Gentian Kaloshi, Mentor Petrela

In their recently published article, Kim et al (1) describe the imaging characteristics of anaplastic oligodendroglioma and anaplastic oligoastrocytoma (AO/AOAs) in an effort to correlate them with molecular alterations. They try to conclude that high-grade oligodendroglial tumors (AO/AOAs) share a similar relationship between radiological characteristics and molecular signatures as in oligodendroglial tumors. More specifically, they found that 1p19q codeleted AO/AOAs involved the frontal areas more frequently, were more frequently bilateral with a tendency towards widespread growth across the midline, and had poorly delineated limits in T1 with irregular aspect in T2. However, they failed to find any association of molecular alterations with contrast enhancement, cortical involvement and other radiological features such as calcification, hemorrhage, cystic formation.

We challenge their findings. Gliomatosis have taught us that tumors with 1p19q loss involve the white matter more frequently than other tumors, suggesting that this radiological characteristic can be related to intrinsic differences in tumor cells and, perhaps, to the different microenvironnement between gray matter and white matter. (2)

In the report of Kim et al, eleven tumor cases were located in multiple lobes making the diagnosis of gliomatosis most probable. Consequently, in our opinion, it would be very useful to further investigate if AO/AOAs share also the same clinical and radiological correlation of gliomatosis. Moreover, the figure 1 in their article is a good example of radio-genetic relationship found in gliomatosis.

How can these studies be reconciled in our daily practice? Surely, the most likely impact is that radiological characteristics may be considered as phenotype of intrinsic characteristics of tumors. Thus, they may have prognostic value as a surrogate marker for molecular alterations.

References:

1. Kim JW, Park CK, Park SH, et al. Relationship between radiological characteristics and combined 1p and 19q deletion in World Health Organization grade III oligodendroglial tumours. J Neurol Neurosurg Psychiatry 2011; 82: 224-227

2. Kaloshi G, Guillevin R, Martin-Duverneuil N, et al. Gray matter involvement predicts chemosensitivity and prognosis in gliomatosis cerebri. Neurology 2009;11;73(6):445-9.

Conflict of Interest:

None declared

Dear Editor

The sterotactic neurosurgical techniques being used to treat pain, movement disorders, and [according to The Sunday Times profile on Professor Aziz this week] potentially depression include radiosurgical ablation, deep brain stimulation and microinjections of pharmacological substances.[1-3]

Might these and other neurocognitive and neuropsychiatric disorders be more sucessfully treated by using these means to optimise tissue enrgetics by modulating tissue pH, temperature, and glucose uptake and utilisation? Might the benfits ascribed to deep brain stimulation be partially or wholly due to changes in these variables?

These metabolic effects might conceivably be accomplished focally or regionally with very low intensity radiosurgical ablative technques, and regionally and even systemically by modulating the thermoregultory set- point with electrical stimulation of the dorsomedial hypothalamus as has been used to modulate heart rate and blood pressure?[4] An alternative approach might be to use the same techniques to modulate the pH set-point of central chemoreceptors thought to be located in the medulla.[5]

The case has been made, largely in a succession of rapid electronic responses to an article published in the BMJ [6] and summarised in a Canadian online conference on fixing damaged brains,[7] for most neurocognitive and neurodegenerative disorders being caused by a potentially reversible intracerebral energy deficit induced by an impairment of ATP resynthesis by oxidative phosphorylation. A deficit might alterntively be induced by an increase in demand for energy from ATP hydrolysis that exceeds the capacity for resynthesis. Any energy deficit present might be focal, regional and/or systemic. Furthermore it might be sporadic, cyclical, sustained and/or progressive.

Heat production is the most objective measure of metabolic rate and hence of the rate of ATP resynthsis by oxidative phosphorylation in a temperature and humidity standardised environment. The body temperature falls rapidly soon after birth and slowly thereafter, the rate of fall accelerating preterminally. In those with advances malignancies the rate can fall prematurely. The prevalence of neuopsychiatric disorders increases in parallel with this fall and is highest in those with advanced malignancies, advanced age, and those near death.

