cerebral atrophy

Can anti-psychotic agents reduce brain volume?

Virginia Thornley, M.D.
Neurologist, Epileptologist
July 10, 2019
Can medications cause cerebral atrophy. Cerebral atrophy refers to shrinkage of the cells causing the appearance of the brain to have less volume than usual.
This question was asked last week. An anti-epileptics such as phenytoin is well-known in the literature and clinically to cause cerebellar atrophy. But what about other agents such as anti-psychotics?
Animal studies
In one animal study, exposure to anti-psychotic drugs showed a reduced volume of brain on volumetric studies. The number of cells remained the same but the volume was increased for cells in the anterior cingulate gyrus which is in the  limbic lobe. The limbic lobe subserves emotions and has influence on memory. Animal studies do not always correlate with human responses.
Human studies
One small study showed that the thalamic volume was reduced after olanzepine administration. This was a small study of 10 patients (2).
While there is some information in the literature, the studies are animal studies and a small human study. More information is needed. Based on the current literature, there are not enough significant studies to correlate atrophy with use of anti-psychotics.
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References
  1. Vernon, A.C., Crum, W.R., Lerch, J.P., Chege, W., Natesan, S., Modo, M., Cooper, J.D., Williams, S.C., Kapur, S. Reduced cortical volume and elevated astrocyte density in rats chronically treated with anti-psychotic drugs-linking magentic resonance imaging findings to cellular pathology. Biol Psychiatry. 2014, Jun. 15, 75(12):982-90
  2. Khorram, B., Lang, D.J., Kopala, L.C., Vandorpe, RF.A., Rui, Q., Goghari, V.M., Smith, G.N., Honer, W.G. Reduced thalamic volume in patients with chronic schizophrenia after switching from typical anti-psychotic medications to olanzepine. Am J sychiatry. 2006, Nov. 163 (11):2005-7
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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
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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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fibromyalgia

Review of scientific literature: can diet alleviate symptoms from fibromyalgia

Virginia Thornley, M.D., Neurologist, Epileptologist
October 15, 2018
Introduction
There is growing interest in lifestyle changes in controlling certain diseases especially those that are related to inflammation. This seeks to review the scientific literature and determine if there is any science supporting any evidence for recommend dietary changes to alleviate symptoms from fibromyalgia.
Possible mechanisms underlying fibromyalgia
Fructose is a molecule that is not absorbed well in the gut and is related to low levels of tryptophan causing tryptophan to be absorbed less in the gut. Tryptophan is the precursor of serotonin or 5-HT which is found to be low in patients with fibromyalgia (1). Fructose is widely seen in the western diet present in honey and sweeteners known as high fructose corn syrup.
Fructose malabsorption in the gut may contribute towards increased fructose and interefere with tryptophan absorption (1).
Low fructose diet
In one case report a diet was devised where fructose was excluded so as to allow increased tryptophan availablility. The diet consisted of eggs, fish, clams, meat, celery, spinach, beets, dark chocolate, walnuts, carrots, potatoes, chard, grape seed oil, thyme, sage, carob powder, millet, green tea, small amount of almonds, coffee and rosemary. Sodas and processed food were deleted from the list. Legumes, cereal, wheat and fructan-containing vegetables and inulin containing vegetables were excluded. The diet is comprised of 25-27% proteins, 9-10% fiber, 31-36% carbohydrates and 30-32% fats. The patient’s previous diet consisted of the Mediterranean diet which has 50% carbohydrates (2). While fructose may be excluded in a diet, this may reduce the caloric intake which would be detrimental. Any diet that is developed should  not neglect the caloric intake.
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After 12 months, the patient was found to have less pain and could do aerobic exercises due to her pain-free state. There were some times she did not strictly adhere to the diet which resulted in a flare-up of the pain. It is also indicative that a modified diet is not curative short-term. This indicates that the results from the diet are not related to a placebo effect. More studies are needed. This study supports the growing interest of low levels of tryptophan, which is a precursor of 5-HT, as contributing towards the mechanisms causing pain in fibromyalgia (2).
 
Other factors that contribute towards fibromyalgia
Women seem to be more prone to symptoms of fibromyalgia. While the level of 5-HT is similar in men and women, women seem to synthesize 5-HT at a reduced rate compared to men (1).
Stress and anxiety leads to increase of glucocorticoids which may also interfere with 5-HT synthesis (1).
 
