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 new diseases emerging in neurology?

Medical futurists predict that scientific advances will lead to more precise definition of diseases. This will inevitably result in the emergence of more diseases and fewer syndromes. This case is made very eloquently in the book, The Innovators Prescription. Many neurological disorders currently wallow at the intuitive end of medical practice, and their journey towards precision medicine is painfully too slow. Neurology therefore has a great potential for the emergence of new disorders.

https://pixabay.com/en/pie-chart-diagram-statistics-parts-149727/
https://pixabay.com/en/pie-chart-diagram-statistics-parts-149727/

In the ‘good old days’, many diseases were discovered by individual observers working alone, and the diseases were named after them. In this way, famous diseases were named after people such as James Parkinson, Alois Alzheimer, and George Huntington. For diseases discovered by two or three people, it didn’t take a great stretch of the imagination to come up with double-barrelled names such as Guillain-Barre syndrome (GBS) or Lambert-Eaton myasthenic syndrome (LEMS).

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
Today, however, new diseases emerge as a result of advances made by large collaborations, working across continents. These new diseases are named after the pathological appearance or metabolic pathways involved (as it will require an act of genius to create eponymous syndromes to cater for all the scientists and clinicians involved in these multi-centre trials). This is unfortunately why new disorders now have very complex names and acronyms. Take, for examples, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and chronic relapsing inflammatory optic neuropathy (CRION). It is a sign that we should expect new neurological diseases to be baptised with more descriptive, but tongue-twisting, names.

 

https://pixabay.com/en/letters-a-abc-alphabet-literacy-67046/
https://pixabay.com/en/letters-a-abc-alphabet-literacy-67046/

New disease categories emerge in different ways. One is the emergence of a new disorder from scratch, with no antecedents whatsoever. Such was the case with autoimmune encephalitis, a category which has come from relative obscurity to occupy the centre stage of eminently treatable diseases. I have posted on this previously as What’s evolving at the cutting edge of autoimmune neurology and What are the dreadful autoimmune disorders that plague neurology? Other disease categories form when different diseases merge into a completely new disease category, or when a previously minor diseases mature and stand on their own feet. These are the stuff of my top 8 emerging neurological disorders.

 

By Photo (c)2007 Derek Ramsey (Ram-Man) - Self-photographed, CC BY-SA 2.5, Link
By Photo (c)2007 Derek Ramsey (Ram-Man) – Self-photographed, CC BY-SA 2.5, Link

1. mTORopathy

This huge monster is ‘threatening’ to bring together, under one roof, diverse disorders such as tuberous sclerosis complex, epilepsy, autism, traumatic brain injury, brain tumours, and dementia. You may explore this further in my previous blog post titled mTORopathy: an emerging buzzword for neurology.

Merging bubbles. Charlie Reece on Flikr. https://www.flickr.com/photos/charliereece/777487250
Merging bubbles. Charlie Reece on Flikr. https://www.flickr.com/photos/charliereece/777487250

2. IgG4-related autoimmune diseases

This new group of neurological diseases is threatening to disrupt the easy distinction between several neurological disorders such as myasthenia gravis (MG), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and Guillain Barre syndrome (GBS). It even includes the newly described IgLON 5 antibody disorder, something I blogged about as IgLON5: a new antibody disorder for neurologists. You may explore IgG4-related disorders in this paper titled The expanding field of IgG4-mediated neurological autoimmune disorders. 

By Aida Pitarch - Own work, CC BY-SA 4.0, Link
By Aida PitarchOwn work, CC BY-SA 4.0, Link

3. Anti-MOG antibody disorders

Now, neurologists have always known about MOG, mostly as a minor bit player, an extra, so to say. No more, it is now all grown up and matured. And the growth is fast and involves many inflammatory demyelinating disease of the CNS such as fulminant demyelinating encephalomyelitis and multiphasic disseminated encephalomyelitis. How far will it go?

http://thebluediamondgallery.com/a/autoimmune.html
http://thebluediamondgallery.com/a/autoimmune.html

4. Hepatitis E virus related neurological disorders

A field which is spurning new neurological disorders is neurological infections, and Hepatitis E virus (HEV) is in the forefront. We are now increasingly recognising diverse Hepatitis E related neurological disorders. HEV has now been linked to diseases such as Guillain Barre syndrome (GBS) and brachial neuritis. And the foremost researcher in this area is Harry Dalton, a hepatologist working from Cornwall, not far from me! And Harry will be presenting at the next WESAN conference in Exeter in November 2017.

By Transferred from en.wikipedia to Commons.This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #5605.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, Link
By Transferred from en.wikipedia to Commons.This media comes from the Centers for Disease Control and Prevention‘s Public Health Image Library (PHIL), with identification number #5605.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, Link

5. Zika virus

Zika virus is another novel infection with prominent neurological manifestations. We are learning more about it every day, and you may check my previous blog post on this, titled 20 things we now know for certain about the Zika virus.

