Kelkar and Parry [1] regard perivascular inflammatory infiltrates as
indicative of an immune microvasculitis that contributes to nerve damage
in diabetes mellitus (DM), in particular mononeuritis multiplex. These
authors believe that the variable therapeutic responses to corticosteroids
alone or in combination with chlorambucil that they observed support the
concept of immunopathogenesis of neural damage...
Kelkar and Parry [1] regard perivascular inflammatory infiltrates as
indicative of an immune microvasculitis that contributes to nerve damage
in diabetes mellitus (DM), in particular mononeuritis multiplex. These
authors believe that the variable therapeutic responses to corticosteroids
alone or in combination with chlorambucil that they observed support the
concept of immunopathogenesis of neural damage in DM.
In sharp contrast to the relatively very short duration of DM in this
cohort,1 diabetic neuropathies tend to occur in the setting of long-
standing hyperglycaemia over decades, whether insulin-dependent or not.[2]
Secondly, diabetic mononeuropathy is characterized by a high degree of
spontaneous reversibility, usually over a several week period. In this
clinical situation, it is difficult to conclude with conviction regarding
the clinical utility of therapy with corticosteroids that, in turn, can
aggravate the diabetic metabolic state. Thirdly, significant weight loss
as seen in three of the four patients with type 2 DM1 is anomalous. Most
patients with uncomplicated type 2 DM are overweight or obese; weight gain
is the usual outcome of therapy with oral hypoglycaemic agents or insulin.
Fourthly, significantly raised erythrocyte sedimentation rate (ESR) (above
50 mm I hour) is not a feature of DM itself. Finally, the metabolic
disturbance in these patients appears to have been well controlled as seen
by near-normal HbA1C levels,[1] which feature generally does not predispose
to neuropathy. In short, the severe but early-onset neuropathy seen in
these diabetic patients1 does not appear to be linked to uncontrolled
hyperglycaemia.
Weight loss, high ESR, and a good response to corticosteroids are
characteristic features of sarcoidosis.[3] At least 25% of patients of DM
(with retinopathy) have serum elevations of angiotensin converting
enzyme.[4] Overall frequency of peripheral neuropathy in neurosarcoidosis is
18%.[5] Mononeuritis multiplex with scattered and asymmetrical sensory and
motor deficits, as described in this cohort,[1] is the most frequently seen
peripheral nerve lesion in neurosarcoidosis.6 Granulomatous T lymphocyte
infiltration in affected tissues, including peripheral nerves, is
diagnostic of sarcoidosis, but tissue evidence of disease cannot always be
obtained.[7]
The mechanism of weight loss [1] in diabetic mononeuropathy as well as
amyotrophy (an uncertain nosologic term)[2] is unknown. In the absence of
markers of vasculitis such as antinuclear antibody and rheumatoid factor,[1]
occult sarcoidosis may underlie weight loss and rapidly evolving steroid-
responsive neuropathy in DM. Corticosteroid refractory neuropathy that
resolves later spontaneously [1] is not likely to be of sarcoid origin and
indicates a miscellaneous vasculitis.
References
(1) Kelkar P, Parry GJ. Mononeuritis multiplex in diabetes mellitus:
evidence for underlying immune pathogenesis. J Neurol Neurosurg Psychiatry 2003;74:803-6.
(2) Asbury AK. Diseases of the peripheral nervous system. In
Harrison’s principles of internal medicine. 12th ed. Wilson JD Braunwald E, Isselbacher KJ, Petersdorf RG, Martin JB, Fauci AS, Root RK, Eds. New York: McGraw–Hill, Inc; 1991:2096-2107.
(3) Mayock RL, Bertrand P, Morrison CE et al. Manifestations of
sarcoidosis. Analysis of 145 patients, with a review of nine series
selected from the literature. Am J Med 1963;35:67-89.
(4) Lieberman J. Angiotensin-converting enzyme in nonpulmonary sarcoidosis.
Semin Res Med 199213:399-401.
(5) James DG, Sharma OP. Neurosarcoidosis. Proc R Soc Med 1967;60:1169-70.
(6) Oksanen V. Neurosarcoidosis. Semin Resp Med 1992;13:459-67.
(7) Gupta VK. Steroid-responsive hypercalcaemic nephropathy in diabetes
mellitus probably due to occult sarcoidosis. Nephron 1996;74:214-5.
We thank Dr Kumar for his interest[1] in our article.[2] I agree, that our data
are not sufficient to evaluate the true risk of recurrence of cerebral
venous and sinus thrombosis (CVST) in women with inherited thrombophilic
disorders. However, we stated in our article that the risk of recurrence
is probably higher if a thrombophilia is present and that all women with
either prior cerebral or extrace...
We thank Dr Kumar for his interest[1] in our article.[2] I agree, that our data
are not sufficient to evaluate the true risk of recurrence of cerebral
venous and sinus thrombosis (CVST) in women with inherited thrombophilic
disorders. However, we stated in our article that the risk of recurrence
is probably higher if a thrombophilia is present and that all women with
either prior cerebral or extracerebral venous thromboembolism who are
pregnant or planning to conceive should be tested for thrombophilia. Our
conclusion was very cautious: "Our data do not justify a negative advice
on pregnancy in women with a history of CVST". We wanted to communicate
that further sucessful pregnancies in women with a history of CVST are
possible. Excluding the one women whose pregnancy was terminated due to a
possible teratogenic risk (because pregnancy occurred during oral
anticoagulation), there were 2 spontaneous abortions. We agree that these
complications might have been due to a thrombophilic state such as an
antiphospholipid antibody syndrome emphasizing the need for thrombophilic
testing. However, all other medical complications (seizures, gestosis)
were controllable and resulted in the birth of healthy children.
