Nagayama and colleagues report on the greatest number of patients
with Parkinsonian syndromes undergoing MIBG scintigraphy sofar. They
calculated a sensitivity of 87.7% and a specificity of 37.4% to correctly
detect 122 patients with idiopathic Parkinson´s disease (PD) in relation
to patients with MSA (n=14), dementia of Lewy body type (DLB) (5), PSP
(7), senile dementia of Alzheimer type (SDAT) (...
Nagayama and colleagues report on the greatest number of patients
with Parkinsonian syndromes undergoing MIBG scintigraphy sofar. They
calculated a sensitivity of 87.7% and a specificity of 37.4% to correctly
detect 122 patients with idiopathic Parkinson´s disease (PD) in relation
to patients with MSA (n=14), dementia of Lewy body type (DLB) (5), PSP
(7), senile dementia of Alzheimer type (SDAT) (15), cerebrovascular
disease (129) and other or unknown disorders (99).
The rather disappointing specificity calculated is underscoring the
true potential to correctly identify idiopathic Parkinson´s disease in
clinical routine using MIBG scintigraphy. The heart/mediastinum ratio´s
lower limit of normal of 1.84 is based on results from 10 normal subjects
and surprisingly high. A meta-analysis of six MIBG studies in
neurodegenerative disorders provided a lower limit of normal of 1,75
based on 69 normal subjects [1], others recently reported 1,69 in 19
normal subjects [2]. This would allow to correctly identify almost all
patients with MSA in this study, as previously reported [3,4].
It is well established that disorders with development of Lewy bodies,
like DLB, are associated with highly reduced cardiac MIBG uptake [5,6,7].
Interestingly none of these 3 studies comparing DLB and SDAT patients
[5,6,7] could identify a single patient out of 34 patients with SDAT
showing a reduced H/M ratio, while grossly reduced H/M ratios were
measured in almost all patients in Nagayama´s study. Therefore inclusion
of these two patient groups in the calculation of the specificity is
contradictory to the current state of knowledge or raises doubts regarding
the correctness of the diagnosis of SDAT. Summing up patients with DLB,
SDAT, other disorders and unknown causes, the majority of 119 patients of
the 269 patients with disorders other than PD provide well known
pathological, surprisingly pathological or open pathological H/M ratios.
This clearly limits the significance of the specificity calculated. The
reduced cardiac uptake in CVD seems to be a clinically important factor
for falsly reduced H/M ratios and needs further clarification in
thoroughly performed studies.
Yours sincerely
Stefan Braune
Corresponding author:
PD Dr. Stefan Braune
Neurozentrum Prien
Bernauer Str. 12
83209 Prien, Germany
Tel. +49-8051-1811
Fax +49-8051-64500
braune@neurozentrum-prien.de
References
1. Braune S. The role of cardiac metaiodobenzylguanidine in the
differential diagnosis of parkinsonian syndromes. Clin Autonom Res 2001;
11:351-355
2. Spiegel J, Mollers MO, Jost WH et al. FP-CIT and MIBG scintigraphy in
early Parkinson's disease Mov Disord. 2005 in press
3. Braune S, Reinhardt M, Schnitzer R et al. Cardiac uptake of [123I] MIBG
separates Parkinson´s disease from multiple system atrophy. Neurology
1999; 53:1020-1025
4. Satoh A, Serita T, Seto M et al. Loss of 123I-MIBG uptake by the heart
in Parkinson's disease: assessment of cardiac sympathetic denervation and
diagnostic value. J Nucl Med. 1999; 40(3):371-375
5. Watanabe H, Ieda T, Katayama T et al. Cardiac (123)I-meta-
iodobenzylguanidine (MIBG) uptake in dementia with Lewy bodies: comparison
with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2001;70(6):781-
783
6. Yoshita M, Taki J, Yamada M. A clinical role for [(123)I]MIBG myocardial
scintigraphy in the distinction between dementia of the Alzheimer's-type
and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry
2001;71(5):583-588.
7. Oide T, Tokuda T, Momose M, et al. Usefulness of
[123I]metaiodobenzylguanidine ([123I]MIBG) myocardial scintigraphy in
differentiating between Alzheimer's disease and dementia with Lewy bodies.
Intern Med 2003;42(8):686-690
The ultimate aims and objectives of the neurologist immersed in
clinical work are no different from those of the academic: put simply, we
all like to understand why we make certain management decisions,
investigative or therapeutic, and yearn for scientific validity and
logical defensibility of our medical or surgical practices and procedures.
