cerebellar ataxia

Genetics of Hereditary Cerebellar Ataxia and Hereditary Spastic Paraplegia

Virginia Thornley, M.D.
Neurologist, Epileptologist
March 18, 2019
Introduction
Cerebellar ataxias are rare disorders, only a few types are treatable. This reviews some of the research regarding the genetics of cerebellar ataxias.
Next generation sequencing is a revolutionary way of DNA sequencing that can sequence an entire genome in one day which previously took 10 years. Clinical applications are still pending (1).
Genetics of hereditary cerebellar ataxias
In one study of 87 patients, the genetics were studies. In the probands meaning the first in a genetic line, triplet repeat testing was done. 58% were male. Genetic variants included ANO10, CACNA1A, SPG7 and DRKCG. The detection rate in probands for the trinucleotide repeat was about 13.8%. Those with variants may have a longer duration of disease and a slower progression of the disorder (2).
 
Genetic testing in hereditary spastic paraparesis
In another study where 306 were genetically tested, next generation sequence testing was performed and different genes were found. These include ATL1 (atlastin 1, SPG3),
PAST (spastin, SPG4),  ITPR1, WASHC5 (SPG8),  KIF1A (SPG30), SPG11 spastacsin), KIF5A (SPG10), CYP27A1, and SETX (3).
There are overlapping genetics and clinical symptoms with spinocerebellar ataxia and amyotrophic lateral sclerosis.
Reference
  1. Behjati, S., Tarpey, P., What is next generation sequencing? Arch Dis Child Educ Pract Ed. 2013 Dec; 98(6)236-238
  2. Kang, C., Liang, C., Ahmad, K.E., Gu, Y., Siow, S.F., Colebatch, J.G., Whyte, S., N, K., Cremer, P.D., Corbett, A.J., Davis, R.L., Roscioloi, T., Cowley, M.J., Park, S.J., Sue, C.M., Kumar, K.R. High Degree of Genetic Hetereogeneity for Hereditary Cerebellar Ataxias in Australia, Cerebellum, 2019, Feb. (1):137-146
  3. Elert-Dobkowska, E., Stepniak, I., Krysa, W., Ziora-Jakutowicz, K., Rakowicz, M., Sobanska, A., Pilch, J., Antczak-Marach, D., Zaremba, J., Sulek, A. Next-generation sequencing reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes. Neurogenetic, 2019, Feb, doi:10.1007/s10048-019-00565-6
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Sleep

Does chronic sleep deprivation affect cognition in shift workers?

Virginia Thornley, M.D.
Neurologist, Epileptologist
March 6, 2019
Introduction
What is the impact of sleep on cognition of shift workers?
 
Does circadian misalignment have impact on cognition?
Those with circadian misalignment such as night shift workers are most affected in terms of sustained attention, visual-motor performance and processing of information(1).
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One study sought to clarify the relationship of circadian cycle misalignment with cognition. It found that on the first night of shift work, attention is markedly impaired which improves after the same schedule is followed. This did not hold true for areas in visual-motor or cognitive throughput. Cognitive throughput means the summation of data going through a network.
Declarative memory is stable while attention was greatly impacted. This may be because memory is not impacted by areas where the sleep-wake cycle is important.
 
Mechanism

It is thought that there is increased GABAergic tone at night which could depress cognition. The natural circadian rhythm allows for maximum cognitive abilities during the daytime. . This is when we get our peak performance. The worse time for vulnerabilities in cognition occurred in the hours between 4-6am(1).
The neurobiology is thought that lack of sleep at night affects the conduction of nerves including the local potential field which affects neuronal activity. This results in reduced reaction time and speed for visual motor performance and tasks requiring sustained attention (2).
Reference
  1. Chellappa, S.L.,Morris, C., Scheer, F.A. Effects of circadian misalignment on cognition in chronic shift workers. Sci. Rep., 2019, 9:699. published online 2019 Jan 24. doi: 10.1038/s41598-018-36762-w
  2. Nir, Y., Andrillon, T., Marmelshtein, A., Suthana, N., Cirelli, C., Tononi, G., Fried, I. Selective neuronal lapses precede human cognitive lapses following sleep deprivation. Nat Med. 2017, Dec: 23(12)1474-1480
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cluster headache

