The 13 most dreadful neurological disorders…and the groups standing up to them

Neurology embodies some of the most dreadful diseases known to man. Every neurological disorder is disheartening, each characterised by unique frustrations for patients and their families. It is difficult to quantify the distress and misery these afflictions impose on their victims, and even harder to appreciate the despair and anguish they evoke in those who care for them.

Brain Art. Ars Electronica on Flikr. https://www.flickr.com/photos/arselectronica/7773544158

It is clearly hard to compare the impact of different neurological diseases. Some neurological disorders however stand out because of the consternation their names evoke, and the terror that follows in their wake. These diseases come with unimaginable physical and psychological burdens, and crushing demands on human and material resources. They impose either a debilitating morbidity, or a hasty mortality.

Neural pathways in the brain. NICHD on Flikr. https://www.flickr.com/photos/nichd/16672073333

The nervous system ailments in the list below pose exacting therapeutic challenges, resistant as they are to all attempts at treatment or cure. This list sets out to emphasise the urgency for neuroscience to find a remedy for each of them, but it does not intend to belittle the horror of the disorders omitted from it. The choice of the number 13 is, sadly, self-evident. Here then are the top 13 most dreadful neurological disorders…all with gold links to the associations helping to defeat them.

Working Brain. Gontzal García del Caño on Flikr. https://www.flickr.com/photos/euskalanato/2052487054

Ataxia

Ataxia, in lay terms, is incoordination. This typically manifests as an unsteady gait and clumsiness. Ataxia converts all activities of daily living into burdensome chores. Whilst many types of ataxia are preventable or reversible, primary ataxias are progressive and carry a dismal outlook. In this category are Spinocerebellar ataxia (SCA)Friedreich’s ataxia, and Ataxia telangiectasia. You may read more about ataxia in these previous blog posts: The 43 spinocerebellar ataxias: the complete checklistsOld drugs, new roles?, and Will Riluzole really be good for cerebellar ataxia?

Brain tumours

Brain cancers hardly need any description. They are either primary, arising from the brain cells, or metastatic, spreading to the brain from other organs. Some primary brain cancers, such as meningiomas and pituitary tumours, are, relatively, treatable. Many others are unfortunately ominously malignant. The most dreadful in this category is surely the spine-chilling glioblastoma multiforme. You may check out these previous blog posts for more on these tumuors: Calming the rage of brain tumours: hope for a dreaded cancerMaggots, viruses and lasers: some innovations for brain tumoursand Are steroids detrimental to survival in brain tumours?

Peripheral neuropathy

Peripheral neuropathy is ubiquitous in the neurology clinic. Neuropathy may result from reversible situations such as overindulgence in alcohol, uncontrolled diabetes, or Vitamin B12 deficiency. Neuropathy is often just a minor inconvenience when it manifests with sensory symptoms such as tingling and numbness. It may however be debilitating when it presents as limb paralysis, or complicated by major skeletal deformities. At the severe end of the spectrum of neuropathy are the hereditary forms such as Charcot Marie Tooth disease (CMT) and Familial amyloid polyneuropathy. Read more in these blog posts: The 52 variants of CMT… and their practical checklistsWhat’s looming at the frontline of peripheral neuropathy? and Will a pill really hold the cure for CMT?

Creutzfeldt Jakob disease (CJD)

CJD is the most iconic of the prion diseases. These disorders are as horrendous as they are enigmatic, defying categorisation as either infections or neurodegenerative diseases. More puzzling is their ability to be either hereditary and acquired. CJD exists in the classic or variant form, but both share a relentlessly rapid course, and a uniformly fatal end. You may read more in these previous blog posts titled Final day of ANA 2015- Prions center stage, and What are the links between Prion diseases and Parkinsonian disorders?

Dementia

Dementia is the scourge of longevity. Its name strikes terror because it insidiously colonises the cells that make us who we are. The most prominent dementia is Alzheimer’s disease, but it has equally dreadful companions such as Frontotemporal dementia (FTD) and Dementia with Lewy bodies (DLB). Read more on dementia in these blog posts: How bright is the future for Alzheimer’s disease?Alzheimer’s disease: a few curious things, and Alzheimers disease and its promising links with diabetes.