In conclusion, we agree that further prospective studies are needed to
determine the true risk of recurrence and that testing for thrombophilic
states is definately necessary. Women with a previous CVST need close
neurological and gynecologic surveillance but a history of CVST does not
exclude the possibility of further sucessful pregnancies.
References
(1) Kumar S, Alexander M, Gnanamuthu C. Risk of recurrent cerebral venous and sinus thrombosis during subsequent pregnancy and puerperium [electronic response to S Mehraein et al. Risk of recurrence of cerebral venous and sinus thrombosis during subsequent pregnancy and puerperium] jnnp.com 2003 http://jnnp.bmjjournals.com/cgi/eletters/74/6/814#53
(2) S Mehraein, H Ortwein, M Busch, M Weih, K Einhäupl, and F Masuhr. Risk of recurrence of cerebral venous and sinus thrombosis during subsequent pregnancy and puerperium. J Neurol Neurosurg Psychiatry 2003; 74:814-816.
Have test, will screen. Screening people with hereditary haemorrhagic
telangiectasia (HHT) for brain arteriovenous malformations (AVMs) could be
relatively easy – and therefore attractive – but where lies the balance
between risk (both physical and psychological) and benefit?
The ideal screening test should aim to detect a disease that
significantly impacts upon public health, before the disease...
Have test, will screen. Screening people with hereditary haemorrhagic
telangiectasia (HHT) for brain arteriovenous malformations (AVMs) could be
relatively easy – and therefore attractive – but where lies the balance
between risk (both physical and psychological) and benefit?
The ideal screening test should aim to detect a disease that
significantly impacts upon public health, before the disease reaches a
critical point (i.e. brain haemorrhage), and detection before this point
should confer a beneficial outcome with intervention (i.e. one or more of
surgical excision, radiotherapy, or endovascular embolisation). The test
itself (MRI and/or catheter angiography) should be sensitive enough to
detect the disease, specific enough to minimise false positives, and it
should be well tolerated with few side effects. Lastly, the population to
be screened should have a high prevalence of the disease, and should be
willing to undergo treatment. If overall there is a fine balance between
benefit and cost (mortality, morbidity, and/or financial), then a
randomised controlled trial (RCT) comparing screening strategies against
each other is called for.
In the case of HHT, it is rare but can cause significant mortality
and morbidity. The exact prevalence of brain AVMs in HHT is uncertain but ³5%. [1] For brain AVMs in general, high quality information about
prognosis and satisfactory evidence for interventional treatment are
lacking: prospective, population-based studies of prognosis are in their
infancy,[2,3] and there are no randomised controlled trials comparing
different interventions either against each other or conservative
management.[4] Catheter angiography is more sensitive than MRI for brain
AVM detection in HHT,[1] and it carries <_0.1 risk="risk" of="of" permanent="permanent" neurological="neurological" complications.5="complications.5" p="p"/>Easey et al. recently addressed the important dilemma of whether or
not to screen for brain AVMs in HHT by assessing the prevalence of stroke
in the families of individuals with HHT.[6] Their sizeable HHT cohort and
collective experience with the condition are invaluable, but their
conclusion that individuals with HHT should be screened for asymptomatic
brain AVMs is not justified by their data. The design of their study does
not address the question they pose and their findings are not
generaliseable.
Easey et al’s study was retrospective and diagnosed HHT on the basis
of clinical diagnostic criteria rather than strictly by mutation analysis
of ALK1 and endoglin genes. This is unfortunate because there is an
increasing body of evidence to suggest that HHT caused by mutations in the
endoglin gene (HHT1) has a distinct and possibly more severe phenotype
than HHT caused by mutations in the ALK1 gene (HHT2).[7]
Of the 98 families studied comprising probands and their relatives in
their generation (n=674), a staggering 200 (30%) were unaffected or
unlikely to have HHT. Strangely, the authors argue against simply studying
the screening group of interest (people with definite HHT) and include
data on strokes in 30% of their cohort who did not, or were unlikely to
have, HHT. Furthermore, all strokes were considered whatever their
aetiology; pulmonary – rather than brain – AVMs may have contributed to
many of these. The total number of people affected by the screening
condition of interest (brain AVMs) is not mentioned, but a brain AVM was
detected on catheter angiography in only 7 of the 35 probable/definite
haemorrhages in the cohort of 674 individuals (table 3). Recurrent events
were not studied. Time-dependent outcome analysis was not used.
The authors then conclude with their finding of a higher relative
risk for stroke by indirect comparison of their heterogeneous cohort with
the Oxford Community Stroke Project. Crucially, they have not directly
established the contribution of the screening condition of interest (brain
AVMs) to this excess risk, nor the effects of treating symptomatic and
incidental brain AVMs.
Our reservations about Easey et al's study are more than pedantic
methodological criticisms; the argument for screening is simply not
persuasive. Their data and the rest of the literature thus far simply do
not justify screening people with HHT for brain AVMs. Screening in this
context does occur in some HHT clinics, but it should not be a practice
standard on the existing evidence.
We are not advocating doing nothing. It may be that screening is
appropriate, but only in certain age groups, or people with particular
mutations. Surely the best solution would be for geneticists, respiratory
physicians, radiologists, radiotherapists, neurosurgeons and neurologists
looking after people with HHT to unite and conduct a properly designed RCT
of screening (and treatment) for brain AVMs?
References
(1) Fulbright RK, Chaloupka JC, Putman CM, Sze GK, Merriam MM, Lee GK,
Fayad PB, Awad IA, White RI, Jr. MR of hereditary hemorrhagic
telangiectasia: prevalence and spectrum of cerebrovascular malformations.
AJNR 1998;19:477-84.
(2) Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis
of arteriovenous malformations of the brain in adults. Brain 2001;124:1900-26.
