The myelin secreted by oligodendrocytes and Schwann cells contains
proteins, lipids and water. The commonest lipid is cholesterol followed by
phospholipids, glycosphinglipids and finally a variety of others in far
lesser amounts.[1] Furthermore lipid lowering drugs[2,3] and rapid
glycaemic control[4] are associated with the development of peripheral
neuropathies. This raises the possibility that myeli...
The myelin secreted by oligodendrocytes and Schwann cells contains
proteins, lipids and water. The commonest lipid is cholesterol followed by
phospholipids, glycosphinglipids and finally a variety of others in far
lesser amounts.[1] Furthermore lipid lowering drugs[2,3] and rapid
glycaemic control[4] are associated with the development of peripheral
neuropathies. This raises the possibility that myelin might contain
nutrient pools including glycogen designed to prevent nerves from the
pathological consequences of reductive/oxidative stresses in periperal
nerves, just as astrocytes do in the brain, possibly by operating a ketone
body shuttle analogous to the lactate shuttle between astrocytes and
neurones.[5]
The Type I—T cell/macrophage associated, Type II—antibody/complement
associated, Type III—distal oligodendrogliopathy, and Type
IV—oligodendrocyte degeneration in the periplaque white matter might,
therefore, be morphological manifestations of sustained
reductive / oxidative stresses. In which case treatment in demyelating
diseases might be profitable directed at maintaining these hypothetical
nutritional stores in oligodendrocytes and Schwann cells recognizing that
demand for lipid in reductive/oxidative might be greatly increased because
of a "lipid shift".[6]
2. Corrao G, Zambon A, Bertu L, Botteri E, Leoni O, Contiero P. Lipid
lowering drugs prescription and the risk of peripheral neuropathy: an
exploratory case-control study using automated databases. J Epidemiol
Community Health. 2004 Dec;58(12):1047-51.
3. G Corrao, A Zambon, L Bertù, E Botteri, O Leoni, and P Contiero
Lipid lowering drugs prescription and the risk of peripheral neuropathy:
an exploratory case-control study using automated databases Heart 2005;
91: 560.
4. M K S Leow and J Wyckoff Under-recognised paradox of neuropathy
from rapid glycaemic control Postgrad Med J 2005; 81: 103-107. eLetter:
Grounds for abandoning "diabetes" as a diagnosis? Richard G Fiddian-Green
(9 March 2005).
We would like to address several of the points raised in a recent editorial in your journal (Killestein J, Uitdehaag BM. Cannabinoids in multiple sclerosis: urgent need for long term trials. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1612), pertaining to the safety and efficacy of cannabis-based medicines in the symptomatic treatment of multiple sclerosis, and propose that the true situation is much mor...
We would like to address several of the points raised in a recent editorial in your journal (Killestein J, Uitdehaag BM. Cannabinoids in multiple sclerosis: urgent need for long term trials. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1612), pertaining to the safety and efficacy of cannabis-based medicines in the symptomatic treatment of multiple sclerosis, and propose that the true situation is much more encouraging than the editorial states, as the most convincing data available in this context were not considered by the authors.
The editorial focused on the results of the cannabinoids in multiple sclerosis (CAMS) long-term study[1] without addressing its methodological problems. The study employed Cannador, an oral cannabis extract with a 2:1 ratio of tetrahydrocannabinol (THC) to cannabidiol (CBD) in a twice daily fixed dosage regimen based on body weight, titrated upwards over one month. Most patients failed to attain established target dosages or optimal therapeutic benefit due to adverse events. Average dosage for daily THC administered was not stated, but seemingly was under the 20mg benchmark for a 70 kg person.
Practical cannabinoid therapeutics demand, in contrast, that these agents, with their variable gastrointestinal absorption and idiosyncratic responses[2], be preferentially administered with highly individualised dosing according to symptomatic need and personal tolerance. Additionally, the provision of greater proportions of CBD may serve to augment therapeutic benefits while blunting adverse events such as intoxication, tachycardia, etc., attendant to THC.[2] In short, the dosing regimen used in the CAMS study was far from optimal.
The CAMS study relied on the Ashworth scale to assess spasticity, despite its proven objective variability and failure to correlate to clinical efficacy. There is now a consensus that patient-reported outcomes are the most appropriate measures of treatment efficacy. Thus, subjective measures of spasticity are just as appropriate as the numerical rating scales now considered mandatory in clinical trials in pain. It was this approach that was applied in studies of various symptoms of MS with the highly standardised Sativex oromucosal cannabis-based medicine containing 2.7 mg of THC and 2.5 mg of CBD per 100 µL spray, in which positive results were noted in an initial Phase III double-blind controlled study with respect to spasticity (p=0.001) and sleep disturbance (p=0.047).[3] A long-term extension study of the same cohort for one to four years established persisting improvement in these symptoms, as well as for central neuropathic pain, tremor, spasms and bladder function in affected individuals with no evidence of tolerance to benefits, or withdrawal syndrome upon sudden cessation.[4] Further clinical trials with Sativex (reviewed[2]) support its statistically significant benefits in Phase II clinical trials of morning pain and stiffness in rheumatoid arthritis and bladder symptoms in MS, and Phase III trials of peripheral neuropathic pain (p=0.004), brachial plexus injury (p=0.005), and intractable cancer pain (p=0.014).
Issues of blinding were raised in the CAMS studies, primarily on the basis of evident intoxication with Cannador. In contrast, outside of initial dose titration periods of 7-10 days, Sativex yields subjective intoxication scores on a visual analogue scale in the single digits out of 100, indistinguishable from placebo.[4] Similarly, the differential benefit of Sativex upon spasticity and sleep acutely,[3] but not other symptoms suggests effective blinding with this preparation.