By Manuel Almagro Rivas - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47941048
By Manuel Almagro RivasOwn work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47941048

6. Multisystem proteinopathy

Multisystem proteinopathy is a genetic disorder which affects muscles and bone, in addition to the nervous system. It is associated with Paget’s disease of the bone and inclusion body myositis, with implications for motor neurone disease (MND) and frontotemporal dementia (FTD). Quite a hydra-headed monster it seems, all quite complex, and perhaps one strictly for the experts.

Hydra. Andrew Jian on Flikr. https://www.flickr.com/photos/andrew_jian/475479747
Hydra. Andrew Jian on Flikr. https://www.flickr.com/photos/andrew_jian/475479747

7. GLUT-1 deficiency syndromes

GLUT-1 stands for glucose transporter type 1. Deficiency of GLUT-1 results in impaired transportation of glucose into the brainGLUT-1 deficiency syndrome presents with a variety of neurological features such as dystonia, epilepsy, ataxia, chorea, and a host of epilepsy types. It starts in infancy and is characterised by a low level of glucose and lactic acid in the cerebrospinal fluid. Expect to hear more on this in the near future.

Sugar Cubes. David pacey on Flikr. https://www.flickr.com/photos/63723146@N08/7164573186
Sugar Cubes. David pacey on Flikr. https://www.flickr.com/photos/63723146@N08/7164573186

8. Progressive Solitary Sclerosis

And this is my favourite paradigm shifter. Neurologists often see people with brain inflammatory lesions and struggle to decide if they fulfil the criteria for multiple sclerosis (MS). The current threshold for concern is when there have been two clinical events consistent with inflammation of the nervous system, or their MRI scan shows involvement of at least two different sites of the nervous system. Well, dot counting may soon be over, going by this paper in Neurology titled Progressive solitary sclerosis: gradual motor impairment from a single CNS demyelinating lesion. The authors identified 30 people with progressive clinical impairment arising from a single inflammatory nervous system lesion. The authors were convinced enough to recommend the inclusion of this new entity, progressive solitary sclerosis, in future classifications of inflammatory disorders of the central nervous system. Move over progressive MS, here comes progressive SS. Neurologists will surely have their job cut out for them.

Solitary tree at Sunset. epcp on Flikr. https://www.flickr.com/photos/epcprince/3418260382
Solitary tree at Sunset. epcp on Flikr. https://www.flickr.com/photos/epcprince/3418260382

Do you have any suggestions of emerging neurological disorders? Please leave a comment

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PS. These disorders are all covered in neurochecklists

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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.

What strange things about IBM leave neurologists puzzled?

Inclusion body myositis (IBM) is classified as an inflammatory muscle disease. It however stands out from all other muscle diseases, inflammatory or not. IBM has quite unique, and often unexplained, characteristics. These features mark it out as an enigma, and the mystery deepens the more neurologists research it.

Puzzled. andy.brandon50 on Flikr. https://www.flickr.com/photos/54027476@N07/4999919941
Puzzled. andy.brandon50 on Flikr. https://www.flickr.com/photos/54027476@N07/4999919941

IBM continues to throw up new and challenging riddles for neurologists, and here are my 6 puzzling things about IBM.

6. Unique muscle distribution

Muscle diseases in adults almost always start in the upper or proximal parts of the limbs. IBM however bucks the trend with a specific predilection for muscles of the middle part of the limbs, the knee extensors in the legs, and the long finger flexors in the arms. This unique pattern of muscle involvement results in a characteristic or pathognomonic clinical picture of IBM: marked wasting of the muscles of the forearms, and of the quadriceps. People with IBM therefore complain of a weak grip, and a tendency to fall. The reason for this unique muscle specificity has me dumbfounded.

5. Unusual muscle biopsy features

By Jensflorian - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11763608
By JensflorianOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11763608

 

The classical inflammatory muscle diseases are polymyositis (PM) and dermatomyositis (DM), and the inflammation in these conditions is easily detected on muscle biopsy. This is however not the case with IBM which shows very little inflammation, and this paucity of inflammation underlies IBM’s unresponsiveness to anti-inflammatory treatment with steroids. IBM muscle biopsy specimens however show typical eosinophilic cytoplasmic inclusions and rimmed vacuoles. The unwary neuropathologist however easily misses these specific but elusive landmarks, making IBM notoriously difficult to diagnose, or worse still, easily misdiagnosed as PM or DM.

4. Association with strange bedfellows

IBM is typically an isolated disease, preferring to roam in solitude. Or so I thought until I came across a paper in Neurology which introduced me to the concept of multisystem proteinopathy. This is the association of IBM with Paget’s disease of the bone (PDP), motor neurone disease (MND), or frontotemporal dementia (FTD). Why IBM should associate with these strange and unrelated diseases leaves me totally baffled.

3. Genetic underpinnings

jeans for genes. susan on Flikr. https://www.flickr.com/photos/certified_su/3803103894
jeans for genes. susan on Flikr. https://www.flickr.com/photos/certified_su/3803103894

 

Neurologists like to keep the geneticists busy with every disease they study, and IBM is no exception. It is not clear exactly when, how or why neurologists went gene-hunting in a condition that is typically sporadic. But hunt they did, and their perseverance paid off; we now know that IBM may also be hereditary or familial. And the genetic spectrum of IBM continues to grow. Take this paper in Neurology Genetics which reports two families with abnormalities in the hnRNPA1 gene. Another genetic association of IBM is GNE. To muddy things up a bit more, IBM has been linked to HLA-DRB1*03. Why any disease should decide to have sporadic and genetic forms leaves me very befuddled.