Might these likely deficiencies in the rate of ATP resyntheis by oxidative phosphorylation be averted or reversed by reducing intracerebral pH, increasing intracerebral temperature, and/or increasing cerebral glucose uptake and utilistion by stereotactic means? Consider the physiological basis for the practical appliction of these possiblities.

ATP resynthesis by oxidative phosphorylation is driven by the protonmotive force [8] which is a function of the pH gradient between mitochondrial matrix and cytosol. The pH of blood and interstitial fluid lies in between these two. The pH gives a better measure of the magnitude of the protonmotive force than the nanomolar concentration of H+ because the behavior of a substance in a chemical system is proportional to its energy (chemical potential), and this, in turn, is a logarithmic function of the activity of the substance.[9]

The pH of blood, and of neutral water, changes linearly with temperature, whereas H+ concentration is a log function of temperature. Consequently the magnitude of the protonmotive force rises and falls in proportion with the magnitude of a rise or fall in temperature for the differences are maintained as temperature changes.[10] More importantly use of the pH-stat protocol, in which the pH is kept low by increasing the PaCO₂, during cooling on cardiopulmonary bypass in preference to the alpha-stat protocol, in which the pH is allowed to rise as the temperature falls, is much less likely to cause a lactic acidosis and brain and cardiac damage than the alpha-stat protocol which allows the pH to rise freely.[11-15]

The energy charge hypothesis was first proposed by Daniel Atkinson in the 1960s. The hypothesis held that ATP-dependent enzymatic reactions were down-regulated from 100% to 0% and those enzymes necessary for oxidative phosphorylation were up-regulated from 0% to 100% as the magnitude of the energy charge fell from 100% to 0%. The energy charge is an empirical formulation derived from [ATP] and selected ATP degradation products. It has no clinical correlates.

The AMP-activated protein kinase cascade is a sensor of cellular energy charge, and its existence provides strong support for the energy charge hypothesis.[16] The system is activated in an ultrasensitive manner by cellular stresses that deplete ATP, either by inhibiting ATP production, or by accelerating ATP consumption. Once activated, it switches on catabolic pathways, both acutely by phosphorylation of metabolic enzymes and chronically by effects on gene expression, and switches off many ATP-consuming processes. One of these is the K+(atp) channel which opens as the availability of ATP falls. This has a cytoprotective effect increasing mitochondrial resistance to oxidative injury.[17]

A fall in tissue pH, seemingly induced by the accumulation of protons from the unreversed ATP hydrolysis that occurs wfrom ATP degradation rather than the accumulation of lactate, is an integral part of the ischaemia [18] used to induce preconditoning. Furthermore vasodilation and hypotension in septic shock are, at least in part, due to activation of the K+ATP channel in vascular smooth muscle, and anaerobic metabolism with acidosis is a sufficient stimulus for channel activation.[19] In intestinal mucosa comparatively small concentrations of H+ compete successfully with Na+ for the cationic binding sites on the carriers mediating cationic-coupled facilitated diffusion of nutrient glucose and amino acids into cells.[20] The effect is immediately apparent from the fall in transmembrane potential difference it induces, potentialy a cytoprotetive action that may occur in the myocardium in ischaemic preconditoning and be caused by the opening of the K+(atp)channel..

Enzyme activity is known to be pH and temperature dependent. Furthermore a fall in pH is a much earlier change in ischaemia than ATP degradation and is highly predictive of the development of organ dyfunctions and fatal outcomes in the acutely ill.[21] The pH might, therefore, be preferable to the empiric formulation of the energy charge used in the Daniel Atkinson nomogram. A fall in pH should improve energy supply/demand balance in a dose-related manner by inhibiting ATP- dependent enzymatic activity such as that responsble for closing the K+(atp) channel. It should also increase the rate of ATP resynthesis by oxidative phosphorylation by increasing the magnitude of the protonmotive force.