Cognitive issues attendant with cannabinoid therapeutics remain a prime concern, but available data to date support a lack of neuropsychological sequelae attached to Sativex usage in another successful Phase III therapeutic trial in central pain in MS (p=0.005),[5] and other studies.[4]
Killestein and Uitdehaag correctly point to the generous safety profile demonstrated by Cannador and Marinol in the CAMS follow-up,[1] but question that the proper risk-benefit ratio has been attained for cannabinoid medicines. They raise the possibility of producing better synthetic cannabinoids, while failing to address the disadvantage inherent in employing more potent full cannabinoid agonists as opposed the current approach of utilising a natural weak partial agonist (THC), particularly coupled with adequate provision of a cannabinoid antagonist (CBD) with its own synergistic benefits.[2]
A comparison between the adverse event profile of Cannador, Marinol, placebo and Sativex (Figure 1) is illuminating, in that the oromucosal spray generally produces comparable or lower rates of complaints, despite the administration of higher net doses of daily THC (mean 29.7 mg). Such illustrations support the premise that cannabinoid therapeutics require strict adherence to specific preparations via defined delivery systems, and results must not be generalised from one preparation to another.
Sativex is currently approved for prescription usage in Canada for treatment of central neuropathic pain in MS under a Notice of Compliance with Conditions, and is also available on named patient prescription basis for any condition in the United Kingdom and Catalunya. Further regulatory submissions are in process. The weight of current evidence amply supports the safety and efficacy of Sativex both acutely and in the long-term in treatment of various symptoms of MS, and other diseases. Further long-term studies will identify whether the theoretical neuroprotective effects of THC and CBD in MS[2] will be realised in practice with Sativex or other cannabinoid agents.
Ethan B. Russo, MD corresponding author
Senior Medical Advisor, GW Pharmaceuticals
2235 Wylie Avenue
Missoula, MT 59802
USA
erusso@gwpharm.com 001-406-542-0151
Geoffrey W. Guy
Stephen Wright
Philip J. Robson GW Pharmaceuticals
Porton Down Science Park
Salisbury
Wiltshire SP4 OJQ
United Kingdom
Competing interest
Dr. Russo is a consultant to GW Pharmaceuticals. Drs. Guy, Wright and Robson are officers in GW Pharmaceuticals, the developer and manufacturer of Sativex, a cannabis-based medicine.
References
1. Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1664-9.
2. Russo EB, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol (THC) and cannabidiol (CBD). Medical Hypotheses. 2005;(in press).
3. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004 Aug;10(4):434-41.
4. Wade DT, Makela PM, House H, Bateman C, Robson PJ. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Multiple Sclerosis. 2006;(in press).
5. Rog DJ, Nurmiko T, Friede T, Young C. Randomized controlled trial of cannabis based medicine in central neuropathic pain due to multiple sclerosis. Neurology. 2005;65(6):812-9.
Figure 1: Comparison of adverse event profiles of Cannador (N=219), Marinol (N=216), placebo (N=222) and Sativex (N=137) in long-term clinical trials in multiple sclerosis patients. Data taken from Zajicek et al.[1], and Wade et al.[4], plus additional data on file from GW Pharmaceuticals. Dosing comparisons are discussed in the text.
Ribi et al.[1] describe an interesting case of neuro Behçets disease
(NB) being successfully treated with the tumour necrosis factor alpha
(TNFα) monoclonal antibody infliximab. We report using the soluble
recombinant human TNFα receptor protein, etanercept in a patient with
longstanding NB. To the best of our knowledge there are no previous
clinical reports on the use of etanercept in NB.
Ribi et al.[1] describe an interesting case of neuro Behçets disease
(NB) being successfully treated with the tumour necrosis factor alpha
(TNFα) monoclonal antibody infliximab. We report using the soluble
recombinant human TNFα receptor protein, etanercept in a patient with
longstanding NB. To the best of our knowledge there are no previous
clinical reports on the use of etanercept in NB.
A 39 year old lady was diagnosed with NB in 1998 on the basis of
recurrent episodes of brainstem signs, oral and genital ulceration,
pathergy, pustulosis, arthralgia, and intermittent pyrexia. She had
episodes of headache, drowsiness, right hemiparesis, dysarthria and
diplopia that lasted 1-2 weeks and occurred every 2-3 months. During
relapses there was evidence of aseptic meningitis with CSF analysis
typically revealing white cell counts greater than 1000 cells/mm3 (90%
neutrophils), negative culture, moderately elevated protein and normal
glucose. Cranial MRI scans showed extensive white matter abnormalities
particularly of the brainstem (figs 1a, 1b) that resolved almost
completely between relapses (fig 1c, 1d).
In April 1998 she was commenced on 30mg prednisolone and 100mg
azathioprine. She had three further neurological and mucocutaneous
relapses and so was switched to 30mg prednisolone and 200mg cyclosporin in
October 1998. She continued to have neurological relapses requiring
hospital admissions for intravenous steroids. In the 1990s TNFα
inhibitors were not available but there was already accumulating evidence
that TNFα played a part in the pathogenesis of Behçets disease.[2]
Therefore in December 1999 thalidomide 200mg daily was started for its
putative anti TNFα activity and the cyclosporin was stopped. Despite
this she continued to relapse over the next six months and so the
thalidomide was stopped. She commenced 10mg methotrexate weekly but the
regular relapses continued.
