Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2-6 months and 25.7% at 9-15 months. At 9-15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 months; this failed to reach significance at 9-15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Posttraumatic functional movement disorders and litigation.

The concept of functional movement disorders has evolved considerably over the past few decades. More specifically, the views on the relation with psychological stressors or personality disorders have substantially changed, emphasizing a shift from the previously dominant dualistic scheme. This evolution is reflected in adaptations to diagnostic criteria and management approaches. Functional movement disorders which arise in a close temporal relationship with a peripheral trauma are specifically challenging with respect to diagnosis and treatment, but similar considerations seem to apply. The relationship of functional disorders with trauma appears to be much closer than is often thought. Clinical and pathophysiological research has identified shared factors underlying functional posttraumatic as well as primary movement disorders. These evolving insights impact on discussions in terms of litigation for compensation after trauma. The literature is reviewed and the consequences for argumentation in litigation are outlined, including ethical and legal considerations. Finally, we formulate a number of recommendations.

Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to m.14487T>C.

BACKGROUND: m.14487T>C, a missense mutation (p.M63V) affecting the ND6 subunit of complex I of the mitochondrial respiratory chain, has been reported in isolated childhood cases with Leigh syndrome (LS) and progressive dystonia. Adult-onset phenotypes have not been reported. OBJECTIVES: To determine the clinical-neurological spectrum and associated mutation loads in an extended m.14487T>C family. METHODS: A genotype-phenotype correlation study of a Belgian five-generation family with 12 affected family members segregating m.14487T>C was carried out. Clinical and mutation load data were available for nine family members. Biochemical analysis of the respiratory chain was performed in three muscle biopsies. RESULTS: Heteroplasmic m.14487T>C levels (36-52% in leucocytes, 97-99% in muscle) were found in patients with progressive myoclonic epilepsy (PME) and dystonia or progressive hypokinetic-rigid syndrome. Patients with infantile LS were homoplasmic (99-100% in leucocytes, 100% in muscle). We found lower mutation loads (between 8 and 35% in blood) in adult patients with clinical features including migraine with aura, Leber hereditary optic neuropathy, sensorineural hearing loss and diabetes mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue. INTERPRETATION: m.14487T>C resulted in a broad spectrum of phenotypes in our family. Depending on the mutation load, it caused severe encephalopathies ranging from infantile LS to adult-onset PME with dystonia. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.

Two cases with postural axial tremor: Consider a genetic origin.

We present two cases with postural axial tremor predominantly involving the head, trunk, and shoulders. In the first patient, the postural tremor occurred in multiple attacks a day lasting approximately 10 min. The second patient developed a progressive tremor of his head and arms, worsened during sitting and standing. Electrophysiological supported the postural axial tremor in both patients with a varying 3-10 Hz tremor frequency between different muscles and within the same muscles at different times. Postural axial tremor is a rare and complex movement disorder. The majority of cases are caused by acquired cerebellar pathology. However, isolated cases with underlying genetic disorders are described in literature. Here, we illustrate how to differentiate paroxysmal axial tremor from other axial hyperkinetic movement disorders and extend the genetic heterogeneity of this intriguing movement disorder phenotype.

Subthalamic nucleus activity in the processing of body and mental action verbs in people with Parkinson's disease.

Local field potentials evoked by body action and mental action verbs were recorded in the subthalamic nucleus (STN) of 18 patients with Parkinson's disease through the electrodes implanted for deep brain stimulation. Compared with the medication on-condition, the medication off-condition showed a difference in activity in the early time segments, mainly in the right STN, with larger amplitudes for body action verbs. In the on-condition a similar pattern was detected in the left STN. These patterns of early differences in activity evoked by different types of verbs might indicate the potential of the STN to rapidly detect relevant behavioural clues in verbal content and to integrate these in subsequent cortico-subcortical interactions. In addition, these lateralizations allow speculations about shifts in processing activity correlating with dopaminergic denervation. Whether this detection relies on phonological, semantic or grammatical clues remains an open question.

