Why is chronic Lyme disease so frustrating to neurology?

Lyme disease is a well-known infection. It takes its name from Lyme, Connecticut, where it was first recognised as a distinct disease in 1975. The disease is caused by the infamous Borrelia species which get into humans through tick bites. The transmission typically occurs when the victim is taking a gingerly walk in deer-inhabited forests, usually in the pleasant months of May or June. The tick may leave a signature skin rash, erythema migrans. In the ideal situation, the clear history and a positive Lyme serology test make the diagnosis. A short treatment course with an antibiotic such as doxycycline or ceftriaxone and, hey presto, Lyme disease is cured, totally and permanently. And doctor and patient live happily ever after….

By USDA photo by Scott Bauer - Image Number: K5437-3.http://www.ars.usda.gov/is/graphics/photos/may01/k5437-3.htm, Public Domain, https://commons.wikimedia.org/w/index.php?curid=245466
By USDA photo by Scott Bauer – Image Number: K5437-3.http://www.ars.usda.gov/is/graphics/photos/may01/k5437-3.htm, Public Domain, https://commons.wikimedia.org/w/index.php?curid=245466

The above scenario, unfortunately, only plays out on planet Utopia. On planet earth, things are rarely that straightforward. In reality, the story is often vague and devoid of ticks, deer, and forests. The Lyme blood test is often ambiguous and frequently misleading. And in many cases, the antibiotic only partially improves the symptoms. The end result is a frustrated patient and a baffled doctor. Several Google searches after and the patient is convinced they have chronic Lyme disease, and demanding extended courses of antibiotic treatment. Several PubMed searches later, the doctor finds no scientific evidence to support prolonged antibiotic use, and refuses to acquiesce (apologies to Captain Barbossa). A vicious pantomime then follows.

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Neurologists tango with Lyme disease in the form of neuroborelliosis. This form of Lyme disease is a nightmare for neurologists because of the varied ways it may present. This was highlighted by a recent excellent review in the American Journal of Neuroradiology titled Lyme Neuroborreliosis: Manifestations of a Rapidly Emerging Zoonosis. These manifestations include a painful lymphocytic meningoradiculitis, cranial nerve palsies, meningoencephalitis, encephalomyelitis, and transverse myelitis. Then there is the nebulous concept of chronic Lyme neuroborreliosis, something the authors say is ‘a focus of ongoing conjecture and controversy‘. They, however, jumped into this minefield and proposed a set of diagnostic criteria which include characteristic symptoms, specific serum antibodies, spinal fluid inflammation, and spinal fluid antibody production. On Utopia, you might add.

By Centers for Disease Control and Prevention (NIH) - Centers for Disease Control and Prevention (NIH), Public Domain, https://commons.wikimedia.org/w/index.php?curid=29608423
By Centers for Disease Control and Prevention (NIH) – Centers for Disease Control and Prevention (NIH), Public Domain, https://commons.wikimedia.org/w/index.php?curid=29608423

To resolve the tricky question, a group of researchers carried out a systematic review of 44 clinical trials that had reported on chronic Lyme neuroborreliosis. They published their findings in the Journal of Neurology under the title Prevalence and spectrum of residual symptoms in Lyme neuroborreliosis after pharmacological treatment: a systematic review. The authors found that, in those studies that were rigorously carried out, there was very little evidence of chronic Lyme disease. They concluded that chronic Lyme disease may just be ‘an artifact of unspecific case definitions in single studies‘.

By Photo Credit:Content Providers(s): CDC - This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #6631.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−Cropped and uploaded originally to (http://en.wikipedia.org/wiki/Image:Borrelia_image.jpg), Public Domain, https://commons.wikimedia.org/w/index.php?curid=4393667
By Photo Credit:Content Providers(s): CDC – This media comes from the Centers for Disease Control and Prevention‘s Public Health Image Library (PHIL), with identification number #6631.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−Cropped and uploaded originally to (http://en.wikipedia.org/wiki/Image:Borrelia_image.jpg), Public Domain, https://commons.wikimedia.org/w/index.php?curid=4393667

This conclusion is supported by another study in the same journal titled Quality of life, fatigue, depression and cognitive impairment in Lyme neuroborreliosis. This study discovered that patients who were adequately treated for Lyme neuroborreliosis hardly ever developed persisting symptoms.

By Childe Hassam - http://www.the-athenaeum.org/art/full.php?ID=19897, Public Domain, https://commons.wikimedia.org/w/index.php?curid=10199778
By Childe Hassam – http://www.the-athenaeum.org/art/full.php?ID=19897, Public Domain, https://commons.wikimedia.org/w/index.php?curid=10199778

I guess this will not be the end of the story with chronic Lyme disease, but research is shedding light on a very controversial subject. Nirvana soon?

Whilst on the subject, you may want to check out these articles that open up another potential can of worms, intracranial hypertension in Lyme neuroborreliosis.

Advances in the management of giant cell arteritis

Giant cell arteritis (GCA), or temporal arteritis, is an affliction of older people. It results in headache and, more worryingly, blindness and stroke.

By Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 508, Public Domain, https://commons.wikimedia.org/w/index.php?curid=541352
By Henry Vandyke CarterHenry Gray (1918) Anatomy of the Human Body (See “Book” section below)Bartleby.com: Gray’s Anatomy, Plate 508, Public Domain, https://commons.wikimedia.org/w/index.php?curid=541352

 

The diagnosis of GCA is a clinical one. GCA diagnostic criteria stipulate, amongst other things, onset over the age of 50 years, and inflammation in the blood. A temporal artery biopsy may help to firm up the diagnosis. This is however not always readily available, and often falsely negative. Treatment with steroids is imperative to prevent sudden and irreversible visual loss.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=37300811
By NephronOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=37300811

 

Not much has changed in the world of giant cell arteritis since I was in medical school. Or so I thought. I couldn’t be more wrong. Here are 3 advances challenging the old order in the management of GCA.

 

1. Antiviral treatment

Varicella zoster virus. NIAID on Flikr. https://www.flickr.com/photos/niaid/5614251360
Varicella zoster virus. NIAID on Flikr. https://www.flickr.com/photos/niaid/5614251360

The cause of GCA is a mystery. One suspect is varicella zoster virus (VZV), of shingles fame. As shingles is also a disease of older people, it is no surprise that some researchers suspected a link between VZV and GCA. Writing in the Journal of Infectious Diseases in a paper titled Varicella Zoster Virus in Temporal Arteries of Patients With Giant Cell Arteritis, the authors detected VZV in the arteries of people with GCA, but did not pick up even a scent of VZV in control subjects who did not have GCA.

Another paper which strengthened the bond between GCA and VZV is in JAMA Neurology titled Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis. The authors of this study found VZV in the temporal arteries of 119 subjects with GCA. On the strength of this finding, the authors suggest GCA should be treated with anti-viral drugs. I am picking up the scent of a guideline on the way.

2. Monoclonal antibodies

B0007277 Monoclonal antibodies Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814713820
B0007277 Monoclonal antibodies
Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814713820

 

Some researchers, obviously uncomfortable with antiviral drugs, have looked elsewhere for ways to improve the treatment of GCA. And they found a champion in the monoclonal antibody Toclizumab. They published their findings in the Lancet under the title Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. The authors showed that adding Toclizumab to steroids in people with GCA led to sustained remission in 85% of cases; only 40% of the people on placebo achieved remission. I didn’t smell a rat here; the evidence seems quite convincing.

3. PET scan imaging

By Hg6996 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860
By Hg6996Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860

 

Temporal artery biopsy is hit and miss because GCA is a patchy process. Furthermore, biopsy is invasive and despised by doctor and patient equally. Ever keen to make things painless, doctors have looked at imaging of the artery as a substitute to biopsy. The imaging modalities on the cards include duplex ultrasound and magnetic resonance imaging (MRI). The prize must, however, go to positron emission tomography (PET) which has great potential as indicated in this review of PET scan in GCA. This suggests that PET scan aids the diagnosis, grading, and follow-up of GCA. Additionally, PET scan also identifies inflammation in other blood vessels. I perceive the end of the days of temporal artery biopsy!

 

The most popular neurology lounge posts at one year

Yesterday was the one-year anniversary of The Neurology Lounge. How time flies.

By User:S Sepp - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2949887
By User:S SeppOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2949887

The Lounge has published 95 posts over the last 12 months. The first tentative post was titled Hello, and the last was What are the most iconic neurological disorders?

Calendar. Dafne Cholet on Flikr. https://www.flickr.com/photos/dafnecholet/5374200948
Calendar. Dafne Cholet on Flikr. https://www.flickr.com/photos/dafnecholet/5374200948

To take stock, here is a countdown of the top 10 most viewed neurology lounge posts! 

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10.

Vagus nerve stimulation: from neurology and beyond!

9.

The most helpful and practical neurology guidelines

8.

6 exciting neuroscience discoveries that will shape neurology

7.

Alzheimer’s disease: a few curious things

6.

How bright is the future for Alzheimer’s disease?

5.

Keeping up with the latest practical guidelines in neurology

4.

Which are the most useful neurological applications?

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What are the dreadful autoimmune disorders that plague neurology?

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Outstanding neurology video channels and sites

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Is neurology research finally breaking the resolve of MND?

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What does the next one year have in stock? Only time will tell!
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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.

Are steroids detrimental to survival in brain tumours?

As I update neurochecklists I come across some papers which make me go, ‘really!’ Such studies challenge established theories and threaten conventional practice. Such is the case with a recent paper in Brain titled, unequivocally, Corticosteroids compromise survival in glioblastoma.

By Christaras A - Created myself from anonymized patient MR, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1247035
By Christaras A – Created myself from anonymized patient MR, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1247035

Glioblastoma is the worst form of primary brain tumour, and survival is already poor. Treatment is usually palliative with debulking surgery and radiotherapy. Dexamethasone, a corticosteroid, effectively reduces the swelling or oedema that the tumour evokes around it. Corticosteroids are therefore often the first treatment for glioblastoma because they  almost immediately improve symptoms such as reduced consciousness, headache, and visual blurring.