(3) Al Shahi R, Bhattacharya JJ, Currie DG, Papanastassiou V, Ritchie V,
Roberts RC, Sellar RJ, Warlow CP. Scottish Intracranial Vascular
Malformation Study (SIVMS): Evaluation of Methods, ICD-10 Coding, and
Potential Sources of Bias in a Prospective, Population-Based Cohort.
Stroke 2003;34:1156-62.
(4) Al-Shahi R, Warlow CP. Interventions for treating arteriovenous
malformations of the brain in adults (Protocol for a Cochrane Review). In:
The Cochrane Library, Issue 2, 2003. Oxford: Update Software 2002.
(5) Cloft HJ, Joseph GJ, Dion JE. Risk of cerebral angiography in patients
with subarachnoid hemorrhage, cerebral aneurysm, and arteriovenous
malformation: a meta-analysis. Stroke 1999;30:317-20.
(6) Easey AJ, Wallace GM, Hughes JM, Jackson JE, Taylor WJ, Shovlin CL.
Should asymptomatic patients with hereditary haemorrhagic telangiectasia
(HHT) be screened for cerebral vascular malformations? Data from 22 061
years of HHT patient life. J Neurol Neurosurg Psychiatry 2003;74:743-8.
(7) Berg J, Porteous M, Reinhardt D, Gallione C, Holloway S, Thisanagayam U,
Lux A, McKinnon W, Marchuk D, Guttmacher A. Hereditary haemorrhagic
telangiectasia – a questionnaire base4d study to delineate the different
phenotypes caused by endoglin and ALK1 mutations. J Med Genet 2003; in press.
Afridi and Goadsby present a case of new onset migraine in a patient who developed a pontine bleeding episode from a cavernous angioma.[1] These
authors believe that the pontine bleed triggered the migraine attacks in
this patient and seek a parallel with the headaches observed following
implantation of stimulating electrodes [2] into the periaqueductal gray
matter (PAG).
Afridi and Goadsby present a case of new onset migraine in a patient who developed a pontine bleeding episode from a cavernous angioma.[1] These
authors believe that the pontine bleed triggered the migraine attacks in
this patient and seek a parallel with the headaches observed following
implantation of stimulating electrodes [2] into the periaqueductal gray
matter (PAG).
Structural changes following pontine bleed are unlikely to predispose
to an intermittent disorder such as migraine and are more likely to lead
to a persistent dysfunction, negative or positive. In 15 out of 175
patients undergoing brain electrode transplantation, significant headache
was observed.[2] Of these 15 patients, 13 had PAG electrodes implanted (with
four of these also receiving thalamic electrodes) while two patients had
thalamic electrodes only. Unlike the present case,1 headache was
continuous at onset in 14 of 15 patients.[2] Reserpine produced dramatic
initial resolution of headache,[2] whereas it causes a typical headache in
most migraine patients.[3,4] No migraine prophylactic agent offered any
benefit.[2] There is, thus, little pathophysiological similarity between
this case1 and the headaches following implantation of electrodes in the
PAG.[2]
Lateralization of migraine headache is one of its most characteristic
features. Simply because the physico-chemical substrate / idiosyncracy
responsible for unilateral headache has not yet been detected, it does not
mean that it is unimportant; what is immeasurable might be more important
than what is measurable.[5] If peripheral frontotemporal application of
nitroglycerine can precipitate ipsilateral headache [6] without any primary
involvement of the PAG in the afferent limb of headache, the relevance of
brain stem neuronal interconnections to lateralization of migraine
headache is limited. Secondly, generalisation is essential to the process
of theorizing.[7] Explaining laterality of headache of migraine (in patients
with bilateral headache) by neuronal interconnections at the pontine
level [1] will create significant conceptual pathophysiological limitations
for strictly unilateral headache in migraine patients as well for other
primary headaches that are strictly unilateral, such as cluster headache
(CH) and chronic paroxysmal hemicrania (CPH). In other words, if crossover
of experimental inhibitory PAG input [8] is indeed clinically relevant, why
does persistently unilateral headache occur at all in migraine or CH or
CPH? Furthermore, while stimulation of the ventrolateral PAG produces
inhibition of nociceptive signals experimentally,[8] PAG stimulation did not
affect headaches in patients.[2] On the contrary, in one patient the
headache was intensified ipsilaterally.[2] Finally, atenolol and nadolol are
effective migraine prophylactic agents that modulate primary
pathophysiological aberrations but do not readily cross the blood-brain
barrier, and, therefore, cannot affect brain function either at the level
of the cortex or the brain stem, including nociceptive mechanisms.[9]
Migraine has not been linked previously to pontine bleeding. Stress
is a common precipitant of migraine.[7] As expected following a neurological
episode with fear of loss of function,[10] this patient1 noted that stress
precipitated her headaches. It is important to consider, in the first
instance, as with other theories of migraine,[11] why antinociception should
be spontaneously altered during remissions and exacerbations of migraine.
Equally important, there is no clinical evidence of impaired nociception
in migraine. The acute phase of migraine attacks (with or without aura) is
associated with substantial increases in plasma methionine-enkephalin
(analgesia mediating opiate peptide) which return to baseline only slowly
in the pain-free period.[12] Also, peripheral pain threshold to low-
intensity stimulation was greater or unchanged during headache than during
the headache-free interval, and pressure-pain threshold was not correlated
to the tenderness scores obtained by manual palpation, thereby eliminating
the possibility of both a general ictal increase in sensitivity to pain as
well as focal dysfunction in the antinociceptive system.[13,14] Activation
of vasopressin related adaptive systems also enhances antinociception
during migraine attacks, the process beginning in the pre-prodromal and
prodromal phases.[15] The onset of migraine in this patient following
haemorrhage in brain stem cavernous angioma1 is a rare coincidence that
offers no support to theories of migraine pathogenesis involving brain
stem nociceptive dysfunction.
