Vol 4-5 Commentary

Commentary: Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS) with Chronic Cough and Preserved Muscle Stretch Reflexes: Evidence for Selective Sparing of Afferent Ia Fibres

José Berciano1*, Antonio García2, Jon Infante1

1Service of Neurology, University Hospital “Marqués de Valdecilla (IDIVAL)”, University of Cantabria, and “Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)”, Santander, Spain

2Service of Clinical Neurophysiology, University Hospital “Marqués de Valdecilla (IDIVAL)”, and “Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)”, Santander, Spain

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a form of ataxia characterized by the combination of bilateral vestibular, cerebellar and somatosensory impairment. In this commentary we summarized our report of five CANVAS cases presenting with spasmodic cough, which antedated the appearance of imbalance in several decades. Furthermore, in the hallmark of a severe sensory ataxia, tendon jerks and T-reflex recordings were almost completely preserved; sparing of muscle spindle afferents (fibres Ia) is probably the pathophysiological basis of normoreflexia.

DOI: 10.29245/2572.942X/2019/5.1257 View / Download Pdf
Vol 4-5 Research Article

In silico Analysis of the Binding Affinities of Antigenic Epitopes of Vaccines Administered to Gulf War Veterans to Specific HLA Class II Alleles Protective for Gulf War Illness

Spyros Charonis1,2, Lisa M. James1,2, Apostolos P. Georgopoulos1,2*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 5541, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Gulf War Illness (GWI) is a chronic, multi-symptom disorder of unknown etiology affecting veterans of the 1990-91 Gulf War. We identified previously1 a set of 6 Human Leukocyte Antigen (HLA) class II alleles that are protective for GWI, namely DPB1*01:01, DPB1*06:01, DQB1*02:02, DRB1*01:01, DRB1*08:11, and DRB1*13:02. Since the function of HLA class II molecules is to connect with matching extracellular antigens of various pathogens (mostly viruses), as an initial step in the sequence of events leading to the development of antibodies against the matched antigen and its subsequent elimination, we hypothesized that GWI may be due, in part, to the persistence of offending antigens which could not be eliminated2,3. We further hypothesized4,5 that such antigens were contained in the 16 vaccines administered to GW veterans against adenovirus, anthrax, botulinum, cholera, diphtheria, hepatitis B, influenza A, Japanese encephalitis, measles, meningococcus, poliomyelitis, rabies, smallpox, tetanus, typhoid, yellow fever6. This hypothesis predicts that antigens present in those vaccines should have a high affinity for matching with the 6 HLA class II protective alleles above. Here we tested this prediction by using the Immune Epitope DataBase (IEDB7) to determine the ranked affinity of each one of the 6 GWI protective alleles to the 10 most frequently assayed epitopes of each pathogen for which a vaccine was administered. We found that our 6 GWI protective alleles above collectively covered all vaccine antigens except for rubella for which all alleles above showed low binding affinity. Affinity strength varied among antigen-allele pairs, with DRB1*01:01 and DRB1*13:02 showing overall higher affinities. These two alleles also had the highest binding affinities for the anthrax antigen contained in the anthrax vaccine administered to GW veterans. These findings document a good match between the 6 GWI HLA protective alleles above and the antigens contained in the GW vaccines, and support the fundamental assumption that the HLA protection for GWI is mediated through the successful elimination of potentially harmful persistent antigens contained in those vaccines.

DOI: 10.29245/2572.942X/2019/5.1254 View / Download Pdf
Vol 4-5 Research Article

The Human Leukocyte Antigen (HLA) DRB1*13:02 Allele Protects against Dementia in Continental Western Europe

Lisa M. James1,2,3,4, Apostolos P. Georgopoulos1,2,3,4,5*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Center for Cognitive Sciences, University of Minnesota, Minneapolis, MN 55455, USA

5Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Human Leukocyte Antigen (HLA) Class II DRB1*13 alleles have recently been found to protect against age-related brain deterioration, even in the presence of apolipoprotein E4 (apoE4),1,2 suggesting a possible protection against dementia. Here we evaluated the association between the population frequency of common DRB1*13 alleles and the prevalence of dementia in Continental Western Europe. Prevalence of dementia in Continental Western Europe was derived from published reports on dementia frequency from the Global Burden of Disease Study 2016 and population totals obtained from the Population Reference Bureau. DRB1*13:01 and DRB1*13:02 allele frequencies were obtained from a publicly available database (allelefrequency.net) and apolipoprotein E was obtained from published reports on the world distribution of apoE4. The prevalence of dementia in 14 Continental Western European (CWE) countries, where life expectancy is practically identical, significantly decreases exponentially with increasing frequency of DRB1*13:02 (R2 = 0.452, P = 0.008), even when adjusted for the prevalence of apolipoprotein E4 allele, a known risk factor for Alzheimer’s disease. This finding documents the protective effect of DRB1*13:02 on dementia prevalence in CWE. Since the function of HLA class II genes is to aid in the elimination of pathogens by enabling the production of antibodies against their antigens in specific immunity, the protective effect of DRB1*13:02 points to the presence of persistent harmful antigens as causal factors in development of dementia, antigens specific to DRB1*13:02 that could not be eliminated in its absence.

