In their paper on unilateral motor ‘deficits’, Young and colleagues [1] report a less-studied aspect of migraine pathophysiology. In contrast to the experience of this tertiary headache-care centre, my own experience
of managing migraine patients between 1976-2006 suggests that a vague upper limb motor involvement is an uncommon feature, not associated with objective weakness or functional limitation or...
In their paper on unilateral motor ‘deficits’, Young and colleagues [1] report a less-studied aspect of migraine pathophysiology. In contrast to the experience of this tertiary headache-care centre, my own experience
of managing migraine patients between 1976-2006 suggests that a vague upper limb motor involvement is an uncommon feature, not associated with objective weakness or functional limitation or disability of the affected limb(s) including writing or typing or walking, not accompanied by any feature of an upper-motor neuron (UMN) deficit, not neurologically lateralizing in relation to the headache or the aura and generally ipsilateral to the headache, not requiring any additional therapy specifically directed at the motor symptom, generally unlinked to the presence or absence of visual aura symptoms, and not present regularly or invariably in repetitive attacks. I have never encountered a patient of
migraine with scintillating scotoma and unilateral UMN weakness; I am not aware that migrainous scintillating scotoma has ever been reported with hemiplegic migraine, whether spontaneous or familial. Even with the first-
attack of typical migraine with upper limb symptoms not consistent with an UMN deficit, there is little justification to seek neurological imaging studies either in the field or in research. I have rarely encountered non-
paretic subjective hemiplegic weakness in association with migraine attacks; also, such patients do not manifest neurological deficit(s). While Young et al. underscore that all their patients had objective evidence of arm and leg weakness [1], weakness in the absence of alteration of deep tendon reflexes or clasp-knife rigidity or extensor
plantar reflex should always arouse suspicion of behavioural alteration. To equate giveway weakness without tonic rigidity to ‘clasp-knife weakness’ with UMN rigidity is fundamentally incorrect and speculative.
Since pathophysiology of migraine is itself poorly comprehended, it is particularly important to distinguish negative phenomena in terms of neurological/paretic or non-paretic ‘deficits’ or ‘accompaniments’. Also, facial weakness in 17% (subjective) or ~8% (objective) of migraine with unilateral motor symptoms (MUMS) patients [1] can be misleading if suggested by direct inquiry in questionnaires or clinical interview in the absence of definitive clinical signs of unilateral facial paresis. In the 2 patients with signs of ‘weakness in the face’, Young et al. [1] do not describe any of the classical clinical signs of facial paresis, unilateral or bilateral. Furthermore, monocular and hemianopic visual symptoms, as
described by Young et al. in 50% and 18% of patients, respectively, are unlikely to reflect brain visual cortical involvement.[2] The general impression among neurologists devoted to migraine research that the
migrainous scintillating scotoma reflects visual cortical involvement is based on belief rather than clinical evidence. There has not been one clearly documented case of bilateral migrainous scintillating scotoma in a
homonymous hemianopic distribution. Migrainous scintillating scotoma is usually monocular or uniocular – hemianopic -- in distribution [2][3].
Over a 6-week period in 2003, I myself experienced and recorded migraine headaches with hemianopic scintillating scotoma; all attacks of scintillating scotoma were strictly monocular, i.e., confined to the left eye. Determination of uniocular or binocular distribution of migrainous scintillating scotoma or other visual aura is an important but neglected difficult-to-evaluate aspect of evaluation of migraine patients.[2][3]. If the migrainous scintillating scotoma is indeed monocular or uniocular in
most cases, a central brain origin of the phenomenon related to CSD can be virtually excluded.[2] Positive migraine aura has never been shown to consistently lateralize neurologically with the side of headache,
unilateral, bilateral or side-shifting. More importantly, Young et al. [1] seek to attribute giveway motor weakness in migraine patients to cutaneous allodynia or to cortical spreading depression (CSD); both phenomena are linked to migraine pathophysiology by serendipity, a series of loosely-linked pathophysiological assumptions, and fragmentary evidences [2][4][5]. Additionally, migraine disability scores (MIDAS) – being ‘housebound’ or ‘losing’ jobs [1] -- cannot strictly substitute as a measure for functional disability due to motor weakness. Finally, while labeling MUMS patients as ‘super-migraineurs’ and underscoring ‘more extreme forms of disability’, Young et al. [1] ignore that their own cohort of MUMS patients with more cutaneous allodynia and more cluster headache-like autonomic activation had markedly shorter (>50%) duration of episodic headaches (Table 3).