By LHcheM - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18648311
By LHcheMOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18648311

It is, therefore, surprising when a study suggests that corticosteroids cause harm. But this is no ordinary study; it is a classic bench-to-bedside research which looked at patients with glioblastoma, and then devised a mouse model to study the real impact of steroids on the tumour.

By Jensflorian - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11814552
By JensflorianOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11814552

 

The authors show that a ‘ dexamethasone-associated gene expression signature correlated with shorter survival’. They pass the verdict that corticosteroids are detrimental to survival and urge caution when prescribing dexamethasone.

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You may be feeling a bit low after reading. You may, however, lift your spirits by reading my previous posts titled maggots, viruses and lasers: some innovations for brain tumours and calming the rage of brain tumours.

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What’s evolving at the cutting-edge of autoimmune neurology?

This is a follow up to my previous blog titled What are the dreadful autoimmune disorders that plague neurology. Autoimmune neurology is a rapidly evolving field; blink and you will miss important developments. So what’s evolving in autoimmune neurology? Below are my top 4.

 

1. Insignificance of isolated VGKC positivity

By The original uploader was Iantresman at English Wikipedia - Transferred from en.wikipedia to Commons., CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1821346
By The original uploader was Iantresman at English Wikipedia – Transferred from en.wikipedia to Commons., CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1821346

Anti VGKC antibody encephalitis is caused by two different antibodies called LGI1 and Caspr2. The immunology laboratory would however only test for these two if the ‘generic’ VGKC test is positive. Neurologists are understandably left scratching their heads when both tests turn out to be negative. Not any more, going by a report in Neurology titled The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. The judgment is out: a positive VGCK antibody test is not significant if both LGI1 and Caspr2 are negative. What a relief.

2. IgG4-mediated autoimmune disorders

By Swharden - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4752456
By SwhardenOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4752456

This is a fairly new group of autoimmune disorders consisting of at least 13 different types. They are bad news because they cause many neurological disorders and also ravage other organs. I have previously discussed IgG4 peripheral neuropathy in my post titled What’s looming at the frontline of peripheral neuropathy. The other neurological diseases associated with IgG4 include, surprisingly, myasthenia gravis (MG), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and neuromyotonia. Less familiar IgG4 disorders are encephalopathyhypertrophic pachymeningitis and  sleep disorders with antibody to Iglon5. Trust the researchers to keep the clinicians ever on their toes.

3. GRIN-1 NMDA receptor encephalitis

DNA strand. Mehmet Pinarci on Flikr. https://www.flickr.com/photos/99843102@N05/14002600832
DNA strand. Mehmet Pinarci on Flikr. https://www.flickr.com/photos/99843102@N05/14002600832

Many acquired neurological disorders have a way of dragging genetics into their fold. Such is the case it seems with anti NMDA receptor encephalitis. This is the case with the GRIN-1 gene which codes for an NMDA receptor subunit. Mutations in this gene results in visual impairmentintellectual disability, and eye movement disorders. This is reported in Neurology by Josep Dalmau and colleagues in a paper titled Delineating the GRIN1 phenotypic spectrum. It is appropriate that the authors call this the genetic sibling of NMDA receptor encephalitis.

4. ECT for anti-NMDA receptor encephalitis 

Medcraft B-24 MarkII ECT. Niall Williams on Flikr. https://www.flickr.com/photos/niftyniall/17654690751
Medcraft B-24 MarkII ECT. Niall Williams on Flikr. https://www.flickr.com/photos/niftyniall/17654690751

The typical treatment of autoimmune encephalitis revolves around steroids, intravenous immunoglobulins (IVIg), and plasma exchange. Neurologists, when pushed to the wall, may use heavy duty agents such as Rituximab and Cyclophosphamide. Because anti-NMDA receptor encephalitis may be associated with ovarian teratomas, neurologists may make the difficult trip across the border to consult their gynaecology colleagues. I thought these were all the treatment options for anti NMDA receptor encephalitis until I read this case report, again in Neurology, which reported an excellent response to Electroconvulsive therapy in anti-NMDA receptor encephalitis. A no-brainer then if you see neurologists exchanging pleasantries with psychiatrists: they are the ECT experts. It is just a case report for now, but well-worth thinking about when all else fails.

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You may check out The Anti NMDA Receptor Encephalitis Foundation which is raising awareness of autoimmune encephalitis.

And here is a recent practical and comprehensive review of anti NMDA encephalitis by Eric Lancaster in the Journal of Clinical Neurology

And indulge me to make another shameless pitch here for neurochecklists which, after all, covers   autoimmune neurology comprehensively!

So what is the secret of neurochecklists?

If you have been following this blog closely, you couldn’t have missed my series of blog posts introducing neurochecklists. If you haven’t, then check them out here:

So what is the secret of neurochecklists? As a picture is worth a thousand words, a video clip must be worth a thousand blogs posts. Enough blogging on this subject then; here is a video glimpse at what makes neurochecklists tick-even if I say so myself!