cerebellar ataxia

Genetics of Hereditary Cerebellar Ataxia and Hereditary Spastic Paraplegia

Virginia Thornley, M.D.
Neurologist, Epileptologist
March 18, 2019
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.
  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

Does chronic sleep deprivation affect cognition in shift workers?

Virginia Thornley, M.D.
Neurologist, Epileptologist
March 6, 2019
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).
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.

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).
  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

What happens with night terrors?

Virginia Thornley, M.D.
Neurologist, Epileptologist
February 1, 2019
Night terrors can be terrifying events. But happens exactly?
There are 3 states of arousal: wakefulness, non-REM (rapid eye movement) and REM sleep.
Non-REM has 4 stages. Stages 1 and 2 are light sleep. Stage 1 is characterized by attenuation of the posterior dominant rhythm and vertex waves can occur centrally. Stage 2 sleep is characterized by the presence of sleep spindles which are seen symmetrically in the central regions. Stage 3 is the deeper stage also called slow wave sleep. Stage 3 has delta wave activity.
When do parasomnias occur?
Parasomnias or disorders of sleep usually occur when one transitions from non-REM slow wave sleep.  Night terror is a type of parasomnia. Night terrors are a disorder of the usual transition. The mechanism of this dysfunctional transition is not clear.
This is in contrast to nightmares which occur during REM when dreaming occurs.
One study found that when there are frequent arousals or complex behaviors in a  polysomnogram this might correlate with night terrors. It might be a potential marker for occurrence of disorders of arousal such as night terrors (1).
  1.  Lopez, R., Shen, Y., Chenini, S., Rassu, A.L., Evangelista, E., Barateau, L., Jaussent, I., Dauvilliers, Y., Diagnostic criteria for disorders of arousal: a video polysomnographic assessment. Ann. Neurol. 2018, Feb; 83(2):341-351

Can depression affect the structures of the brain?

Virginia Thornley, M.D., Neurologist, Epileptologist
January 26, 2019
The current model for depression is that it is a combination of genetic and environmental factors that come into play.

How traumatic events can change brain structures and function
It has been found that negative influences from childhood can affect the structures in the brain including the amygdala and hippocampus which may relate to mood disorders.
The interaction of genes with exposure to negative childhood experiences was shown to produce abnormal changes in the serotonin transporter and the FKBP5 gene. These play significant roles in the development of depression and other mood disorders (1).
In another study of 34 patients, it was found that those who had maltreatment during childhood had  a change in autobiographical memory. There was reduced activation in areas controlling positive reactions and increased activation for negative responses. Children who suffered maltreatment were at risk of suffering from depression and post-traumatic stress disorder later on in life (2).
Childhood trauma might affect the stress axis as well as the inflammatory-immune system. The association may be related to a pharmacoresistent state with anti-depressants (1).
  1. Jaworska-Andryszewska, P., Rybakowski, J.K. Childhood trauma in mood disorders:neurobiological mechanisms and implications for treatment. Pharmacol Rep 2018 Oct. 11;71(1):112-120
  2. Mccrory, E.J., Puetz, V.B., Maguire, E.A., Mechelli, A., Palmer, A., Gerin, M.I., Kelly, P.A., Koutoufa, I., Viding, E. Autobiographical memory: a candidate latent vulnerability mechanism for psychiatric disorder following childhood maltreatment. Br. J. Psychiatry 2017, Oct. 211(4)216-222
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.
  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.

Parkinson's disaese

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

Virginia Thornley, M.D., Neurologist, Epileptologist
December 17, 2018
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).
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).
  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

Review of scientific literature: can diet alleviate symptoms from fibromyalgia

Virginia Thornley, M.D., Neurologist, Epileptologist
October 15, 2018
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.
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.
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.