Mechanism and novel approaches to treatment of cluster headache

Virginia Thornley, M.D., Neurologist
January 2, 2019
Cluster headache is a debilitating neurological condition which may be difficult to control. Novel approaches to treatment have been explored because of its refractory response to treatment.
Mechanisms involved in cluster headache
The pathophysiology involves the trigeminovascular pathway. This involves innervation to the  cerebral blood vessels and trigeminal complex including the nerves and ganglion. The ganglion has connections with the blood vessels of the cerebrum, the trigeminocervical complex and the dorsal horns of the C1 and C2 levels. In cluster headaches, certain chemicals are found to be increased during an attack  including calcitonin gene-related peptide and neurokinins which are neuropeptide vasodilators (1).
Calcitonin gene-related peptide antibody therapies
Some of the new anti-CGRP (calcitonin gene-related peptide antibody) therapies recently introduced to migraine patients have been applied to patients with cluster headache, including fremazunab and galcanezumab (2). it has been found that CGRP is released from the trigeminal ganglion and its transcription is increased when there are conditions that mimic those of migraine which includes an neurogenic inflammatory state (3).
There has been some success in its treatment although its application is not yet indicated for these drugs (2).
Botulinum toxin injection
Injection of onabotulinum toxin into the sphenopalatine ganglion was studied in 7 patients with chronic cluster headache. Of these, 3 dropped out. The patients were followed 24 months. There was a 50% reduction in occurrence of pain, after repeated injections. Due to the small size results should be interpreted with caution, however, because of repeated injections, its effectiveness may be significantly underestimated. This is a small pilot observational study. Larger studies are needed (4).
 
Vagal nerve stimulation
Vagal nerve stimulation was employed in 30 patients and a mean reduction of 26 attacks/week to 9.5 over a 3-6 month period was seen. Mean attack duration was 51.9 to 29.5 minutes. Larger studies are needed (5).
In summary 
Several new novel approaches include vagal nerve stimulation and botulinum toxin injections. Anti-CGRP antibodies are another novel treatment but have not yet been submitted for an indication. Larger studies are needed.
@VThornley_MD
Reference
  1. Goadsby, P.J., Edvinson, L., Human in vivo evidence for trigeminovascular activation in cluster headache.Neuropeptude chanes and effects of acute attackes therapies. Brain. 1994 Jun; 117 (Pt 3):427-34
  2. Ashehoug, I., Bratbak, D.F., Tronvik, E.A. Long-term outcome of patients with intractable chronic cluster headache treated with injection of onabotulinumtoxin A toward the sphenopalatine ganglion – an observational study. Headache, 2018, Nov; 58(10):1519-1529
  3. P.L. Durham, Calcitonin gene-related peptide and migraine. 2006, Jun. 46 (Suppl 1):S3-S8
  4. Tepper, S.J. Anti-calcitonin gene-related peptide (CGRP) therapies: update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018
  5. Marin, J., Giffin, N., Consiglio, E., mcClure, C., Liebler, E., Davies, B. Non-invasive vagus nerve stimulation for treatment of cluster headache: early UK clinical experience. J. Headache Pain. 2018, Nov. 23; 19

Disclaimer: This is for informational purposes only and is not medical advice. Please see your physician. Reading this does not constitute a physician-patient relationship.

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Parkinson's disaese

Parkinson’s disease: a look at a novel biomarker, immunogenetic & mitochondrial studies

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Virginia Thornley, M.D., Neurologist, Epileptologist
December 17, 2018
Introduction
Parkinson’s disease is typically diagnosed through clinical evaluation. At times, it may be difficult to differentiate from other disorders if all cardinal features are not present. This looks at the literature to review biomarkers that may be helpful in evaluation of the diagnosis of Parkinson’s disease.
 
