The 75 most challenging neurological diagnoses

Neurologists typically see run-of-the-mill disorders in their usual practice. Not to underestimate the seriousness of these syndromes, but these are not conditions that keep the neurologist awake at night – they are not difficult to diagnose, and most neurologists don’t break into a sweat in managing them. What really get neurologists bristling are the esoteric diseases; these are disorders that give us goosebumps, and these make up the bulk of our offerings at our altar – the neuropathological conference.

"Une leçon clinique à la Salpêtrière" by André Brouillet - Photo prise dans un couloir de l'université Paris V. Licensed under Public Domain via Commons -

What are these esoteric diseases that set the blood of neurologists on fire? Which are the most challenging to diagnose? To investigate, I had a quick look at the index of Neurochecklists, and I came up with 75 that fit the bill. I have classified these into three according to the difficulty they pose to the neurologist:

  1. Strenuous – 25 diseases which require some hard thinking and reading-up to solve.
  2. Arduous – 25 conditions which will require a phone call to a nearby expert to resolve.
  3. Herculean – 25 conditions which only a few worldwide experts can help save the day.

Below then, in order of difficulty, are the 75 most challenging neurological diagnoses




Alexander disease

Benign hereditary chorea

CANVAS syndrome

Cerebrotendinous xanthomatosis (CTX)


Dentatorubral pallidolyusian atrophy (DRPLA)

Doose syndrome

Fatal familial insomnia (FFI)

Fragile X tremor ataxia syndrome (FXTAS)

Generalised epilepsy with febrile seizures plus (GEFS+)

Gerstmann Straussler Scheinker (GSS) syndrome

Lafora body disease

Menke’s disease

Miller Dieker syndrome


Myofibrillar myopathy

Neuro Sweet syndrome

Ornithine transcarbamylase (OTC) deficiency

Potassium aggravated myotonias

Progressive encephalomyelitis rigidity and myoclonus (PERM)

Pyridoxine-responsive epileptic encephalopathy

Rapid onset dystonia parkinsonism (RDP)

Refsum’s disease

Rippling muscle disease (RMD)

Tyrosine hydroxylase deficiency (THD)



Adult polyglucosan body disease

Alpers syndrome

Barth syndrome

Brown Vialetto Van Laere syndrome (BVVL)


Facial onset sensory and motor neuronopathy (FOSMN)

Hemiconvulsion hemiplegia (HH) syndrome

Hereditary myopathy with early respiratory failure (HMERF)

Jeavon’s syndrome

Joubert syndrome

Kufor Rakeb

Landau Kleffner syndrome

Melkersson Rosenthal syndrome

Nemaline myopathy

Neuronal ceroid lipofuscinosis (NCL)

Ohtahara syndrome

Pelizaeus Marzbacher disease 

Panayiotopoulos syndrome (PS) 

Pantethonate kinase associated neurodegeneration (PKAN)

Perry syndrome

Raeder’s paratrigeminal syndrome

Rett syndrome


Tangier disease

Tarui disease


 1q deletion syndrome 


Biotin responsive basal ganglia disease

Brody disease

Calsequestrin storage myopathy

Coffin Lowry syndrome 

Congenital cataracts facial dysmorphism neuropathy (CCFDN)

Curranino syndrome

Danon disease

Nasu Hakola disease

PHARC syndrome

POL3 related leukodystrophy

Pourfour du petit syndrome

Sandhoff disease

Satoyoshi syndrome

Schwartz Jampel syndrome

Sepiapterin reductase deficiency

SEPN-1 related myopathy 

Sialic acid storage diseases

Sjogren Larsson syndrome

Unverricht Lundborg disease

Vici syndrome

Wolf Hirschhorn syndrome

Woodhouse Sakati syndrome

Zellweger syndrome

"Pagoda Burr Puzzle" by Meronim - Own work. Licensed under CC BY-SA 3.0 via Commons -

The is of course a personal and non-evidenced list. Understandably, there will be differing opinions about what each person finds challenging. Therefore please challenge the inclusion, or misclassification, of any items on the list, or make suggestions of other challenging neurological disorders.


To explore these and many other comprehensive neurology checklists…

Go online at


Or get the book, 700 Essential Neurology Checklists

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