References
(1) Afridi S, Goadsby PJ. New onset migraine with a brain stem cavernous
angioma. J Neurol Neurosurg Psychiatry 2003;74:680-683.
(2) Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of
brain. Headache 1987;27:416-20.
(3) Kimball RW, Friedman AP, Vallejo E. Effect of serotonin in migraine
patients. Neurology 1960;10:107-111.
(4) Anthony MA, Hinterberger H, Lance JW. Plasma serotonin in migraine and
stress. Arch Neurol 1967;16:544-554.
(5) Gupta VK. Regional cerebral blood flow patterns in migraine: what is
the contribution to insight into disease mechanisms? Eur J Neurol
1995;2:586-587.
(6) Bonuso S, Marano E, Stasio ED, Sorge F, Barbieri F, Ullucci E. Source
of pain and primitive dysfunction in migraine: an identical site? J Neurol
Neurosurg Psychiatry 1989;52:1351-1354.
(7) Blau JN. Migraine: theories of pathogenesis. Lancet 1992;339:1202-1207.
(8) Knight YE, Goadsby PJ. The periaqueductal grey matter modulates
trigeminovascular input: a role in migraine? Neuroscience 2001;106:793-
800.
(9) Gupta VK. Nitric oxide and migraine: another systemic influence
postulated to explain a lateralizing disorder. Eur J Neurol 1996;3:172-
173.
(10) Spierings ELH, Reinders MJ, Hoogduin CAL. The migraine aura as a cause
of avoidance behaviour. Headache 1989;29:254-255.
(11) Blau JN. The challenge of unexplained disease: migraine. J R Soc Med
1993;86:245-246.
(12) Mosnaim AD, Diamond S, Wolf ME, Puente J, Freitag FG. Endogenous
opioid-like peptides in headache. An overview. Headache 1989; 29:368-372.
(13) Drummond, P.D. Scalp tenderness and sensitivity to pain in migraine
and tension headache. Headache 1987; 27: 45-50.
(14) Jensen K, Tuxen C, Olesen J. Pericranial muscle tenderness and
pressure-pain threshold in the temporal region during common migraine.
Pain 1988;35:65-70.
(15) Gupta VK. A clinical review of the adaptive role of vasopressin in
migraine. Cephalalgia 1997;17:561-569.
I read with great interest the recent article by Mehraein et al.[1]
They have studied an important aspect of risk of recurrence of cerebral
and venous sinus thrombosis (CVST) and concluded that subsequent
pregnancies can be safely advised in women with this condition. However,
we would like to make certain observations.
As the authors have mentioned, thrombophilic states have not b...
I read with great interest the recent article by Mehraein et al.[1]
They have studied an important aspect of risk of recurrence of cerebral
and venous sinus thrombosis (CVST) and concluded that subsequent
pregnancies can be safely advised in women with this condition. However,
we would like to make certain observations.
As the authors have mentioned, thrombophilic states have not been
investigated for in most of their cases. It is well known that women with
postpartum CVST may have multiple factors responsible for their
thrombosis. Derex et al reported a case of postpartum cerebral venous
thrombosis associated with congenital protein C deficiency and activated
protein C resistance due to heterozygous factor V Leiden mutation.[2]
Gokcil et al. reported a case of cerebral venous thrombosis in pregnancy in
association with factor S deficiency.[3] Other studies have reported cases
of cerebral venous thrombosis in women on oral contraceptive pills who
also had combined protein C deficiency and activated protein C resistance [4] or activated protein C resistance alone.[5] These case reports
highlight that many women in whom pregnancy, puerperium or use of oral
contraceptive pills seem to be the obvious predisposing conditions for
thrombosis, a variety of inherited thrombophilic states could also be co-
existent. It is also known that inherited thrombophilic states may be
asymptomatic if present in isolation, however, may be symptomatic in the
presence of other associated prothrombotic states such as pregnancy or use
of oral contraceptive pills. Therefore, there is a need to do large
prospective studies in women with postpartum CVST, looking for the
presence of associated inherited thrombophilc states, as those patients
are at a higher risk of recurrence.
The group of women who underwent subsequent pregnancies had a
significantly higher rate of complications. Four out of a total of 14
(28.5%) women had complications (one case each of medical termination of
pregnancy, spontaneous abortion, still birth and generalized seizures).
The authors speculate that these may not be attributable to thromboembolic
complications. However, antiphospholipid antibody (APLA) syndrome with or
without associated collagen vascular diseases is known to cause
spontaneous abortions and venous thrombosis. In a Spanish study, 61% of
women with primary APLA syndrome were found to have miscarriage or foetal
death.[6] Data regarding APLA status of women with complications have not
been provided in this study. Seizures are also known to occur as part of
APLA [6] or CSVT. Authors have excluded CSVT based on a questionnaire but
MR imaging of the brain is required to definitely exclude the condition.
Seizures occurring in one case in the current study may be related to the
APLA syndrome.
In conclusion, data provided in this study is insufficient for us to
recommend future pregnancies in women with CSVT. We need to know the exact
prevalence of co-existing thrombophilic states (inherited or acquired) to
decide on the long-term approach to treatment in these patients. Another
cause for worry is that a significant number of women who underwent repeat
pregnancies had complications.
References
(1) S Mehraein, H Ortwein, M Busch et al. Risk of recurrence of
cerebral venous and sinus thrombosis during subsequent pregnancy and
puerperium. J Neurol Neurosurg Psychiatry 2003; 74:814-816
(2) Derex L, Philippeau F, Nighoghossian N et al. Postpartum cerebral
venous thrombosis, congenital protein C deficiency, and activated protein
C resistance due to heterozygous factor V Leiden mutation. J Neurol
Neurosurg Psychiatry 1998; 65: 801-2.