Novel serum marker LAG-3
One study correlates the serum marker LAG-3 lymphocyte activation gene 3  (LAG-3). It is thought to be related to the transmission of alpha-synuclein which could be connected to the degenerative process in Parkinson’s disease. Serum LAG-3 was found to be higher in the serum levels compared to patients with essential tremors and a control group that was sex and age matched. LAG-3 can potentially serve as a biomarker when the diagnosis is in question (1).
 
Immunogenicity
As the population ages, there is a proliferation of neurodegenerative disorders. Familial disorders account for a small portion of these about 5-10%. It is thought that there are genetic and environmental component to the familial types of neurodegenerative diseases. Gene variants are found on HLA (human leukocyte antigen) which code for MHL II (major histocompatibility complex class II) which is found in microglia which has an immunologic component. Microglia phagocytizes unnecessary proteins but also produces an inflammatory response. How the immune system responds to environmental factors resulting in neurodegenerative disease is a subject of research and needs to be elucidated further (2). 
 
The role of the mitochondrial dysfunction in Parkinson’s disease
Mitochondrial dysfunction and oxidative damage is found in the cells of patients with Parkinson’s disease. Mitochondrial abnormalities have been hypothesized to correlate with the pathophysiology of Parkinsons disease. Recent research has shown a tying of both genetic and environmental factors in relation to the pathophysiology of Parkinson’s disease. The PINK1 and Parkin gene are related to mitochondrial function and are present in Parkinson’s disease and the pathways involved with the  quality control in the mitochondrion. When oxidative stress is present and the cells cannot detoxify this can affect mitochondrial functioning which is the powerhouse of cells producing ATP or the energy source (3).
Reference
  1. Cui, S., Du, J.J., Liu, S.H., Meng, J., Lin, Y.Q., Li, G., He, Y.X., Zhang, P.C., Chen, S., Wang, G., Serm soluble lymphocyte activation gene-3 as a diagnostic biomarker in Parkinson’s disease: a pilot multicenter study,” Mov Disord 2018, Nov. doi:10.1002/mds.27569 (epub ahead of print)
  2. Aliseychik, M.P., Andreeva, T.V., Rogaev, E.I., “Immunogenetic factors of neurodegenerative diseases: the role of HLA Class II,” Biochemistry, 2018, Sep. 83(9):1104-1116
  3. Sato, S., Hattori, N., “Genetic mutations and mitochondrial toxins shed new light on the pathogenesis of Parkinson’s disease.” Parkinsons Dis. 2011; 2011:979231
 
 
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multiple sclerosis

Review of literature:  stem cell therapy in multiple sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist
October 8, 2018
 
Introduction
Stem cell therapy is explored for certain types of cancer such as bone marrow cancer. Its therapeutic options have been experimentally being expanded to other disease such as multiple sclerosis. This seeks to review some of the literature on current research for stem cell therapy in multiple sclerosis. As yet, there are still ongoing research and experiments and is not yet  approved by the FDA as treatment for multiple sclerosis. This seeks to review mechanisms, small studies and experimental studies in multiple sclerosis.
Some mechanisms through which stem cell therapy may help
Natural killer cells are thought to attenuate Th17 cells which are pro-inflammatory after autologous hematopoietic stem cell treatment. It may not have effect on the Th1 cell but it seems to reduce the number of Th17 cells (1).
Comparing Wharton Jelly mesenchymal cell with bone marrow mesenchymal stem cell
One study shows that Wharton Jelly mesenchymal stem cell may be comparable to the gold standard bone marrow stem cell and may be more easily extracted. There is a different gene phenotype and are found to overexpress genes that impact neurotrophic support making it a great candidate for stem cell source in neurodegenerative diseases such as amyotrophic lateral sclerosis or Parkinson’s disease. It was found to cause greater neuronal maturation in neuroblastoma cells compared to bone marrow mesenchymal cells. Genes that influenced adhesion, proliferation and the immune system were found to be greater expressed in Wharton jelly mesenchymal stem cell (2).
 