By placing great emphasis on nosologic sophistication in...
The ultimate aims and objectives of the neurologist immersed in
clinical work are no different from those of the academic: put simply, we
all like to understand why we make certain management decisions,
investigative or therapeutic, and yearn for scientific validity and
logical defensibility of our medical or surgical practices and procedures.
By placing great emphasis on nosologic sophistication in primary headache
research, we have blurred the distinction between ‘biology’ and
‘physiology’. Whereas biology of an illness elucidates the forces
(physiological processes or events) that push the patient towards health
(headache-free state) or disease (headache), terms such as ‘laboratory,’
‘physiological,’ ‘functional neuroimaging’ and ‘genetic’ have become
generally accepted as biological markers or surrogates in primary headache
research [1,2]. That ‘lumping’ or ‘splitting’ of primary headaches in the
classifications of the International Headache Society will itself yield
insight into disease mechanism is unlikely [1,3]. The very purpose of
research is to improve bedside comprehension of clinical conundrums and
improve clinical practice but ‘lumping’ of cluster headache (CH),
paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache
attacks with conjunctival injection and tearing (SUNCT), and probable
trigeminal autonomic cephalalgia under the rubric of ‘trigeminal autonomic
cephalalgias’ (TACs) [4] offers no clue to the origin of the autonomic
accompaniments of these headache variants, thus relegating these clinical
features to the status of phenomenological events without any definite
causal physiological mechanism. In general, the clarity of pathophysiology
is not improved upon by simple clinical ‘lumping’ or ‘splitting’.
The key issue is the mechanism of excessive cranial parasympathetic
autonomic reflex activation secondary to nociceptive input in the
ophthalmic division of the trigeminal nerve. This task cannot be
dissociated from the origin of the headaches associated with trigeminal
autonomic activation. A pharmacological overview finds little in direct
support for a central or brain neuronal origin of CH [5]. It cannot be
overemphasized that given the current state of knowledge about
pathophysiology of CH and other primary headaches grouped under TACs, the
only absolute window that offers definitive insight is pharmacological.
Also, the striking immediate to short-term results of surgical procedures
on the trigeminal nerve in the face of an intact central central neural
axis, including the caudal trigeminal spinal nucleus with intact
connections to spinal nerves such as the greater occipital nerve indicate
a peripheral origin for the headache [5]. The critical limitations of
therapeutic hypothalamic stimulation and of the pathogenetic
extrapolations arising from such experimental management have been
recently discussed at length [6]. Whereas CH is a strictly unilateral
headache, functional and structural hypothalamic alterations [7] have not
been shown to be lateralizing. The pathognomonic periodicity of CH is the
main clinical feature that suggests a hypothalamic origin but in the
absence of any neural / extra-neural lateralizing mechanism such a theory
remains, at best, remotely plausible. We have no clue why periodic
activation of the hypothalamus, in the first instance, should occur at
all. Additionally, why should a periodic hypothalamic discharge affect
only the first two divisions of the trigeminal nerve as is evident in CH?
Since there is no physiological or anatomical explanation for such a
directed or selective predominant stimulation of the ophthalmic trigeminal
and to a lesser extent the maxillary division, a paradigm shift in
thinking about the origin of CH and other primary headaches under the term
TAC is essential [5,6].
If the hypothalamus is indeed the site of origin of TACs, it is not
possible to explain the absence of salivation in disorders characterized
by lacrimation and nasal congestion / rhinorrhoea; diffuse antidromic
trigeminal nerve excitation also cannot explain the lack of salivation [5,8]. For this reason, surgery on the sphenopalatine ganglion as a
definitive therapeutic measure does not appear rational; the results of
such surgery as reported previously are also inconsistent [5,8]. Lacrimal
gland and nasal innervation is associated with the branches of the
ophthalmic nerve. Rapid rise of intraocular pressure in CH and PH – in
less than 30 seconds in PH – [9] might be critical to the triggering of an
antidromic ophthalmic division trigeminal discharge that results in
‘autonomic’ manifestations. Non-parasympathetic peripheral / local
orthodromic-antidromic reflexes probably drive lacrimation and nasal
congestion / rhinorrhoea in CH and PH. This concept obviates the need to
invoke a theoretically unacceptable ‘selective’ cranial parasympathetic
barrage [5,8].
The basic pathophysiology underlying CH, PH, and SUNCT syndromes is
very likely identical. Practically, the only difference between these
primary headache variants is the duration of the painful episode. The
primary physiological system(s) involved in these headaches should be
capable of generating painful impulses that can last from a few seconds
(SUNCT) to a few hours (CH).
