Benzi M. Kluger

Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy.

Fatigue is commonly reported in many neurologic illnesses, including multiple sclerosis, Parkinson disease, myasthenia gravis, traumatic brain injury, and stroke. Fatigue contributes substantially to decrements in quality of life and disability in these illnesses. Despite the clear impact of fatigue as a disabling symptom, our understanding of fatigue pathophysiology is limited and current treatment options rarely lead to meaningful improvements in fatigue. Progress continues to be hampered by issues related to terminology and assessment. In this article, we propose a unified taxonomy and a novel assessment approach to addressing distinct aspects of fatigue and fatigability in clinical and research settings. This taxonomy is based on our current knowledge of the pathophysiology and phenomenology of fatigue and fatigability. Application of our approach indicates that the assessment and reporting of fatigue can be clarified and improved by utilizing this taxonomy and creating measures to address distinct aspects of fatigue and fatigability. We review the strengths and weaknesses of several common measures of fatigue and suggest, based on our model, that many research questions may be better addressed by using multiple measures. We also provide examples of how to apply and validate the taxonomy and suggest directions for future research.

Nonmotor manifestations of dystonia: A systematic review

Nonmotor symptoms are increasingly recognized as important determinants of quality of life and disability in a wide range of movement disorders. There is a limited body of research suggesting that many of these symptoms are also commonly associated with primary and other genetic forms of dystonia. However, the significance, etiology, pathophysiology, and treatment of these symptoms remain poorly described. The following is a review of the literature that focuses primarily on the association of these types of dystonia with psychiatric disorders, cognition, sleep, pain, and autonomic symptoms. We will also discuss potential mechanisms and approaches to treatment for nonmotor features of dystonia.

Abnormalities in zinc homeostasis in young infants with cystic fibrosis.

Low plasma zinc concentrations have been reported in approximately 30% of young infants with cystic fibrosis identified by newborn screening. The objective of this study was to examine zinc homeostasis in this population by application of stable isotope methodology. Fifteen infants with cystic fibrosis (9 male, 6 female; 7 breast-fed, 8 formula-fed) were studied at a mean (±SD) age of 1.8 ± 0.7 mo. On d 1, 70Zn was administered intravenously, and 67Zn was quantitatively administered with all human milk/formula feeds during the day. Three days later, a 3-d metabolic period was initiated, during which time intake was measured and complete urine and fecal collections were obtained. Fractional zinc absorption, total absorbed zinc, endogenous fecal zinc, and net absorbed zinc were measured; fecal fat excretion was also determined. Fractional absorption was significantly higher for the breast-fed infants (0.40 ± 0.21) compared with the formula-fed group (0.13 ± 0.06) (p = 0.01), but with the significantly higher dietary zinc intake of the formula-fed group, total absorbed zinc was higher for those receiving formula (p = 0.01). In 11 infants with complete zinc metabolic data, excretion of endogenous zinc was twofold greater for the formula-fed infants (p < 0.05); net absorption (mg zinc/d) was negative for both feeding groups: −0.04 ± 0.52 for breast-fed; −0.28 ± 0.57 for formula-fed. Endogenous fecal zinc losses correlated with fecal fat excretion (r = 0.89, n = 9, p = 0.001), suggesting interference with normal conservation of endogenously secreted zinc. These findings indicate impaired zinc homeostasis in this population and suggest an explanation for the observations of suboptimal zinc status in many young infants with cystic fibrosis prior to diagnosis and treatment.

Palliative care and neurology Time for a paradigm shift

Palliative care is an approach to the care of patients and families facing progressive and chronic illnesses that focuses on the relief of suffering due to physical symptoms, psychosocial issues, and spiritual distress. As neurologists care for patients with chronic, progressive, life-limiting, and disabling conditions, it is important that they understand and learn to apply the principles of palliative medicine. In this article, we aim to provide a practical starting point in palliative medicine for neurologists by answering the following questions: (1) What is palliative care and what is hospice care? (2) What are the palliative care needs of neurology patients? (3) Do neurology patients have unique palliative care needs? and (4) How can palliative care be integrated into neurology practice? We cover several fundamental palliative care skills relevant to neurologists, including communication of bad news, symptom assessment and management, advance care planning, caregiver assessment, and appropriate referral to hospice and other palliative care services. We conclude by suggesting areas for future educational efforts and research.