(3) Gokcil Z, Odabasi Z, Vural O et al. Cerebral venous thrombosis in
pregnancy: the role of protein S deficiency. Acta Neurol Belg 1998;98:
36-8.
(4) Pugliese D, Nicoletti G, Andreula C et al. Combined protein C
deficiency and protein C activated resistance as a cause of caval,
peripheral, and cerebral venous thrombosis--a case report. Angiology 1998;49: 399-401.
(5) Dulli DA, Luzzio CC, Williams EC et al. Cerebral venous thrombosis
and activated protein C resistance. Stroke 1996; 27:1731-3.
(6) Vivancos J, Lopez-Soto A, Font J et al. Primary antiphospholipid
syndrome: clinical and biological study of 36 cases. Med Clin (Barc).
1994; 102: 561-5 (Abstract)
I read with interest the recent article by Wet CJ de et al.[1] Their
finding of a higher prevalence of asthma patients among pseudoseizures is
an interesting one. However, I feel that this could be a mere chance
association.
It is well known that psychosomatic disorders are more common among
patients with chronic medical conditions including hypertension,[2]
diabetes mellitus [3] and...
I read with interest the recent article by Wet CJ de et al.[1] Their
finding of a higher prevalence of asthma patients among pseudoseizures is
an interesting one. However, I feel that this could be a mere chance
association.
It is well known that psychosomatic disorders are more common among
patients with chronic medical conditions including hypertension,[2]
diabetes mellitus [3] and stable angina pectoris.[4] Asthma is also a
chronic disease and it is likely that asthmatics suffer from various
psychiatric symptoms including depressive features and pseudoseizures.
Also, as the authours point out, the diagnosis of asthma was based on
history alone and this may not be reliable in patients with pseudoseizures
as many of them have hyperventilation as part of their symptomatology that
can be confused with asthma.
Their study findings would have become stronger if they had observed
the patients during attacks of asthma or at least interviewed the
physicians treating their asthma.
In conclusion, the finding of asthma being commoner in patients with
pseudoseizures is an interesting one and should be pursued further.
References
(1) Wet CJ de, Miller JDC, Gardner WN, Toone BK. Pseudoseizures and
asthma. J Neurol Neurosurg Psychiatry 2003; 74: 639-641.
(2) Gurgenian SV, Pogosova GV, Vartanian ZhG, Vatinian SKh, Nikogosian
KG.Psychosomatic correlations in patients with hypertension and renal
arterial hypertension. Ter Arkh 1995;67(12):21-5 (Abstract)
(3) Gardner N. Emotional and behavioural difficulties in children with
diabetes: a controlled comparison with siblings and peers. Child Care Health Dev 1998 Mar;24(2):115-28
(4) Billing E, Hjemdahl P, Rehnqvist N. Psychosocial variables in
female vs male patients with stable angina pectoris and matched healthy
controls. Eur Heart J 1997 Jun;18(6):911-8.
Schwarz et al. report neuroendocrine alterations in critically ill
patients with large infarctions of the brain.[1] They regard suppression of
plasma adrenocorticotropic hormone (ACTH) and cortisol levels as
indicating absence of endogenous stress response while attributing
sustained elevation of prolactin levels to impaired central suprapituitary
inhibition involving dopaminergic pathways. Also, t...
Schwarz et al. report neuroendocrine alterations in critically ill
patients with large infarctions of the brain.[1] They regard suppression of
plasma adrenocorticotropic hormone (ACTH) and cortisol levels as
indicating absence of endogenous stress response while attributing
sustained elevation of prolactin levels to impaired central suprapituitary
inhibition involving dopaminergic pathways. Also, they view hormonal
changes of “non-thyroidal illness syndrome/ sick euthyroid syndrome” (SES)
as reflecting a functional impairment that may adversely affect such
patients. Finally, they suggest that correction of such deficiencies of
cortisol and thyroxine might have a role in the management of patients
with space occupying ischaemic brain infarctions.
SES is well accepted to represent an adaptive process that allows the
organism to resume a less intense metabolic state,[2] and does not reflect a
state of thyroid deficiency. Besides, treatment of intensive care unit
patients with low T4 and T3 concentrations with exogenous T4 has no
beneficial effect and does not improve outcome.[3] It must not be assumed
that suppression of thyroid function in this patient group1 is maladaptive
or detrimental. Induction of moderate hypothermia for neuroprotection, as
also used in this study,[1] is based on the same premise, that is, to
decrease the catabolic rate.
Stress-induced hyperprolactinaemia does not involve removal of
inhibitory influences to prolactin release through hypothalamic and/ or
pituitary stalk structural disease. In this cohort,[1] such structural
change has not been demonstrated. Moreover, patients with hypothalamic
disease usually show a doubling of basal prolactin values in response to
thyrotropin-releasing hormone (TRH),[4] rather than the blunted response
seen in these patients.[1] A blunted thyrotropin (TSH) response to TRH is
seen in seriously ill patients with the low thyroxine (T4) variant of
SES.[5] While blunted TSH response to TRH support the diagnosis of SES in
this cohort, blunted prolactin responses do not, as suggested,[1] support
loss of suprapituitary inhibitory influences. In contrast to healthy
subjects, stress-induced prolactin hypersecretion is not expected to
further respond significantly to TRH stimulation. Blunted prolactin
response to TRH cannot be construed to reflect absence of stress response
in these patients.
Since thyroxine accelerates degradation of cortisol, thyroid and
adrenal function is generally closely correlated. The neuroendocrine
system must be viewed as a whole. Suppression of ACTH and cortisol in the
early days following massive infarctions in this cohort1 is consistent
with the concurrence of adaptive SES and indicates an overall stress-
activated neuroendocrine adaptation. In this context, basal prolactin
elevations should also be viewed as a concomitant stress-related
phenomenon. Stress does not invariably increase cortisol secretion. For
example, in post-traumatic stress disorder, cortisol secretion is lowered
early in the illness and rises later,[6] indicating that there are some
clinical situations in which cortisol suppression might be an adaptive
process.