DOI: 10.29245/2572.942X/2019/5.1253 View / Download Pdf
Vol 4-5 Research Article

Transcutaneous Vagus Nerve Stimulation in Private Healthcare Center: A Small-Scale Investigation Targeting Anxiety, Irritable Bowel Syndrome and Chronic Pain

Pascal J.D. Grolaux

Department of Osteopathy, Kinesis Health Associates, 2d floor, 155 Ochterloney Street, Dartmouth, B2Y1C9, Nova Scotia, Canada

Background: Generalized anxiety disorder (GAD), chronic pain (CP) and irritable bowel syndrome (IBS) are debilitating inflammatory disorders that are frequently seen in primary care facilities but not sufficiently addressed by classical medical treatments. Transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic tool for a wide range of conditions that showed already encouraging clinical results. However, the effects of tVNS, on GAD, IBS and CP, were not yet explored in the context of an investigation conducted in a private healthcare center.

Objective: In an uncontrolled, open label, small investigation scale study, we investigated the feasibility, safety and the effects of tVNS for patients suffering from GAD, CP and IBS in a multidisciplinary healthcare center.

Methods: The effects of tVNS on GAD, CP and IBS in 10 participants (anxiety, 40%; chronic pain, 30%; IBS, 30%) were investigated during a 4-week period and a 2-month follow-up. GAD, CP and IBS were assessed using the Generalized Anxiety Disorder GAD-7, the Brief Pain Inventory Short Form questionnaire and the Irritable Bowel Syndrome Severity Scoring System. Transcutaneous vagus nerve stimulation was performed using a transcutaneous electrical nerve stimulation device and ear clip electrodes plugged in the concha area of the ear. All participants, received a bi-weekly 30-minute stimulation for 4 weeks. The tVNS parameters, (GAD: 20Hz-80µs), (CP: 5Hz-200 µs), (IBS: 3Hz-250µs), were set for each group to target different physiological effects meditated by the vagus nerve.

Results: The anxiety and the IBS group showed a non-statistically significant improvement but an improved clinical status (mean score from “severe” to “moderate”) both at the end of the stimulation period (4 weeks) and at 2-month follow-up. The CP group didn’t show any significant clinical improvement (mean score from “moderate” to “moderate”). Furthermore, tVNS was demonstrated to be likely safe and was well tolerated.

Conclusions: Due to low sample size, this study failed to demonstrate significant clinical effects of tVNS on GAD, IBS and CP. However, trend analysis may carefully suggest tVNS to be a noteworthy clinical alternative to be used in private healthcare center in the treatment of chronic inflammation disorders like GAD and IBS. Acute tVNS was well-tolerated and is likely safe. Powerful, double-blind controlled studies are needed to support the use of tVNS on these disorders.

Clinical Trial Registration: http:/www.clinicaltrials.gov. Unique identifier: NCT03440255.

Abbreviations: α7nAChR, alpha7 nicotinic acetylcholine receptor; ABVN, auricular branch of the vagus nerve; CAN, central autonomic network; CAP, cholinergic anti-inflammatory pathway; CP, chronic pain; DMVN, dorsal motor nucleus of the vagus; GABA, γ-aminobutyric acid; GAD, general anxiety disorder; HR, heart rate; HPA, hypothalamic pituitary adrenal; HRV, heart rate variability; IBS, irritable bowel syndrome; IL, Interleukin; fMRI, functional magnetic resonance imagery; NF-κB, nuclear factor kappa B; NTS, nucleus tractus solitarius; pNN50, percentage of successive R-R intervals that differ by more than 50ms from the preceding one; PW, pulse width; RMSSD, root mean square of successive R-R interval differences; RR, respiratory rate; RSA, respiratory sinus arrhythmia; SD1, standard deviation of the distance of each point from the y = x axis in a Poincaré plot; TENS, transcutaneous electrical nerve stimulation; TNF, tumor necrosis factor; VN, vagus nerve; nVNS, non-invasive vagus nerve stimulation; tVNS, transcutaneous vagus nerve stimulation.

DOI: 10.29245/2572.942X/2019/5.1251 View / Download Pdf