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.

What are the prospects of stamping out Huntington’s disease?

Huntington’s disease (HD) is, without doubt, one of the most dreaded neurological disorders. It is named after George Huntington, but the first description is probably by Charles Oscar Waters in 1842. It is dominantly inherited, each child carrying a 50% chance of acquiring the faulty gene. The genetics is slightly tricky because HD is also a tricnucleotide repeat expansion disorder, similar to some other neurological diseases such as Friedreich’s ataxia (FA), Kennedy disease, myotonic dystrophyspinocerebellar ataxia (SCA), and oculopharyngeal muscular dystrophy (OPMD). In these diseases, a section of the genetic code duplicates itself repeatedly, producing abnormally long segments; worse still, these segments get longer which each transmission down the family line. This is called genetic anticipation, and it leads to later generations of the family developing the disease at an earlier age, and manifesting it more severely.

By Zephyris from en.wikipedia.org, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2118354
By Zephyris from en.wikipedia.org, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2118354

HD is not a nice disease. It is accompanied by chorea, probably the most distressing abnormal movement to torment the human body. This is a continuous, writhing muscle activity which involves all the body, and generating very grotesque and painful postures. As if this wasn’t enough, dementia eventually sets in, as does almost every other neurological symptom one could imagine. HD is a problem neurology needs to solve. And thankfully there is some activity in that direction. Here are 4 recent hope-raising developments.

1. Gene silencing with ISIS-HTTRx

RNA molecules. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/24148252722
RNA molecules. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/24148252722

The manufacturers of ISIS-HTTRx must surely be rueing the unfortunate choice of name for their gene silencing drug. But they will take comfort in its promise to crush HD. It is the first trial of a new drug for HD, and it is touted as probably ‘one of the most important developments since the gene for Huntington’s disease was discovered‘. ISIS-HTTRx neutralises huntingtin, the toxic product which accumulates in, and damages, the nerves of people with HD. The only snag…it has to be delivered directly into the spinal fluid. I’m sure an oral tablet will eventually follow, but ISIS-HTTRx is still a long way off; it has to be tested in human volunteers first. One eye then on Sarah Tabrizi, the trial lead, and the other eye on the drug’s name; ISIS pharmaceuticals is now IONIS.

2. Suppressing Huntingtin by enhancing PPAR-δ

By Emw - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8820973
By EmwOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8820973

PPAR-δ stands for peroxisome proliferator-activated receptor delta, and it is a good guy. Researchers have shown that enhancing the activity of PPAR-δ in mouse models of HD has a beneficial effect on mitochondrial function, motor activity, neurodegeneration, and survivalHuntingtin, the infamous bad protein in HD, suppresses PPAR-δ activity. But the wily researchers found a way to reverse this suppression by using an agent called KD3010. They announced their findings in Nature Medicine under the refreshingly self-explanatory title, PPAR-δ is repressed in Huntington’s disease, is required for normal neuronal function and can be targeted therapeutically. (OK, it could be a little shorter). The question now is whether this can be translated to humans. We don’t have too long to wait to find out because the Food and Drug Administration (FDA) has just approved KD3010 human trials

3. Removing cholesterol by boosting CYP46A1

By Jynto (talk) - Own workThis chemical image was created with Discovery Studio Visualizer., CC0, https://commons.wikimedia.org/w/index.php?curid=37702275
By Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer., CC0, https://commons.wikimedia.org/w/index.php?curid=37702275

CYP46A1 is an enzyme which regulates the breakdown of cholesterol. And what has cholesterol got to do with HD? Well…wait for this…cholesterol accumulates in the nerve cells of people with HD, and may contribute to nerve damage. The good news is that CYP46A1 helps to get rid of cholesterol, and some researchers postulate that medicines which enhance the activity of CYP46A1 will improve HD. This all comes from a paper in the journal Brain titled CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease. We are still at the proof of concept stages, but it will help if the CYP46A1-enhancing drugs come as handy pills! 

4. Controlling chorea with deutetrabenazine

By (bencbartlett (talk)) - I (bencbartlett (talk)) created this work entirely by myself., CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=27611647
By (bencbartlett (talk)) – I (bencbartlett (talk)) created this work entirely by myself., CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=27611647

Neurologists are familiar with tetrabenazine, the best treatment for chorea. And Star Trek fans are familiar with the heavy hydrogen atom, deuterium. Put the two together and, voila, you get deutetrabenazine (SD809). The heavy hydrogen of deuterium makes deutetrabenazine a more stable drug. This should make it last longer in the body, and also cause less side effects. Considering that the adverse effects of tetrabenazine include depression and parkinsonism, this is not an insignificant advantage (pardon the double negative…I couldn’t help it).

