Anke H. Snijders

Neurological gait disorders in elderly people: clinical approach and classification

Gait disorders are common and often devastating companions of ageing, leading to reductions in quality of life and increased mortality. Here, we present a clinically oriented approach to neurological gait disorders in the elderly population. We also draw attention to several exciting scientific developments in this specialty. Our first focus is on the complex and typically multifactorial pathophysiology underlying geriatric gait disorders. An important new insight is the recognition of gait as a complex higher order form of motor behaviour, with prominent and varied effects of mental processes. Another relevant message is that gait disorders are not an unpreventable consequence of ageing, but implicate the presence of underlying diseases that warrant specific diagnostic tests. We next discuss the core clinical features of common geriatric gait disorders and review some bedside tests to assess gait and balance. We conclude by proposing a practical three-step approach to categorise gait disorders and we present a simplified classification system based on clinical signs and symptoms.

Gait-related cerebral alterations in patients with Parkinson’s disease with freezing of gait

Freezing of gait is a common, debilitating feature of Parkinsons disease. We have studied gait planning in patients with freezing of gait, using motor imagery of walking in combination with functional magnetic resonance imaging. This approach exploits the large neural overlap that exists between planning and imagining a movement. In addition, it avoids confounds introduced by brain responses to altered motor performance and somatosensory feedback during actual freezing episodes. We included 24 patients with Parkinsons disease: 12 patients with freezing of gait, 12 matched patients without freezing of gait and 21 matched healthy controls. Subjects performed two previously validated tasks--motor imagery of gait and a visual imagery control task. During functional magnetic resonance imaging scanning, we quantified imagery performance by measuring the time required to imagine walking on paths of different widths and lengths. In addition, we used voxel-based morphometry to test whether between-group differences in imagery-related activity were related to structural differences. Imagery times indicated that patients with freezing of gait, patients without freezing of gait and controls engaged in motor imagery of gait, with matched task performance. During motor imagery of gait, patients with freezing of gait showed more activity than patients without freezing of gait in the mesencephalic locomotor region. Patients with freezing of gait also tended to have decreased responses in mesial frontal and posterior parietal regions. Furthermore, patients with freezing of gait had grey matter atrophy in a small portion of the mesencephalic locomotor region. The gait-related hyperactivity of the mesencephalic locomotor region correlated with clinical parameters (freezing of gait severity and disease duration), but not with the degree of atrophy. These results indicate that patients with Parkinsons disease with freezing of gait have structural and functional alterations in the mesencephalic locomotor region. We suggest that freezing of gait might emerge when altered cortical control of gait is combined with a limited ability of the mesencephalic locomotor region to react to that alteration. These limitations might become particularly evident during challenging events that require precise regulation of step length and gait timing, such as turning or initiating walking, which are known triggers for freezing of gait.

Histamine inhibits the production of interleukin-12 through interaction with H2 receptors.

IL-12 is essential for T helper 1 (Th1) development and inhibits the induction of Th2 responses. Atopic diseases, which are characterized by Th2 responses, are associated with the overproduction of histamine. Here we present evidence that histamine, at physiological concentrations, strongly inhibits human IL-12 p40 and p70 mRNA and protein production by human monocytes. The use of specific histamine receptor antagonists reveals that this inhibition is mediated via the H2 receptor and induction of intracellular cAMP. The inhibition of IL-12 production is independent of IL-10 and IFN-gamma. The observation that histamine strongly reduces the production of the Th1-inducing cytokine IL-12 implies a positive feedback mechanism for the development of Th2 responses in atopic patients.

Clinimetrics of freezing of gait.

The clinical assessment of freezing of gait (FOG) provides great challenges. Patients often do not realize what FOG really is. Assessing FOG is further complicated by the episodic, unpredictable, and variable presentation, as well as the complex relationship with medication. Here, we provide some practical recommendations for a standardized clinical approach. During history taking, presence of FOG is best ascertained by asking about the characteristic feeling of “being glued to the floor.” Detection of FOG is greatly facilitated by demonstrating what FOG actually looks like, not only to the patient but also to the spouse or other carer. History taking further focuses on the specific circumstances that provoke FOG and on its severity, preferably using standardized questionnaires. Physical examination should be done both during the ON and OFF state, to judge the influence of treatment. Evaluation includes a dedicated “gait trajectory” that features specific triggers to elicit FOG (gait initiation; a narrow passage; dual tasking; and rapid 360° axial turns in both directions). Evaluating the response to external cues has diagnostic importance, and helps to determine possible therapeutic interventions. Because of the tight interplay between FOG and mental functions, the evaluation must include cognitive testing (mainly frontal executive functions) and judgment of mood. Neuroimaging is required for most patients in order to detect underlying pathology, in particular lesions of the frontal lobe or their connections to the basal ganglia. Various quantitative gait assessments have been proposed, but these methods have not proven value for clinical practice.

On state freezing of gait in Parkinson disease: a paradoxical levodopa-induced complication.