In June 2001 bi-monthly infusions of infliximab 3mg/kg were commenced
and the daily dose of prednisolone was tapered down to 5mg. She continued
taking 10mg methotrexate weekly to prevent the formation of antibodies to
infliximab. She responded extremely well with only two clinical relapses
in the following 3 years. In May 2004 the methotrexate and infliximab
regime was discontinued due to raised liver enzyme levels and she was
started on twice weekly subcutaneous injections of 25mg etanercept.
Following this she had no further relapses over the next year and the
prednisolone was discontinued for the first time in 6 years.
In June 2005 the etanercept was stopped when the patient had a
cholecystectomy for acute cholecystitis. She remained off
immunosuppression altogether for 3 months. In September 2005 she
presented with a severe neurological relapse. She was treated with
intravenous steroids and recommenced on etanercept. There have been no
further relapses.
We would like to add a few points to Ribi at al.’s[1] excellent
review of the role of TNFα blockade in NB. Etanercept is a dimer of
recombinant soluble human TNFα receptor proteins (p75) and the Fc
portion of IgG1.[3] It acts by competitively inhibiting the binding of
TNFα to its cell surface receptor. It is administered by subcutaneous
injections at a dose of 25mg twice weekly or 50mg once weekly [4] and can
be self-administered by the patient. This represents a significant
advantage over infliximab which requires hospital admission for
intravenous administration. Comparing a maintenance dose of infliximab at
3mg/kg given every eight weeks and etanercept at 50mg per week etanercept
costs marginally more. However there are several additional costs
necessary for a patient to receive infliximab: a concurrent methotrexate
prescription, higher doses of infliximab for the initial doses and regular
hospital admissions for intravenous infusions. Etanercept may be
particularly useful for patients who have difficult venous access, who are
intolerant to methotrexate or for those who develop neutralising
antibodies to infliximab.
Other novel treatments with anti-TNFα activity such as
adalimumab (a TNFα monoclonal antibody) and pentoxifylline (which
acts to inhibit the production of proinflammatory cytokines including
TNFα) may hold useful therapeutic potential in Behçets disease
although clinical trials have not yet been published.
This report highlights several important points about the role of
TNFα blockade in NB. We describe the efficacy of TNFα blockade
in a longstanding case of NB poorly responsive to azathioprine,
cyclosporin, thalidomide and methotrexate. TNFα blockade requires
regular administration to be effective in suppressing NB and the patient
is likely to relapse when the TNFα blockade is discontinued.
Different modes of action to block TNFα are effective in treating NB
i.e. monoclonal antibodies to TNFα (infliximab) and soluble
recombinant TNFα receptor protein (etanercept). Etanercept appeared
to be superior to infliximab in preventing NB relapses in our patient
although this is only the first case described and further studies are
needed.
References
1. C Ribi, R Sztajzel, J Delavelle, et al. Efficacy of TNF blockade
in cyclophosphamide resistant neuro-Behçet disease. J Neurol Neurosurg
Psychiatry 2005;76:1733-1735.
2. Mege JL, Dilsen N, Sanguedolce V, et al. Overproduction of
monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and
increased neutrophil superoxide generation in Behçet’s disease. A
comparative study with familial Mediterranean fever and healthy subjects.
J Rheumatol 1993;20(9):1544–9.
3. Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid
arthritis. Ann Rev Med 2000;51:207-29.
With widely divergent therapeutic options and uncertain, largely
indefensible underlying theoretical premises varying widely from closure
of patent foramen ovale[1] 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...
With widely divergent therapeutic options and uncertain, largely
indefensible underlying theoretical premises varying widely from closure
of patent foramen ovale[1] 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 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[4], or the ability of both
serotonergic agonists (like amitriptyline) and serotonergic antagonists
(like cyproheptadine) to prevent migraine[5], or the prophylactic role of
agents that might increase (amitriptyline) or decrease (anti-convulsants)
brain cortical excitability[4], 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.[8] 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[8]; 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.[9]
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[10] 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.[4] 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.[16] Migraine is not,
in direct contrast to the general impression, a pan-trigeminal nerve
disorder; CSD cannot explain selective involvement of the ophthalmic nerve.[16]
There is a crucial difference between scintillating scotoma and other
varieties of migraine aura. Ophthalmologically, it is accepted that the
scintillating scotoma is monocular[17] but migraine researchers have
unquestioningly accepted it as a binocular phenomenon akin to homonymous
hemianopia.[8] 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.[19] The basis
for retinal origin of the migrainous scintillating scotoma has been
presented recently.[16]
In a placebo-controlled trial, lamotrigine was not found effective
for migraine prophylaxis.[20] Topiramate is also not effective in
preventing aura in migraine patients.[21] 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.[22] 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.
References
1. Gupta VK. PFO / ASD closure and migraine: searching the rationale
for the procedure. J Am Coll Cardiol 2005, 46: 737-738.
2. Gupta VK. Botulinum toxin type A therapy for chronic tension-type
headache: fact versus fiction. Pain 2005, 116: 166-167.
3. Gupta VK. Botulinum toxin: a treatment for migraine? A critical
review. Pain Med 2005 (In press).
4. Gupta VK. Migraine, cortical excitability and evoked potentials: a
clinico-pharmacological perspective. Brain 2005; 128: E36.
5. Gupta VK. Amitriptyline versus cyproheptadine: opposite influences
on brain 5-HT function. Headache 2005 (In press).
6. Gupta VK. Caffeine and migraine: analgesia and intrinsic brain
noradrenergic activation. Headache 2005 (In press).