Cutaneous allodynia is not a specific or pathognomonic feature of migraine [5]. Cutaneous allodynia is a common non-specific feature of pain neurophysiology in health as well as in disease [6][7][8][9][10]. Second, pain levels are not significantly different between migraine attacks with allodynia or without allodynia [11]. Third, on different occasions, the same migraine patient may manifest allodynic or non-allodynic attacks [5] just like MUMS patients might manifest headache both with or without
weakness. [1] Fourth, the suggested role of the parasympathetic nervous system in occurrence of cutaneous allodynia in some migraine patients, and, its presumed link with pathogenetic central and peripheral neuronal
sensitization [12,13] is conceptually striking but counter-intuitive [4]. While donepezil – a parasympathomimetic agent -- offers significant prophylaxis to migraine patients comparable to propranolol (40 mg b.i.d),
evidence for a potent antinociceptive effect of nicotine [14] and the rationale for use of parasympathomimetic nicotine agonists as analgesics is rapidly evolving [15][16][17]. Nicotine readily crosses the blood-brain
barrier (BBB) and releases acetylcholine as well as arginine vasopressin, β-endorphin, nor-epinephrine, dopamine, serotonin and adrenocorticotropic hormone [17]. With marked shortening of headache duration in migraine patients with allodynia in this cohort [1], an adaptive role for allodynia appears biologically plausible. [17]
Young et al. also invoke cortical neuronal excitation and depression as a possible mechanism for march of motor symptoms in some migraine patients. [1] CSD is a classic example of the seduction of common-sense by an attractive hypothesis [2][17]18]. A large number of factors raise
caution regarding the role of CSD as a pathogenetic mechanism in migraine or in the ischaemic human brain: (i) The distinction between physiology of the normal and the injured human brain must be maintained. As reviewed by
Fabricius et al. [19], CSD in the intact normo-perfused brain does not lead to cell-death [20]. Basically, the brain of migraine patients does not mirror the pattern(s) of the injured human brain. A belief persist that the BBB might be disrupted during migraine attacks but disruption of BBB due to vasogenic œdema is a rare and transient occurrence. In addition, it is commonly known that vasogenic edema affects mainly the white matter; also, lack of contrast enhancement in some cases argues
against BBB breakdown and suggests cytotoxic œdema.[21] (ii) Influence of CSD on brain functioning is basically not deleterious. CSD by itself does not affect ATP levels, mitochondrial aconitase activity, or induce neuronal injury.[22] Conversely, a large and growing body of evidence indicates that CSD is biologically adaptive or neuroprotective. CSD influences the expression of many (to date, over 40) genes associated with inflammation and induces a long-lasting ischemic tolerance that results in
smaller subsequent infarcts and stimulates persistent neurogenesis [23][24][25][26][27][28]. (iii) The association of recurrent peri-infarct depolarisations (PIDs) in the injured brain of experimental animals with
larger final infarct volume [19] is circumstantial, without elucidation of the cause-effect conundrum. We have no idea how CSDs or PIDs might induce further tissue damage in brain-injured humans or experimental animals.
Transient reductions in tissue perfusion or pO2 or decline in dialysate glucose [19] are as likely, if not more likely, to reflect the effect of repetitive cycles of PID/CSD and neuronal recovery. Recovery from spreading depression is an oxidative, energy-dependent process [29].
Hyperaemia, rather than oligaemia, is a more prominent feature of CSD. Massive depolarizations of neurons and glia characteristic of CSD or slow potential change (SPC) with dramatic changes in intra- and extra-cellular
ion concentrations are likely to induce a repetitive neuronal ‘functional silence’ that overall lowers the metabolic requirement of the injured tissue. (iv) In unanaesthetized rats, CSD does not induce aversion as an
immediate or delayed reaction [30]. Conversely, 4-8 minutes after electrophoretic injection of potassium ions into occipital cortices, aggressive and stereotyped eating, drinking, and exploratory behavior were elicited by unilateral and bilateral spreading depression [31]. (v) After cortical recovery from CSD, a prolonged hypesthesia persists [32]. Hypesthesia is a typical feature of CSD. (vi) CSD blocks significantly the hyperthermic influence of prostaglandin E1 and E.coli endotoxin [33]. (vi)
In cats, furosemide inhibits CSD [34] while valproate does not [35]; while furosemide does not prevent migraine, valproate can offer prophylaxis. [36] Also, dihydroergotamine, acetylsalicylic acid, and metoprolol do not affect CSD in the cat. [35] (vii) CSD-augmented matrix metalloproteases (MMP) upregulation may have a pathogenetic role in vascular permeability changes in migraine, besides stroke and trauma [37][38][39]. While nitric oxide (NO) has been implicated in MMP activation and NO increases within brain tissue during CSD, NO is essential for recovery of ionic homeostasis[40][41]. Remarkably, neuronal NO aggravates cortical hyperemia observed during CSD in rabbits [42]. Paradoxically, the NO-donor nitroglycerin generally rapidly reverses migraine aura while serving as the best experimental human model for migraine headache; [43] nitroglycerin, however, enhances CSD-induced NO release.[40] (viii) Nifedipine and
isoproterenol do not freely cross the intact BBB but can instantaneously abort migraine aura.[43]. (ix) While chronic daily administration of migraine prophylactic drugs -- topiramate, valproate, propranolol, amitriptyline, and methysergide -- dose-dependently suppressed CSD frequency by 40 to 80% and increased the cathodal stimulation threshold in rats [44], intriguingly, noradrenergic agonists (norepinephrine and
clonidine) also reversibly block migration of CSD in anaesthetized adult rats.[45] Suppression of CSD by both noradrenergic agonists and antagonists in rat confounds any rational or definitive hypothesis – including the biobehavioral model of migraine that envisions a central key pathogenetic role intrinsic noradrenergic activation [46] -- or conclusion about the pathogenetic role of CSD in migraine patients. (x) While both neurogenic inflammation and stimulated c-fos (early immediate response gene) expression within postsynaptic brain stem neurons of the trigeminal nucleus caudalis following trigeminovascular stimulation are blocked by