In summary
There is increasing biochemical information that fructose may contribute towards the pathophysiology involved in fibromyalgia. Growing interest is directed towards the use of certain diets to control the symptoms of fibromyalgia, however, large clinical human trials are needed.
While there is scientific biochemical information, large human trials are needed. There is not enough information to recommend this until large human clinical trials are performed.
References
1. Lattanzio, S.M. Fibromyalgia syndrome: a metabolic approach grounded in the biochemistry for the remission of symptoms Front. Med. 2017, Nov. 4:198
2. Lattanzio, S.M., Imbesi, F. Fibromyalgia syndrome: a case report on controlled remission of symptoms by a dietary strategy. Front med. 2018, 5:94
This is for informational purposes only and does not constitute medical advice, see your physician. Large human randomized controlled clinical trials are needed.
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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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multiple sclerosis

Review of literature: can the Wahls diet (modified Paleolithic diet) and low saturated fat Swank diet have any effect on multiple sclerosis?

Virginia Thornley, M.D., Neurologist, Epileptologist

September 17, 2018

@VThornleyMD

Introduction

Patients are seeking complementary treatments aside from conventional agents. Agree with it or not, if doctors do not listen to their patients they will seek it elsewhere so it is good to be up to date on the review of literature. While alternative treatments are commonly lacking in evidence based medicine it does not necessarily have to work in opposition with conventional agents. There are studies by Mauskop, (1) a headache specialist who found that 50% of migraineurs are magnesium deficient and magnesium can be a effective preventative agent in selected patients. Instead of being instantly dismissive, review of the literature should be sought to have an evidence-based understanding from a scientific level.

What is the modified Paleolithic diet?

In the modified Paleolithic diet, there is stress on meat, fruit and vegetables, excluding legumes, dairy and grains (2). Night shade vegetables such as tomatoes and eggplants are excluded.

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What is the Swank diet?

Dr. Roy Swank from Norway hypothesized that a diet rich in saturated fat likely caused a faster progression of the disease state in multiple sclerosis relapsing-remitting type. He followed 144 patients for 34 years. The patients consumed less than 20g of saturated fat in their diet and followed. It was observed that the relapses and progression correlated with the amount of saturated fat that was consumed. The greatest benefits were seen in those with mild symptoms at the start of the study. The patients were followed 50 years, however, there were no case controls patients for comparision (3).

Review of literature of the Wahl’s diet on Multiple sclerosis

One study focusing mainly on the dietary component seeks to understand an effect using the randomized controlled clinical trial method. The study is ongoing (2). It seeks to study the anecdotal information that diet low in saturated fat may lessen  the debilitating symptom of fatigue in patients with multiple sclerosis. While there have been anecdotal data, many patients have been found to drop out of the control group because of poor tolerability making results unreliable (2). In addition, the studies available provide a multi-prong approach including factors of stress reduction, exercise and muscle stimulation.

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Multimodal approach: exercise, stress reduction, meditation, massage and diet

One small study of 20 patients demonstrated some benefits of modifying diet, reducing stress and stimulating muscles in relation to multiple sclerosis symptoms.  They found that patients who presented with mild symptoms of progressive multiple sclerosis received some benefit to a multi-prong approach with regard to gait improvement compared to those who were more advanced in their disorder (4).

In summary

To summarize, at present there is insufficient data to support the Wahl’s diet as an effective treatment option based on the available current studies.  However, having said that there has been some anecdotal and very small studies indicating benefits in multiple sclerosis. Randomized controlled clinical trials which are the gold standard in research are ongoing which will be shed more light on its effectiveness.

In the meantime, while there are no completed large randomized controlled clinical trials, these types of diets and modalities are complementary with the current treatment and would do no harm. However, until large randomized controlled clinical trials are completed, it is difficult to ascertain if they are indeed effective and recommend it advocating it as effective.

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Reference

  1. Mauskop, et al, All migraine patients should be treated with magnesium. Journ. Neural Trans. 2012, May, 119(5):575-579
  2. Wahls, T., Scott, M.O., Alshare, Z., Rubenstein, L. Darling, W., Carr, L., Smith, Chenard, C.A., LaRocca, N., Snetselaar. Dietary appraoches to treat MS-related fatigue: comparing the modified Paleolithic (Wahls elimination) and low saturated fat (Swank) diets on perceived fatigue in persons with relapsing-remitting multiple sclerosis: a study protocol for randomized controlled trial. Trial. 2018, Jun. 4, 19(1):309
  3. Swank, R.L., Duggan, B.B., Effect of low saturated fat diet in early and late cases of multiple ssclerosis. Lancet, 1990, Jul., 7, 336 (8706)
  4. Bisht, B., Darling, W., White, E.C., White, K.A., Shivapour, E.T., Zimmerman, M.B., Wahls, T. Effects of a multimodal intervention on gait and balance of subjects with multiple sclerosis: a prospective longitudinal pilot study. Degen. Neurol. Neuromuscul Dis. 2017, Jun. 26, 7:79-93

 

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