7. Gupta VK. Amphetamine, migraine, and brain noradrenergic
activation: contradictions in headache research. Headache (In press).
9. Gupta VK. A clinical review of the adaptive role of vasopressin in
migraine. Cephalalgia 1997; 17: 561-569.
10. Gupta VK. Management of migraine aura: basic theoretical and
clinical reconsiderations. Headache 2005 (In press).
11. Gupta VK. Non-lateralizing brain PET changes in migraine:
phenomenology versus pharmacology? Brain 2004, 127:E12.
12. Gupta VK. MRI in primary headaches. Radiology (In press).
13. Gupta VK. Cortical spreading depression is neuroprotective: the
challenge of basic sciences. Headache 2005, 45:177-178.
14. Thompson CS, Hakim AM. Cortical spreading depression modifies
components of the inflammatory cascade. Mol Neurobiol 2005, 32:51-58. 16.
15. Yanamoto H, Miyamoto S, Tohnai N, Nagata I, Xue JH, Nakano Y,
Nakajo Y, Kikuchi H. Induced spreading depression activates persistent
neurogenesis in the subventricular zone, generating cells with markers for
divided and early committed neurons in the caudate putamen and cortex.
Stroke 2005, 36:1544-1550.
16. Gupta VK. Migrainous scintillating scotoma and headache is ocular
in origin: a new hypothesis. Med Hypotheses 2005 (In press).
19. Leão AAP. Spreading depression of activity in the cerebral
cortex. J Neurophysiol. 1944;7:359-390.
20. Steiner TJ, Findley LJ, Yuen AWC. Lamotrigine versus placebo in
the prophylaxis of migraine with and without aura. Cephalalgia 1997;17:109-12.
21. Lampl C, Bonelli S, Ransmayr G. Efficacy of topiramate in
migraine aura prophylaxis: preliminary results of 12 patients. Headache
2004;44:174-6.
22. Gupta VK. Topiramate for migraine prophylaxis: addressing the
blood-brain barrier related pharmacokinetic-pathophysiological disconnect.
IJCP (In press).
Van der Flier and Scheltens[1] provide an interesting overview on the
different diagnostic strategies in dementia taking into consideration
several diagnostic approaches including neurophysiology. In this specific
field, they discuss the contribution of electroencephalography but do not
consider different neurophysiological tests. We want to draw attention to
a recently introduced technique, based on t...
Van der Flier and Scheltens[1] provide an interesting overview on the
different diagnostic strategies in dementia taking into consideration
several diagnostic approaches including neurophysiology. In this specific
field, they discuss the contribution of electroencephalography but do not
consider different neurophysiological tests. We want to draw attention to
a recently introduced technique, based on transcranial magnetic
stimulation (TMS) of the brain, that makes it possible to test several
intracortical circuits of the human brain including central cholinergic
circuits.[2] Using TMS related techniques it is possible to recruit specific
neuronal circuits of the human brain and to evaluate in vivo several
neurotransmitter systems.[3]
Several groups have investigated patients with Alzheimer disease (AD)
using TMS documenting an increase in motor cortex excitability.[4-11] It has
been proposed that the hyperexcitability of the motor cortex in AD
patients could be the hallmark of an impaired glutamatergic transmission
representing the consequence of an imbalance between non-NMDA and NMDA
neurotransmission in favour of the non-NMDA transmission.[11-12]
More recently, a TMS related technique that may give direct information
about the function of some cholinergic circuits in the human brain has
been described.[13] This technique relies on the phenomenon of short latency
afferent inhibition (SAI) of the motor cortex produced by coupling of
peripheral nerve stimulation with TMS of the contralateral motor cortex.
SAI tests an inhibitory circuit in motor cortex that is controlled by
central cholinergic activity.[13] SAI is decreased by the muscarinic
receptor antagonist scopolamine in normal subjects,[14] is significantly
reduced in Alzheimer’s disease patients[8] and, in these patients, can be
increased by acetylcholinesterase inhibitors.[15]
Most of the patients with a clinical diagnosis of AD - about seventy
percent - have an abnormal SAI.15 The change in SAI appears unrelated to
the motor cortex hyperexcitability suggesting that these are two
independent abnormalities. In the patients with abnormal SAI, afferent
inhibition can be increased within hours of the administration of a single
oral dose of rivastigmine.[8,15] However, the change in SAI after the
administration of a single oral dose of rivastigmine varies widely
between individual patients. Interestingly, the baseline SAI and the
increase in SAI after a single dose of rivastigmine seem to be correlated
with the response to long term treatment, as evaluated under the Global
Deterioration Scale and with an extensive neuropsychological test
battery.[15] A normal SAI , or an abnormal SAI that is not greatly increased
by a single oral dose of rivastigmine, is invariably associated with a
poor response to long-term treatment. While an abnormal SAI in conjunction
with a large increase in SAI after a single dose of rivastigmine is
associated with a favourable response to long term treatment in most of
the patients. The extent of change in SAI after a single dose of
rivastigmine is also strongly correlated with changes in cognitive
functions assessed by neuropsychological tests after one year of
treatment.[15]
The study of SAI, together with the evaluation of the effects of a single
oral dose of an acetylcholinesterase inhibitor, may contribute to the
management of AD patients because it is currently impossible to predict
the individual therapeutic response in AD patients.
Cumulatively, the studies of SAI in AD patients suggest this test may be
useful in the differential diagnosis between the cholinergic forms and the
non-cholinergic forms of dementia, and among patients with a central
cholinergic dysfunction in an identification of patients who are more
likely to respond to the treatment with acetylcholinesterase inhibitors.