sumatriptan and ergot alkaloids [47][48], c-fos expression in the trigeminal caudal nucleus following KCL application appear to be a non-specific response to hyperosmolar KCl/NaCl milieu rather than to CSD. [49]
(xi) Single neuron activity in the trigemino-cervical caudal nucleus remains unchanged during and after CSD in cats [50] and rats [51] following single or repetitive waves of CSD. CSD also did not alter ipsilateral dural plasma extravasation or alter the release of calcitonin
gene-related peptide and prostaglandin E2 from the dura in an in vitro model.[51] Experimental studies in animals with experiments performed in anaesthetetized animals or slice preparations are limited by species differences with humans; additionally, CSD has been produced by artificial
physical or chemical stimuli, thereby limiting validity of extrapolation of the conclusions to human migraine. Up to now no appropriate animal model exits for human migraine; consequently, results of animal experiments might be applied to human migraine models only with a great
deal of circumspection. (xii) Red-green checkerboard visually triggered headache in migraine patients -- in contrast to the initial pronounced cerebral hyperaemia seen in experimental CSD -- is accompanied by a
spreading suppression of initial neuronal activation and increased occipital cortex oxygenation.[52] Visual cortical stimulation by retinal stimuli is not specific to migraine patients. As demonstrated by Leão’s experiments more than 5 decades ago, retinal stimulation with brief
flashes of light can also elicit spreading cortical silence and depression.[53][54] (xiii) Bowyer et al. have shown spreading depression-like propagating direct current magnetoencephalographic (DC MEG) signal during spontaneous aura with fortification spectra but bilateral DC MEG
signals following checkerboard stimulation.[55] CSD-like or equivalent phenomenon in migraine patients must be viewed in a broad clinical context rather than as conclusive evidences for a pathogenetic role for CSD. (xiv)
As atenolol or nadolol or verapamil – drugs that do not readily cross the intact BBB or critically influence brain neuronal function -- prevent migraine, a pathogenetic role for CSD or for primary brain neuronal dysfunction in migraine is considerably attenuated if not eliminated.
[5][17][18][46] (xv) Neither the headache nor the aura represents the true beginning of a migraine attack; onset of migraine attacks lies in the ‘pre-prodromal’ phase while the prodromal phase itself might last several
hours or a few days. [2][5][17][56][57]. Neuro-physiologically, CSD cannot support the characteristic clinical feature of delayed or post-stress onset of migraine attacks in a wide variety of situations and
circumstances. (xvi) Majority of migraine patients do not develop aura; CSD does not appear relevant to this large subset.[45] (xvii) Contrary to the general perception, neuro-anatomically migraine is not a pan-trigeminal disorder; a predominant or selective involvement of the
ophthalmic division of the trigeminal nerve (V1) is suggested by neuroanatomical distribution of only V1 fibres to the upper cervical segments, occurrence of photophobia, and absence of typical migraine headache or aura in the cohort of patients having undergone enucleation or evisceration of the eye.[2][58] Dental extraction (upper or lower jaw) with intense stimulation of maxillary or mandibular divisions of the trigeminal nerve is only rarely associated with migraine headache.[59] CSD cannot rationalize selective involvement of V1 nerve fibres.[2] (xviii) If CSD in migraine patients is indeed the outcome of enhanced brain neuronal excitability, the ability of amitriptyline – a potentially pro-convulsive agent – to prevent migraine creates a conceptual impasse.[2][17] (xix) Migraine has characteristic periods of onset (exacerbations) and offset
(remissions). The basis for propensity for the migraine patient to develop CSD or become resistant to occurrence of CSD is completely unknown. The theory that hypomagnesemia or brain magnesium depletion might aggravate cortical neuronal excitability and precipitate CSD [60] is neither specific to migraine patients nor consistent with known patterns of both distribution of magnesium in cerebrospinal fluid and walls of cranial
blood vessels as well as the pharmacokinetics of exogenously administered magnesium.[17] Oral or intravenously administered magnesium does not readily cross the intact BBB.[17]
Leão’s chance discovery in 1944 of “marked, enduring reduction of the “spontaneous” electrical activity of the cortex” has struck a chord of consensus among most neuro-physiologists and neurologists. More than half a century later, we are no closer to unraveling the biological purpose of the electrophysiological phenomenon. Occurrence of CSD in the compromised human brain has been established; whether the nature of the phenomenon is
pathogenetic or adaptive continues to seem elusive. To neurologists in pursuit of migraine mechanisms, it is nothing short of gospel truth that migrainous scintillating scotomata originate at the level of the visual brain cortex. In migraine pathophysiology, the entire concept of CSD, however, has been hitherto maintained by default.[18] Scientific equipoise, nevertheless, mandates careful consideration of facts on the other side of a conceptual divide. That a fundamental physiological process such as CSD will exert diametrically opposite biological influences in the normo-oxygenated human brain (protective/boon) or in the injured compromised human brain (pathogenetic/bane) is a highly unlikely proposition bordering on irrational sceticism. Recently, a plausible mechanistic hypothesis based on retinal spreading depression has been advanced to explain the phenomenon of monocular or uniocular hemianopic
migrainous scintillating scotoma.[2][18]
The pseudo- or neurologically non-lateralizing ‘weakness’ of MUMS without functional motor deficit or accompaniments of UMN impairment very likely represents an aberrant behavioural response to recurrent cycles of pain-related arousal. As a new term in the vast, inexhaustible lexicon of migraine, giveway weakness arouses both curiosity and hope. Nevertheless, to link MUMS to cutaneous allodynia or to CSD [1] is to stray further into the formidable maze of migraine.