In a life-threatening clinical situation, such as a space-occupying
ischaemic stroke,[1] it is surprising that the hypothalamo-pituitary-adrenal
axis should be suppressed early in the course of the illness.
Histopathologically, lymphocytes and monocytes begin to appear at the
edges of the ischaemic infarct by the second or third day. Since
corticosteroids inhibit lymphocytic function, cortisol suppression in
large brain infarcts during the first week may be designed to attenuate a
lymphocyte-inhibiting influence and thereby promote infarct healing.
Remarkably, stress-related prolactin release counters many of the
immunosuppressive effects of corticosteroids.[7]
Cortisol administration in the early phase of massive infarction, as
suggested,[1] might impair infarct healing. In addition, higher blood
pressures generally exacerbate brain oedema in damaged areas.[8] In this
critical clinical situation, adaptive cortisol (and corticosterone)
suppression may also limit surges of blood pressure or maintain relative
hypotension. On day 7 and 9 -- at which time partial healing of the
infarcts would have occurred in those who survived -- ACTH and cortisol
levels returned towards normal in association with rises in TSH, T4 and
T3,[1] again manifesting a well-coordinated neuroendocrine response.
References
(1) Schwarz S, Schwab S, Klinga K, Maser-Gluth C, Bettendorf M.
Neuroendocrine changes in patients with acute space occupying ischaemic
stroke. J Neurol Neurosurg Psychiatry 2003;74:725–7.
(2) Reincke M, Lehmann R, Karl M, Magiakou A, Chrousos GP, Allolio.
Severe illness. Neuroendocrinology. Ann N Y Acad Sci 1995;771:556--69.
(3) Burman KD, Wartofsky L. Thyroid function in the intensive care
unit setting. Crit Care Clin 2001;17:43--57.
(5) Wartofsky L, Burman KD. Alterations in thyroid function in
patients with systemic illness. the “euthyroid sick syndrome.” Endocr Rev
1982;3:164--217.
(6) Kellner M, Yehuda R, Arlt J, Wiedemann K. Longitudinal course of
salivary cortisol in post-traumatic stress disorder. Acta Psychiatr Scand
2002;105:153-5.
(7) Ader R, Cohen N, Felten D. Psychoneuroimmunology: interactions
between the nervous system and the immune system. Lancet 1995;345:99-103.
(8) Chamorro A, Vila N, Ascaso C, Elices E, Schonewille W, Blanc R.
Blood pressure and functional recovery in acute ischaemic stroke. Stroke 1998;29:1850-3.
Cagli et al.[1] did not detect Chlamydia pneumoniae (C. pneumoniae) DNA
in aneurysmal sac tissue. In a process as complex as atherosclerosis that
will continue throughout life in all individuals, seroepidemiological
studies and direct detection of the organism in atherosclerotic plaques
should not be regarded as strong links between C. pneumoniae and
pathogenesis of atheroscler...
Cagli et al.[1] did not detect Chlamydia pneumoniae (C. pneumoniae) DNA
in aneurysmal sac tissue. In a process as complex as atherosclerosis that
will continue throughout life in all individuals, seroepidemiological
studies and direct detection of the organism in atherosclerotic plaques
should not be regarded as strong links between C. pneumoniae and
pathogenesis of atherosclerosis.
Serological evidence for an intracellular organism such as C. pneumoniae (or other organisms) can hardly support a pathogenetic role.
“Several autoantibodies function as biological, diagnostic or
pathognomonic markers but only few of these have been conclusively linked
pathogentically”.[2] As reviewed by these authors,[1] even serological
evidence for C. pneumoniae is highly variable among patients with well-
established atherosclerotic lesions. It is highly unlikely that such
extreme dissociation between different series will ever be resolved by
undertaking further seroepidemiological studies.
In several previous studies, C. pneumoniae has been detected variably
in atheromatous lesions, but in locations that are related to clinically
relevant features, including the distribution of atherosclerosis.[1] In
patients with atherosclerosis, cell culture and two polymerase chain
reaction assays in two different laboratories failed to detect C. pneumoniae in punch specimens of aortic wall and carotid atheromas.[3] As C. pneumoniae neither affects plaque instability [4] nor accelerates atherogenic
changes in the aortic root of apolipoprotein E-deficient mice,[5] the task
of concluding a definitive role in pathogenesis of atherosclerosis is
truly formidable. The most likely (but seemingly simplistic) explanation
of variable detection of C. pneumoniae in parallel with the natural
distribution of atheromatous lesions is that in the phase of bloodstream
dissemination during the original infection (clinical or subclinical) the
organism is rheologically deposited (seeded or embedded) variably in those
atheromatous plaques that do not have an intact intima at that point of
time.
Because randomization is not a scientific method but does enable
investigative clinicians to do scientifically credible research without
having to discern crucial clinical phenomena,[6] it is understandable -- but
disquieting -- why, even while the mechanism(s) of contribution of C. pneumoniae to pathogenesis of atherosclerosis remains unknown,
prophylactic antibiotic trials are being planned for people at high risk
for coronary disease and abdominal aortic aneurysm.[1] Ongoing larger and
longer lasting treatment trials could provide better measures of the
effects of antibiotic treatment, although they will not clarify the role
of C. pneumoniae.[7] Moreover, persistence of C. pneumoniae antigens rather
than viable bacteriae might be involved,[8] practically excluding any role
for antibiotics. Finally, since infection-related autoimmunity might also
be involved,1 why should an extended (lifelong ?) role for
immunosuppression in prevention of atherosclerosis in high risk
individuals also not be considered? The excitement generated by detection
of C. pneumoniae in atheromatous lesions has swept aside gaps in logic and
heralds the evolution of yet another scientific myth with staggering cost
implications. Antibiotic trials for prevention or regression of
atheromatous lesions are rather premature. As randomized controlled trials
(RCT) overlook individual idiosyncracies,6 the results of such trials can
remain ambiguous. Basically, RCT have not been designed to answer
questions regarding pathogenesis and cannot supplant balanced conceptual
groundwork.