References
1. W M van der Flier and P Scheltens. Use of laboratory and imaging
investigations in dementia. J Neurol Neurosurg Psychiatry 2005;76 v45-v52.
2. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Mazzone
P, Insola A, Tonali PA, Rothwell JC. The physiological basis of
transcranial motor cortex stimulation in conscious humans. Clinical
Neurophysiology 2004;115:255-266.
3. Ziemann, U. TMS and drugs. Clin Neurophysiol 2004;115:1717-1729.
4. de Carvalho M, de Mendonca A, Miranda PC, Garcia C, Luis ML.
Magnetic stimulation in Alzheimer's disease. J Neurol 1997; 244:304-307.
5. Pepin JL, Bogacz D, de Pasqua V, Delwaide PJ. Motor cortex
inhibition is not impaired in patients with Alzheimer's disease: evidence
from paired transcranial magnetic stimulation. J Neurol Sci. 1999;170:119-
23.
6. Liepert J, Bar KJ, Meske U, Weiller C. Motor cortex disinhibition
in Alzheimer's disease. Clin Neurophysiol 2001; 112:1436-1441.
7. Alagona G, Bella R, Ferri R, Carnemolla A, Pappalardo A, Costanzo
E, Pennisi G. Transcranial magnetic stimulation in Alzheimer disease:
motor cortex excitability and cognitive severity. Neurosci Lett 2001;
314:57-60.
8. Di Lazzaro V, Oliviero A, Tonali PA, Marra C, Daniele A, Profice
P, Saturno E, Pilato F, Masullo C, Rothwell JC. Noninvasive in vivo
assessment of cholinergic cortical circuits in AD using transcranial
magnetic stimulation. Neurology 2002; 59:392-7.
9. Pennisi G, Alagona G, Ferri R, Greco S, Santonocito D, Pappalardo
A, Bella R. Motor cortex excitability in Alzheimer disease: one year
follow-up study. Neurosci Lett 2002; 329:293-6.
10. Ferreri F, Pauri F, Pasqualetti P, Fini R, Dal Forno G, Rossini
PM. Motor cortex excitability in Alzheimer's disease: A transcranial
magnetic stimulation study. Ann Neurol 2003; 53:102-8.
11. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra
C, Daniele A, Ghirlanda S, Gainotti G, Tonali PA. Motor cortex
hyperexcitability to transcranial magnetic stimulation in Alzheimer's
disease. J Neurol Neurosurg Psychiatry. 2004;75:555-9.
12. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Tonali
PA. Motor cortex hyperexcitability to transcranial magnetic stimulation in
Alzheimer's disease: evidence of impaired glutamatergic neurotransmission?
Ann Neurol. 2003;53:824.
13. Tokimura, H., Di Lazzaro, V., Tokimura, Y., Oliviero, A.,
Profice, P., Insola, A., Mazzone, P., Tonali, P. & Rothwell, J. C..
Short latency inhibition of human hand motor cortex by somatosensory input
from the hand. J Physiol 2000;523:503-513.
14. Di Lazzaro, V., Oliviero, A., Profice, P., Pennisi, M. A., Di
Giovanni, S., Zito, G., Tonali, P. & Rothwell, J. C. Muscarinic
receptor blockade has differential effects on the excitability of
intracortical circuits in human motor cortex. Exp Brain Res 2000;135:455-
461.
15. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra
C, Ghirlanda S, Ranieri F, Gainotti G, Tonali P. Neurophysiological
predictors of long term response to AChE inhibitors in AD patients. J
Neurol Neurosurg Psychiatry. 2005;76:1064-9.
The most critical influence on the psychiatric morbidity of patients
with chronic daily headache (CDH) is the underlying pathophysiological and
therapeutic belief of the therapist / general practitioner. While a
diagnosis of migraine appears less sinister to lay persons, CDH might seem
more formidable. CDH certainly appears more formidable than its more
benign but unfashionable older hyphenated version,...
The most critical influence on the psychiatric morbidity of patients
with chronic daily headache (CDH) is the underlying pathophysiological and
therapeutic belief of the therapist / general practitioner. While a
diagnosis of migraine appears less sinister to lay persons, CDH might seem
more formidable. CDH certainly appears more formidable than its more
benign but unfashionable older hyphenated version, tension-type headache
(TTH). TTH is a much less alarming diagnosis that is readily understood
and accepted (and probably volunteered as an explanation) by most patients
but acronyms have gripped medicine and its practitioners. Nevertheless, by
removing the term “tension” from CDH, we are no wiser about the origin of
the disorder. It is not generally appreciated that the overly elaborate
1988 headache classification of the International Headache Society and its
newer version of 2004 is purely phenomenological and not based on any
fundamental pathophysiological differences.[1] To believe that each of
the several divisions and subdivisions of migraine and TTH / CDH
represents a distinct pathophysiological entity is a classic form of
irrational scepticism that demands complete suspension of clinical
disbelief.
Primary headache research is a long chain of loosely-connected
assumptions held together by serendipity.[2,3] The basis for the notion
that migraine is the direct outcome of brain / brainstem aberration is
completely nebulous but is central to the rationale for advising (by the
therapist) and expecting or demanding (by the patient) advanced
neuroimaging for management of primary headaches, including CDH.
Transmission of the therapist’s belief, howsoever nuanced, to the patient
is inevitable. If both beta-blockers and antidepressants can prevent
migraine as well as CDH, the presumed pathophysiological difference(s)
between the two are very likely to be inconsequential.
