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With widely divergent therapeutic options and uncertain, largely
indefensible underlying theoretical premises varying widely from closure
of patent foramen ovale to use of biological toxins like scalp
injection of botulinum toxin[2,3], untrammeled but vigorous research
efforts have converted migraine into a giant, virtually insoluble puzzle.
A miniscule fraction of the effort spent in the e...
A miniscule fraction of the effort spent in the elaboration of newer
versions of an unwieldy and purely phenomenological system of
classification of primary headache would have been sufficient to
appropriately underscore the importance of atenolol, a first-line migraine
prophylactic agent that does not cross the blood-brain barrier (BBB) or
alter any brain or peripheral neural function, or the ability of both
serotonergic agonists (like amitriptyline) and serotonergic antagonists
(like cyproheptadine) to prevent migraine, or the prophylactic role of
agents that might increase (amitriptyline) or decrease (anti-convulsants)
brain cortical excitability, or the fact that caffeine or cocaine
withdrawal rather than consumption predictably precipitates migraine
headache.[6,7] While shifting stance between vascular and neuronal
theories of migraine or rigidly espousing either theory, researchers have
paid scant attention to the characteristic phenomeon of post-stress
headache in migraine that clearly signposts the primary involvement of a
cranial physiological system that enjoys a significant but variable
protection from dysfunction during stress. Claiming significant
biological advances in migraine research on the basis of genetic research
and a limited link to ion channelopathies, migraine researchers have not
felt the need to define the biology of migraine into physiological
processes that push patients towards attacks or keep them in remission; this critical need has been substituted by elaborating upon
precipitating and remitting clinical features. The first major theoretical
effort in this direction was the elaboration of the possible role
vasopressin in delaying onset of migraine headache as well as maintaining
significant periods of remission.
The psyche of the migraine researcher is (?irretrievably) buried deep
in the mystery of cortical spreading depression (CSD). To neurologists, it
is nothing short of gospel truth that the migraine aura originates at the
level of the brain cortex. Maintenance of this belief in the face of
evidence that drugs that do not readily or freely cross the intact BBB --
like nifedipine or isoproterenol -- can instantaneously abort migraine
aura is a tribute to a peculiar human trait to steadfastly preserve a
preconception in the face of contrary evidences. Use of advanced
neuroimaging to record activation of the brain / brainstem as a surrogate
for CSD / brain activation is a classic example of the reductionist nature
of laboratory findings – equating and elevating, as such efforts do, the
laboratory to biology. The primary pathogenetic aberrations in migraine
are buried in the completely inaccessible “pre-prodromal” phase and to a
lesser extent in the largely inaccessible prodrome. Recording of
physiological changes in brain after onset of headache or of aura and
extrapolating it to signify primary pathogenetic alterations is a faulty
research premise; equating spreading oligaemia in migraine patients to CSD
in animals is intrinsically incorrect.[11,12] Second, the neuroprotective
effect of CSD is increasingly being recognized[13-15], indicating a wide
and irreconcilable contemporary diversion of scientific beliefs. Finally,
the peculiar neuroanatomical distribution in humans of ophthalmic pain and
temperature fibres only to the first cervical spinal segment, occurrence
of photophobia, and absence of migraine in cohorts of patients having
undergone enucleation or evisceration of the eye reflect a selective
involvement of the ophthalmic division in migraine. Migraine is not,
in direct contrast to the general impression, a pan-trigeminal nerve
disorder; CSD cannot explain selective involvement of the ophthalmic nerve.
There is a crucial difference between scintillating scotoma and other
varieties of migraine aura. Ophthalmologically, it is accepted that the
scintillating scotoma is monocular but migraine researchers have
unquestioningly accepted it as a binocular phenomenon akin to homonymous
hemianopia. If the migrainous scintillating scotoma is indeed
monocular in distribution, it cannot arise at the visual cortex. In
headache research, a most well guarded secret – besides the BBB-related
pharmacokinetics of atenolol -- is that Leão also recorded spreading
cortical silence / depression after retinal stimulation. The basis
for retinal origin of the migrainous scintillating scotoma has been
In a placebo-controlled trial, lamotrigine was not found effective
for migraine prophylaxis. Topiramate is also not effective in
preventing aura in migraine patients. To maintain that lamotrigine is
highly effective for prophylaxis of migraine aura while topiramate is not
does not appear to theoretically impregnable. The limitations for a
migraine prophylactic role for topiramate and other neuronal ion-channel
inhibitors has been discussed. In a highly variable condition such as
migraine, the value of statistical significance in uncontrolled studies is
severely limited. Stratification of results by frequency of headache is
also important. Long neglected basic science issues require to be knitted
into our perception of migraine.
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