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we read with great interest the paper by Cruz de Souza et al (1) ,
since we conducted a similar clinical experience, with slightly different
findings
In order to achieve data regarding the usability and reliability in the
"real world" of CSF biomarkers in the early differentiation of Alzheimer
Disease (AD) from frontal variant of Fronto-Temporal Dementia (fvFTD) , we
designed a prospective study in w...
we read with great interest the paper by Cruz de Souza et al (1) ,
since we conducted a similar clinical experience, with slightly different
findings
In order to achieve data regarding the usability and reliability in the
"real world" of CSF biomarkers in the early differentiation of Alzheimer
Disease (AD) from frontal variant of Fronto-Temporal Dementia (fvFTD) , we
designed a prospective study in which patients with initial doubtful
diagnoses underwent lumbar puncture besides usual clinical,
neuropsychological and neuroimaging tools. These patients were then
followed up for at least 3 years, in order to confirm their diagnoses:
the accuracy of the initial CSF diagnosis was assessed by comparison with
the final clinical diagnosis
The CSF samples have been collected by lumbar puncture in the morning,
immediately centrifuged and stored at -80? until analysis. Beta-amyloid
peptide 1-42 (bA) , tau and Ptau (phosphorilated at 181 Thr) were measured
with ELISA kits (Innogenetics, Ghent, Belgium) in a laboratory where the
operators were blinded to clinical information. The typical CSF AD
profile was defined as a score below 1 calculated with the formula: bA/
240+1.18 tau, which is known to distinguish AD from controls and from
other dementias with optimal sensitivity and specificity (2)
This prospective study started on January 2006. All consecutive
patients admitted to our tertiary Memory Clinic with a doubtful diagnosis
of AD or fvFTD according to current research criteria underwent lumbar
puncture as a diagnostic tool. On the basis of full clinical,
neuropsychological and bioimaging evaluations, they were initially
classified as AD or fvFTD independently from CSF metabolites levels..
Afterwards, they were evaluated at six months intervals by two expert
neurologists (MF and MZ), blind to the CSF results, who had to confirm
or discard the previous diagnosis.
Thirty nine patients with AD and 37 patients with fvFTD showed
significantly different CSF levels of tau and Ptau (increased in AD, p=
0.0004 and p= 0.009, respectively), bA (reduced in AD, p = 0.018), and
ratios of tau and Ptau to bA (p = 0.0009 and p = 0.014, respectively).
Seventy-seven per cent of AD and 30% of fvFTD patients showed the typical
AD CSF pattern, with a K-index of concordance of CSF and clinical
diagnoses of 47% .
The not negligible prevalence of CSF AD pattern in fvFTD was unexpected
but coherent with the findings of Visser et al (3) who found a typical AD
CSF pattern in 31% of their 89 healthy controls.
The sensitivity and the specificity of typical CSF AD pattern were 77%;
the positive predictive value (PPV) was 73% and negative predictive value
(NPV) was 80%
When we tried to correlate CSF metabolites with main clinical and
demographic features, only the ratio tau/bA negatively correlated with
MMSE scores, both in AD (r = - 0.33; p = 0.022) and fvFTD (r = - 0.34; p
= 0.030)
These results are similar to those of Pijnenburg et al (4) who studied CSF
tau and bA of 35 FTD and 51 AD patients, clinically defined but not
followed up. They found significant differences in the comparison of the
two groups, but concluded that the "measurement of tau and bA is not
useful for the diagnosis of FTD"
Notwithstanding similarities in sizes of AD and fvFTD groups, methological
design, diagnostic criteria and biochemical measurements, our findings are
less optimistic than those of Cruz de Sousa et al. A major limitation
of both studies is the lack of pathological confirmation of the
diagnoses. Until now there is only one paper (5) in which the diagnoses
were definite neuropathologically or genetically. The CSF biomarkers of
19 AD were compared with those of 30 FTD patients and, using ROC analysis,
the ratio tau/bA at a cut-off value of 1.06 had a sensitivity of 79% and a
specificity of 97% at distinguishing AD from FTD. We suggest that until
there will be a convincingly ample study comparing CSF markers from
autopsy-verified AD and FTD patients, the CSF analysis must be
considered useful but not definite diagnostic criteria
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1) Cruz de Sousa L, Lamari F, Belliard S, Jardel C, Houillier C, de
Paz R, Dubois B, Sarazin M.