Currently, few headache therapists can make sense of the science and
the myths that surround primary headaches. There is little reason to
maintain, as Dr. Sudhir Kumar suggests, that “informing” patients could
help in the decision making process for patients with CDH (or migraine).
The ethical façade of informing patients about issues that we ourselves
are not yet comfortable with merely (? hopefully) lessens legal liability
whenever a secondary cause for headache subsequently becomes apparent.
While anxiety-provoking therapists might recommend neuroimaging to all
their headache patients, astute therapists might evolve their own
algorithms when not to offer neuroimaging. The longer the history of CDH,
the lesser is the likelihood for positive “embarrassing” neuroimaging
findings. In atypical daily headache of recent onset with failure to
respond to therapy within 4 weeks, neuroimaging is a sensible option.[4]
We should be thankful for the occasional patient who defies such
commonsense thinking and compels us to maintain a higher index of
suspicion at all times in order to recommend neuroimaging earlier.
To cut down on associated psychiatric morbidity in CDH, early
institution of established therapies is important. Not unexpectedly, the
placebo effect of negative neuroimaging is short-lasting. Ideally, cost
considerations and Government funding policies must not colour scientific
perspective. In the far-less-than-ideal world that we all live in, let us
work to minimize the impact of such non-scientific guidelines.
2. Gupta VK. Sleep remits and precipitates migraine: role of the
monoaminergic-vasopressin system. J Neurol Neurosurg Psychiatry (10
November 2005). Available at:
http://jnnp.bmjjournals.com/cgi/eletters/76/10/1467.
3. Gupta V. Migraine, cortical excitability and evoked potentials:
a clinico-pharmacological perspective. Brain. 2005;128:E36.
4. Gupta VK. MRI imaging in primary headaches. Radiology (In press).
I am a 71 year old male who has never had such a scary medical
problem. And what made it more scary is the fact that I have no pre-existing medical conditions and I am on no medications. My only health vice is having three or four glasses of wine daily.
I am very fit and jog religiously and following my attack 6 miles
three times a week for the past 35 years 365 days a year including some
ver...
I am a 71 year old male who has never had such a scary medical
problem. And what made it more scary is the fact that I have no pre-existing medical conditions and I am on no medications. My only health vice is having three or four glasses of wine daily.
I am very fit and jog religiously and following my attack 6 miles
three times a week for the past 35 years 365 days a year including some
very serious hill work. I weigh 152 lbs and I am 6 feet tall. Hardly a
candidate for something like this.
I got up as usual shaved and had my two cups of coffee as I usually
do and then went on my computer for about an hour and then got up to go
jogging. And that was the last thing I was conscious of until I returned an
hour and twenty minutes later. I obviously did the entire jog in that
state.
As I came through my front door my memory began to come back slowly
and I have made a full recovery with no lasting impairment, or ongoing
symptoms of any kind. My doctor said he did not have a clue what happened.
On researching the matter on the web I knew immediately I had
suffered a TGA attack.
We have read with interest the paper by Hilker and co-workers.1 However, we disagree with the emphasis of the editorial commentary by Warnke.
(i) Indeed, the results of several animal studies using functional or structural lesioning of the subthalamic nucleus (STN) have suggested that the inhibition of hyperactive STN neurons could decrease glutamatergic excitotoxicity in Parkinson’s disease (...
We have read with interest the paper by Hilker and co-workers.1 However, we disagree with the emphasis of the editorial commentary by Warnke.
(i) Indeed, the results of several animal studies using functional or structural lesioning of the subthalamic nucleus (STN) have suggested that the inhibition of hyperactive STN neurons could decrease glutamatergic excitotoxicity in Parkinson’s disease (PD) and might thus have neuroprotective effects.2-6 Although high frequency stimulation (HFS) of the STN inhibits the activity of subthalamic neuronal cell bodies,7-10 there is increasing evidence that glutamatergic STN efferents, i.e. the axons, are excited.11-13 Thereby, lesion and STN-HFS cannot be considered as equivalent while the behavioural outcome might resemble. It is thus not surprising that STN-HFS is not neuroprotective since those recent results rather suggest it might amplify neurodegeneration through glutamatergic excitotoxicity.
(ii) STN-HFS is currently applied in late stage PD14;15 where already 80 to 90 percent of the dopamine neurons of the substantia nigra pars compacta are lost.16 Thus, even if STN-HFS (or any other approach) would be neuroprotective, it seems difficult to prove such properties in late stages of the disease. Furthermore, glutamatergic excitotoxicity could contribute to nigral cell loss in earlier but not in late stages of the disease as suggested in experimental models.17 In this view, only carefully designed animal studies will be able to provide satisfying answers.
(iii) The shortcomings of tracer imaging in assessing neuroprotection in PD have been impressively summarized in a recent review article.18 Moreover, a recent consensus conference concludes that “Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials”.19
Without doubt, the work of Hilker et al1 deserves attention, but the sea-snake of a treatment that combines symptomatic relief and disease-modifying outcome would remain an unreachable goal for PD patients if the above mentioned methological issues are not solved.
References
1. Hilker R, Portman AT, Voges J, Staal MJ, Burghaus L, Van Laar T, Koulousakis A, Maguire RP, Pruim J, de Jong BM, Herholz K, Sturm V, Heiss WD, Leenders KL. Disease progression continues in patients with advanced Parkinson's disease and effective subthalamic nucleus stimulation. J Neurol Neurosurg Psychiatry 2005;76:1217-21.
2. Piallat B, Benazzouz A, Benabid AL. Subthalamic nucleus lesion in rats prevents dopaminergic nigral neuron degeneration after striatal 6-OHDA injection: behavioural and immunohistochemical studies. Eur J Neurosci 1996;8:1408-14.