The basal metabolic rate and oxygen consumption, which is a function of the rate of oxidative phosphorylation, increase some 10% for every degree rise in body temperature increases. One explanation for this Q10 effect is that protonmotive force is increased by the rise in temperature and hence the availability of ATP. Another is that it is the product of an increase in Brownian movement. Either of these could account for the neurological effects of changing the ambient temperature of poikilotherms.

Lionel Opie claims that in myocytes heat production is a function of the proton leak rate across the mitochondrial membrane, the leak rate and generation of heat increasing as the degree of uncoupling occurs.[22] In hibernating animals the generation of heat is confined to brown fat and is induced by the endogenous uncoupling proteins.[10] In man endogenous uncoupling proteins have a similar effect.[23]

Thyroid hormones may also uncouple oxidative phosphorylion and increase body temperature. The benefical neuropsychiatic benefits of thyroid supplements in myxoedema might, therefore, be due to an increase ATP resynthesis by oxidative phosphorylation induced by an increase in metabolic rate and accompanying rate of oxidative phosphorylation. The effect might alternatively be induced by increasing cellular uptake and utilisation of glucose by releasing catecholamines.

A thyroid storm is a potentially lethal condition seen in patients with thyrotoxicosis in which heart rate and temperature are greatly increased. Its potentially lethal effects may be reversed with beta blockers. This suggests that catecholamines are responsble for them be they due to the cellulr efects of the thyroid hormones themselves and/or to the malignant hyperthermia and severe energy defict and accompanying tissue acidosis they appear to induce.[24] The effects of thyroid hormones are analogous to those caused by KCN, a potent uncoupler. Futile substate cycling may be induced greatly increasing proton leak rate and hence endogenous heat production. pH falls and if excessive releases free radicals and compounds the severity of the problem.

Epinephrine is released in response to any stressful stimulus. A major action is stimulating glucose uptake and utilisation by stimulating cAMP. It might increase temperature by increasing the metabolic rate. Epinephrine increases the availability of glucose in glial cells which rely principally upon increased glycolytic turnover for their ATP resynthesis, the lactate and pyruvate they produce being the preferred substate by contiguous and oxygenated neurons. This effect is not compromised by the insulin resistance that may develop concurrently in stressful circumstances. If, however, stimulation by epinephrine is excessive and the demand for energy from ATP hydrolysis outstrips the capacity for resynthesis an energy deficit may be induced.

It is possible that the established therapeutic benefits of stereotactic electrical stimulation for Parkinson's and other disorders might be partially or wholly due to improvements in ATP resynthesis by oxidative phosphorylation induced by contiguous and even remote changes in intracerebral pH, temperature and/or glucose uptake and utilisation. It is also possible that a energy defict might have been induced by precipitating a supply/demand mismatch and causing dyfunction or even apoptosis and necrosis. Knowing the intracerebral temperature and pH might aid in the more effective application of these innovative techniques by improving their precision and effectiveness and reducing the risk of adverse effects. The possibility that improving intracrebral tissue energetics should be the primary objective in the management of these conditions is worthy of consideration.

Most analgesics might relieve pain by inducing an energy deficit that if excessive could cause not only dysfunction but also apoptosis and even necrosis.[26] Pain relief might alternatively be induced without causing tissue damage either by deceasing and possibly even by increasing the availability of ATP but one or more of the proposed metabolic means. It is conceivable that pain relief might be achieved without radioablation by applying these metabolic principles to a modification of the steroiotactic radiosurgical means used in this report.

References

1. B C Lopez, P J Hamlyn, and J M Zakrzewska Stereotactic radiosurgery for primary trigeminal neuralgia: state of the evidence and recommendations for future reports J Neurol Neurosurg Psychiatry 2004; 75: 1019-1024

2. Aziz TZ, Nandi D, Parkin S, Liu X, Giladi N, Bain P, Gregory RG, Joint C, Scott RB, Stein JF. Targeting the subthalamic nucleus. Stereotact Funct Neurosurg. 2001;77(1-4):87-90.

3. Nandi D, Aziz TZ, Giladi N, Winter J, Stein JF. Reversal of akinesia in experimental parkinsonism by GABA antagonist microinjections in the pedunculopontine nucleus. Brain. 2002 Nov;125(Pt 11):2418-30.