4. Goadsby PJ. Trigeminal autonomic cephalalgias: fancy term or
constructive change to the IHS classification? J Neurol Neurosurg
Psychiatry 2005;76:301-305.
5. Gupta VK. Surgery for cluster headache: desperate measures for a
desperate syndrome? J Neurol Neurosurg Psychiatry 2005; published online
14 February 2005. Available at:
http://jnnp.bmjjournals.com/cgi/eletters/76/2/218#401.
6. Gupta VK. Intractable cluster headache and therapeutic stimulation
of the hypothalamus: pathophysiological and management insights from a
rare experiment. Brain 2005 (In press).
7. May A, Ashburner J, Buchel C, McGonigle DJ, Friston KJ, Frackowiak
RS, Goadsby PJ. Correlation between structural and functional changes in
brain in an idiopathic headache syndrome. Nat Med 1999;5:836-838.
I read with interest the article by Nedeltchev et al. [1].
Using their standard protocol, thrombophilia screen only managed to
identify 2 patients with Factor V Leiden deficiency and 1 patient with
Protein C deficiency. Thrombophilia is well known to cause venous
thrombosis but only very rarely associated with arterial occlusive disease
in adulthood. In contrast, thrombophilia is significant...
I read with interest the article by Nedeltchev et al. [1].
Using their standard protocol, thrombophilia screen only managed to
identify 2 patients with Factor V Leiden deficiency and 1 patient with
Protein C deficiency. Thrombophilia is well known to cause venous
thrombosis but only very rarely associated with arterial occlusive disease
in adulthood. In contrast, thrombophilia is significantly associated with
childhood strokes; one study found that 57% of paediatric stroke patients
had at least one thrombophilia marker (10% had two or more markers)
compared with only 15% of age-matched controls [2]. Even when
thrombophilia screen is found to be positive, it does not necessarily
imply causation. e.g. Factor V Leiden deficiency is present in around 10%
of healthy population [3].
This low yield is consistent with previous reports [4,5], and call
into question whether thrombophilia screening should be routinely
performed in unselected young stroke patients, as is the practice in many
stroke centres. In general, thrombophilia screen should be considered in
stroke patients who are young AND have a family history of thrombosis or
have suffered recurrent strokes. Also thrombophilia screen should be
considered in all paediatric stroke patients, and those with intracranial
venous thrombosis. In view of the high costs associated with the screening
test, a cost-effectiveness analysis may be helful in informing decision-making.
References
1. K Nedeltchev, et al. Ischaemic stroke in young adults: predictors
of outcome and recurrence. J Neurol Neurosurg Psychiatry 2005;76:191-5.
2. Duran R, et al. Factor V Leiden Mutation and Other Thrombophilia
Markers in Childhood Ischemic Stroke. Clin Appl Thromb Hemost 2005;11:83-
8.
3. Atasay B, et al. Factor V Leiden and prothrombin gene 20210A
variant in neonatal thromboembolism and in healthy neonates and adults: a
study in a single center. Pediatr Hematol Oncol 2003;20:627-34.
4. Bushnell C, et al. Screening for hypercoagulable syndromes
following stroke. Curr Atheroscler Rep 2003;5:291-8.
5. Bushnell CD, et al. Improving patient selection for coagulopathy
testing in the setting of acute ischemic stroke. Neurology 2001;57:1333-5.
Donnet, Valade and Régis did not find gamma knife radiosurgery
clinically useful in the intermediate or long-term management of patients
with severe cluster headache (CH) refractory to other therapies;
intriguingly, immediate / short-term results are dramatic and definitely
encouraging but rather unpredictable. [1] The disconnect between these two
set of results remains unexplained but may hold the vi...
Donnet, Valade and Régis did not find gamma knife radiosurgery
clinically useful in the intermediate or long-term management of patients
with severe cluster headache (CH) refractory to other therapies;
intriguingly, immediate / short-term results are dramatic and definitely
encouraging but rather unpredictable. [1] The disconnect between these two
set of results remains unexplained but may hold the vital clue to the
nature of the disorder. These authors as well as others who have performed
therapeutic surgical interruption of the trigeminal nerve for management
of severe CH persist in drawing a parallel with trigeminal neuralgia to
justify these surgical procedures. There are prominent clinical and
pharmacotherapeutic differences between trigeminal neuralgia and CH;
carbamazepine, the drug of choice for trigeminal neuralgia has never been
shown to be effective for CH. The analogy between these two entities
involving the trigeminal nerve is incongruous and therefore misleading.