How well does deutetrabenazine translate to clinical practice? Sufficiently well enough it seems, going by the trial published in JAMA Neurology titled Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease. The authors compared the drug to placebo and showed that deutetrabenazine effectively improved chorea at 12 weeks. It is not surprising that the trial compared deutetrabenazine to placebo rather than the existing alternative; head-to-head drug trials are as rare as hen’s teeth in medicine (I wonder why that is). Anyway, deutetrabenazine may be coming to a pharmacy near you soon…we hope. 

Hope. Sign pointing to the village of Hope, Derbyshire UK. Paul Sifter on Flikr. https://www.flickr.com/photos/polsifter/4047982682
Hope. Sign pointing to the village of Hope, Derbyshire UK. Paul Sifter on Flikr. https://www.flickr.com/photos/polsifter/4047982682

There is still a long way to go yet, but each  small step is a glimmer of hope for a neurodegenerative disease such as HD.

Remember, you can have everything HD at your fingertips with neurochecklists (and pardon the shameless pitch).

Addendum

Shortly after posting this blog I came across these articles on HD prospects

  • From Huntington’s Disease News comes Pridopidine. One more to add to the hope for neuroprotection against HD.
  • From the Hazard Gazette comes SIRT2 as a future treatment target for HD

What are the most iconic neurological disorders?

Neurology is a broad specialty covering a staggering variety of diseases. Some neurological disorders are vanishingly rare, but many are household names, or at least vaguely familiar to most people. These are the diseases which define neurology. Here, in alphabetical order, is my list of the top 60 iconic neurological diseases, with links to previous blog posts where available.

 

1. Alzheimer’s disease

By uncredited - Images from the History of Medicine (NLM) [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=11648572
By uncredited – Images from the History of Medicine (NLM) [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=11648572

2. Behcet’s disease

By Republic2011 - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=17715921
By Republic2011Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=17715921

3. Bell’s palsy

By http://wellcomeimages.org/indexplus/obf_images/69/f2/8d6c4130f4264b4b906960cf1f7e.jpgGallery: http://wellcomeimages.org/indexplus/image/M0011440.html, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=36350600
By http://wellcomeimages.org/indexplus/obf_images/69/f2/8d6c4130f4264b4b906960cf1f7e.jpgGallery: http://wellcomeimages.org/indexplus/image/M0011440.html, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=36350600

4. Brachial neuritis

5. Brain tumours

6. Carpal tunnel syndrome

7. Cerebral palsy (CP)

8. Cervical dystonia

9. Charcot Marie Tooth disease (CMT)

By http://wellcomeimages.org/indexplus/obf_images/66/09/4dfa424fe11bb8dc56b2058f04ba.jpgGallery: http://wellcomeimages.org/indexplus/image/V0026141.html, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=36578490
By http://wellcomeimages.org/indexplus/obf_images/66/09/4dfa424fe11bb8dc56b2058f04ba.jpgGallery: http://wellcomeimages.org/indexplus/image/V0026141.html, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=36578490

10. Chronic inflammatory demyelinating polyneuropathy (CIDP)

11. Cluster headache

12. Creutzfeldt-Jakob disease (CJD)

By Unknown - http://www.sammlungen.hu-berlin.de/dokumente/11727/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4008658
By Unknownhttp://www.sammlungen.hu-berlin.de/dokumente/11727/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4008658

13. Duchenne muscular dystrophy (DMD)

By G._Duchenne.jpg: unknown/anonymousderivative work: PawełMM (talk) - G._Duchenne.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9701531
By G._Duchenne.jpg: unknown/anonymousderivative work: PawełMM (talk) – G._Duchenne.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9701531

14. Encephalitis

15. Epilepsy

16. Essential tremor

17. Friedreich’s ataxia

By Unknown - http://www.uic.edu/depts/mcne/founders/page0035.html, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3960759
By Unknownhttp://www.uic.edu/depts/mcne/founders/page0035.html, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3960759