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3) Visser PJ, Verhej F, Knol DL, et al. Prevalence and prognostic value of
CSF markers of Alzheimer's disease pathology in patients with subjective
cognitive impairment or mild cognitive impairment in the DESCRIPA study :
a prospective cohort study. Lancet Neurol 2009; 8: 619-627.
4) Pijnenburg YAL, Schoonenboom NSM, Rosso SM, et al. CSF tau and bA are
not useful in the diagnosis of frontotemporal lobe degeneration. Neurol
2004; 62:1649
5) Bian H, van Swieten JC, Leight S, et al. CSF biomarkers in
frontotemporal lobar degeneration with known pathology Neurol 2008; 70:
1827-1835.
More evidence needed before retiring the Wada test
We thank Dr. Baxendale and colleagues for her useful comments
regarding our meta-analysis and the opportunity to clarify a few points.
The study of Janacek and colleagues provides important information on
the question of validity of the Wada test and fMRI. Although at the time
of submission we were not aware of this publication, we do address this
issu...
More evidence needed before retiring the Wada test
We thank Dr. Baxendale and colleagues for her useful comments
regarding our meta-analysis and the opportunity to clarify a few points.
The study of Janacek and colleagues provides important information on
the question of validity of the Wada test and fMRI. Although at the time
of submission we were not aware of this publication, we do address this
issue in the beginning of the discussion , and cite studies that have
shown Wada to be incorrect. We also discuss the potential caveats in fMRI
that could lead to incorrect classification, such as parameter settings.
Brain areas that are involved in, but are not critical for, language
function are detected by fMRI but not by the Wada test. We agree that
these non-critical areas may indeed have supportive function for recovery,
but we believe more evidence needs to be provided before this can be
stated with any certainty
Rather than advocating the use of the Wada test as a standard, we
suggest to use fMRI as standard screen, thereby reducing the number of
invasive procedures. Given the potential severity of inadvertent surgery-
induced deficits we believe a conservative diagnostic approach is at this
point still warranted. Hence, If fMRI results are unclear, inconclusive or
if they suggest atypical lateralization (which may also be caused by scan
artifacts, poor task performance or poor fMRI contrast-to-noise), we
recommend an additional test to evaluate laterality, such as the Wada test
if that is a local standard procedure, or cortical stimulation during
surgery. Novel techniques such as TMS may eventually be of use but they
also require rigorous validation tests.
We know that in some parts of the world, notably in the UK, the Wada
test has already been largely replaced by fMRI. In the Netherlands, and
other countries, clinical decision making still heavily relies on the Wada
test, although fMRI is increasingly used as a complementary technique.
fMRI may some day replace the Wada test for most cases, but we believe
that complete replacement requires more evidence, indeed based on outcome
research. The aim of our analysis is to encourage further steps towards
routine use of non- invasive techniques.
Mattes and coworkers report an interesting case of Pourfour du Petit
syndrome which is very useful because the ‘opposite of Horner syndrome’ is
largely unknown [1]. The authors describe that the classical signs of
Pourfour du Petit syndrome are mydriasis, lid retraction, exophthalmos,
sweating and paleness of the affected side.
However, it is probably a misconception that exophthalmos is a clinical
s...
Mattes and coworkers report an interesting case of Pourfour du Petit
syndrome which is very useful because the ‘opposite of Horner syndrome’ is
largely unknown [1]. The authors describe that the classical signs of
Pourfour du Petit syndrome are mydriasis, lid retraction, exophthalmos,
sweating and paleness of the affected side.
However, it is probably a misconception that exophthalmos is a clinical
sign of human Pourfour du Petit syndrome. Firstly, enophthalmos (the
opposite of exophthalmos) is not present in human Horner syndrome [2-5].
Secondly, there are no pathophysiological mechanisms to explain
exophthalmos in Pourfour du Petit syndrome. Thirdly, there was no evidence
of exophthalmos in the presented case [1].
Therefore we believe that exophthalmos is not present in human Pourfour du
Petit syndrome.
REFERENCES
1. Mattes D, Mayer M, Feichtinger M, Lindner S. Neurological picture.
A case of Pourfour du Petit syndrome following tumour surgery of the
mandible.
J Neurol Neurosurg Psychiatry 2009;80:69.
2. van der Wiel HL, van Gijn J. No enophthalmos in Horner's syndrome.
J Neurol Neurosurg Psychiatry 1987;50:498-9.
3. Loewenfeld IE. The Pupil: Anatomy, physiology, and clinical
applications,
Volume 1. Boston: Butterworth-Heinemann; 1999, p. 1139.
4. Thompson HS, Miller NR. Disorders of pupillary function,
accommodation, and lacrimation. In: Miller NR, Newman NJ, editors.
Walsh
and Hoyt's Clinical Neuro-ophthalmology, Volume1, 5th ed. Baltimore:
Williams and Wilkins; 1998, pp. 961-1040.
5. Daroff R. Enophthalmos is not present in Horner syndrome.
PLoS Med
2005;2:e120.
We read with great interest the excellent review about delirium by Burns et al.[1]
We have noticed the absence of eyedrops containing
anticholinergic drugs such as atropine and cyclopentolate in the list of
drugs that may cause delirium, showed in Table 5. These drugs are
frequently prescribed for the elderl...