The authors have correctly emphasized the requirement of total resistance
to pharmacotherapy before surgical procedures might be considered, which
inclusion criterion has not always been followed. [2] Among alternative
therapeutic strategies, these authors believe that external stimulation of
the posterior hypothalamus [3] appears to be a viable option. Leone et
al., [3] nevertheless, did not use verapamil in their patient of CH with
short-lasting hypertensive crises. [2]
The case for using surgery to interrupt transmission along the
trigeminal nerve in CH rests on the assumption that the origin of this
primary headache is due to central brain dysfunction at the level of the
hypothalamus. Several pharmacological absolutes challenge this assumption.
(i) Neither verapamil nor indomethacin freely cross the blood-brain
barrier; such drugs practically cannot significantly influence brain
neuronal function at the level of the cortex or the brain stem, including
anti-nociceptive mechanisms. [2,4] Blocking of activation of subcortical
structures by indomethacin has been misconstrued [5] as representing a
neuronal influence of indomethacin. [6,7]
(ii) Lithium does not influence anti-nociceptive mechanisms. [2]
(iii) Whereas methylprednisolone appears to have a sustained
analgesic effect, bolus steroids showed only transient effects in the CH
patient [3] who underwent hypothalamic stimulation. [2]
(iv) Persistent lateralization of headache in CH (or migraine or
chronic paroxysmal hemicrania or hemicrania continua) does not accord with
the concept of defective antinociception as a persistent or constitutional
defect. [2,4]
(v) Very wide lag periods between onset of positive effect of
hypothalamic stimulation (1-46 days) and recurrence of symptoms of CH
following cessation of the stimulation (2-290) days [3] raise serious
concerns both about the efficacy of the surgical procedure as well as the
nature of the brain function being modulated by such stimulation. [2]
(vi) Excellent response to sumatriptan post trigeminal nerve section
does not support a central neuronal origin of CH, as has been suggested,
[8] because the brain penetrability of sumatriptan is poor, suggesting
negligible neuronal influence. [2,4,6,7,9]
(vii) Alcohol, sublingual nitroglycerine or subcutaneous histamine can
provoke CH but no aberration of brain neuronal function clearly linked to
any of these pharmacological agents has been implicated in the
pathogenesis of CH. [2]
A pharmacological overview, therefore, finds but little in direct
support for a central or brain neuronal origin of CH. [2,6,7] If a new
antiepileptic drug such as topiramate can indeed effectively prevent CH,
[10] we should be able to explain why an older agent such carbamazepine
cannot. Till then, the role of any anti-epileptic in CH management remains
empirical and is to be viewed critically. Additionally, the case for a
peripheral origin of CH appears to be logically defensible.
Despite the overall negative assessment of the procedure, the
immediate and short-term results of gamma knife radioablation of the
trigeminal nerve in patients with CH are strikingly positive in many
subjects in this study. [1] What is the basis of this remarkable temporal
dichotomy of results and does it offer any pathophysiological insight into
the biological nature of CH itself? The variation of responses in this
cohort of 10 CH patients indicates that a standard does of 80 to 85 Gy
produces a variably reversible axonopraxia of the trigeminal nerve. The
complete or near-total cessation of CH painful-episodes in 8 of 10
patients despite preservation of the central neural axis, including the
caudal trigeminal spinal nucleus with intact connections to spinal nerves
such as the greater occipital nerve, indicates a complete cessation of
afferent neurotransmission in the proximal (outside the brain stem)
section of the trigeminal nerve. More importantly, it unambiguously
indicates that the source of origin of CH does not lie in the central
neural axis (brain stem – hypothalamic nexus). Neural recovery from the
radiofrequency-induced trauma to the trigeminal nerve, at rates that
differ from patient to patient, probably allows expression of the CH
symptomatology again. It is entirely feasible that such trigeminal
axonopraxia may be minimal or negligible in a given patient, in which
situation CH episodes will continue unabated. The striking therapeutic
effect blockade of the greater occipital nerve post-radiosurgery in
patient 3 [1] strongly supports such a hypothesis.