3. Paul G, Meissner W, Rein S, Harnack D, Winter C, Hosmann K, Morgenstern R, Kupsch A. Ablation of the subthalamic nucleus protects dopaminergic phenotype but not cell survival in a rat model of Parkinson's disease. Exp Neurol 2004;185:272-80.
4. Nakao N, Nakai E, Nakai K, Itakura T. Ablation of the subthalamic nucleus supports the survival of nigral dopaminergic neurons after nigrostriatal lesions induced by the mitochondrial toxin 3-nitropropionic acid. Ann Neurol 1999;45:640-51.
5. Blandini F, Nappi G, Greenamyre JT. Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson's disease. Ann Neurol 2001;49:525-9.
6. Carvalho GA, Nikkhah G. Subthalamic nucleus lesions are neuroprotective against terminal 6-OHDA-induced striatal lesions and restore postural balancing reactions. Exp Neurol 2001;171:405-17.
7. Welter ML, Houeto JL, Bonnet AM, Bejjani PB, Mesnage V, Dormont D, Navarro S, Cornu P, Agid Y, Pidoux B. Effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients. Arch Neurol 2004;61:89-96.
8. Filali M, Hutchison WD, Palter VN, Lozano AM, Dostrovsky JO. Stimulation-induced inhibition of neuronal firing in human subthalamic nucleus. Exp Brain Res 2004;156:274-81.
9. Meissner W, Leblois A, Hansel D, Bioulac B, Gross CE, Benazzouz A, Boraud T. Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations. Brain 2005;128:2372-82.
10. Tai CH, Boraud T, Bezard E, Bioulac B, Gross C, Benazzouz A. Electrophysiological and metabolic evidence that high-frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata. FASEB J 2003;17:1820-30.
11. Stefani A, Fedele E, Galati S, Pepicelli O, Frasca S, Pierantozzi M, Peppe A, Brusa L, Orlacchio A, Hainsworth AH, Gattoni G, Stanzione P, Bernardi G, Raiteri M, Mazzone P. Subthalamic stimulation activates internal pallidus: evidence from cGMP microdialysis in PD patients. Ann Neurol 2005;57:448-52.
12. Windels F, Bruet N, Poupard A, Urbain N, Chouvet G, Feuerstein C, Savasta M. Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat. Eur J Neurosci 2000;12:4141-6.
13. Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL. Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J Neurosci 2003;23:1916-23.
14. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 1998;339:1105-11.
15. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD, Benazzouz A, Lebas JF, Benabid AL, Pollak P. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 2003;349:1925-34.
16. Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain - II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain 1999;122:1437-48.
17. Obeso JA, Rodriguez-Oroz MC, Lanciego JL, Rodriguez DM. How does Parkinson's disease begin? The role of compensatory mechanisms. Trends Neurosci 2004;27:125-7.
18. Morrish PK. How valid is dopamine transporter imaging as a surrogate marker in research trials in Parkinson's disease? Mov Disord 2003;18 Suppl 7:S63-S70.
19. Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M, Dhawan V, Feigin A, Fahn S, Guttman M, Gwinn-Hardy K, McFarland H, Innis R, Katz RG, Kieburtz K, Kish SJ, Lange N, Langston JW, Marek K, Morin L, Moy C, Murphy D, Oertel WH, Oliver G, Palesch Y, Powers W, Seibyl J, Sethi KD, Shults CW, Sheehy P, Stoessl AJ, Holloway R. The role of radiotracer imaging in Parkinson disease. Neurology 2005;64:208-15.
We thank Dr Stepan and colleagues for their interest in our work.(1)
We agree with the possible reasons that they have figured out for the
difference between the results of our prevalence study in the Netherlands
and their study in Vienna.(2) We confirm that the results remain sizeably
different, even if we compare the prevalence of a vegetative state (VS) in
all of the nursing homes in our largest city Amste...
We thank Dr Stepan and colleagues for their interest in our work.(1)
We agree with the possible reasons that they have figured out for the
difference between the results of our prevalence study in the Netherlands
and their study in Vienna.(2) We confirm that the results remain sizeably
different, even if we compare the prevalence of a vegetative state (VS) in
all of the nursing homes in our largest city Amsterdam (4/1,000,000) with
the results of all of the nursing homes in Vienna (11/1,000,000).
We hypothesise that medical decisions to withhold or withdraw medical
treatment in previous years may be an explanation for the low prevalence
of VS in our study. We have investigated these decisions in Dutch nursing
homes, but we agree that it might be important to include hospital data as
well for a complete analysis and comparison with other countries. This
type of data is not available as far as we know. However, it can be
inferred from the literature pertaining to physicians’ attitudes towards
end-of-life decisions that withholding or withdrawing futile medical
treatment is becoming more practice routine in several countries in
Northern Europe.(3) We do not have figures of the attitudes of Austrian
physicians in this matter.
In our view, different inclusion criteria, different residence groups
and different times of investigation could explain the lower prevalence in
comparison with the studies by Higashi (Japan) and Ashwal (California).
During the last thirty years in the Netherlands, the incidence of traffic
accidents resulting in severe brain injury has been reduced by preventive
measures, such as the obligation to wear safety belts and helmets.(4)
Moreover, it is a known fact that Japanese physicians are very reluctant
to abandon life prolongation for patients in a VS.(5)
Stephan et al. announced a follow-up of their prevalence study, and
we are also planning to repeat our study. This will allow us the
opportunity to compare the results of our four studies in more detail in
the near future.