Dystonia

Dystonia marks its presence by distressing movements and painful postures. At its most benign, dystonia is only a twitch of the eyelid (blepharospasm) or a flicker of one side of the face (hemifacial spasm). At the extreme end, it produces continuous twisting and swirling motions, often defying all treatments. The causes of dystonia are legion, but the primary dystonias stand out by their hereditary transmission and marked severity. Read more on dystonia in these blog posts: Why does dystonia fascinate and challenge neurology? and Making sense of the dystonias: the practical checklists.

Huntington’s disease (HD)

Huntington’s disease is an iconic eponymous neurological disorder which is marked by the vicious triumvirate of chorea, dementia, and a positive family history. It is an awful condition, often driving its victims to suicide. It is a so-called trinucleotide repeat expansion disorder, implying that successive generations manifest the disease at an earlier age, and in more severe forms (genetic anticipation). You may read more on HD in the previous blog post titled What are the prospects of stamping out Huntington’s disease? 

Motor neurone disease (MND) 

Also known as Amyotrophic lateral sclerosis (ALS), MND is simply devastating. Recognising no anatomical boundaries, it ravages the central and peripheral nervous systems equally. MND creeps up on the neurones and causes early muscle twitching (fasciculations) and cramps. It then gradually devours the nerves resulting in muscle wasting, loss of speech, ineffectual breathing, and impaired swallowing. It is no wonder that one of the most read post on this blog is titled Is neurology research finally breaking the resolve of MND? Other previous blog posts on MND are The emerging links between depression and MNDWhat is the relationship of MND and cancer?Does diabetes protect from MND?, and MND and funeral directors-really?

Multiple sclerosis (MS)

Multiple sclerosis is a very common disease, and gets more common the further away you get from the equator. It is the subject of intense research because of the devastation it foists on predominantly young people. Many drugs now ameliorate, and even seem to halt the progression of, relapsing remitting MS (RRMS). This is however not the case with primary progressive MS (PPMS) which, until the introduction of ocrelizumab, defied all treatments. There are many contenders vying for the cause of MS, but the reason nerves in the central nervous system inexplicably lose their myelin sheaths remains elusive. You may read more on MS in these blog posts: The emerging progress from the world of MS , What are the remarkable drugs which have transformed the treatment of MS?, and Is low vitamin D a cause of multiple sclerosis?

Muscular dystrophy 

Muscular dystrophy is an umbrella term that covers a diverse range of inherited muscle diseases. The most devastating, on account of its early onset and unrelenting progression, is Duchenne muscular dystrophy (DMD). Adult neurologists will be more familiar with late onset muscular dystrophies such as Myotonic dystrophy and Facioscapulohumeral muscular dystrophy (FSHD). Read more on muscular dystrophy in these previous blog posts: How is neurology stamping out the anguish of Duchenne? and The A–Z of limb girdle muscular dystrophy (LGMD).

Rabies

Rabies, a rhabdovirus, is a zoonosis-it is transmitted to man by a wide range of animals such as dogs, bats, racoons, and skunks. It is the quintessential deadly neurological disease, popularised by the Steven King book and film, Cujo. Rabies manifests either as the encephalitic (furious) or the paralytic (dumb) forms. It wreaks havoc by causing irritability, hydrophobia (fear of water),  excessive sweating, altered consciousness, and inevitably death. Whilst there are vaccines to protect against rabies, a cure has eluded neuroscientists. This blog is yet to do justice to rabies but it is, at least, listed in the post titled What are the most iconic neurological disorders? But you could better by checking neurochecklists for details of the clinical features and management of rabies.