Another issue that clouds comprehension is the occurrence of CH
attacks in the face of persistent hypoaesthesia following a surgical or
radiofrequency procedure on the trigeminal nerve. Following a complete
section of the trigeminal nerve root, the brain would not perceive either
vasodilatation or a peripheral neural inflammatory process through the
usual neuroanatomic pathway, as underscored by Matharu and Goadsby. [8]
Nevertheless, the suggestion that such an occurrence suggests a central
origin for CH attacks by default [8] is untenable. [2] It is much more
likely that alternative aberrant routes develop after trigeminal nerve
section or radiofrequency procedure. The trigeminal nerve is peripherally
connected to the III, IV, VI, and VII nerves. Aberrant conduction to the
brain stem may set up during CH attacks through some of these neural inter
-connections after functional or structural interruption of the trigeminal
nerve. [2]
The sphenopalatine ganglion is another structure that seems to merit
consideration; radiosurgery to this neural structure has also been
suggested. [1] If the central component of CH appears unlikely to have a
central brain neuronal origin, the autonomic accompaniment – that
otherwise logically supports the compulsion to invoke central mechanisms -
- might also be explained by a similar regional mechanism. The lack of
salivation in disorders characterized by lacrimation and nasal congestion
/ rhinorrhoea as well as the inconsistency of perioperative findings and
postoperative results in connection with procedures directed on
parasympathetic structures remains unexplained; diffuse antidromic
trigeminal nerve excitation also cannot explain the lack of salivation.
[11] Lacrimal gland and nasal innervation is associated with the branches
of the ophthalmic nerve. Rapid rise of intraocular pressure in CH and
chronic paroxysmal hemicrania (CPH) – in less than 30 seconds in CPH –
[12] might be critical to the triggering of an antidromic ophthalmic
division trigeminal discharge that results in ‘autonomic’ manifestations.
Non-parasympathetic peripheral / local orthodromic-antidromic reflexes
probably drive lacrimation and nasal congestion / rhinorrhoea in CH and
CPH. This concept obviates the need to invoke a theoretically unacceptable
‘selective’ cranial parasympathetic barrage. [11] Surgery on the
sphenopalatine ganglion, therefore, is unlikely to provide lasting
remissions in refractory CH.
To elucidate further the pathophysiology of CH, a paradigm shift that
squarely meets the challenge of the basic sciences involved is essential.
References
(1). Donnet A, Valade D, Régis J. Gamma knife treatment for refractory
cluster headache: prospective open trial. J Neurol Neurosurg Psychiatry
2005;76:218-21.
(2). Gupta VK. Intractable cluster headache and therapeutic stimulation
of the hypothalamus: pathophysiological and management insights from a
rare experiment. Brain 2005 (In press).
(3). Leone M, Franzini A, Broggi G, May A, Bussone G. Long-term follow
-up of bilateral hypothalamic stimulation for intractable cluster
headache. Brain 2004;127:2259-64.
(4). Gupta VK. Migraine following haemorrhage in brain stem cavernous
angioma: pathophysiological considerations [23 June 2003] [electronic
response to Afridi S and Goadsby PJ, New onset migraine with a brain stem
cavernous angioma]. J Neurol Neurosurg Psychiatry. Available at:
http://jnnp.bmjjournals.com/cgi/eletters/74/5/680#55
(5). Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RS,
Goadsby PJ. Posterior hypothalamic and brainstem activation in hemicrania
continua. Headache 2004;44:747-61.
(6). Gupta VK. Neuroimaging in hemicrania continua: dissociation
between technology and basic sciences? Headache (in press).
(7). Gupta VK. Verapamil for cluster headache patients: does brain
penetrability of therapeutic agents really not matter? Headache (In
press).
(8). Matharu MS, Goadsby PJ. Persistence of attacks of cluster
headache after trigeminal nerve root section. Brain 2002;125:976-84.
(9). Hargreaves R. New concepts in migraine--old things explained in
new ways? Headache 2004;44:736-8.
(10). Lainez MJ, Pascual J, Pascual AM, et al. Topiramate in the
prophylactic treatment of cluster headache. Headache 2003;43:784-9.
We read with interest the article “Wilson’s disease: diagnostic
errors and clinical implications”, written by Prasanth et al, in your
journal, 2004;75:907-909. [1]
We would like to thank the authors for bringing to light the
difficulties in diagnosing Wilson’s disease (WD) and the protean
manifestations that often masquerade as other diseases in India. We would
like to share our expe...
We read with interest the article “Wilson’s disease: diagnostic
errors and clinical implications”, written by Prasanth et al, in your
journal, 2004;75:907-909. [1]
We would like to thank the authors for bringing to light the
difficulties in diagnosing Wilson’s disease (WD) and the protean
manifestations that often masquerade as other diseases in India. We would
like to share our experience on two such cases that we encountered in
recent times.