We read with great interest the excellent review about delirium by Burns et al.[1]
We have noticed the absence of eyedrops containing
anticholinergic drugs such as atropine and cyclopentolate in the list of
drugs that may cause delirium, showed in Table 5. These drugs are
frequently prescribed for the elderly, a group of higher risk to side-
effects.
Anticholinergic drugs constitute an important cause of acute and chronic
confusional states.[2] Several cases of anticholinergic toxicity have
been reported following the administration of commonly used cycloplegics
and mydriatics. Systemic side effects, mainly cerebellar or cerebral such
as visual and tactile hallucinations, incoherent speech, agitation,
disorientation, memory loss and acute psychotic reactions have been
described after topical administration of ocular cyclopentolate. These
reactions appear to be dose-related, with high concentrations, high doses
or repeated instillation of 1 % solution, but have rarely been reported in
adults receiving normal doses.[3,4] Systemic absorption can occur
transconjuntivally or through the nasolacrimal duct and Central Nervous
System toxicity is due to anticholinergic action causing stimulation of
the medulla and cerebral centres. They usually occur within 20-30 minutes
of administration and wear off within 4-6 hours without sequelae.[4] The
risk of developing mental status changes due to anticholinergic ophthalmic
drugs is of particular concern in the elderly. Physicians should be
aware of the potential complications of these drugs monitoring the changes
of mental status and taking appropriate action (3,5).
References
1. Burns A, Gallagley A, Byrne J. Delirium. J Neurol Neurosurg
Psychiatry 2004; 75: 362-367.
2. Moore AR, O´Keeffe ST. Drug –induced cognitive impairment in the
elderly. Drug & Ageing 1999; 15: 15-28.
3. Wüthrich B, Biger M, Kuhn M, Zimmerli B, Priske S. Systemic
anticholinergic side-effects. Allergy 2000; 55: 788.
4. Bhatia SS, Vidyashankar C, Sharma RK, Dubey AK. Systemic toxicity with
cyclopentolate eye drops. Indian Pediatrics 2000; 7:329-331
5. Barker DB, Solomon DA. The potential for mental status changes
associated with systemic absorption of anticholinergic ophthalmic
medications:concerns in the
elderly. DICP 1990; 24: 847-850.
We read with great interest the case report titled “Verapamil induced
gingival enlargement in cluster headache” by Matharu MS et al. in the
Journal of Neurology, Neurosurgery and Psychiatry, year 2005, volume 76,
pages 124-127. We wish to highlight an experience we had with another
calcium channel blocker, amlodipine, whose association with gum
hyperplasia is not clear from the available literature....
We read with great interest the case report titled “Verapamil induced
gingival enlargement in cluster headache” by Matharu MS et al. in the
Journal of Neurology, Neurosurgery and Psychiatry, year 2005, volume 76,
pages 124-127. We wish to highlight an experience we had with another
calcium channel blocker, amlodipine, whose association with gum
hyperplasia is not clear from the available literature.
Amlodipine is a dihydropyridine derivative calcium channel blocker.
The drug is used widely for hypertension and angina pectoris. There are
some reports of gingival hyperplasia following use of amlodipine.[1][2]
Here, we report one patient with hypertension who developed gingival
hyperplasia after use of amlodipine. Doctors using amlodipine should be
aware of this side effect (which can even lead to dental loss), reversible
with stopping the drug and preventable with dental hygiene.[3]
A 64 year old female presented to our institute with a
cerebrovascular accident. She was detected to have hypertension. She was
started on amlodipine 2.5 mg/day and ecospirin 150 mg per day. Twenty
months later she came with complaints of hypertrophy of both upper and
lower gums. The enlarged gingiva was red, smooth and shiny. The
hypertrophic area was painless and did not bleed on touch. There were no
signs of inflammation, or discomfort during eating. She was not on any
other drug. There was no evidence of any haematological malignancy. She
did not have pallor, hepatosplenomegaly or lymphadenopathy. Hematological
investigations including peripheral smear were normal. The patient was
advised to stop the drug. Four months after discontinuation, the patient
showed signs of regression of the gingival hyperplasia.