Useful Field of View as a Reliable Screening Measure of Driving Performance in People With Parkinson's Disease: Results of a Pilot Study

Purpose: To determine the correlations of the Useful Field of View (UFOV), compared to other clinical tests of Parkinsons disease (PD); vision; and cognition with measures of on-road driving assessments and to quantify the UFOVs ability to indicate passing/failing an on-road test in people with PD. Methods: Nineteen randomly selected people with idiopathic PD, mean age = 74.8 (6.1), 14 (73.7%) men, 18 (94.7%) Caucasians, were age-matched to 104 controls without PD. The controls had a mean age of 75.4 (6.4), 59 (56.7%) men, 96 (92.3%) Caucasians. Both groups were referred for a driving evaluation after institutional review board approval. Results: Compared to neuropsychological and clinical tests of vision and cognition, the UFOV showed the strongest correlations (r > .75, p < 0.05) with measures of failing a standardized road test and number of driving errors. Among PD patients, the UFOV Risk Index score of 3 (range 1–5) was established as the optimal cutoff value for passing the on-road test, with sensitivity 87 percent and specificity 82 percent, AUC = 92 percent (SE 0.61, p = .002). Similarly, the UFOV 2 (divided attention) optimum cutoff value is 223 ms (range 16–500 ms), sensitivity 87.5 percent, specificity 81.8 percent, AUC = 91 percent (SE 0.73, p = .003). The UFOV 3 (selected attention) optimal cutoff value is 273 ms (range 16–500 ms), sensitivity 75 percent, specificity 72.7 percent, AUC = 87 percent (SE 0.81, p = .007). Conclusion: In this pilot study among PD patients, the UFOV may be a superior screening measure (compared to other measures of disease, cognition, and vision) for predicting on-road driving performance but its rigor must be verified in a larger sample of people with PD.

The therapeutic potential of cannabinoids for movement disorders.

There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid‐based chemicals within the medical community and, particularly, for neurological conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science as well as preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. The pharmacology of cannabis is complex, with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits, but more consistently suggest potential neuroprotective effects in several animal models of Parkinsons (PD) and Huntingtons disease (HD). Clinical observations and clinical trials of cannabinoid‐based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia, or ataxia and nonexistent for myoclonus or RLS. Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological, and therapeutic effects of this class of drugs in movement disorders.

Teratogenicity of Antiepileptic Medications

Antiepileptic drugs (AEDs) are frequently used to treat several conditions that are common in women of childbearing age, including epilepsy, headaches, and mood disorders. Moreover, as in the case of epilepsy and severe psychiatric disease, clinicians frequently do not have the option of stopping these medications or switching to another class of drugs. Overall, AEDs have been associated with an increased risk of major congenital malformations, minor anomalies, specific congenital syndromes, and developmental disorders seen in childhood. However, the differential effects of individual AEDs remain uncertain. Data are accumulating which strongly suggest that these risks are highest in patients receiving polypharmacy and valproate. There is also modest evidence to suggest an increased risk for phenobarbital. While other older AEDs appear to carry some teratogenic risk, there is not adequate evidence to further stratify their risk. Clinical and basic science research regarding newer AEDs suggests equivalent, if not safer, profiles compared with older AEDs, but these data are inconclusive. Management of women with epilepsy should include a discussion of these risks, prophylactic treatment with folic acid, and the minimal use of polypharmacy and valproate needed to maintain optimum seizure control.