The white matter architecture underlying semantic processing: A systematic review.

From a holistic point of view, semantic processes are subserved by large-scale subcortico-cortical networks. The dynamic routing of information between grey matter structures depends on the integrity of subcortical white matter pathways. Nonetheless, controversy remains on which of these pathways support semantic processing. Therefore, a systematic review of the literature was performed with a focus on anatomo-functional correlations obtained from direct electrostimulation during awake tumor surgery, and conducted between diffusion tensor imaging metrics and behavioral semantic performance in healthy and aphasic individuals. The 43 included studies suggest that the left inferior fronto-occipital fasciculus contributes to the essential connectivity that allows semantic processing. However, it remains uncertain whether its contributive role is limited to the organization of semantic knowledge or extends to the level of semantic control. Moreover, the functionality of the left uncinate fasciculus, inferior longitudinal fasciculus and the posterior segment of the indirect arcuate fasciculus in semantic processing has to be confirmed by future research.

The potential value of a pictorial atlas for aid in the visual diagnosis of 123I FP-CIT SPECT scans.

The aim of our study was to evaluate the value of a pictorial atlas of 123I FP-CIT SPECT images for aid in the visual diagnosis. PATIENTS, MATERIALS, METHODS: Sixty patients, of whom 20 were clinically diagnosed as 'non-parkinsonian' and 40 as having Parkinson's disease or any related disorder, were included in the study. An atlas consisting of 12 123I FP-CIT SPECT images was constructed first. Validity of the atlas was investigated by performing a receiver operating characteristic (ROC) analysis with the clinical diagnosis as the gold standard. The remaining 48 SPECT images were visually assessed twice by 5 observers, first with and secondly without consulting the atlas, or vice versa. The added value of the atlas was investigated by comparing the diagnostic accuracy and the interobserver variability for both methods. RESULTS: ROC analysis performed on the atlas yielded an area under the curve of 1 for a threshold discriminating between clinically non-parkinsonian and parkinsonian patients that was situated between image 4 and 5 of the atlas. For the diagnostic accuracy, we found that the area under the ROC curve was systematically higher if observers had access to the atlas compared to when they had not (Wilcoxon's test, p<0.05). Also, the interobserver variability was significantly lower when observers used the atlas when compared to when they did not (p = 0.05). CONCLUSION: Diagnostic accuracy was significantly higher and interobserver variability significantly lower if observers had access to the atlas compared to when they had not. Hence, having a pictorial atlas available may facilitate the visual assessment of 123I FP-CIT SPECT scans.

Saccadic ping pong gaze in coma.

In this report, we describe the peculiar eye movements of a young man who became comatose after a head injury. The eyes moved rhythmically from one side to another, without pausing in the lateral positions. This phenomenon has been described as "ping pong gaze" (PPG), referring to short-cycling periodic alternating gaze with smooth eye deviations. In the present patient, however, a saccadic type of PPG could be confirmed by oculography. Possible clinical and pathophysiological implications are discussed.

Catatonia and neuroleptic malignant syndrome: two sides of a coin?

Catatonia was first described by Kahlbaum in 1874. Ever since, the concept of catatonia has been the focus of debate, a major point of discussion being its nosological status. The question rises whether it is to be considered a syndrome with a wide variety of causes and clinical signs or a distinct clinical entity. Since catatonia shares a number of symptoms with the neuroleptic malignant syndrome (NMS) and similar treatments can be used in both conditions, it has also been suggested that NMS and catatonia are two variants of the same disorder In this article we describe five cases of catatonia and NMS in order to approach this nosological question. The clinical similarity between both syndromes is demonstrated in our cases. On the level of pathophysiology however, catatonia and NMS are quite different, with catatonia rather being a cortical psychomotor syndrome and NMS a subcortical motor disorder. Similarities can be explained by means of well-known models of basal ganglia function. The nosological problem, however; can only be resolved when the concept of catatonia is better defined.