References
(1) Cagli S, Oktar N, Dalbasti T, Erensoy S, Özdamar N, Göksel S,
Sayiner A,Bilgiç A. Failure to detect chlamydia pneumoniae DNA in cerebral
aneursymal sac tissue with two different polymerase chain reaction methods
J Neurol
Neurosurg Psychiatry 2003;74:756–759.
(2) Gupta VK. Migrainous stroke: are antiphospholipid antibodies
pathogenetic, a biological epiphenomenon, or an incidental laboratory
aberration? Eur Neurol
1996;36:110-111.
(3) Bishara J, Pitlik S, Kazakov A, Sahar G, Haddad M, Vojdani A,
Rosenberg S, Samra Z. Failure to detect chlamydia pneumoniae by cell
culture and polymerase chain reaction in major arteries of 93 patients
with atherosclerosis [epub ahead of print] [Record Supplied By Publisher]
Eur J Clin Microbiol Infect Dis 2003 May 9; pS0934-9723
(4) Gibbs RGJ, Sian M, Mitchell AWM, et al. Chlamydia pneumoniae does
not influence atherosclerotic plaque behavior in patients with established
carotid
artery stenosis. Stroke 2000;31:2930–5.
(5) Aalto-Setala K, Laitinen K, Erkkila L, Leinonen M, Jauhiainen M,
Ehnholm C, Tamminen M, Puolakkainen M, Penttila I, Saikku P. Chlamydia
pneumoniae does not increase atherosclerosis in the aortic root of
apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2001;21:578
-584.
(6) Feinstein AR. Clinical judgment revisited: the distraction of
quantitative models. Ann Intern Med 1994;120:799-805.
(7) Larsen MM, Morn B, Andersen PL, Ostergaard LJ. [Atherosclerosis and
Chlamydia pneumoniae] [Aterosklerose og Chlamydia pneumoniae.] Ugeskr
Laeger 2002 Dec 9;164(50):5920-5924.
(8) Hoymans VY, Bosmans JM, Ieven M, Vrints CJ. Chlamydia pneumoniae
and atherosclerosis. Acta Chir Belg 2002;102:317-22
We read with interest the paper by Carod-Artal et al.[1] that showed
the relevance of Chagas' disease as a stroke risk factor in patients of
South American origin.
They also confirmed a textbook view [2] (not
demonstrated until this paper) that cardioembolism is the main cause of
stoke in Chagas' disease (52%). This reflects in part the underlying
chagasic cardiomyopathy, characterised by...
We read with interest the paper by Carod-Artal et al.[1] that showed
the relevance of Chagas' disease as a stroke risk factor in patients of
South American origin.
They also confirmed a textbook view [2] (not
demonstrated until this paper) that cardioembolism is the main cause of
stoke in Chagas' disease (52%). This reflects in part the underlying
chagasic cardiomyopathy, characterised by congestive heart failure and
arrhythmias, that was present in 46% of chagasic patients, a greater
percentage than in non-chagasic patients (25%).
Despite not performing a comparison of stroke characteristics between both
groups, one very interesting finding was the significant percentage of
chagasic patients who developed stroke without any vascular risk factors
and cardiopathy. As the authors stated, undetected cardiovascular disease
could account for, at least, part of this finding. In fact, 25 % of the
chagasic patients classified as possessing the indeterminate form of the
disease (defined by the presence of infection confirmed by serological
tests, the absence of symptoms and of electrocardiographic and radiologic
abnormalities) may present significant structural and/or functional
abnormalities when they are fully evaluated by more sensitive methods,
such as ergometry and autonomic tests.[3] Another possible explanation
proposed by the authors would be vasculitis phenomenon.
Although there is
good experimental evidence to suggest that changes in the microvasculature
may contribute to chagasic heart disease,[4] there is much less known about
the possible involvement of central nervous system microvasculature in
Chagas' disease. Indeed, most studies point to an important role of
endothelin in the pathogenesis of microvascular changes in chagasic
heart [4,5] but we are unaware of similar studies in the central nervous
system.
The authors also suggest the need for primary prevention in all patients
with Chagas' disease cardiomyopathy.[1] This is a strong recommendation as
most patients derive from poor social economic backgrounds and have poor
access to the health system. Chronic oral anticoagulant therapy is known
to cause frequent clinical complications, especially bleeding. One
alternative approach could be the use of low dose anticoagulant therapy
that has been recently suggested for the treatment of deep vein
thrombosis.[6] However, further studies are still needed to investigate this
possibility specifically in Chagas' disease.
References
(1) Carod-Artal FJ, Vargas AP, Melo M, Horan TA. American trypanosomiasis
(Chagas' disease): an unrecognised cause of stroke. J Neurol Neurosurg
Psychiatry 2003; 74: 516-518.
(2) Kirchhoff LV. Trypanosoma species (American trypanosomiasis, Chagas'
disease). In: Principles and practice
of infectious disease Mandell GL, Bennet JE, Dolin R, (Eds). New York: Churchill Livingstone, 1995: 2442-2449.
(3) Rocha MOC, Ribeiro ALP, Teixeira MM. Clinical management of chronic
Chagas cardiomyopathy. Frontiers in Bioscience 2003;8: 44-54.