We agree with the authors that the term "gingival hyperplasia" is
inappropriate because enlargement results mainly from an increase in
extracellular tissue volume with an inflammatory infiltrate, and not from
an increase in the number of cells.[3] Gingival hyperplasia can occur
during use of drugs such as diphenylhydantoin, cyclosporine and calcium
channel blockers.[3][4] The most common cause of drug induced gum
hyperplasia is diphenylhydantoin.[5]
Exact cause of induction of the hyperplasia is not known. Individual
variation in metabolism of the drug may be a factor.[4] The induction of
gingival hyperplasia may not be always a class effect, because one report
suggests that the gingival byperplasia disappeared in a person who was
switched over to isradipine from nifedipine.[6] Local factors such as
inflammation has been implicated,[6] but our patient did not had any
feature of inflammation. It is believed that for some unknown reason these
drugs may cause tissue collagen proliferation.[5]
The prevalence of gingival overgrowth induced by chronic medication with
calcium channel blockers is uncertain.[4] In spite of widespread use, only
one report on gingival hyperplasia induced by calcium channel blockers had
been received by the Norwegian Adverse drug reaction committee until
1992.[7] Although there have been several studies examining this question,
the results are conflicting, with previous estimates ranging from 20% to
83%.[8] [9] Miller and Damm identified one patient with gingival
enlargement out of 24 dentate patients who used verapamil for more than
one year giving an incidence of 4.2%.[10]
Until 1997, six cases had been published indicating that amlodipine may
also promote gingival hyperplasia.[11] But, Jorgensen MG noted mild
hyperplasia (less than one-third the clinical crown) in only five
patients-a prevalence of 3.3%, out of one hundred and fifty dentate
patients on amlodipine, 5 mg per day for at least 6 months . This is
significantly less than the rates reported for patients taking nifedipine,
and not significantly different from rates previously reported in control
groups. Jorgensen concluded that amlodipine, 5 mg per day, did not induce
gingival hyperplasia.[11]
Similarly, Ellis JS et al. reported a community-based study on nine hundred
eleven subjects (442 were taking nifedipine, 181 amlodipine, and 186
diltiazem) and 102 control subjects. 6.3% of subjects taking nifedipine
were seen to have significant overgrowth. The prevalence of gingival
overgrowth induced by amlodipine or diltiazem was not statistically
significant when compared to the control group. The study concluded that
the prevalence of clinically significant overgrowth related to chronic
medication with calcium channel blockers is low, i.e., 6.3% for
nifedipine. Males are 3 times as likely as females to develop clinically
significant overgrowth.[8]
Regarding other calcium channel blockers , one study looked at the
prevalence of gum overgrowth induced by diltiazem and the estimate was a
high 74%.[8] Shouda J reported gingival hyperplasia in three patients
on long-acting nifedipine and one patient on felodipine out of a total of
54 continuous ambulatory peritoneal dialysis patients .No patients were
taking other calcium antagonists. After discontinuation of calcium
antagonists, gingival hyperplasia disappeared within 1 month. [9]
Therapeutic options for drug related gum hypertrophy include drug
discontinuation, providing supplements of folic acid and ascorbic acid,
and reconstructive surgery.[5]
The prevalence of gingival overgrowth induced by chronic medication
with amlodipine is uncertain. However, physicians and cardiologists should
be aware of this rare side effect of amlodipine therapy especially because
it is eminently reversible with discontinuation of drug use. We suggest
that it is important to routinely examine whether the gingiva is overgrown
in all patients taking calcium channel antagonists.
2. Infante Cossio P, Torello Iserte J, Espin Galvez F, et al. Gingival
hyperplasia associated with amlodipine. An Med Interna 1997 ;14(2):83-5.
3. M S Matharu, J A van Vliet, M D Ferrari and P J Goadsby. Verapamil
induced gingival enlargement in cluster headache. J Neurol Neurosurg
Psychiatry 2005 ;76(1):124-7.
4. Routray SN, Mishra TK, Pattnaik UK, Satapathy C, Mishra CK, Behera M.
Amlodipine-induced gingival hyperplasia. J Assoc Physicians India. 2003
Aug;51:818-9.
6. Westbrook P, Bednarczyk EM, Carlson M, et al. Regression of nifedipine-
induced gingival hyperplasia following switch to a same class calcium
channel blocker isradipine. J Periodontol 1997;68:645-50.
7. Lokken P, Skomedal T. Gingival hyperplasia induced by calcium channel
blockers. Rare or frequent in Norway? Tidsskr Nor Laegeforen
1992;112(15):1978-80.
8. Ellis JS, Seymour RA, Steele JG, et al. Prevalence of gingival
overgrowth induced by calcium channel blockers: a community-based study. J
Periodontol 1999;70(1):63-7.
9. Shouda J, Nakamoto H, Sugahara S, et al. Incidence of gingival
hyperplasia caused by calcium antagonists in continuous ambulatory
peritoneal dialysis patients. Adv Perit Dial 1999;15:153-5.
10. Miller CS, Damm DD. Incidence of verapamil-induced gingival
hyperplasia in a dental population. J Periodontol 1992;63:453–6.
I read the case reports of Gotkine et al 1 with great interest and definitely agree with their suggestion that an increase in sympathetic activity may reverse the pain in cluster headache.
We saw already in the late 1960´s that spontaneous attacks of cluster headache are not seldom preceded by a shift of the vegetative tone in a parasympathetic direction. Furthermore, the attacks are fairly often associated...
I read the case reports of Gotkine et al 1 with great interest and definitely agree with their suggestion that an increase in sympathetic activity may reverse the pain in cluster headache.
We saw already in the late 1960´s that spontaneous attacks of cluster headache are not seldom preceded by a shift of the vegetative tone in a parasympathetic direction. Furthermore, the attacks are fairly often associated with symptoms indicative of increased parasympathetic activity,
e.g. bradycardia. Two of our patients noticed that heavy physical exercise had a positive effect on spontaneous headache attacks. We therefore suggested that an increased tone of the sympathetic nervous system might have a favourable influence on the headache. We investigated 2 the effect on the pain of a rise in blood pressure induced by constant prolonged physical exercise on a cycle ergometer or intravenous infusion of noradrenaline in 11 male cluster headache sufferers. Both procedures started 15 min after administration of nitroglycerin and lasted for 60 min. It was found that both maximal intensity and duration of provoked headache attacks were significantly reduced compared with control attacks observed following nitroglycerin administration. In one patient noradrenaline was successfully induced during a spontaneous attack. Our
results are in some way similar to the most interesting observations by Gotkine et al. The activity of the sympathetic nervous system relative to attacks of cluster headache definitely deserves further studies.