Comparison of age of onset and development of motor complications between smokers and non-smokers in Parkinson's disease.

BACKGROUND: There is growing evidence from case-control and from cohort studies that smoking is inversely related to the risk of developing Parkinson's disease (PD). However, it is still controversial if PD starts at an older age in ever-smoking patients compared to never-smoking ones. PATIENTS AND METHODS: The present retrospective study compares in a large series of 512 out-patients, collected over the last 24 years, the age of onset of the complaints, the age at which PD was diagnosed and the start of levodopa treatment between ever- and never-smokers. Also, the occurrence of long-term side-effects of the drug was evaluated. 184 PD patients with a history of smoking were compared with 328 who had never smoked. The subgroups with and without a family history of PD were analysed separately. RESULTS: In the overall ever-smoking group, as well as in the subgroup without a family history, the onset of the disease and the time of the diagnosis of PD and the time at which levodopa was started occurred at an older age than in the never-smoking group. This difference could not be demonstrated in the patients with a family history, due to the low number of cases and the lack of statistical power. Although the follow-up period was the same in both study groups, motor fluctuations and dyskinesia were more frequent and appeared earlier after levodopa treatment in the non-smoking compared to the ever-smoking PD patients. Only for cognitive impairment there was a non-significant trend in the smoking group. CONCLUSION: The present study confirms the protective action of smoking on PD and also suggests some modulating effect of smoking on the dopaminergic system.

Cobalt-57 and technetium-99m-HMPAO-labeled leukocytes for visualization of ischemic infarcts.

UNLABELLED: Previous studies have shown the usefulness of divalent cobalt isotopes to visualize cerebral damage after stroke. The site of accumulation of cobalt ion is unknown but may be explained by neuronal influx, analogous to that of calcium ion. Additionally, uptake may be due to infiltrating leukocytes or protein-bound cobalt. The aims of this study were to compare 57Co-SPECT with leukocyte SPECT and to compare the SPECT findings with clinical outcome as scored by the Orgogozo scale. MATERIALS: Ten patients with a CT scan positive for middle cerebral artery infarcts were included in the study (7 men, 3 women; mean age 70 yr). Technetium-99m leukocyte and cobalt-SPECT (interval 2-4 days) were made with a double-headed gamma camera, after the injection of 10-15 mCi 99mTc-HMPAO-labeled leukocytes and 0.4 mCi 57Co, respectively. Scans were performed within 5-30 days after onset of the first symptoms. Regions of interest (ROI) containing the area of infarction in the slices displaying enhanced radioactivity or the middle cerebral artery (MCA) region in four successive slices were defined for calculating enhancement ratios. The 99mTc leukocyte enhancement ratio (LER) and cobalt enhancement ratio (CER) were defined as the quotient of radioactivity in the ROI and an identical contralateral ROI. The MCA stroke-scale according to Orgogozo was used to assess neurological deficits at the time of scanning and discharge. RESULTS: Cobalt-57 and 99mTc-HMPAO showed uptake in the infarcted brain area in five patients; the quantitative uptake in the infarcted brain area of the two tracers correlated significantly (p < 0.05). Both the LER and the CER correlated significantly (p < 0.05) with the Orgogozo score at the time of scanning. Only the LER correlated significantly (p < 0.05) with the Orgogozo score at discharge. CONCLUSION: Uptake of cobalt and leukocytes in the peri-infarct tissue suggests that 57Co may visualize a component of the inflammatory response. Divalent 57Co may be convenient to predict clinical prognosis after stroke.

Biodistribution and dosimetry of carbon-11-methoxyprogabidic acid, a possible ligand for GABA-receptors in the brain.