4. Thornton JM, Aziz T, Schlugman D, Paterson DJ. Electrical stimulation of the midbrain increases heart rate and arterial blood pressure in awake humans. J Physiol. 2002 Mar 1;539(Pt 2):615-21.

5. Severson CA, Wang W, Pieribone VA, Dohle CI, Richerson GB. Midbrain serotonergic neurons are central pH chemoreceptors. Nat Neurosci. 2003 Nov;6(11):1139-40.

6. David Taggart About impaired minds and closed hearts BMJ 2002; 325: 1255-1256 Plus rapid responses.

7. Fiddian-Green RG. Fixing damaged brains. Redflagsweekly.com.

8. Reid RA, Moyle J, Mitchell P. Synthesis of adenosine triphosphate by a protonmotive force in rat liver mitochondria. Nature. 1966 Oct 15;212(59):257-8.

9.JOHN W. SEVERINGHAUS, POUL ASTRUP, and JOHN F. MURRAY Blood Gas Analysis and Critical Care Medicine Blood Gas Analysis and Critical Care Medicine

10. Hochachka PA, Somero GW. Biochemical adaptation. Oxford University Press, New York, NY, 2002.

11. Sakamoto T, Zurakowski D, Duebener LF, Hatsuoka S, Lidov HG, Holmes GL, Stock UA, Laussen PC, Jonas RA. Combination of alpha-stat strategy and hemodilution exacerbates neurologic injury in a survival piglet model with deep hypothermic circulatory arrest. Ann Thorac Surg. 2002 Jan;73(1):180-9; discussion 189-90.

12. Pokela M, Dahlbacka S, Biancari F, Vainionpaa V, Salomaki T, Kiviluoma K, Ronka E, Kaakinen T, Heikkinen J, Hirvonen J, Romsi P, Anttila V, Juvonen T. pH-stat versus alpha-stat perfusion strategy during experimental hypothermic circulatory arrest: a microdialysis study. Ann Thorac Surg. 2003 Oct;76(4):1215-26

13. Nagy ZL, Collins M, Sharpe T, Mirsadraee S, Guerrero RR, Gibbs J, Watterson KG. Effect of two different bypass techniques on the serum troponin-T levels in newborns and children: does pH-Stat provide better protection? Circulation. 2003 Aug 5;108(5):577-82. Epub 2003 Jul 21.

14. Sakamoto T, Kurosawa H, Shin'oka T, Aoki M, Isomatsu Y The influence of pH strategy on cerebral and collateral circulation during hypothermic cardiopulmonary bypass in cyanotic patients with heart disease: results of a randomized trial and real-time monitoring. J Thorac Cardiovasc Surg. 2004 Jan;127(1):12-9.

15. Fiddian-Green RG. Rapid responses to: Vipin Zamvar, David Williams, Judith Hall, Nicola Payne, Clare Cann, Karen Young, S Karthikeyan, and John Dunne Assessment of neurocognitive impairment after off-pump and on-pump techniques for coronary artery bypass graft surgery: prospective randomised controlled trial BMJ 2002; 325: 1268

16. Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001 Dec;23(12):1112-9.

17. Duchen MR. Roles of mitochondria in health and disease. Diabetes. 2004 Feb;53 Suppl 1:S96-102.

18. Fiddian-green RG. Gastric intramucosal pH, tissue oxygenation and acid-base balance. Br J Anaesth. 1995 May;74(5):591-606.

19. Landry DW, Oliver JA. The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog. J Clin Invest. 1992 Jun;89(6):2071-4.

20. Fiddian-Green RG, Silen W Mechanisms of disposal of acid and alkali in rabbit duodenum. Am J Physiol. 1975 Dec;229(6):1641-8.

21. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement. Chest. 1999 Dec;116(6):1839-41.

22. Lionel H. Opie. The Heart: Physiology, From Cell to Circulation Lippincott Williams & Wilkins 2004.

23. Kadenbach B. Intrinsic and extrinsic uncoupling of oxidative phosphorylation. Biochim Biophys Acta. 2003 Jun 5;1604(2):77-94.