References:
1.Gotkine M, Steiner I, Biran I. Now dear, I have a headache! Immediate improvement of cluster headache after sexual activity. J Neurol Neurosurg Psychiat 2006; 77: 1296.
2.Ekbom K, Lindahl J. Effect of induced rise of blood pressure on pain in cluster headache. Acta Neurol Scand 1970; 46: 585-600.
Karl E.Ekbom
Karolinska University Hospital
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...
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.
I read with interest the research paper by Massager et al. and the
accompanying editorial by Schramm on the long term outcome of surgical
disconnection of the epileptic zone in patients with medically refractory
nonlesional mesial temporal lobe epilepsy (MTL) 1, 2. High functioning
patients with MTL in whom WADA testing reveals bihemispheric dominance for
memory frequently experience a decline in either verbal or non-verb...
I read with interest the research paper by Massager et al. and the
accompanying editorial by Schramm on the long term outcome of surgical
disconnection of the epileptic zone in patients with medically refractory
nonlesional mesial temporal lobe epilepsy (MTL) 1, 2. High functioning
patients with MTL in whom WADA testing reveals bihemispheric dominance for
memory frequently experience a decline in either verbal or non-verbal
memory after standard anterior temporal lobectomy (ATL) with
amygdalohippocampectomy (AH). Do the authors have any data to share
whether their surgical disconnection technique leads to less memory
dysfunction than seen after standard ATL.?
References
1. Massager N, Tugendhaft P, Depondt C, Coppens T, Drogba L,
Benmebarek N, De Witte O, Van Bogaert P, Legros B. Long-term outcome of
surgical disconnection of the epileptic zone as an alternative to
resection for nonlesional mesial temporal epilepsy. J Neurol Neurosurg
Psychiatry 2013; 84:1378-83.
2. Schramm J. Disconnecting epileptogenic zone is as effective as
resection. J Neurol Neurosurg Psychiatry 2013; 84:1300-1.
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 u...
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
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Dear Editor,
In their paper on unilateral motor ‘deficits’, Young and colleagues [1] report a less-studied aspect of migraine pathophysiology. In contrast to the experience of this tertiary headache-care centre, my own experience of managing migraine patients between 1976-2006 suggests that a vague upper limb motor involvement is an uncommon feature, not associated with objective weakness or functional limitation or...
Dear Sirs,
we read with great interest the paper by Cruz de Souza et al (1) , since we conducted a similar clinical experience, with slightly different findings In order to achieve data regarding the usability and reliability in the "real world" of CSF biomarkers in the early differentiation of Alzheimer Disease (AD) from frontal variant of Fronto-Temporal Dementia (fvFTD) , we designed a prospective study in w...
More evidence needed before retiring the Wada test
We thank Dr. Baxendale and colleagues for her useful comments regarding our meta-analysis and the opportunity to clarify a few points.
The study of Janacek and colleagues provides important information on the question of validity of the Wada test and fMRI. Although at the time of submission we were not aware of this publication, we do address this issu...
Dear Editor,
Mattes and coworkers report an interesting case of Pourfour du Petit syndrome which is very useful because the ‘opposite of Horner syndrome’ is largely unknown [1]. The authors describe that the classical signs of Pourfour du Petit syndrome are mydriasis, lid retraction, exophthalmos, sweating and paleness of the affected side. However, it is probably a misconception that exophthalmos is a clinical s...
Dear Editor
We read with great interest the excellent review about delirium by Burns et al.[1]
We have noticed the absence of eyedrops containing anticholinergic drugs such as atropine and cyclopentolate in the list of drugs that may cause delirium, showed in Table 5. These drugs are frequently prescribed for the elderl...
Dear Editor,
We read with great interest the case report titled “Verapamil induced gingival enlargement in cluster headache” by Matharu MS et al. in the Journal of Neurology, Neurosurgery and Psychiatry, year 2005, volume 76, pages 124-127. We wish to highlight an experience we had with another calcium channel blocker, amlodipine, whose association with gum hyperplasia is not clear from the available literature....
Dear Editor,
I read the case reports of Gotkine et al 1 with great interest and definitely agree with their suggestion that an increase in sympathetic activity may reverse the pain in cluster headache. We saw already in the late 1960´s that spontaneous attacks of cluster headache are not seldom preceded by a shift of the vegetative tone in a parasympathetic direction. Furthermore, the attacks are fairly often associated...
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...
I read with interest the research paper by Massager et al. and the accompanying editorial by Schramm on the long term outcome of surgical disconnection of the epileptic zone in patients with medically refractory nonlesional mesial temporal lobe epilepsy (MTL) 1, 2. High functioning patients with MTL in whom WADA testing reveals bihemispheric dominance for memory frequently experience a decline in either verbal or non-verb...
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 u...
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