2. Association with hepatitis C virus (HCV)

By HCV_pictures.png: Maria Teresa Catanese, Martina Kopp, Kunihiro Uryu , and Charles Ricederivative work: TimVickers (talk) - HCV_pictures.png, Public Domain, https://commons.wikimedia.org/w/index.php?curid=10903740
By HCV_pictures.png: Maria Teresa Catanese, Martina Kopp, Kunihiro Uryu , and Charles Ricederivative work: TimVickers (talk) – HCV_pictures.png, Public Domain, https://commons.wikimedia.org/w/index.php?curid=10903740

 

Just when you start adjusting your mindset to a disease that may be genetic, sporadic and inflammatory, the neurologists do it again. This time in cahoots with the infectious disease specialists. They ask you once more to adjust your mindset, and see IBM as a possible fallout of a viral invasion, the culprit here being hepatitis C virus (HCV). Writing in Neurology, the authors boldly suggest a possible pathomechanistic link between the 2 conditions. Mindset tuning in progress.

1. Autoimmune pathogenesis

Immune cell detects disease. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/16233121363/in/photolist-qJsZqP
Immune cell detects disease. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/16233121363/in/photolist-qJsZqP

 

Just before you lose it all, the neurologists take you gently back to familiar territory, autoimmunity. But even here there are strange undertones. The autoimmune antibody associated with IBM is rather unique, as you have now learnt to expect. The reported association of anti cN-1A and IBM comes from the Annals of the Rheumatic Diseases, letting the neurologist off this time. The authors looked at autoantibodies to cytosolic 5′-nucleotidase 1A in sporadic IBM. The significance of the association is still not clear. One thing is however obvious-neurologists need to start working on the reasons they will give to their immunologists to justify sending off that blood sample for anti cN-1A. I foresee a drawn-out battle!

1_________0____________1____________0___________1___________0

These and many other things go to show why IBM is such a conundrum for neurologists. It has the neurologists vigorously scratching their heads, wishing for an enigma cipher machine. In the meantime all they can do is assure their patients of the therapeutic advances in IBM. As with all mysteries however, it shall all be revealed in time… and neurologists and their patients will be all smiles!

smiley. susan on Flikr. https://www.flickr.com/photos/certified_su/3802633000/in/photostream/
smiley. susan on Flikr. https://www.flickr.com/photos/certified_su/3802633000/in/photostream/

 

Fronto-temporal brain sagging syndrome

Frontotemporal dementia (FTD) is a progressive untreatable condition. It causes the frontal and temporal lobes of the brain to shrink and it manifests as a behavioural disorder or with speech difficulties. I was unaware of any mimics of FTD  (differential diagnoses) that were not equally untreatable.

"LobesCaptsLateral" by Sebastian023. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:LobesCaptsLateral.png#/media/File:LobesCaptsLateral.png
“LobesCaptsLateral” by Sebastian023. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:LobesCaptsLateral.png#/media/File:LobesCaptsLateral.png

 

I was therefore surprised by this article in Neurology which reported 8 patients with the frontotemporal brain sagging syndrome. In this condition, FBSS, there is leakage of cerebrospinal fluid (CSF) which results in low pressure in the brain (intracranial hypotension). The result is that the brain, well, sags.

"1317 CFS Circulation" by OpenStax College - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013.. Licensed under CC BY 3.0 via Commons - https://commons.wikimedia.org/wiki/File:1317_CFS_Circulation.jpg#/media/File:1317_CFS_Circulation.jpg
“1317 CFS Circulation” by OpenStax College – Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013.. Licensed under CC BY 3.0 via Commons – https://commons.wikimedia.org/wiki/File:1317_CFS_Circulation.jpg#/media/File:1317_CFS_Circulation.jpg

 

It i typically the back of the brain that sags in intracranial hypotension, and this leads to distortion of the brainstem. In FBSS however there is in addition, somehow, a reduction in the metabolic activity of the frontal lobe of the brain. It is this frontal hypometabolism that produces the clinical picture that mimics frontotemporal dementia.

"NPH MRI 272 GILD" by © Nevit Dilmen. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:NPH_MRI_272_GILD.gif#/media/File:NPH_MRI_272_GILD.gif
“NPH MRI 272 GILD” by © Nevit Dilmen. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:NPH_MRI_272_GILD.gif#/media/File:NPH_MRI_272_GILD.gif

 

There is an added twist to the story as reported, again in Neurology, of a patient whose syndrome spontaneously resolved when he accidentally fell and hit his chest on a chair. The authors said ‘…the fall may have caused a contusion injury and given him an auto-blood patch‘. In plain English, his injury caused a bleed which clotted and (again somehow), sealed the site of cerebrospinal fluid leakage.

Surely a not-to-miss differential next time you are about to diagnose frontotemporal dementia. A reversible dementia!