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.

SCAN SCORE VS. SCAN-- WHICH IS JUSTIFIED

PK Sethi*, A Batra**, L Khanna*** Department of Neurology, Sir Gangaram Hospital, New Delhi - 60, India

While going through the article, The Scan Rule, published in JNNP of March 2010, Vol; 81 explaining the utility of scan score over conventional CT scans in diagnosing or ruling out small intra cerebral haemorrhages, we think that SCAN SCORES cannot score over conventional CT scans, given such reasons like the lack of CT scans and neuroinfrastructure facilities.

It may be a useful method to rule out minor intra cerebral bleeds utilising this score at places where there are scarcity of CT scans, so that early antiplatelet therapy can be started to prevent early recurrent ischemic stroke.

However, if we look at all aspects of the discussion, it can be said that it is unreasonable for a stroke patient to keep waiting for radiological confirmation for 7-10 days before an intracranial haemorrhage is diagnosed. It is worth noting that even in a developing country like India, there is no scarcity of CT scan centres. CT scans are available in all small diagnostic centres in the city. All this has been started as a private partnership in healthcare where the CT scan machines are installed at a huge cost. In India, CT scans are done at reasonable rates which include the cost of interpreting the scan and a waiting time of less than 12 hours. The cost of each CT scan is not more than $20. The scan centers earn their revenue not by high charges, but by increasing their numbers of patients and by working all days in the week. If we compare different parts of the country, we see that metropolitan cities like Delhi in India have nearly 90 CT scan centres and smaller cities like Meerut have 26 CT scans machines.

So, instead of waiting for a CT scan and clinically ruling out an intracerebral haemorrhage by the SCAN rule it is advisable to start an entrepreneurship making available more number of CT scans to avoid the possibility of treating a small intra cerebral haemorrhage with apparently ZERO SCAN score with the antiplatelet agents. Also, one could probably avert the dangers of misdiagnosing intracerebral hemorrhage for infarction caused by the delays in scanning.

*Senior Consultant Neurologist, **Consultant Neurologist, ***Senior Resident,. Department of Neurology, Sir Gangaram Hospital, New Delhi - 60, India

Conflict of Interest:

None declared

Dear Editor,

We read with interest the report by Kuoppamäki et al. on their case of a young man with bilateral globus pallidus lesions and signs of parkinsonism [1]. We have recently come across a patient with similar clinical and MRI findings following a single head trauma. We propose that lesion in this brain region regardless of causes can produce features of parkinsonism.

Five years ago, this 60 year-old man sustained a closed head injury when assaulted. He was unconscious for 24 hours before making a slow recovery.

Features of parkinsonism include mild hypomimia, generalised bradykinesia, asymmetric cogwheel rigidity and intermittent rest tremor of the right leg. He had a mild shuffling gait and impaired postural recovery reflexes.

MRI scan showed hypointensity in both basal ganglia on T2 axial image (Figure 1), corresponding to haemosiderin deposition. This is consistent with the patient’s CT brain 5 years ago which showed bilateral basal ganglia haemorrhage, a small right frontal subdural haematoma, and an undisplaced fracture of right frontal cranium.

Figure 1. Hypointensity in both basal ganglia on T2 axial image.

There are a few reported cases of post-traumatic parkinsonism following a single head injury, usually severe, associated with substantia nigra and/or basal ganglia lesions [2,3]. This case provides further neuroimaging evidence of post-traumatic parkinsonism following a single head trauma.

References

1. Kuoppamäki. M., et al. Parkinsonism following bilateral lesions of the globus pallidus: performance on a variety of motor tasks shows similarities with Parkinson’s disease. J Neurol Neurosurg Psychiatry, 2005. 76: p. 482-90.

2. Doder, M., et al., Parkinson's syndrome after closed head injury: a single case report. J Neurol Neurosurg Psychiatry, 1999. 66(3): p. 380-5.

3. Bhatt, M., et al., Posttraumatic akinetic-rigid syndrome resembling Parkinson's disease: a report on three patients. Mov Disord, 2000. 15(2): p. 313-7.

Sadjadi and colleagues show that in IBM, as in most chronic illness, mood plays a role in QoL. It would be a surprise if mood didn't play a role in measured QoL. QoL assessment uses subjective measures, for example "how would you rate your health?", and a patient's response to such a question is likely to be altered by mood. Hence QoL questionnaires can also act as mood questionnaires. Indeed, the awkward realisation is that if QoL didn't reflect mood then it wouldn't be a subjective scale. A consequence is that anti-depressant medication or cognitive behavioural therapy might well improve QoL (by changing the way an individual perceives and reports their disability) without making any impact on functional ability. Perhaps the only way around this would be to correct each patient's QoL result for that individual's mood at the time of questionnaire completion.

Conflict of Interest:

None declared