Spinal cord injury

Nothing is quite as heart-wrenching as the sudden loss of body function that results from spinal cord trauma. This often causes paralysis of both legs (paraplegia), or all four limbs (quadriplegia). This life-changing disorder is often accompanied by loss of control over bowel and bladder functions, and complications such as bed sores and painful spasms. You may read about the heroic efforts to treat spinal cord injury in the blog posts titled 6 innovations in the treatment of spinal cord injury and Head transplant, anyone?

Tetanus

Tetanus is an eminently preventable disease, now almost wiped out in developed countries by simple immunisation. It however continues its pillage and plunder in the developing world. It strikes young and old alike, often invading the body through innocuous wounds. Tetanus is caused by tetanospasmin and tetanolysin, the deadly toxins of the bacterium Clostridium tetani. The disease is classified as generalised, localised, cephalic, or neonatal tetanus. It is characterised by painful spasms which manifest as lockjaw (trismus), facial contortions (risus sardonicus), trunkal rigidity (opisthotonus), and vocal cord spasms (laryngospasm). The disease is awfully distressing and, when advanced, untreatable. It is a stain on the world that this avoidable disorder continuous to threaten a large number of its inhabitants. Check neurochecklists for more on the pathology, clinical features, and management of tetanus.

 

Light brain. Mario D’Amore on Flikr. https://www.flickr.com/photos/kidpixo/3470448888

As for all lists, this will surely be subject to debate, or perhaps some healthy controversy. Please leave a comment.

Calming the rage of brain tumours: hope for a dreaded cancer

"Glioblastoma - MR coronal with contrast" by Christaras A - Created myself from anonymized patient MR. Licensed under CC BY 2.5 via Commons.
Glioblastoma – MR coronal with contrast” by Christaras A – Created myself from anonymized patient MR. Licensed under CC BY 2.5 via Commons.

 

Brain cancer is a horrible disease even among cancers. Apart from benign tumours such as meningioma, very few brain tumours have happy endings. It is however not all doom and gloom- there are many advances raising hope for the future of brain cancer. Here are 10 hope-raisers.

10. Nanotechnology-guided radiation treatment

"Nanob". Licensed under ">CC BY-SA 3.0 via Wikimedia Commons.
Nanob“. Licensed under CC BY-SA 3.0 via Wikimedia Commons.

 

Nanotechnology is promising a lot for neurology, and I discussed this in my previous post on 10 remarkable breakthroughs that will change neurology. It is heart-warming to learn that nanotechnology is stepping into brain cancer treatment. Their role is in reducing the damage that normal tissues sustain when brain cancer is treated with conventional radiation. Scientists hope to minimise this damage by delivering the radiation treatment through nanomolecules; because of their small size it is presumed this approach should cause less harm. In this article in Neuro-Oncology titled Rhenium-186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma, the authors report the efficacy of liposomally encapsulated radionuclides in rat models of glioblastoma. It is complicated stuff but Science Daily’s headline says it all: Treating deadly brain tumors by delivering big radiation with tiny tools.

9. Ultrasonic screwdriver

11th Doctor Who Sonic Screw Driver Open. Tony Buser on Flikr. https://www.flickr.com/photos/tbuser/4778412914
11th Doctor Who Sonic Screw Driver Open. Tony Buser on Flikr. https://www.flickr.com/photos/tbuser/4778412914

 

The challenge for every drug cancer treatment is to deliver the drug as close as possible to the tumour cells. This is particularly difficult for brain cancer because of the protective brain blood barrier (BBB). This shield is composed of the walls of the blood vessels, and the triple-layered sheath covering the brain called the dura.

What if the drugs could be sent across this barrier without breaching it? More Dr. Who than neuroscience, but this is what the ultrasonic screwdriver recently achieved to wide acclaim. Using ultrasound, the scientists successfully delivered chemotherapy drugs across the BBB. This press release from Sunnybrook Health Sciences Centre explains it further. The neurosurgeons used an MRI-guided focused low-intensity ultrasound to force drug microbubbles in the bloodstream across the blood-brain barrier. “The waves repeatedly compress and expand the microbubbles, causing them to vibrate and loosen tight junctions of the cells comprising the BBB. Once the barrier was opened, the chemotherapy flowed through and deposited into the targeted regions”. Very exciting SciFi stuff. Here is a simplified version from IFL Science titled Scientists Have Breached The Blood-Brain Barrier For The First Time And Treated A Brain Tumor Using An “Ultrasonic Screwdriver”.

