Essential tremor, Uncategorized

Deep brain stimulation and essential tremor

Virginia Thornley, M.D.
Neurologist, Epileptologist
November 6, 2019
Essential tremor is now treated with implantation of a deep brain stimulating device. It has been approved for treatment for Parkinson’s disease, essential tremor, dystonic tremor and obsessive compulsive disorder (1).
Basically, within the brain, there is a recurrent loop that is not inhibited by the correct feedback inhibition resulting in repetitive actions. In obsessive-compulsive disorders, there are repetitive thoughts and actions since this loop is not controlled.
In one study, the ventral intermediate nucleus (VIM) was stimulated in 98 patients with Parkinson’s disease, essential tremor and dystonic tremor with sustained improvement. There was significant long-term improvement even after 10 years(2).
The mechanism is unclear. However, certain nuclei stimulated were found to result in side effects. Thalamic stimulation resulted in fatigue. Subthalamic nuclear implantation was found to give rise to depression and suicidality(3).
Neurologybuzz.com
References
  1. Naestromm, M., Blomstedt, P., Hariz, M., Bodjund, O., Deep brain stimulation for obsessive-compulsive disorder: knowledge and concerns among psychiatrists, psychotherapists and patients,  Surg. Neurol Int. 2017; 8:298 
  2. Cury, R.G., Fraix, V., Castrioto, A.,Perez-Fernandez, M.A., Krack, P., Chabardes, S., Seigneuret, E., Alho, E.J., Benabid, A.L., Moro, E. Thalamic deep brain stimulation in Parkinson disease, essential tremor and dystonia. Neurology. 2017 Sep 26;89(13):1416-1423
  3. Zarzycki, M.Z., Domitrz, I., Stimulation-induced side effects after deep brain stimulation-a systematic review. Acta Neuropsychiatr. 2019, Aug 27:1-24
Standard
multiple sclerosis, Uncategorized

The impact of immunomodulating agents used in multiple sclerosis on the risk of cancer

Virginia Thornley, M.D., Neurologist, Epileptologist
June 14, 2019
Introduction
Multiple sclerosis is already an illness where the immune system recognizes the nervous system specifically the white matter tracts as foreign and attacks it. The complex cascade of mechanisms make adequate treatment challenging. Many treatments focus on the inflammatory mechanism with little attention on the degenerative mechanism involved.
Presentation of symptoms come in a wide variety depending on the the location of the multiple sclerosis plaque in the brain.
Patients may have concomitant morbidities which may make treatment challenging.
 
Immunomodulating agents and its impact on cancer
Many of the newer treatments for multiple sclerosis work at the level of the immune system through immunosuppression, the newer ones tend to be very potent. With greater efficacy comes greater risks including the risk of cancer.
Some of the newer medications can potentially increase the risk of cancer. Higher risk of cancer was found in many reports to occur with use of cyclophosphamide, azathioprine and mitoxanthrone. Fingolimod, natalizumab and alemtuzamab  can potentially increase the risk of cancer, these agents lack long-term data and work through the immune system. Dimethyl fumarate, terifluonimide, ocrelizumab, daclizumab and cladribine merit mandatory risk management plans to detect cancer before its use.
Reference
  1. Lebrun, C., Rocher, F., Cancer risk in patients with multiple sclerosis: potential impact of disease-modifying drugs. CNS Drugs. 2018, Oct. 32(10):939-949 doi:10.1007/s40263-018-0564-y
Disclaimer: This is medical information only not medical advice. Please consult your physician
Standard
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.

Standard
Parkinson's disaese

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

CEABD0AF-08E7-436B-B4FF-F4593B22B95B
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
 
 
Standard
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.
37608_434615273840_1627543_n
 
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.
safe_image
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.

If you’re burned out reading this article check out  Medicine, The Musical brought to you by colleague Writer, Lyricist, Composer – Michael Ehrenreich, M.D. 

Just helping a colleague promote their dream.

Save the date for Medicine. The Musical
safe_image
 
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
Standard
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.

IMG_6486_preview

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

Standard
Cancer research and cannabinoids

Cannabinoids: potential role in the detection and reduction of pancreatic tumor load in pre-clinical studies

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

August 1, 2018

Introduction

Cannabinoids are gaining more recognition in treatment not only of pain, seizures and mood disorder but also in a wide variety of conditions. There have been 3 decades of pre-clinical research studying the mechanisms as it relates to the different organ systems. There has been an exponential increase in cannabinoid research especially in light of the demand by grassroot movements for it availability in treating a wide variety of conditions.

As more and more physicians start to recommend it, more symptoms are coming to light which can be ameliorated with medical cannabis. One of the most sought after answer is the deadliest of diseases which is cancer. This seeks to study the mechanisms by which cannabinoids may play a role in reduction of tumor load.

