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• Migrainous scintillating scotoma and high-grade ICA stenosis: Why the link to CSD is plausible
  Jens P. Dreier
  Published on: 13 April 2016
• Migrainous scintillating scotoma and high-grade ICA stenosis: is the link to CSD plausible?
  Vinod K Gupta
  Published on: 13 April 2016

• Published on: 13 April 2016

  Migrainous scintillating scotoma and high-grade ICA stenosis: Why the link to CSD is plausible

  • Jens P. Dreier, Neurology

  Dear Editor

  Leão discovered the spreading negative slow voltage variations in response to either direct current electrical stimulation or bilateral occlusion of the internal carotid artery in 1947. Both neurones and astrocytes depolarise during a spreading negative slow voltage variation, thereby inducing transmembraneous ionic shifts and intracellular oedema [1]. Under anoxia or severe ischaemia, this spreading...

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  Dear Editor

  Leão discovered the spreading negative slow voltage variations in response to either direct current electrical stimulation or bilateral occlusion of the internal carotid artery in 1947. Both neurones and astrocytes depolarise during a spreading negative slow voltage variation, thereby inducing transmembraneous ionic shifts and intracellular oedema [1]. Under anoxia or severe ischaemia, this spreading depolarisation is permanent and referred to as anoxic depolarisation (AD) whereas, under normal conditions, it is transient and referred to as spreading depression(SD). AD and SD share similar, dramatic intra- and extracellular ionic changes and propagate similarly in the tissue [1]. However, in contrast to SD, AD initiates the cascades of neuronal death and is insensitive to N-methyl-D-aspartate receptor (NMDAR) antagonists [1]. The insensitivity of AD to NMDAR antagonists is possibly related to the recruitment of additional cation channels. Energy depletion is not a ‘conditio sine qua non’ to induce AD and the subsequent neuronal necrosis but inhibition of the Na,K-ATPase with persistent breakdown of the double Donnan equilibrium is sufficient for this purpose.

  Leão coined the fundamental concept in 1947 that SD and AD in the cerebral cortex are of the same principal nature and represent the two extremes of a continuous spectrum of spreading depolarisations dependent on the energy status. In short, he based this concept on his observations that SD becomes what was later called AD if the circulation is interrupted during SD and, vice versa, AD becomes SD if the circulation is restored during AD.

  The full spectrum of spreading depolarisations is observed in focal ischaemia since gradients of perfusion, oxygen, and glucose exist between the core ischaemic region and the normal tissue. Thus, the spreading negative slow voltage variation starts in the ischaemic core as persistent AD, becomes an intermediate depolarisation as it spreads through the metabolically compromised penumbra, and traverses the surrounding healthy tissue as SD. This process is repetitive. While recurrent spreading depolarisations arise, each event causes the lesion to grow in a stepwise fashion since it increases the ATP consumption and simultaneously constricts the cortical arterioles. As a consequence, the periods of spreading depression of the high-frequency electrocorticographic activity become increasingly prolonged during the cluster of spreading depolarisations, evolving to a state of persistent electrocorticographic depression. In patients with subarachnoid haemorrhage, these characteristic electrocorticographic features have now been unequivocally recorded using subdural electrode strips during the development of delayed ischaemic stroke in the recording area[2].

  That spreading depolarisations recruit tissue at risk into necrosis has been conclusively shown in a number of experimental studies in which artificially triggered spreading depolarisations invaded a mildly ischaemic zone from the outside. E.g., this was demonstrated in a rat cranial window model using brain topical application of the vasoconstrictor endothelin-1 (ET-1). At an ET-1 concentration of 1µM underhalothane, at which only 50% of animals generated spreading depolarisations, a microarea with selective neuronal death was found only in those animals showing spreading depolarisations. In selected animals, which had not developed spreading depolarisations in response to ET-1, one spreading depolarisation was triggered at a second cranial window by KCl and propagated from there to the window exposed to ET-1. This treatment also resulted in a microarea of neuronal damage. In contrast, spreading depolarisations invading from outside did not induce neuronal damage in the absence of ET-1 or in the presence of ET-1 if ET-1 was coapplied with an ETA receptor antagonist [3].