Objective: To describe the phenotype of levodopa-induced “on” freezing of gait (FOG) in Parkinson disease (PD). Methods: We present a diagnostic approach to separate “on” FOG (deterioration during the “on state”) from other FOG forms. Four patients with PD with suspected “on” FOG were examined in the “off state” (>12 hours after last medication intake), “on state” (peak effect of usual medication), and “supra-on” state (after intake of at least twice the usual dose). Results: Patients showed clear “on” FOG, which worsened in a dose-dependent fashion from the “on” to the “supra-on” state. Two patients also demonstrated FOG during the “off state,” of lesser magnitude than during “on.” In addition, levodopa produced motor blocks in hand and feet movements, while other parkinsonian features improved. None of the patients had cognitive impairment or a predating “off” FOG. Conclusions: True “on” FOG exists as a rare phenotype in PD, unassociated with cognitive impairment or a predating “off” FOG. Distinguishing the different FOG subtypes requires a comprehensive motor assessment in at least 3 medication states.

Freezing of gait: a practical approach to management

Freezing of gait is a common and disabling symptom in patients with parkinsonism, characterised by sudden and brief episodes of inability to produce effective forward stepping. These episodes typically occur during gait initiation or turning. Treatment is important because freezing of gait is a major risk factor for falls in parkinsonism, and a source of disability to patients. Various treatment approaches exist, including pharmacological and surgical options, as well as physiotherapy and occupational therapy, but evidence is inconclusive for many approaches, and clear treatment protocols are not available. To address this gap, we review medical and non-medical treatment strategies for freezing of gait and present a practical algorithm for the management of this disorder, based on a combination of evidence, when available, and clinical experience of the authors. Further research is needed to formally establish the merits of our proposed treatment protocol.

Enhanced prostaglandin E2 production by monocytes in atopic dermatitis (AD) is not accompanied by enhanced production of IL-6, IL-10 or IL-12

AD is associated with a bias of the T helper cells to show increased IL‐4 and reduced interferon‐gamma (IFN‐γ) production. The production of IFN‐γ and IL‐4 and the development of Th cells into either high IFN‐γ or high IL‐4 producers is strongly influenced by factors produced by antigen‐presenting cells (APC), like IL‐12 and prostaglandin E2 (PGE2). IL‐12 selectively enhances IFN‐γ production and favours the development of IFN‐γ‐producing Th cells, whereas PGE2 selectively inhibits IFN‐γ production by Th cells. The aim of this study was to test whether the increased IL‐4/IFN‐γ production ratio by Th cells in AD can be explained by an increased PGE2/IL‐12 production ratio by the APC. Monocytes were used as APC source. PGE2 and IL‐12 production by lipopolysaccharide (LPS)‐stimulated monocytes from 12 AD patients and 12 non‐atopic controls was determined using two complementary experimental systems, whole blood cultures and purified monocytes. In addition, we determined IL‐6 production as a measure of monocyte activation, and IL‐10 production because IL‐12 production by monocytes is highly influenced by endogenously produced IL‐10. The monocytes from AD patients showed normal production levels of IL‐6 and IL‐10, a two‐fold, but non‐significant decrease in IL‐12 production, and a significantly (three‐fold) higher PGE2 production than those from non‐atopic controls. Here we show for the first time that enhanced PGE2 production by monocytes in AD is not accompanied by a general rise in cytokine production. We conclude that AD is indeed associated with an increased PGE2/IL‐12 production ratio by monocytes.

Bicycling Breaks the Ice for Freezers of Gait

Patients with freezing of gait (FOG) have episodic problems with generating adequate steps. This phenomenon is both common and debilitating in patients with Parkinsons disease (PD) or atypical parkinsonism. We recently presented a video case of a patient with longstanding PD and severe FOG, who showed a remarkably preserved ability to ride a bicycle. Here, we comment on the scientific and clinical implications of this single case observation, and show the video of a similar case. We first consider several pathophysiological explanations for this striking discrepancy between walking and cycling in PD. We then discuss the merits and shortcomings of cycling as a potential new avenue for rehabilitation and exercise training in patients grounded by FOG. Finally, we provide some directions for future research stimulated by this fascinating observation.

Objective detection of subtle freezing of gait episodes in Parkinson's disease†‡

Freezing of gait (FOG) is a clinically defined phenomenon of Parkinsons disease (PD). Recent evidence suggests that subtle FOG episodes can be elicited in a gait laboratory using suddenly appearing obstacles during treadmill walking. We evaluated which quantitative gait parameters identify such subtle FOG episodes. We included 10 PD patients with FOG, 10 PD patients without FOG, and 10 controls. Subjects walked on a motorized treadmill while avoiding unexpectedly appearing obstacles. Treadmill walking was videotaped, and FOG episodes were identified by two independent experts. Gait was also analyzed using detailed kinematics. Knee joint signals were processed using time–frequency analysis with combinations of sliding fast Fourier transform and wavelets transform. Twenty FOG episodes occurred during treadmill walking in 5 patients (all with clinically certified FOG), predominantly in relation to obstacle avoidance. FOG was brief when it occurred just before or after obstacle crossing and was characterized by short, rapid steps. Frequency analysis showed a typical qualitative pattern: before the FOG episode an increase in dominant frequency in the 0 to 3 Hz band (festination), followed by decreased power in 0 to 3 Hz band and an increased power in the 3 to 8 Hz band during the FOG episode. This pattern led to an increased FOG index as a qualitative measure. These approaches detected even very brief FOG with acceptable sensitivity (75–83%) and specificity (>95%). We conclude that time–frequency analysis is an appropriate approach to detect brief and subtle FOG episodes. Future work will need to decide whether this approach can support or even replace expert clinical opinion.

Cycling for Freezing of Gait

A 58-year-old man with Parkinsons disease presented with an incapacitating freezing of gait. Despite this, the patients ability to ride a bicycle was remarkably preserved.