aHSCT in fatigue
In one small study in 23 patients the use of autologous human stem cell treatment helped with symptoms of fatigue using the FIS or the fatigue impact scale (1). The median score in FIS was reduced by 36% with 4 patients with a complete reduction. Some even had gainful employment and returned to driving, measured with the EDSS or expanded disability status scale(3).
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A pilot study shows mesenchymal stem cell injection slows progression
In a pilot study of 4 patients, 3 had secondary progressive type while 1 was in the relapsing-remitting stage. Autologous bone marrow stem cells were injected and patients were followed for 2 years. Those with secondary progressive type stabilized with no further deterioration while the patient with relapsing remitting type had an attack. None of the MRI tests showed any new plaques or abnormalities(4).
Mesenchymal stem cell treatment is thought to be helpful as a neuroprogenitor and slows the neurodegeneration where standard medications may be ineffective (5).
Hematopoietic cell transplant  for relapsing-remitting multiple sclerosis
In one study of 25 patients looking at high dose immunotherapy and autologous hematopoietic stem cell therapy, peripheral blood stem cell grafts were CD34+ chosen. Immunosuppression was given beforehand. It was found to reduce relapses over a course of 3 years in patients with relapsing-remitting multiple sclerosis without serious adverse effects(6).
In summary
There is growing interest in stem cell therapy as a novel treatment in multiple sclerosis.  Research has shown that Wharton’s jelly from the umbilical cord may have features making it a better therapeutic alternative compared to bone marrow mesenchymal stem cells. So far, small studies have shown promise. Larger human trials are needed.
Reference
    1. Darlington, P.J., Stopnicki, B., Touil, T., Doucet, J.S., Fawaz L.,  Roberts, M.E., Boivin, M.N., Arbour, N., Freedman, M.S., Atkins, H.L., Bar-Or, A., Canadian MS/BST Study Group. Natural killer cells regulate Th17 cells after autologous hematopoietic stem cell transplantation for relapsing remitting Multiple Sclerosis. Front Immunol. 2018, 9:834
    2. Donders, R., Bogie, J.F.J., Ravanidis, S., Gervois, P., Vanheusden, M., Maree, R., Schrynemackers, M., Smeets, H.J.M., Pinxteren, J., Gijbels, K., Walbers, S., Mays, R.W., Deans, R., Van Den Bosch, L., Stinnissen, P., Lambrichts, I., Gyselaers, W., Hellings, N. Human Wharton’s jelly-derived stem cells display a distinct immunomodulatory and preregenerative transcriptional signature compared to bone marrow-derived stem cells. Stem Cells Dev. 2018, Jan. 27(2):65-84
    3. Bose G., Atkins, H.L., Bowman, M., Freedman, M.S. Autologous hematopoietic stem cell transplantation improves fatigue in multiple sclerosis. Mult. Scler. 2018, Sep: 1352458518802544 (epub: ahead of print)
    4. Sahraian, M.A., Mohyeddin Bonab, M., Baghbanian, S.M., Naser Moghadasi, A. Therapeutic use of intrathecal mesenchymal stem cells in patients with Multiple Sclerosis: a pilot study with booster injection. Immunol Invest 2018, Aug. 29:1-9
    5. Holloman, J.P., Ho, C.C., Huntley, J.L., Gallicano, G.I. The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis. Am. J. Stem Cells. 2013, Jun. 30, 2(2):95-107
    6. Nash, R.A., Hutton, G.J., Racke, M.K., Popat, U., Devine, S.M., Griffith, L.M., Muraro, P.A., openshaw, H., Savre, P.H., Stuve, O., Arnold, D.L., Spychala, M.E., McConville, K.C., Harris, K.M., Phippard, D., Georges, G.E., Wundes, A., Kraft, G.H., Bowen, J.D., High-dose immunosuppressive therapy and autologous hematopoeitic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3 year interim report. JAMA Neurol 2015, Feb. 72(2):159-69

This is for informational purposes only not medical advice see your physician.