  Our clinical case is interesting since it is consistent with the pathophysiological basis and we speculated whether spreading depolarisations arose in our patient from the ischaemic zones of the left internal carotid artery territory and then propagated as normal SDs to healthy cortical regions supplied by the posterior circulation. There they gave rise to the recurrent hallucinations of visual migraine auras. In fact it has been studied extensively that spreading depolarisations typically cross the vascular boundary zones. Conclusively, they can also be elicited in animal and human brain slices that are devoid of the circulation [1].

  The patient clearly and repetitively stated that the scintillation scotoma always affected his right visual hemifield. This can hardly be explained by a retinal spreading depression since there is no anatomical or functional border in the midline of the retina. A retinal spreading depression usually spreads concentrically in the whole retina and, therefore, would have affected both right and left visual fields. In 1941, Lashley has written a brillant paper why the pathophysiological correlate of migraine aura in a visual hemifield likely occurs in the contralateral visual cortex but not in the retina. SPECT and functional MRI during the aura phase in migraineurs have strongly supported Lashley’s suggestion [1].

  It is controversial whether SD is the cause of headache in migraineurs. There seem to be two opposing hypotheses: Weiller and colleagues [4] have suggested that migraine headache is generated in the brainstem independently of SD using pooled PET data from migraineurs without aura. However, Sanchez del Rio and colleagues [5] were not able to reproduce these observations of a brainstem generator in individual patients using perfusion weighted MRI. They suggested that migraine headache is caused by a sterile inflammation in the dura mater in response to SD. Migraine headache is certainly an interesting issue but why some of the SD opponents believe that the existence or non-existence of a relation between SD and migraine headache is of any major importance for the unequivally established relation of spreading depolarisations with stroke and traumatic brain injury remains enigmatic.

  In conclusion, strong experimental evidence suggests that spreading depolarisations are not an epiphenomenon but a causal component of acute neuronal damage. Furthermore, spreading depolarisations have now been recorded abundantly in patients with traumatic brain injury, intracerebral haematoma, subarachnoid haemorrhage, delayed ischaemic stroke and malignant ischaemic stroke (compare www.cosbid.org) [2]. Therefore, it would be unethical if this field does not become a focus of clinical research in stroke and traumatic brain injury. It would be as absurd not to study this extensively as it would be absurd not to study epileptic electrocorticographic activity because some think that epileptic electrocorticographic activity is an epiphenomenon of epilepsy.

  Jens P Dreier

  References

  1. Somjen GG. Ions in the brain. Normal function, seizures, and stroke. New York: Oxford University Press, 2004.

  2. Dreier JP, Woitzik J, Fabricius M, et al. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain 2006;129: 3224-37.

  3. Dreier JP, Kleeberg J, Alam M, et al. Endothelin-1-induced spreading depression in rats is associated with a microarea of selective neuronal necrosis. Exp Biol Med 2007; 232: 204-13.

  4. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1: 658-60.

  5. Sanchez del Rio M, Bakker D, Wu O, et al. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 1999; 19: 701-7.

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  Conflict of Interest:
  None declared.

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• Published on: 13 April 2016

  Migrainous scintillating scotoma and high-grade ICA stenosis: is the link to CSD plausible?

  • Vinod K Gupta, Physician

  Dear Editor

  In a patient with high-grade internal carotid artery (ICA) stenosis and frequent migraine aura-like symptoms, Dreier et al [1] demonstrated widely scattered focal laminar cortical infarcts and resolution of visual symptoms following corrective surgery. These authors carry forward the speculation that brain ischemia-related cortical spreading depression (CSD) underlies the associated visual phenomena....

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  Dear Editor

  In a patient with high-grade internal carotid artery (ICA) stenosis and frequent migraine aura-like symptoms, Dreier et al [1] demonstrated widely scattered focal laminar cortical infarcts and resolution of visual symptoms following corrective surgery. These authors carry forward the speculation that brain ischemia-related cortical spreading depression (CSD) underlies the associated visual phenomena.

