimulation in Patients with Tardive Dystonia Without a History of Major Psychosis

Tardive dystonia usually occurs with a delay after neuroleptic exposure in patients with major psychosis. A subgroup of patients, however, is given such medication for “mild depression” or “neurasthenia.” Tardive dystonia, in general, may respond favorably to pallidal deep brain stimulation (DBS). Nevertheless, it remains unclear thus far whether or not similar beneficial outcome is achieved with pallidal DBS in different subgroups of patients with tardive dystonia. Four women (mean age 59 years at surgery) underwent stereotactic pallidal DBS in the frame of an observational study. Tardive dystonia occurred secondary to medication with fluspirilene and haloperidol, and injection of long‐acting depot neuroleptics prescribed for mild depression or “nervousness.” Assessment included the Burke‐Fahn‐Marsden (BFM) scale preoperatively and at 12 months follow‐up. Extended follow‐up was available at a mean of 27.3 months postoperatively (range 16–36 months). There were no surgically related complications. All 4 patients experienced sustained statistically significant benefit from pallidal DBS. Mean improvement at 12 months was 77% for the BFM motor score (range, 45–91%; P = 0.043), and 84% at the last available follow‐up (range, 70–91%; P = 0.03). This was paralleled by improvement of the BFM disability score. Chronic pallidal DBS in patients with tardive dystonia without a history of major psychosis provides sustained improvement which is similar to that in other subgroups of patients with tardive dystonia. This effect is stable on extended follow‐up for up to 3 years.

Patterns of reoccurrence of segmental dystonia after discontinuation of deep brain stimulation

The pattern of reoccurrence of symptoms after discontinuation of deep brain stimulation (DBS) has not been systematically studied in dystonia. Eight patients (mean age (SD) 53.8 (14.4) years) with segmental dystonia at a mean follow-up of 11.3 (4.2) months were studied after implantation of bilateral DBS electrodes in the internal globus pallidus using a standard video protocol and clinical rating scales, immediately and at 2 and 4 h after switching off DBS. Dystonic signs returned sequentially, with a rapid worsening of phasic and a slower worsening of tonic dystonic components. In all patients, phasic dystonic features appeared within a few minutes, whereas the tonic elements of dystonia reoccurred with a more variable delay. Differential clinical effects when withdrawing DBS might reflect its influence on different pathophysiological mechanisms in dystonia.

Tremor reduction by subthalamic nucleus stimulation and medication in advanced Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor in Parkinson’s disease (PD). Most of the recent studies used only clinical data to analyse tremor reduction. The objective of our study was to quantify tremor reduction by STN DBS and antiparkinsonian medication in elderly PD patients using an objective measuring system. Amplitude and frequency of resting tremor and re-emergent resting tremor during postural tasks were analysed using an ultrasound-based measuring system and surface electromyography. In a prospective study design nine patients with advanced PD were examined preoperatively off and on medication, and twice postoperatively during four treatment conditions: off treatment, on STN DBS, on medication, and on STN DBS plus medication. While both STN DBS and medication reduced tremor amplitude, STN DBS alone and the combination of medication and STN DBS were significantly superior to pre- and postoperative medication. STN DBS but not medication increased tremor frequency, and off treatment tremor frequency was significantly reduced postoperatively compared to baseline. These findings demonstrate that STN DBS is highly effective in elderly patients with advanced PD and moderate preoperative tremor reduction by medication. Thus, with regard to the advanced impact on the other parkinsonian symptoms, STN DBS can replace thalamic stimulation in this cohort of patients. Nevertheless, medication was still effective postoperatively and may act synergistically. The significantly superior efficacy of STN DBS on tremor amplitude and its impact on tremor frequency in contrast to medication might be explained by the influence of STN DBS on additional neural circuits independent from dopaminergic neurotransmission.

Chronic deep brain stimulation for segmental dystonia.

Fourteen consecutive patients with segmental dystonia underwent chronic deep brain stimulation (DBS) surgery in the frame of a prospective study protocol. Twelve patients received chronic pallidal stimulation, while 2 patients with prominent dystonic tremor received chronic thalamic ventrointermediate nucleus stimulation. Twelve patients had primary dystonia, and 2 patients secondary dystonia. The Burke-Fahn-Marsden dystonia rating scale (BFM motor) showed a mean relative improvement of 57.3% at the first follow-up (FU1, mean 7 months) and 57.8% at the second follow-up (FU2, mean 16 months). The mean BFM scores were 34.9 ± 17.7 preoperatively, 14.9 ± 11.7 at FU1, and 14.8 ± 10.3 at FU2. Scores of the disability subscale improved by 43% at FU1 and 36% at FU2. Improvement was comparatively less in those patients with secondary dystonia. Dysarthria was a limitation of DBS in 4 patients when using high voltage. Overall, chronic DBS is a very effective treatment option for medically refractory segmental dystonia.