Hubert H. Fernandez

Diffusion, spread, and migration of botulinum toxin

Botulinum toxin (BoNT) is an acetylcholine release inhibitor and a neuromuscular blocking agent used for the treatment of a variety of neurologic and medical conditions. The efficacy and safety of BoNT depends on accurate selection and identification of intended targets but also may be determined by other factors, including physical spread of the molecule from the injection site, passive diffusion, and migration to distal sites via axonal or hematogenous transport. The passive kinetic dispersion of the toxin away from the injection site in a gradient‐dependent manner may also play a role in toxin spread. In addition to unique properties of the various BoNT products, volume and dilution may also influence local and systemic distribution of BoNT. Most of the local and remote complications of BoNT injections are thought to be due to unwanted spread or diffusion of the toxins biologic activity into adjacent and distal muscles. Despite widespread therapeutic and cosmetic use of BoNT over more than three decades, there is a remarkable paucity of published data on the mechanisms of distribution and its effects on clinical outcomes. The primary aim of this article is to critically review the available experimental and clinical literature and place it in the practical context.

Interrater agreement in the assessment of motor manifestations of Huntington's disease

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntingtons disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy‐five clinicians experienced in the evaluation of patients with early HD and six non‐clinicians were shown a videotape compiled from the film archives of the United States–Venezuela Collaborative HD Research Project. Observers were asked to rate a 2–3‐minute segment of the motor examination for each of 17 at‐risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted κ statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted κ = 0.67; standard error (SE) = 0.09). Agreement among the non‐clinicians was only fair (weighted κ = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients.

Who is helping whom? Manuscript support and transfer of value

We thank Thom and colleagues for their letter addressing human papilloma virus (HPV) in focal cortical dysplasia (FCD) and other epilepsy-associated brain pathologies. They suggest that what was previously reported as the HPV E6 oncoprotein in FCDIIB is “a cross-reaction with an as-yet unidentified neuroglial protein.” We appreciate their findings, because validation or refutation of the previous findings of HPV in FCD and glioblastoma has important public health relevance. However, several issues limit the conclusions of Thom et al, including a very small sample size, a limited description of experimental methods, incomplete experimental approaches to validate their claims, and most importantly, a failure to identify the proposed neuroglial protein. Furthermore, their report does not adequately explain the detection of the HPV viral capsid protein L1 in FCD. If the E6 oncoprotein detection is artifactual or nonpathogenic, then L1 should not be detected, because L1 and E6 are entirely nonhomologous proteins encoded by distinct genes in the HPV genome. It is puzzling that both L1 and E6 would be expressed in FCD as experimental artifact. The theory that an in utero viral infection plays a pathogenic role in brain malformations is not new and there is evidence, for example, that cytomegalovirus can cause pachygyria and smaller focal malformations. As we stated previously, the detection of E6 suggests an association between HPV and FCD but does not prove HPV pathogenicity in FCD, and further comprehensive studies are warranted to critically assess existing data sets. Until adequately powered studies are published, we stand by our original report.

Oral and infusion levodopa therapy in the management of Parkinson's disease

Introduction: The clinical diagnosis of Parkinson’s disease (PD) is based on the identification of bradykinesia and at least one additional feature among rigidity, resting tremor and postural instability. These clinical features have been estimated to appear when at least 50% of the nigral dopamine neurons and 70% of putaminal dopamine tissue contents are lost [1]. Dopaminergic imaging suggests that at least 30% of the dopamine storage capacity (measured by 18 F-DOPA uptake) and 50% of putamen dopamine transporters have been lost by the onset of contralateral limb bradykinesia and rigidity [2]. In addition to the above motor symptoms, a number of nonmotor symptoms are associated with PD. These include gastrointestinal, cardiovascular, urological and psychiatric symptoms, as well as problems with vision, pain and sleep [3]. There is general agreement that the typical motor features of PD depend on putaminal dopamine depletion. Indeed, these features respond well to dopaminergic treatments, the most effective being levodopa (l-DOPA), a dopamine precursor that can cross the blood-brain barrier. Treatment with levodopa contributes significantly to improvements in the quality of life of people with PD and increases their expected life length (reviewed in [4]). Moreover, treatment with peroral levodopa is relatively well tolerated and inexpensive [5]. Many of nonmotor symptoms may also respond to levodopa treatment [3]. Because of the above reasons, levodopa is currently considered the “gold standard” for the symptomatic treatment of PD [4, 5]. However, the response to levodopa changes with disease progression, becoming complicated by motor fluctuations and dyskinesias in a majority of patients within a few years. As will be discussed below, these motor complications can become disabling, calling for a reduction in oral levodopa dosage and/or for its replacement with advanced invasive treatments. Moreover, levodopa is poorly effective against clinical features that mainly depend on the degeneration of nondopaminergic systems. These include some nonmotor symptoms as well as motor features that occur in advanced disease stages, such as freezing of gait and falls [6]. In this chapter, we will review the history of levodopa pharmacotherapy in PD, the complications of this therapy, the options currently available to optimize oral treatment with levodopa, and recent advances in developing methods for a more continuous levodopa delivery. (Less)

Treatment of Parkinsonism in Patients with Non-Parkinson Dementia

Parkinsonism and dementia can co-occur in patients without Parkinson’s disease, and most of patients with neurodegenerative parkinsonism develop significant cognitive impairment. Parkinsonism–dementia syndromes notably include dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome, normal-pressure hydrocephalus, vascular parkinsonism and dementia, drug-induced parkinsonism and dementia, frontotemporal lobe dementia, and Alzheimer’s disease. Therapeutic options for parkinsonism in these patients are limited, and data are scarce. In this chapter, we summarize the available information on this topic.