  Key areas of concern include: (i) Dissociation between headache and visual phenomenon. While CSD has been assumed as the brain aberration that underlies migraine, the factual basis for an etiological role in scintillating scotoma sine headache is even more uncertain [2,3]. (ii) The importance of precise delineation between binocular and monocular as well as between displaceable and non-displaceable visual phenomena cannot be overemphasized [2, 3]. In the index case, scintillating scotoma in the “right visual field” [1] cannot be translated to a monocular or uniocular, a binocular, or a homonymous defect. The clinical opportunity to test for such key ophthalmological features presents only uncommonly and must be fully explored in future. Even in patients with background neuro-ophthalmologic knowledge, unless the laterality and the displaceability of scintillating scotomata are formally determined, we will get no closer to the truth [2]. (iii) There is a distinct need to conceptually segregate the visual and non-visual neurological phenomena in this case. While the lateralizing negative neurological features (right sided-facial paresis and global aphasia) can be acceptably linked to left cortical brain ischemia, the “right-sided” scintillating scotoma merits further analysis. (iv) Rarity of lateralizing visual scintillating phenomenon in the relatively much more common aberration of cerebral ischemia is another red flag. (v) High-frequency scintillating scotomatous attacks in this patient (up to 10 attacks/day) [1] in the absence of associated lateralizing negative neurological deficits (possibly barring the first episode) make an ischemic etiology further unlikely. If cerebral ischemia did provoke recurrent CSDs, why should associated negative neurological features not also be manifest? (vi) High-frequency occurrence of CSD in humans with complete recovery of neuronal function on each occasion in an ischemic field is another assumption that creeps into the equation. (vii) The fundamental nature of CSD in cerebral ischemia – adaptive or pathogenetic – has not yet been resolved [2,3]. Recording of CSD in human brain [4] does not prove the biological nature of the phenomenon. (viii) Prevention of migraine and aborting of migraine aura with drugs that do not cross the blood-brain barrier or significantly influence cortical neuronal function is a pharmacotherapeutic absolute that rallies against CSD-based pathophysiological algorithms [2, 3]. (ix) Occurrence of scintillating scotomata in some patients with migraine with aura after onset of headache is a clinical absolute that also challenges currently prevalent theories. (x) Contrary to the assertion in the discussion [1], lateralizing laminar cortical infarcts relevant to the scintillating scotomata have not been seen in this patient. (xi) The possibility of aggravation of pre-existing energy depletion in the cortex [1], while theoretically intriguing, is unlikely in the absence of a lateralizing lesion as well the repetitive nature of the scintillating scotoma. With 95% left ICA stenosis, each wave of CSD would further lower the available cortical energy with little likelihood of repletion sufficient to initiate the next phase/flurry of scintillating scotomata. (xii) Propagation of CSD across cerebrovascular arterial territories [1] has no experimental or theoretical basis and is a highly speculative proposal. Overall, there is a real possibility of perpetuating circular arguments and the only definitive way forward is a careful clinical neuro-ophthalmological assessment as and when such opportunity presents. Neuro-imaging, howsoever sophisticated, will not settle such key pathophysiological issues in migraine-related phenomenology [5].

  Spreading depression is known to involve the retina [2, 3] and has been suggested as a possible mechanism for scintillating scotoma related to ICA dissection [6]. Following 95% left ICA stenosis, augmented flow in the right ICA is distinctly possible and might have set the stage for ophthalmic artery flow-related spreading depression in the right eye in this patient.

  As a possible disease mechanism, the concept of CSD has guided our thinking as a default pathophysiological process over the last five decades. As scientists, however, we are obliged to dispassionately search for gaps in our comprehension.

  Vinod K Gupta

  References

  1. Klingebiel R, Friedman A, Shelef I, Dreier JP. Clearance of a status aurae migraenalis in response to thrombendarterectomy in a patient with high grade internal carotid artery stenosis. J Neurol Neurosurg Psychiatry 2008;79:89-90.

  2. Gupta VK. Monocular and "binocular" scintillating scotomata in migraine: a semantic and theoretical paradox. CMAJ (23 November 2006). Available at: http://www.cmaj.ca/cgi/eletters/173/12/1441#6490.

  3. Gupta VK. Migrainous scintillating scotoma and headache is ocular in origin: a new hypothesis. Med Hypotheses 2006;66: 454-460.

  4. Dreier JP, Woitzik J, Fabricius M, et al. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain 2006;129: 3224–37.

  5. Gupta VK. MR imaging in primary headaches. Radiology 2006; 238:754-755.

  6. Ramadan NM, Tietjen GE, Levine SR, et al. Scintillating scotomata associated with internal carotid artery dissection: report of three cases.Neurology 1991;41:1084–7.

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  Conflict of Interest:
  None declared.

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