24. Grimes CM, Muniz H, Montgomery WH, Goh YS. Intraoperative thyroid storm: a case report. AANA J. 2004 Feb;72(1):53-5

25. Guo ZL, Moazzami AR. Involvement of nuclei in the hypothalamus in cardiac sympathoexcitatory reflexes in cats. Brain Res. 2004 Apr 23;1006(1):36-48

26. Hitosugi N, Hatsukari I, Ohno R, Hashimoto K, Mihara S, Mizukami S, Nakamura S, Sakagami H, Nagasaka H, Matsumoto I, Kawase M. Comparative analysis of apoptosis-inducing activity of codeine and codeinone. Anesthesiology. 2003 Mar;98(3):643-50.

Dear Editor,

I read with interest the recent article regarding the role of neuroimaging in patients with chronic daily headache (CDH). Though Howard et al. conclude that patients with CDH could be managed without a brain imaging;[1] I would be hesitant to avoid a brain scan in several such patients.

Firstly, there are no randomized controlled trials on the usefulness or otherwise of neuroimaging in patients with headache. In large series with headache, 2-4% of the scans are abnormal;[2] and the figure is even higher in some retrospective case series.[3] These figures could be important from a public point of view and for the Governmental agencies responsible for funding scans, but have no meaning from an individual patient’s perspective. For example, if a patient is denied neuroimaging and a treatable pathology such as hydatid cyst of the brain diagnosed at a later date, it could be embarrassing for the treating physician.[4] A recent publication highlighted that cerebral venous thrombosis could also present with headache alone, and the diagnosis could be missed without MR venogram.[5]

Secondly, there are legal implications of missing an abnormality by not offering scans.

Therefore, a safer protocol would be to counsel the patient regarding the option of neuroimaging, the likelihood of getting an abnormal CT/MR finding and its implication on the treatment, besides the cost of scanning. Informed patients could help in the decision-making process.

References

1. Howard L, Wessely S, Leese M, et al. Are investigations anxiolytic or anxiogenic? A randomised controlled trial of neuroimaging to provide reassurance in chronic daily headache. J Neurol Neurosurg Psychiatry. 2005;76:1558-64.

2. Goadsby PJ. To scan or not to scan in headache? BMJ. 2004;329:469- 70.

3. Valenca MM, Valenca LP, Menezes TL. Computed tomography scan of the head in patients with migraine or tension-type headache. Arq Neuropsiquiatr. 2002;60:542-7.

4. Kumar S. A patient’s opinion is often valuable. J Postgrad Med 2004; 50:216.

5. Cumurciuc R, Crassard I, Sarov M, Valade D, Bousser MG. Headache as the only sign of cerebral venous thrombosis: a series of 17 cases. J Neurol Neurosurg Psychiatry. 2005; 76:1084-7.

Most authorities, from Samuel Johnson's to the current Oxford University Dictionary, define "progression" as a change for the better stemming from the Latin "prograde" to improve continuously and "deterioration" as a change for the worse (Latin "deteriore"). Yet most neurological journals appear to accept "disease progression" (as in secondary progressive multiple sclerosis and progressive supranuclear palsy) to indicate that the natural history of an illness is deteriorating in character; most patients and their families would not agree. The most insensitive of neurologists would hardly tell an anxious family that their dear one's terminal illness was progressing. While lexicographers emphasise the dynamic flexibility of language, I doubt whether they would favour contrary ambiguity. Nor would they agree with a definition expressed in "Alice through the looking glass". "When I use a word "Humpty Dumpty said in a rather scornful tone, "it means just what I choose it to mean - neither more nor less". It seems legitimate to propose that "progression" should be applied to the disease process and hopefully to its elucidation, and that "deterioration" should apply to the history of a patient's illness. Perhaps the author's conventional confessions at the end of a submitted article, such as competing interests, provenance and particularly patient's consent should also indicate whose side they are on: the disease or the patient?

Gerald Stern

University College Hospitals, Queen Square, London WC1

Conflict of Interest:

None declared