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8. Electromagnetic field therapy

"Felder um Dipol" by Averse - http://de.wikipedia.org/wiki/Datei:Felder_um_Dipol.jpg. Licensed under CC BY-SA 3.0 via Commons.
Felder um Dipol” by Aversehttp://de.wikipedia.org/wiki/Datei:Felder_um_Dipol.jpg. Licensed under CC BY-SA 3.0 via Commons.

 

Electromagnetic field therapy is a new area of brain tumour treatment and not conventional in any way. It however promises to improve survival of patients with glioblastoma who have received conventional radiotherapy and chemotherapy. I came across this in MNT under the title Use of type of electromagnetic field therapy improves survival for patients with brain tumor. This treatment is a form of tumor-treating fields (TTFields), “a treatment that selectively disrupts the division of cells by delivering low-intensity, intermediate-frequency alternating electric fields via transducer arrays applied to the shaved scalp”. The evidence for this is a trial reported in the Journal of the American Medical Association (JAMA) titled Alternating electric fields for the treatment of glioblastoma. It is not a panacea but any light at the end of the dreadful tunnel of brain cancer is worth exploring. It is a good sign that the FDA has approved this technology.

7. Pulsed electric field (PEF)

Electric storm. Romain Guy on Flikr. https://www.flickr.com/photos/romainguy/3712378856
Electric storm. Romain Guy on Flikr. https://www.flickr.com/photos/romainguy/3712378856

 

Another technique that is under investigation for treatment of brain cancer is pulsed electric field (PEF). This was the focus of a recent paper in Scientific Reports titled Targeted cellular ablation based on the morphology of malignant cells. PEF preferentially targets and destroys malignant cells relatively sparing normal cells. The mechanism, if you are curious to know, is called high frequency irreversible electroporation (HFIRE). Or, in plain English, electric disruption of cells. This has reportedly been effective in dogs, and the challenge is to translate the benefits to humans.

6. Vacquinols

"Cancer cells- death (step 1)" by Susan Arnold (Photographer) - This image was released by the National Cancer Institute, an agency part of the National Institutes of Health, with the ID 2368 (image) (next).This tag does not indicate the copyright status of the attached work. A normal copyright tag is still required. See Commons:Licensing for more information.English | Français | +/−. Licensed under Public Domain via Wikimedia Commons.
Cancer cells- death (step 1)” by Susan Arnold (Photographer) – This image was released by the National Cancer Institute, an agency part of the National Institutes of Health, with the ID 2368 (image) (next).This tag does not indicate the copyright status of the attached work. A normal copyright tag is still required. See Commons:Licensing for more information.English | Français | +/−. Licensed under Public Domain via Wikimedia Commons.

 

Touted as the drug that makes cancer cells explode, Vacquinols are experimental agents which have shown remarkable efficacy in rat models of glioblastoma. The research reported in the journal Cell is titled Vulnerability of glioblastoma cells to catastrophic vacuolization and death induced by a small molecule. The article is quite ‘scientific’ as reflected by the tortuous title, but the whole idea is that vacquinols target some cellular processes and  cause the cell membranes of glioblastoma cells to rupture . There is some way to go but imagine this advance translating into clinical practice!

5. aCT1

"Temozolomide-3D-spacefill" by Jynto (talk) - Own workThis chemical image was created with Discovery Studio Visualizer.. Licensed under CC0 via Wikimedia Commons.
Temozolomide-3D-spacefill” by Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer.. Licensed under CC0 via Wikimedia Commons.

