Diagnostic parsimony


J Neurol. 2016 Apr 25. [Epub ahead of print]

Multiple sclerosis and chronic progressive external ophthalmoplegia associated with a large scale mitochondrial DNA single deletion.

Gaetani L, Mignarri A, Di Gregorio M, Sarchielli P, Malandrini A, Cardaioli E, Calabresi P, Dotti MT, Di Filippo M.

The patient had a history of progressive bilateral ptosis and
ophthalmoparesis which started at the age of 7 and slowly evolved into
almost complete bilateral external ophthalmoplegia. Her family history
was unremarkable. At the age of 41, she experienced for 2 weeks
persistent gait instability. She underwent a brain and cervical spine
MRI that revealed multiple T2-hyperintense lesions in periventricular,
juxtacortical and infratentorial white matter (Fig. 1a, b) and in the cervical spinal cord. Three brain lesions showed gadolinium enhancement (Fig. 1c).
Cerebrospinal fluid (CSF) examination showed intrathecal IgG synthesis,
and a serological screening for autoimmune and infectious conditions
was negative. The patient was treated with high-dose steroids and had a complete
recovery from the relapse. Given the external ophthalmoplegia, she
underwent muscle biopsy that showed ragged red fibers (RRF) and 1 % of
cytochrome c oxidase (COX) negative fibers (Fig. 1d).

Fig 1 a,b MRI showing bilateral periventricular hyperintense T2 lesions (inflammatory lesions). c Post-gadolinium (or contrast study) showing one enhancing lesion. d COX staining of muscle biopsy showing a COX (cytochrome C oxidase – part of complex IV which makes up a chain of enzymes that produce energy in the mitochondria)  negative fiber (asterisk). e
Long-range PCR performed on the patient’s
muscle mtDNA (P) compared to the normal control (C), showing the
presence of a deleted mtDNA species, f (P) amplifying a single small species of about
2 kb, compared to a molecular weight marker (M). g Electropherogram showing the breakpoints of the novel 8.2 kb deletion spanning nucleotides 6902 and 15103 of the mtDNA.

Occam’s razor, which is a reductionist approach in science and medicine states ‘among competing hypotheses, the one with the fewest assumptions should be selected’ – William of Ockham c.1287-1347. As a clinician, this is now second nature to my way of thinking, whereby I formulate a unifying diagnosis that could explain all/most of my patients symptoms (diagnostic parsimony). If the same logic is applied to this case (as the authors are doing), then logically the two presentations must be linked, i.e. 1) the mitochondrial disorder caused by a mutation in the mitochondrial DNA and 2) multiple sclerosis.

This is by no means the first case of this description. In fact, mitochondrial disorders and MS occurring together has been previously reported, in particular with Leber’s hereditary optic neuropathy (LHON) – a mitochondrial disorder characterised by visual loss starting in the teens.

As we learn more about the importance mitochondrial respiratory deficient neurones in MS, based on these naturally occurring associations, we also start to question whether mutations in mtDNA can kick start MS? That is, can the degeneration in cells caused by mtDNA mutations trigger in susceptible individuals an inflammatory reaction? This is difficult to say as the incidence of mitochondrial disorders is rare in the population, as is MS.

I am also a believer of Hickam’s dictum (the medical counterargument to Occam’s razor), which simply states that ‘patients can have as many diseases as they damn well please’! Why is this also plausible in this case? Well, attempts at searching for mtDNA mutations in progressive MS patients did not reveal an excess of those with mutations compared to age-matched controls (Campbell GR, Reeve AK, Ziabreva I et al. (2013) No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis. Mult Scler 19(14):1858–1866).

About the author

Neuro Doc Gnanapavan


  • NDG I can only imagine your minds clinical in front of a complex disease such as MS, especially when it comes with other comorbidities … Science is who has to prove cause and effect, but I see the damage, the bad mitochondrial function in MS (when directly related to it) as a consequence of constant inflammatory state and lesional damage thus not MS disease of mitochondrial origin, but a consequence of them…

    And NDG excuse me for ignorance but there is a more specific test for viral load in the CSF than IgM and IgG?

  • The most specific way would be to check for the DNA/RNA. Surface proteins, nuclear fragments can also be tested. The antibody response may not always be present at first response in sufficient quantities. Hope that answers your question.

    • Thanks NDG, answer yes. o//

      But then this check DNA/RNA isn't a routine process, i.e., not part of clinical usual?

    • The tests are performed based on clinical suspicion, for example JCV testing. Also you need to know what virus you're looking for.

    • NDG, I asked about since because the CSF obtained by muito lumbar puncture which had only said search for OCB (positive), serum IgG (1.400 mg / dl), CSF IgG (3.8 mg / dL), ie without specific virological investigation, that os Why my curiosity…

    • Ok, so the IgG levels you discuss here are a quantification of your oligoclonal bands. As your aware these IgG are oligoclonal (and react with a number of candidates) not only viral proteins. You can check for viral specific IgG bands also – which measures whether you've had an immune response to specific virus, but this is not routinely done. Your result therefore informs us that you've got an intrathecal immune response. If you want to read up more about it put IgG index into Google.

    • Thank NDG! Excellent explanation, no one had ever explained this to me.
      I'll research now on Google to learn me about that… o//



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