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multiple sclerosis

Ketogenic diet: can it play a role in treating symptoms of Multiple sclerosis?

Virginia Thornley, M.D., Neurologist, Epileptologist
September 19, 2018
@VThornleyMD
Introduction
Multiple sclerosis has no cure at this current moment. It is unclear what is the exact etiology otherwise there would be a cure. Based on research, genetic and environmental factors play a role. Based on MRI observations, there are inflammatory and degenerative components to the pathogenesis.
 
What is the ketogenic diet and how does it pertain the brain
The ketogenic diet was initially found to be effective in treatment of medically refractory seizures. But the underlying concept might be applied to other diseases as well.
Instead glucose as the energy substrate, ketones are utilized, If the supply of glucose is reduced, the energy source is shifted towards the beta-oxidation of fatty acids into ketone bodies. These ketones become the new source of energy and allows increased ATP formation which is the source of energy in the mitochondria, which is the powerhouse of the cell where energy is formed.
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Different lines of thinking regarding pathogenesis of Multiple Sclerosis
There are lines of thought that Multiple sclerosis can be inflammatory versus neurodegenerative. Because of this many agents are directed towards the autoimmune component of the disease process. It is commonly thought that the autoimmune process results in the neurodegeneration seen on MRI.
As evidenced by the “black holes” seen on MRI after acute attacks, there is evidence there is a neurodegenerative aspect. This other line of thinking suggests that it is a degenerative process that triggers the inflammatory response.
It’s been found  that degenerating axons have abnormal mitochondria.
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Ketogenic diet and inflammation
In one animal study, it was found that the ketogenic diet reduced inflammatory cytokines after 14 days in animals (2).
 
Ketogenic diet and increased ATP
In one animal model with a control group and a group on ketogenic diet, after 3 weeks it was found that those on the ketogenic diet had a higher ATP/ADP ratio which is speculated to contribute towards neuronal stability.

How can the ketogenic diet help with Multiple Sclerosis?
The ketogenic diet reduces the formation of reactive oxygen species. It preserves ATP production when the mitochondria fails. The thought is that the axons start to degenerate once the mitochondria are dysfunctional (1).
In summary
There are no human clinical studies on ketogenic diet and the improvement of multiple sclerosis. Based on pre-clinical studies, there is indication that ketogenic diet may help improve the ATP stores when the mitochondria becomes dysfunctional which may potentially slow neurodegeneration of axons.
The ketogenic diet might reduce inflammation which is thought to be triggered by a neurodegenerative process in Multiple Sclerosis. However, more studies are needed especially human clinical trials. Currently there is not enough evidence to support this based on the available studies as pre-clinical studies do not always correlate in human trials. More studies are needed.

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Reference
  1. Storoni, M., Plant, G. The therapeutic potential of the ketogenic diet in treating progressive multiple sclerosis. Mult. Scler. Int. 2015. doi 10.1155/2015/681289
  2. Dupuis, N., Curatolo, N., Benoist, J.F., Auvin, S., Ketogenic diet exhibits anti-inflammatory properties. Epilepsia, 2015. 56(7):e95-98
  3. DeVivo, D.C., Leckie, M.P., Ferrendell, J.S., McDougal, D.B., Jr. Chronic ketosis and cerebral metabolism. Ann Neurol. 1978, Apr. 394):331-337
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Epilepsy

Dravet Syndrome: morphologic abnormalities, role of precision medicine, novel mechanisms for treatment and treatment options

Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD

August 13, 2018


Introduction

Dravet syndrome is characterized by developmental delay and intractable predominantly myoclonic seizures related to an abnormality in the SCN1A gene. The SCN1A gene encodes for sodium channel Nav1.1 which is voltage gated. It is one of the most pharmacologically resistant types of epilepsy syndromes.