Temozolomide is a conventional treatment for glioblastoma but unfortunately some patients become resistant to this useful drug. Scientist have observed that glioblastoma cells achieve temozolomide-resistance via a protein called connexin 43 (Cx43).  Working on this knowledge, they have developed a Cx43 inhibitor called aCT1. I came across this agent in a piece in EurekaAlert titled Scientists find way to make resistant brain cancer cells sensitive to treatment. The scientific paper, published in Cancer Research, is titled Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide. A lucid title for a scientific paper for a change!

4. Propentofylline

"Glioblastoma (1)" by No machine-readable author provided. KGH assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims).. Licensed under CC BY-SA 3.0 via Commons.
Glioblastoma (1)” by No machine-readable author provided. KGH assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims).. Licensed under CC BY-SA 3.0 via Commons.

I came across propentofylline in the blog brainmysteries.com under the title Drug that could limit spread of deadly brain tumours. Propentofylline seems to enhance the effects of temozolomide and radiotherapy, the conventional treatments of brain cancer. In this way propentofylline may slow the spread of the brain tumour cells. It seems to work by inhibiting TROY, the protein that enables glioblastomas to spread to healthy brain cells. For the small print you may read the paper published in Journal of Neuro-oncology titled Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway.

3. Medical Marijuana

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A recent study published in Molecular Cancer Therapeutics appears to show that constituents of cannabis drastically increase the anti-cancer effects of conventional radiotherapy. The authors suggest that ‘these cannabinoids can prime glioma cells to respond better to ionizing radiation’. A couple of caveats; this is an in vitro (in a dish) study, and it was carried out in mice. Some way to go then, but you wouldn’t think so going by this headline from the Huffington Post which says Marijuana drastically shrinks aggressive form of brain cancer.

2. New cellular targets for cancer treatment

"Cell membrane3" by Boumphreyfr - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.
Cell membrane3” by BoumphreyfrOwn work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.

 

Two recent papers have reported on cellular proteins which brain tumours depend on. These are therefore potential targets for future therapeutic interventions. The first is hypoxia inducible factor-1 (HIF-1) which cancer cells produce when their oxygen supply is threatened. HIF-1 enables the cancer cells to produce new blood vessels (angiogenesis) thereby maintaining their supply of nourishing oxygen. This process is under investigation by researchers at Emory University.

The second property is related to proteins called sterol regulatory element-binding proteins (SREBPs). SREBP’s control the metabolism of glucose and fat in all cells, and researchers at Ohio State University are looking at ways to inhibit these proteins. This would potentially impair the ability of cancer cells to build their cell walls (membranes). Yes, only in mice again but still, hope. Here is a review of SREBP’s and cancer.

1. Pembrolizumab

"Melanoma" by Unknown - National Cancer Institute (AV Number: AV-8500-3850; Date Created: 1985; Date Entered: 1/1/2001), http://visualsonline.cancer.gov/details.cfm?imageid=2184. Licensed under Public Domain via Commons.
Melanoma” by Unknown – National Cancer Institute (AV Number: AV-8500-3850; Date Created: 1985; Date Entered: 1/1/2001), http://visualsonline.cancer.gov/details.cfm?imageid=2184. Licensed under Public Domain via Commons.

 

The news that Jimmy Carter has melanoma, and this had spread or metastasised to his brain, came as a shock to many of his admirers. It was therefore a relief when they learnt later that Carter’s cancer has all but cleared away. Very unusual to say the least, especially with a cancer as dreadful as melanoma. This remarkable achievement is attributable to an immunotherapy drug called Pembrolizumab, one of several types of drugs called humanised monoclonal antibodies.

Pembrolizumab has demonstrated effectiveness in melanoma and there are now NICE Guidelines for Pembrolizumab in melanoma. But how good is it in primary brain cancers? A trial is currently in progress to assess the efficacy of Pembromizumab in glioblastoma, the most dreaded of brain cancers. There are several other immune therapies that may be effective in brain metastases, and these are reviewed in an article in Current Treatment Options in Neurology titled Targeted therapies in brain metastases.

 

Brain tumours rage on, but the science is hopefully catching up. Victory beckons over this dreaded disease.

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