Studies

There are many studies demonstrating the involvement of the endocannabinoid system in modulating the pathogenesis of tumors.

There are no published human clinical trials using cannabinoids in the treatment of the actual underlying pancreatic cancer. Cannabis is labelled under the schedule 1 classification, with that comes the difficulty with procuring the agent because of the bureaucracy and legal red tape that accompanies it. Regardless, there has been an exponential increase in pre-clinical studies in in vitro and in vivo studies.

Detection of pancreatic duct cancer using a CB2 probe

A study showed that the CB2 receptor is highly expressed in pancreatic duct cancer which seems to correlate with  the aggressiveness of the tumor (1). One study reports on using fluorescence imaging on pancreatic duct cancer using an NIR (near infrared) CB2 receptor targeted probe (2). The study found a high level of expression of CB2 receptors in patient samples with pancreatic cancer compared to normal pancreatic tissue. This is significant because it gives information on a specific target for diagnostic and treatment purposes.

CAA11F12-A957-4FAF-B74D-6C7D2CE6E613

Cannabinoid involvement in autophagy through the AMPK pathway

In one study the cannabinoid receptor ligands were discovered to cause autophagy and activate AMPK in pancreatic cancer.  In previous works by the same authors, cannabinoids were found to increase the radical oxygen species. In another study ROS was found to interact with the mitochondria where ATP is produced. AMP is upregulated instead leading to AMPK production which reduces mTOR1c and leads to an increase in autophagy and reduction of cell growth (3).

Possible therapeutic role of CB1 and CB2 receptor ligands on pancreatic cancer

In another study using pancreatic cancer cell lines Panc1, 2 cannabinoid receptor ligands were applied to study the mechanisms of cannabinoids and its possible anti-tumor effect. Cannabinoid ligands GW405833 and arachidonoyl cyclopropramide. The study showed that the cannabinoid ligands were involved in the down-regulation and up-regulation of proteins associated with regulation of cell growth and their energy metabolism. This could be a potential target for therapeutic approaches in pancreatic cancer (4).

Synergistic responses occur when CBD is combined with radiation

Cannabidiol can augment the tumor killing potential when combined with radiation therapy in pancreatic cancer which was studied under in vitro studies. Synergistic responses were noted when 5 micrograms of CBD was combined with 4Gy of radiation therapy in a clonogenic assay. In the same study using mice, there was increased survival in mice with pancreatic tumor using CBD compared to a  control cohort. When CBD was added with SRB or smart biomaterials (agents which are sensitive to environmental factors that allow delivery of other agents in this case CBD to the tumor cells) the mice survived compared to the control cohort with just CBD application alone. This study demonstrates that CBD in conjunction with radiation therapy enhances the tumor killing properties in the treatment of pancreatic cancer (5).

SRB’s or smart radiotherapy biomaterials allow the insertion of payloads which allow the abscopal effects of radiation therapy thereby boosting its results (6). Abscopal refers to the idea that radiation treatment can affect tumors distant from the area treated.

In summary

While there may be a dearth of human clinical trials using cannabinoids for treatment in pancreatic cancer, the pre-clinical studies demonstrate that the endocannabinoid system may play a potential role in the mechanisms, diagnosis and treatment of pancreatic cancer, one of the deadliest tumors, and should not be discounted. More studies are needed especially human clinical trials.

This is info only not medical advice.

References

1. Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzman, M., Velasco, G., Iovanna, J.L. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006, Jul, 66(13):6748-55
2. Guo, X., Ling, X., Du., F., Wang, Q., Huang, W., Wang, Z., Ding, X., Bai, M., Wu, Z. Molecular imaging of pancreatic duct adenocarcinoma using the type 2 cannabinoid targeted near-infrared fluorescent probe. Transl Oncol. 2018, Jul. 11(5):1065-1073
3. Dando, I., Donadelli, M., Costanzo, C., Dalla Pozza, E., D’Alessandro, A., Zolla, L., Palmieri, M. Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis. 2013, Jun 13, 4 e664
4. Brandi, J., Dando, I., Palmieri, M., Donadelli, M., Cecconi, D. Comparative proteomic and phosphosproteomic profiling of pancreatic adenocarcinoma treated with CB1 and CB2 agonists. Electrophoresis. 2013, May, 34(9-10):1359-1368
5. Moreau, M., Yasmin-Karim, S., Kunjachan, S., Sinha, N., Gremse, F., Kumar, R., Fan Chow, K., Ngwa, W. Priming the abscopal effect using multifunctional smart radiotherapy biomaterials loaded with immunoadjuvants, Front Oncol 2018, 8:56
6. Yasmin-Karim, S., Moreau, M., Mueller, R., Sinha, N., Dabney, R., Herman, A., Ngwa, W. Enhancing the therapeutic efficacy of cancer treatment with cannabinoids. Front Oncol 2018 Apr 24 (8):114
Standard