Functional and morphological studies

One animal study using SCN1a(E1099x/HET mouse model for Dravet syndrome demonstrated early seizures which reached its maximum at post-natal week 4. There were less GABAergic neurons that expressed the Nav1.1 subunit in the dentate gyrus in the Het mice. There was a reduced number of inhibitory inputs travelling to the dentate gyrus cells in the Het mice. There was an increase in transmissions of excitatory impulses. The dentate gyral cells were noted to be abnormal morphologically with less arborization and a greater number of spines(1). This correlated with the abnormal excitation and reduced inhibition.

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Fenfluramine

Fenfluramine has been revisited as a treatment option for Dravet syndrome. It is metabolized into norfenfluramine. Fenfluramine and its metabolite norfenfluramine uncouples the association of sigma 1 receptor from the NR1 subunit of NMDA receptors (glutamate N-methyl-D-aspartate). Fenfluramine has serotonergic activity at the 5HT2AR receptor in addition to the activity at the sigma 1 receptor which reduces convulsive activity. Fenfluramine influences the cannabinoid type 1 receptor uncoupling with NMDARs which allowed greater restriction of the NMDAR actions (2).

Ketogenic diet

Ketogenic diet should not be discounted as a therapeutic option (3). In a study of 52 patients with pharmacoresistent epilepsy, spike and sharp wave complexes were reduced on the electroencephalograms of 26 patients which was significant (p<0.5). After a treatment of 12 weeks, there was a noticeable effective rate if seizure reduction of 42%. Motor, language and cognition was found to be improved in 23 patients, although the degree of improvement was not thought to be significant. Some adverse reactions included digestive problems and elevated liver enzymes.

Precision medicine

Because Dravet syndrome is related to a de novo loss of function mutation, great interest has been generated towards precision medicine. This involves targeting the genetic abnormality with treatments tailored towards a patient’s particular genetic make-up.

In one study using precision medicine, the selective activation of the Nav1.1 through the venom Hm1a restored the inhibitory mechanism of the neurons that are responsible for causing seizures in the mice model for Dravet syndrome (4). This may be a novel target for a therapeutic option using precision medicine in the treatment of Dravet syndrome.

Summary

In summary, while Dravet syndrome continues to be a devastating neurological disorder, there is research in precision medicine and other novel therapeutic options that can pave the way for more studies in this area.



https://neurologybuzz.com/
This is info only not medical advice.

Reference

1. Tsai, M.S., Lee, M.L., Chang, C.Y., Fan, H.H., Yu, I.S., You, J.Y., Chen, C.Y., Chang, F.C., Hsiao, J.H., Khorkova, O., Liou, H.H.,Yanagawa, Y., Lee, L.J., Lin, S.W. Functional and structural deficits of the dentate gyrus network coincide with the emerging spontaneous seizures in an Scn1a mutant Dravet syndrome model during development. Neurobiol Dis 2015, May, 77:35-48
2. Rodriguez-Munoz, Maria, Sanchez-Blasquez, Pilar, Garzon, Javier. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018, May, 9(34):23373-23389
3. Qiong, W., Hua, W., Yu, Y., Mei Zhang, J., Yan Liu, X., Ying Fang, X., Hua Yang, F., Jun Cao, Q., Qi, Ying. Ketogenic diet effects on 52 children with pharmacoresistent epileptic encephalopathy: a clinical prospective study. Brain Behav. 2018, May, 8(5):e00973
4. Richards, K.L., Milligan C.J., Richardson, R.J., Jancovski, N., Grunnet, M., Jacobson, L.H., Undheim, EAB, Mobli, M., Chow, C.Y., Herzig, V., Csoti, A., Panvi, G., Reid, C.A., King, G.F., Petrou, S. Selective Nav1.1 activation rescues Dravet syndrome mice from seiuzres and premature death. Proc. Natl. Acad. Sci. U.S.A. 2018, Aug. pii:201804764

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