UNLABELLED: Carbon-11-methoxyprogabidic acid (11C-MPGA) was recently synthetized as a possible ligand for PET studies of gamma-amino-butyric acid (GABA) receptors in the brain. The data for human absorbed dose estimates are calculated based on the biodistribution of 11C-MPGA in mice and humans. METHODS: Eighteen mice were killed at preset time intervals after an intravenous bolus injection of 3.7 MBq (100 microCi) 11C-MPGA. Time-activity curves were reconstructed for several organs. Three healthy men each had whole-body PET scans after an intravenous bolus injection of 37 MBq (1 mCi) to determine activity in the critical organs. Animal data were fitted into these human findings to calculate residence times, and the MIRDOSE 3 protocol was used to calculate the radiation absorbed dose. RESULTS: Animal studies demonstrated a rapid distribution of 11C-MPGA in several organs. The highest activity was detected in the intestines, liver and kidneys. Brain activity was low throughout compared to these organs. The human whole-body study yielded similar results, with the intestines, liver and kidneys showing the highest activity. The estimated dose to the urinary bladder compartment turned out to be significant. The mean effective dose was 4.8 microSv/MBq (s.d.= 0.5 microSv/MBq). CONCLUSION: PET studies using 185 MBq (5 mCi) 11C-MPGA are within the International Commission on Radiological Protection risk Category II for healthy volunteers.

Single-voxel proton MR spectroscopy and positron emission tomography for lateralization of refractory temporal lobe epilepsy.

PURPOSE: We compared the metabolic information obtained from single-voxel proton MR spectroscopy and positron emission tomography (PET) in patients with temporal lobe epilepsy. METHODS: Twenty-nine patients with temporal lobe epilepsy were screened for metabolic abnormalities with both proton MR spectroscopy and PET. Lateralization with MR spectroscopy was possible by using NAA/(Cho+Cr) and an asymmetry index. Hypometabolism as determined by PET was classified as typical or complex. RESULTS: Twenty-four (96%) of 25 patients whose seizure onset could be lateralized to one temporal lobe showed ipsilateral lateralization with either MR spectroscopy or PET, whereas concordant lateralization with both techniques was possible only in 14 (56%) of the 25 patients. MR spectroscopy showed 42 abnormal temporal lobes whereas PET showed only 25 lobes with decreased metabolism. All temporal lobes with hypometabolism at PET also had a low NAA/(Cho+Cr). Five patients (20%) with negative PET studies had seizures lateralized correctly with MR spectroscopy. CONCLUSION: Proton MR spectroscopy is more sensitive in depicting metabolic abnormalities than is PET in patients with temporal lobe epilepsy. Patients with negative PET studies will benefit from MR spectroscopy for the purpose of lateralization.

Cobalt-55 positron emission tomography in vascular dementia: significance of white matter changes.

BACKGROUND: Vascular dementia (VaD) is still used as a covering term to indicate the relationship between cerebrovascular disease and the progressive cognitive disorder. The contribution of white matter changes (WMCs), seen with computed tomography (CT) and magnetic resonance imaging (MRI) of the brain, to dementia had not been fully elucidated. Cobalt-55 (55Co) positron emission tomography (PET) allows us to distinguish between recent and old infarcts. PURPOSE: The present study investigates whether 55Co PET can detect the lesions responsible for the progression of the cognitive disorder in VaD patients. PATIENTS AND METHODS: 20 consecutive patients with a previous history of repeated strokes occurring more than 6 months before and with multiple cortical infarcts, lacunes and WMCs on CT and 5 age-matched controls were investigated with 55Co PET. The stroke patients were divided in two groups: 8 with and 12 without VaD. Average 55Co counts in cerebral cortex, deep gray nuclei and white matter were compared to the value in the cerebellum used as reference. RESULTS: In the control group, the 55Co uptake was identical in the cerebral cortex and in the cerebellum, but lower in the deep gray nuclei and the cerebral white matter. When comparing the stroke groups with the control, the 55Co uptake was similar for the cerebral cortex and deep gray nuclei, but significantly increased in the cerebral white matter. The 55Co uptake was also more increased in the stroke group with VaD compared to the non-demented group. CONCLUSION: 55Co PET shows that the WMCs are due to the ongoing damage of probably ischaemic origin which is more prominent in stroke patients with progressive cognitive decline.

