Jasper E. Visser

The clinical utility of posturography.

Postural instability and falls are common and devastating features of ageing and many neurological, visual, vestibular or orthopedic disorders. Current management of these problems is hampered by the subjective and variable nature of the available clinical balance measures. In this narrative review, we discuss the clinical utility of posturography as a more objective and quantitative measure of balance and postural instability, focusing on several areas where clinicians presently experience the greatest difficulties in managing their patients: (a) to make an appropriate differential diagnosis in patients presenting with falls or balance impairment; (b) to reliably identify those subjects who are at risk of falling; (c) to objectively and quantitatively document the outcome of therapeutic interventions; and (d) to gain a better pathophysiological understanding of postural instability and falls, as a basis for the development of improved treatment strategies to prevent falling. In each of these fields, posturography offers several theoretical advantages and, when applied correctly, provides a useful tool to gain a better understanding of pathophysiological mechanisms in patients with balance disorders, at the group level. However, based on the available evidence, none of the existing techniques is currently able to significantly influence the clinical decision making in individual patients. We critically review the shortcomings of posturography as it is presently used, and conclude with several recommendations for future research.

Attenuated variants of Lesch-Nyhan disease

Lesch–Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine–guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch–Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch–Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine–guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch–Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine–guanine phosphoribosyltransferase deficiency.

Role of the basal ganglia in balance control.

In this review paper, we summarize the important contributions of the basal ganglia to the regulation of postural control. After a brief overview of basal ganglia circuitries, the emphasis is on clinical observations in patients with focal lesions in parts of the basal ganglia, as the impairments seen here can serve to highlight the normal functions of the basal ganglia nuclei in postural control. Two particularly relevant functions are discussed in detail: first, the contribution of the basal ganglia to flexibility and to gaining control of balancecorrecting responses, including the ability to lend priority to the elements of a postural task; and second, processing afferent information by the basal ganglia, which is increasingly recognized as being highly relevant for postural control.

Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder

Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.

Parkinson disease and comorbid cerebrovascular disease

Optimal management of chronic diseases not only requires tackling of the primary disease processes, but also necessitates timely recognition and treatment of comorbid conditions. In this article, we illustrate this two-pronged approach for two common age-related disorders: Parkinson disease (PD) and cerebrovascular disease (CVD). We first discuss the pathophysiological mechanisms that could provide a link between PD and CVD. Patients with PD have a series of risk factors that could promote development of CVD, but also have several protective factors. We then review the available clinical, radiological and neuropathological evidence to support an association between these two conditions. We conclude by discussing the potential implications for clinical practice, highlighting how comorbid CVD could alter the clinical presentation of PD and reviewing the possibilities for prevention and secondary prophylaxis. Additional research will be needed to fully evaluate the prevalence and clinical relevance of comorbid CVD in PD. Pending further evidence, we recommend that cerebral neuroimaging should be considered if patients with initially uncomplicated PD develop—either acutely or chronically—prominent and/or treatment-resistant gait impairment, postural instability, depression, cognitive decline, or urinary incontinence. Finding comorbid CVD in such patients could have prognostic implications, and could necessitate treatment to arrest further progression of CVD.

Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease.

Lesch-Nyhan disease, a neurogenetic disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase, is associated with a prominent loss of striatal dopamine. The current studies address the hypothesis that oxidant stress causes damage or dysfunction of nigrostriatal dopamine neurons in a knockout mouse model of the disease, by assessing several markers of oxidative damage and free radical scavenging systems. Some of these measures provided evidence for an increase in oxidative stress in the mutant mice (aconitase activity, oxidized glutathione, and lipid peroxides), but others did not (superoxide dismutase, protein thiol content, carbonyl protein content, total glutathione, glutathione peroxidase, catalase, and thiobarbituric reducing substances). Immunolocalization of heme-oxygenase 1 provided no evidence for oxidative stress restricted to specific elements of the striatum or midbrain in the mutants. Striatal dopamine systems of the mutant mice were more vulnerable to a challenge with the neurotoxin 6-hydroxydopamine, but they were not protected by cross-breeding the mutants with transgenic mice over-expressing superoxide dismutase. Overall, these data provide evidence for increased oxidative stress, but the failure to protect the knockout mice by over-expressing SOD1 argues that oxidative stress is not the sole process responsible for the loss of striatal dopamine.

Dynamic posturography in Parkinson's disease: diagnostic utility of the "first trial effect".