(4) Petkova SB, Huang H, Factor SM, et al. The role of endothelin in the
pathogenesis of Chagas' disease. Int J Parasitol 2001; 31:499-511.
(5) Camargos ERS, Machado CRS, Teixeira-Jr AL, et al. Role of endothelin
during experimental Trypanosoma cruzi infection in rats. Clinical Science
2002; 103 (suppl): 64S-67S.
(6) Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity
warfarin therapy for the prevention of recurrent venous tromboembolism. N
Engl J Med 2003; 348: 1425-1434.
I would like to comment on the table which appeared on page 412 of the editorial by Watson et al.[1] There is no evidence that what is needed is "access to a
monitored bed with one-to-one nursing". In fact, it is not clear what
monitoring means: in my country (Italy), monitoring means some mechanical control
of blood pressure, heart rate, oxygen, etc; however, British colleagues seem to
consid...
I would like to comment on the table which appeared on page 412 of the editorial by Watson et al.[1] There is no evidence that what is needed is "access to a
monitored bed with one-to-one nursing". In fact, it is not clear what
monitoring means: in my country (Italy), monitoring means some mechanical control
of blood pressure, heart rate, oxygen, etc; however, British colleagues seem to
consider that good specialised nursing is "monitoring". There is only one
small trial on mechanical monitoring, and no firm conclusion can be drawn;
monitoring might save nursing time, but could also cause delay in
rehabilitation (which, I do agree, must be "aggressive").
In my region, small peripheral hospitals admit a high number of
stroke patients (up to 100 in an average 20-30 bed medical unit); nursing
is usually based on a one-to-8 (or 10) rate. To say that stroke patients
need a one-to-one nursing rate would therefore mean that nothing would
change in the future (because of obvious lack of resources), apart perhaps
for very specialised units in large hospitals, where the lucky patient
would happen to be admitted. A more reasonable project is needed, to
improve the care of all stroke patients everywhere. For instance, our new
regional health plan states that each hospital should have a few "stroke
beds" (4 to 8) with a nursing 1 to 4 rate, applying the principle that
more care is better than nothing.
We should aim at the possible progress in the shorter time, not just
to perfection.
Reference
(1) TWJ Watson, JE Simon, AM Buchan. Stroke care: the way forward. J Neurol Neurosurg Psychiatry 2003;74: 411-412.
Dear Editor
Kelkar and Parry [1] regard perivascular inflammatory infiltrates as indicative of an immune microvasculitis that contributes to nerve damage in diabetes mellitus (DM), in particular mononeuritis multiplex. These authors believe that the variable therapeutic responses to corticosteroids alone or in combination with chlorambucil that they observed support the concept of immunopathogenesis of neural damage...
Dear Editor
We thank Dr Kumar for his interest[1] in our article.[2] I agree, that our data are not sufficient to evaluate the true risk of recurrence of cerebral venous and sinus thrombosis (CVST) in women with inherited thrombophilic disorders. However, we stated in our article that the risk of recurrence is probably higher if a thrombophilia is present and that all women with either prior cerebral or extrace...
Dear Editor
Have test, will screen. Screening people with hereditary haemorrhagic telangiectasia (HHT) for brain arteriovenous malformations (AVMs) could be relatively easy – and therefore attractive – but where lies the balance between risk (both physical and psychological) and benefit?
The ideal screening test should aim to detect a disease that significantly impacts upon public health, before the disease...
Dear Editor
Afridi and Goadsby present a case of new onset migraine in a patient who developed a pontine bleeding episode from a cavernous angioma.[1] These authors believe that the pontine bleed triggered the migraine attacks in this patient and seek a parallel with the headaches observed following implantation of stimulating electrodes [2] into the periaqueductal gray matter (PAG).
Structural changes fol...
Dear Editor
I read with great interest the recent article by Mehraein et al.[1] They have studied an important aspect of risk of recurrence of cerebral and venous sinus thrombosis (CVST) and concluded that subsequent pregnancies can be safely advised in women with this condition. However, we would like to make certain observations.
As the authors have mentioned, thrombophilic states have not b...
Dear Editor
I read with interest the recent article by Wet CJ de et al.[1] Their finding of a higher prevalence of asthma patients among pseudoseizures is an interesting one. However, I feel that this could be a mere chance association.
It is well known that psychosomatic disorders are more common among patients with chronic medical conditions including hypertension,[2] diabetes mellitus [3] and...
Dear Editor
Schwarz et al. report neuroendocrine alterations in critically ill patients with large infarctions of the brain.[1] They regard suppression of plasma adrenocorticotropic hormone (ACTH) and cortisol levels as indicating absence of endogenous stress response while attributing sustained elevation of prolactin levels to impaired central suprapituitary inhibition involving dopaminergic pathways. Also, t...
Dear Editor
Cagli et al.[1] did not detect Chlamydia pneumoniae (C. pneumoniae) DNA in aneurysmal sac tissue. In a process as complex as atherosclerosis that will continue throughout life in all individuals, seroepidemiological studies and direct detection of the organism in atherosclerotic plaques should not be regarded as strong links between C. pneumoniae and pathogenesis of atheroscler...
Dear Editor
We read with interest the paper by Carod-Artal et al.[1] that showed the relevance of Chagas' disease as a stroke risk factor in patients of South American origin.
They also confirmed a textbook view [2] (not demonstrated until this paper) that cardioembolism is the main cause of stoke in Chagas' disease (52%). This reflects in part the underlying chagasic cardiomyopathy, characterised by...
Dear Editor
I would like to comment on the table which appeared on page 412 of the editorial by Watson et al.[1] There is no evidence that what is needed is "access to a monitored bed with one-to-one nursing". In fact, it is not clear what monitoring means: in my country (Italy), monitoring means some mechanical control of blood pressure, heart rate, oxygen, etc; however, British colleagues seem to consid...
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