Positron emission tomography in vascular dementia.

BACKGROUND: Vascular dementia (VaD) is an ill-defined entity. It is not known how acute brain failure related to stroke becomes chronic leading to dementia. PURPOSE: The present study investigates whether positron emission tomography (PET) can detect different metabolic patterns in VaD. PATIENTS AND METHODS: Four groups of stroke patients were selected. The PET findings of 14 stroke patients with multiple large infarcts and dementia (MID) and 14 without dementia (MS) were compared. Sixteen stroke patients with lacunes, leukoaraiosis and dementia (LD) were assessed against nine without dementia (LS). The PET examination utilised the 15-O-steady-state technique in order to determine regional cerebral blood flow (rCBF), regional oxygen extraction rate (rOER) and regional cerebral metabolic rate for oxygen (rCMRO2) in different pre-established cortical, subcortical and cerebellar regions. RESULTS: Decreased coupled mean rCBF and rCMRO2 with comparable rOER values were observed in all cerebral regions except in the cerebellum of the MID compared to the MS group. In the LD group mean rCBF and rCMRO2 were decreased with increased rOER in all cerebral regions except in the cerebellum compared to the LS group. CONCLUSIONS: The PET findings in demented patients with multiple large infarcts are in agreement with the concept of multi-infarct dementia. In demented patients with lacunes and leukoaraiosis, the PET pattern suggests a state of misery perfusion not only in the deep structures but also in the whole cerebral cortex. The present PET study argues that there are at least two possible mechanisms that can explain the occurrence of VaD in stroke patients.

Cobalt-55 positron emission tomography in late-onset epileptic seizures after thrombo-embolic middle cerebral artery infarction.

The pathogenesis of late-onset epileptic seizures after thrombo-embolic cerebral infarction is poorly understood. Our previous positron emission tomographic (PET) studies with 15O have demonstrated that post-apoplectic epilepsy is associated with more severe brain ischemia, but we were unable to determine if this was the cause or the consequence of the seizures. Using cobalt-55 (55Co) as PET tracer we can now distinguish recurrent, recent infarction in patients with a previous old infarct in the same vascular territory. In seven out of twelve patients with post-apoplectic seizures an increased uptake of 55Co was observed in the border area and in two of them also within the old infarct core. In the control group, composed of eight seizure-free patients with also an old infarct involving the cortical territory of the middle cerebral artery, no increase in 55Co uptake was observed on PET examination. The present study indicates that in a significant number of patients late-onset epilepsy is the clinical expression of recurrent strokes, occurring in the same vascular territory.

Pharmacological evaluation of [11C]donepezil as a tracer for visualization of acetylcholinesterase by PET.

Donepezil is a highly potent and selective reversible achetylcholinesterase inhibitor. [(11)C]Donepezil is prepared by methylation with [(11)C]CH(3)I of the corresponding 6'-O-desmethylprecursor. Tissue distribution in mice revealed a high uptake in brain and rapid clearance from the blood. Metabolization studies in mice indicated the formation of one (11)C-labeled polar metabolite that didn't penetrate the blood-brain barrier. Regional brain distribution in rabbits didn't reflect the measured achetylcholinesterase distribution in rabbit brain.

Posterior cortical atrophy. Two case reports and a review of the literature.

We present two cases of progressive early-onset dementia with apraxia and visuospatial disability as initial manifestations. In the later stages of the illness Gerstmann's and Balint's syndromes developed. Structural neuroimaging demonstrated parieto-occipital atrophy and functional imaging revealed bilateral hypometabolism and hypoperfusion in these areas. These cases fulfil the diagnostic criteria of posterior cortical atrophy (PCA). Frontal lobe involvement became evident as the disease progressed. Alzheimer's disease also typically features this anterior spread and possibly this is the underlying pathological substrate for this clinical syndrome, although definite pathology is lacking. In this report, we describe longitudinal evolution in these two cases of PCA.