Previous dynamic posturography studies demonstrated clear abnormalities in balance responses in Parkinsons disease (PD) patients compared to controls at the group level, but its clinical value in the diagnostic process and fall risk estimation in individual patients leaves for improvement. Therefore, we investigated whether a new approach, focusing on the balance responses to the very first and fully unpractised trial rather than a pooled mean response to a series of balance perturbations, could further improve the diagnostic utility of dynamic posturography. Following the first trial, subjects were exposed to repeated balance perturbations, which also permitted us to investigate the training responses. Fourteen patients with PD and 18 age-matched controls were enrolled, who received a series of multidirectional postural perturbations, induced by support surface rotations. We measured trunk and upper arm kinematics and electromyographic responses, and evaluated group differences at three levels: the postural response to the very first backward perturbation; pooled first and habituated postural responses; and habituation rates. Analysis of the first trial responses yielded similar results as evaluation of the mean response over trials: forward flexion of the trunk induced by backward perturbations was decreased in patients, accompanied by increased muscle responses present. Moreover, trunk movement and muscle activity were equally present in both groups-suggesting a preserved training response in PD patients. Early masseter activity in both groups might be indicative of a startle-like component to the balance response. In terms of diagnostic utility, focusing on the first trial response or habituation rate is no better than analysis of pooled responses to a series of perturbations. The apparently preserved training response in PD patients suggests that balance reactions in PD can be improved by repeated exposure, and this may have implications for future exercise studies. Early masseter activity warrants further studies to evaluate a potential startle component in the pathophysiology of balance disorders.

Effect of subthalamic nucleus deep brain stimulation on axial motor control and protective arm responses in Parkinson's disease

Stereotactic surgical interventions for Parkinsons disease (PD) can considerably improve appendicular motor signs, but their effect on axial motor signs--especially balance control under optimal drug therapy--remains unclear. Here, we investigated the effect of bilateral subthalamic nucleus (STN) stimulation on levodopa-resistant axial and appendicular postural impairment in PD. Fourteen patients (11 with young-onset PD) and 18 age-matched controls were included. Patients were tested after intake of a suprathreshold levodopa dose, ensuring optimal response to drug therapy, and with stimulators both turned on and off. Balance control was assessed using multidirectional dynamic posturography. Outcome measures included full body kinematics and surface electromyography of paraspinal and deltoid muscles. Patients with stimulators turned off showed early decreased trunk roll with a loss of directional dependency, followed by increased and abnormally directed--i.e. destabilizing--trunk roll. Pelvis pitch motion showed decreased directional dependency in these patients. The abnormal trunk motion was not corrected by STN stimulation, but directional dependency of both trunk and pelvis motion partially improved, along with a general decrease in muscle activity. Even with stimulators off, protective arm movements were similar in the optimally treated patients and controls, indicating that these appendicular signs respond better to dopaminergic treatment than axial motor control. Our findings indicate that instability in PD results from a reduced flexibility of the trunk and pelvis that is largely resistant to STN stimulation combined with optimal drug treatment. These postural abnormalities are therefore likely associated with non-dopaminergic pathology. In contrast, protective arm movements did appear to be levodopa-responsive. Future studies should focus on identifying subgroups of optimal responders, particularly patients with levodopa-induced dyskinesias.

Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease

Lesch–Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine‐guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy.

PRKCG mutation (SCA-14) causing a Ramsay Hunt phenotype.

Progressive myoclonic ataxia, also referred to as Ramsay Hunt syndrome, is characterized by a combination of myoclonus and cerebellar ataxia, infrequently accompanied by tonic–clonic seizures. Its differential diagnosis overlaps with progressive myoclonic epilepsy, a syndrome with myoclonus, tonic–clonic seizures, progressive ataxia and dementia. In patients with progressive myoclonic epilepsy, specific diseases can frequently be recognized, but the diagnostic yield in progressive myoclonic ataxia is much lower. We describe a patient who presented with multifocal myoclonus in his thirties and who later developed cerebellar ataxia and focal dystonia. His father was similarly affected. Genetic studies revealed a mutation in the protein kinase C gamma (PRKCG) gene, known to cause spinocerebellar ataxia type 14 (SCA‐14). This case illustrates that both myoclonus and dystonia are part of the clinical spectrum in SCA‐14 and that myoclonus can even be the presenting symptom. We suggest that SCA‐14 should be considered in the differential diagnosis of progressive myoclonic ataxia.