Quadriceps Muscle Weakness, Activation Deficits, and Fatigue With Parkinson Disease

Background. People with Parkinson disease (PD) typically have complaints of weakness. The mechanisms underlying this deficit have not been well established, although many factors may contribute. Objective. This investigation aimed to characterize quadriceps muscle weakness and activation failure in people with PD and explore whether these deficits were related to disease severity. The authors further sought to examine quadriceps muscle fatigability. Methods. This was a cross-sectional comparison of 17 people with mild-severe PD and 17 healthy adults matched by age, sex, and body mass index (BMI). The Unified Parkinson’s Disease Rating Scale motor score (UPDRS motor) ranged from 9.5 to 61.0. Participants were divided into those with low-PD motor signs (UPDRS motor < 31.7) and high-PD motor signs (UPDRS motor ≥ 31.7). Measures of quadriceps performance included isometric torque, central activation using doublet interpolation, and an isokinetic fatigue test. Results. Participants with high-PD motor signs had significantly more quadriceps weakness and central activation deficits than those with low-PD motor signs or healthy controls. Strength and activation deficits correlated strongly with UPDRS motor score. Quadriceps muscle fatigue was present in healthy controls and in those with low-PD motor signs but not in those with high-PD motor signs. Conclusions. These findings provide additional evidence for lower-extremity strength loss with PD; central activation deficits may account for some of the strength deficits, especially with increased PD motor signs. Also, muscle fatigue did not occur in individuals with a greater degree of PD motor signs, most likely because of insufficient central activation to allow for muscle overload to induce metabolic fatigue.

Parkinson's disease‐related fatigue: A case definition and recommendations for clinical research

Fatigue is one of the most common and disabling symptoms in Parkinsons disease (PD). Since fatigue was first described as a common feature of PD 20 years ago, little progress has been made in understanding its causes or treatment. Importantly, PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. In response, the Parkinson Disease Foundation and ProjectSpark assembled an international team of experts to create recommendations for clinical research to advance this field. The working group identified several areas in which shared standards would improve research quality and foster progress including terminology, diagnostic criteria, and measurement. Terminology needs to (1) clearly distinguish fatigue from related phenomena (eg, sleepiness, apathy, depression); (2) differentiate subjective fatigue complaints from objective performance fatigability; and (3) specify domains affected by fatigue and causal factors. We propose diagnostic criteria for PD‐related fatigue to guide participant selection for clinical trials and add rigor to mechanistic studies. Recommendations are made for measurement of subjective fatigue complaints, performance fatigability, and neurophysiologic changes. We also suggest areas in which future research is needed to address methodological issues and validate or optimize current practices. Many limitations in current PD‐related fatigue research may be addressed by improving methodological standards, many of which are already being successfully applied in clinical fatigue research in other medical conditions (eg, cancer, multiple sclerosis).

Corticospinal and intracortical excitability of the quadriceps in active older and younger healthy adults

Age-related declines in neuromuscular function are well-documented, though the mechanisms underlying these deficits are unclear. Specific changes in corticospinal and intracortical neurophysiology may contribute, but have not been well studied, especially in lower extremity muscles. Furthermore, variations in physical activity levels may potentially confound the interpretation of neurophysiologic findings. Therefore, the purpose of this study was to quantify differences in transcranial magnetic stimulation (TMS) measures of corticospinal and intracortical excitability of the quadriceps between healthy, active older and younger adults. Twenty younger (age: 25.2 ± 2.4 years; body mass index [BMI]: 22.1 ± 3.0 kg/m(2); 11 males and 9 females) and twenty older (age: 67.7 ± 5.5 years; BMI: 26.8 ± 3.8 kg/m(2); 11 males and 9 females) subjects who exercised regularly (at least 30 min, 3 times/week) completed testing. Motor evoked potentials (MEPs) were measured by superficial electromyographic recordings of the vastus lateralis (VL). Measures of corticospinal excitability using a double cone TMS coil included resting motor thresholds (RMT), resting recruitment curves (RRCs) and silent periods (SP). Intracortical excitability was measured using paired pulse paradigms for short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). No statistically significant differences between older and younger adults were found for RMT, RRC slopes, SP, SICI or ICF measures (p>0.05). The physically active nature of the older adults included in this study may have contributed to the lack of differences in corticospinal and intracortical excitability since physical activity in older adults attenuates age-related declines in neuromuscular function.