18. Frontotemporal dementia (FTD)

19. Guillain-Barre syndrome (GBS)

By Anonymous - Ouvrage : L'informateur des aliénistes et des neurologistes, Paris : Delarue, 1923, Public Domain, https://commons.wikimedia.org/w/index.php?curid=28242077
By Anonymous – Ouvrage : L’informateur des aliénistes et des neurologistes, Paris : Delarue, 1923, Public Domain, https://commons.wikimedia.org/w/index.php?curid=28242077

20. Hashimoto encephalopathy

21. Hemifacial spasm

22. Horner’s syndrome

By Unknown - http://ihm.nlm.nih.gov/images/B15207, Public Domain, https://commons.wikimedia.org/w/index.php?curid=19265414
By Unknownhttp://ihm.nlm.nih.gov/images/B15207, Public Domain, https://commons.wikimedia.org/w/index.php?curid=19265414

23. Huntington’s disease (HD)

https://en.wikipedia.org/wiki/George_Huntington#/media/File:George_Huntington.jpg
https://en.wikipedia.org/wiki/George_Huntington#/media/File:George_Huntington.jpg

24. Idiopathic intracranial hypertension (IIH)

25. Inclusion body myositis (IBM)

26. Kennedy disease

27. Korsakoff’s psychosis

28. Lambert-Eaton myasthenic syndrome (LEMS)

29. Leber’s optic neuropathy (LHON)

30. McArdles disease

31. Meningitis

32. Migraine

33. Miller-Fisher syndrome (MFS)

By J3D3 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34315507
By J3D3Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34315507

34. Motor neurone disease (MND)

35. Multiple sclerosis (MS)

36. Multiple system atrophy (MSA)

37. Myasthenia gravis (MG)

38. Myotonic dystrophy

39. Narcolepsy

40. Neurofibromatosis (NF)

41. Neuromyelitis optica (NMO)

42. Neurosarcoidosis

43. Neurosyphilis

44. Parkinson’s disease (PD)

45. Peripheral neuropathy (PN)

46. Peroneal neuropathy

47. Progressive supranuclear palsy (PSP)

48. Rabies

49. Restless legs syndrome (RLS)

50. Spinal muscular atrophy (SMA)

51. Stiff person syndrome (SPS)

52. Stroke

53. Subarachnoid haemorrhage (SAH)

54. Tension-type headache (TTH)

55. Tetanus

56. Transient global amnesia (TGA)

57. Trigeminal neuralgia

58. Tuberous sclerosis

59. Wernicke’s encephalopathy

By J.F. Lehmann, Muenchen - IHM, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9679254
By J.F. Lehmann, Muenchen – IHM, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9679254

60. Wilson’s disease

By Carl Vandyk (1851–1931) - [No authors listed] (July 1937). "S. A. Kinnier Wilson". Br J Ophthalmol 21 (7): 396–97. PMC: 1142821., Public Domain, https://commons.wikimedia.org/w/index.php?curid=11384670
By Carl Vandyk (1851–1931) – [No authors listed] (July 1937). “S. A. Kinnier Wilson“. Br J Ophthalmol 21 (7): 396–97. PMC: 1142821., Public Domain, https://commons.wikimedia.org/w/index.php?curid=11384670

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The Neurology Lounge has a way to go to address all these diseases, but they are all fully covered in neurochecklists. In a future post, I will look at the rare end of the neurological spectrum and list the 75 strangest and most exotic neurological disorders.

Top 10 abstracts from ANA 2015

Finally from ANA 2015, here are my top 10 abstracts/posters. My main criterion is posters that made me go ‘hmmm-that’s interesting!’

  • Musical hallucinosis occur in neurodegenerative disorders especially Lewy body disease (LBD)
  • Transcranial direct current stimulation (tDCS) may improve multiple sclerosis (MS) fatigue
  • Subjects with larger and closely knit social networks present earlier to hospital after ischaemic stroke

 

  • Patients with epilepsy are prone to orthostatic intolerance
  • Medical marijuana may be effective in controlling intractable seizures
  • Dropped head syndrome in multiple system atrophy (MSA) may respond to Amantadine

  • Hyponatraemia may predict in-hospital mortality in myasthenia gravis (MG)
  • Prostate cancer metastases to the ventricles may cause obstructive hydrocephalus
  • Rsing the leg off the couch elicits the Babinski response pyramidal tract dysfunction (the Pasupuleti sign)
  • Retinal fiber layer thickening may be a biomarker of Huntington’s disease (HD)