References
1. Lavrijsen J. Prevalence and characteristics of patients in a
vegetative state in Dutch nursing homes. J Neurol Neurosurg Psychiatry
2005;76:1420-24.
2. Stepan C, Haidinger G, Binder H. Prevalence of persistent
vegetative state/appalic syndrome in Vienna. European Journal of Neurology
2004;11:461-66.
3. Grubb A, Walsh P, Lambe N. Reporting on the Persistent Vegetative
State in Europe. Medical Law Review 1998;6:161-219.
4. Minderhoud JM. Traumatische hersenletsels [traumatic brain
injuries]. Houten/Mechelen: Bohn Stafleu van Loghum; 2003.
5. Asai A, Maekawa M, Akiguchi I, Fukui T, Miura Y, Tanabe N, et al.
Survey of Japanese physicians' attitudes towards the care of adult
patients. Journal of Medical Ethics 1999;25:302-8.
Baurmann was the first to explain the physilogical conditions of the
central retinal venous pulse (collapse). We reassessed the experimental
setting by a new technical model. We could confirm the results of
Baurmann. The experiment as well as clinical investigations show that
venous collapse can be used to exactly measure the intravasal pressure in
the outflow vein (therefore we created the term - venou...
Baurmann was the first to explain the physilogical conditions of the
central retinal venous pulse (collapse). We reassessed the experimental
setting by a new technical model. We could confirm the results of
Baurmann. The experiment as well as clinical investigations show that
venous collapse can be used to exactly measure the intravasal pressure in
the outflow vein (therefore we created the term - venous outflow
pressure). As the outflow vein (extraocular part of the central retinal
vein) passes for a short strech through the optic nerve - which is
enclosed in a sleeve of cerebrospinal fluid, the intraocular pressure
cannot be lower than the pressure within the optic nerve. This is why we
can assess the intracranial pressure by the venous outflow pressure.
But there is a peculiarity in detecting the venous pulse: Beside the
wellknown venous pulse we also have a non pulsating venous "collapse".
This peculiarity may have prevented a broadly accepted explanation for the
central retinal venous pulse / collapse.
References
Rolf Meyer-Schwickerath et al. Central retinal venous outflow pressure.
Graefe's Arch Clin Exp Ophthalmol (1995)233: 783-788
Dear Editor,
The myelin secreted by oligodendrocytes and Schwann cells contains proteins, lipids and water. The commonest lipid is cholesterol followed by phospholipids, glycosphinglipids and finally a variety of others in far lesser amounts.[1] Furthermore lipid lowering drugs[2,3] and rapid glycaemic control[4] are associated with the development of peripheral neuropathies. This raises the possibility that myeli...
Dear Editor,
We would like to address several of the points raised in a recent editorial in your journal (Killestein J, Uitdehaag BM. Cannabinoids in multiple sclerosis: urgent need for long term trials. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1612), pertaining to the safety and efficacy of cannabis-based medicines in the symptomatic treatment of multiple sclerosis, and propose that the true situation is much mor...
Dear Editor,
Ribi et al.[1] describe an interesting case of neuro Behçets disease (NB) being successfully treated with the tumour necrosis factor alpha (TNFα) monoclonal antibody infliximab. We report using the soluble recombinant human TNFα receptor protein, etanercept in a patient with longstanding NB. To the best of our knowledge there are no previous clinical reports on the use of etanercept in NB.
A...
Dear Editor,
With widely divergent therapeutic options and uncertain, largely indefensible underlying theoretical premises varying widely from closure of patent foramen ovale[1] 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...
Dear Editor,
Van der Flier and Scheltens[1] provide an interesting overview on the different diagnostic strategies in dementia taking into consideration several diagnostic approaches including neurophysiology. In this specific field, they discuss the contribution of electroencephalography but do not consider different neurophysiological tests. We want to draw attention to a recently introduced technique, based on t...
Dear Editor,
The most critical influence on the psychiatric morbidity of patients with chronic daily headache (CDH) is the underlying pathophysiological and therapeutic belief of the therapist / general practitioner. While a diagnosis of migraine appears less sinister to lay persons, CDH might seem more formidable. CDH certainly appears more formidable than its more benign but unfashionable older hyphenated version,...
Dear Editor,
I am a 71 year old male who has never had such a scary medical problem. And what made it more scary is the fact that I have no pre-existing medical conditions and I am on no medications. My only health vice is having three or four glasses of wine daily.
I am very fit and jog religiously and following my attack 6 miles three times a week for the past 35 years 365 days a year including some ver...
Dear Editor
We have read with interest the paper by Hilker and co-workers.1 However, we disagree with the emphasis of the editorial commentary by Warnke.
(i) Indeed, the results of several animal studies using functional or structural lesioning of the subthalamic nucleus (STN) have suggested that the inhibition of hyperactive STN neurons could decrease glutamatergic excitotoxicity in Parkinson’s disease (...
We thank Dr Stepan and colleagues for their interest in our work.(1) We agree with the possible reasons that they have figured out for the difference between the results of our prevalence study in the Netherlands and their study in Vienna.(2) We confirm that the results remain sizeably different, even if we compare the prevalence of a vegetative state (VS) in all of the nursing homes in our largest city Amste...
Dear Editor
Baurmann was the first to explain the physilogical conditions of the central retinal venous pulse (collapse). We reassessed the experimental setting by a new technical model. We could confirm the results of Baurmann. The experiment as well as clinical investigations show that venous collapse can be used to exactly measure the intravasal pressure in the outflow vein (therefore we created the term - venou...
Pages