A boy, aged about 10 years, presented with weakness of the
proximal muscles of the lower limbs for some years and was found to have
wasted muscles in the shoulder and hip girdles. The calf muscles were
hypertrophied and Gowers’ sign was positive. He was diagnosed as a case of
Duchenne Muscular Dystrophy (DMD) and was admitted for investigations. The
next morning he was found to exhibit dystonic posturing of the right hand.
Slit lamp examination revealed Kayser-Fleischer (KF) rings and the tests
for copper profile were positive. The patient improved substantially
after the initiation of penicillamine and zinc sulphate therapy. Later,
when the problem was presented in a clinical meeting, a senior
neurologist commented that one such case was also seen by him who was
admitted with the same provisional diagnosis, where a later bout of
hematemesis prompted him to look for the KF rings. Since then, the authors
have formulated the dictum that in a suspected case of DMD, at least in
India, one must look for the inauspicious rings immediately, lest a
potentially treatable condition is missed.
The second case in point, was a 32-year old man who presented with
persistently open lower jaw for some months. He visited a dentist and was
diagnosed as a case of ‘lock jaw’. Wiring of the jaws was performed, which
was ineffective. When he was eventually referred to us, he was found
anarthric and dysphagic with evidence of jaw opening dystonia. Slit-lamp
examination revealed KF rings and the copper profile was grossly abnormal.
MRI examination of the brain revealed symmetrical hyperintense signals in
the basal ganglia in the T2-weighted image and the diagnosis of WD was
established. He responded dramatically to d-penicillamine.
These two cases once again underline the odd presentations of WD
which should be kept in mind, particularly in India, where osseo-muscular
presentation is not uncommon. Dastur et al, [2] described the high incidence
of renal rickets without central nervous system involvement or elevation
of the hepatic enzymes in their patients. They proposed that these
features could be the result of the modification of one gene or even due
to involvement of multiple alleles. Later, Manghani et al, [3] observed
abnormally low values of serum copper oxidase and an inordinately high
value of direct-reacting copper in serum in these patients. The authors
felt that these biochemical aberrations were indicative of a milder nature
of the disease, a fact that is supported by the observation that WD in
India runs a comparatively benign course and the onset of the disease is
somewhat late. Features like, amino aciduria, cysteineuria, calcuria and
phosphaturia are common and Fanconi’s syndrome was considered concomitant
in these patients by the authors. Similarly, renal rickets and
osteomalatic myopathy with myopathic clinical presentation have been
reported by Arjundas et al, from India as well. [4] It is also noteworthy
that one case has been reported from this country, presenting with
priapism. [5]
Indeed, like in the United Kingdom, as suggested by Walshe, [6] WD in
India have only one feature in common; they differ from each other in
every conceivable aspect and a high index of suspicion is necessary to
diagnose the condition.
(2). Dastur DK, Manghani DK, Wadia NH. Wilson’s disease in India. I.
Geographic, genetic, and clinical aspects in 16 families.
Neurology 1968;18:21-31.
(3). Manghani DK, Dastur DK. Wilson’s disease in India. Wilson's disease in
India. II. Biochemical and pathogenetic considerations in patients,
parents, and siblings. Neurology 1968;18:117-26.
(4). Arjundas G. Wilson’s disease. A study of 21 cases. Proc Inst Neurology
197;7:46.
(5). Nair KR, Pillai PG. Trunkal myoclonus with spontaneous priapism and
seminal ejaculation in Wilson’s disease.
J Neurol Neurosurg Psychiatry. 1990;53:174.
Eriksen, Thomsen and Olesen present data underpinning the new
criteria for migraine with aura (MA) in the International Headache Society
-2 Classification. The research as well as clinical utility of being able
to delineate a more homogeneous sample of MA patients or the evolution of
a system that can be used at different levels of specialisation is
debatable. At the research level, increasing nosolog...
Eriksen, Thomsen and Olesen present data underpinning the new
criteria for migraine with aura (MA) in the International Headache Society
-2 Classification. The research as well as clinical utility of being able
to delineate a more homogeneous sample of MA patients or the evolution of
a system that can be used at different levels of specialisation is
debatable. At the research level, increasing nosologic sophistication has
probably impeded both the understanding of the biology of migraine as well
as the creation of an overarching or comprehensive theory for migraine.
[1,2] In effect, in migraine research, the term ‘biological’ has been
substituted by the terms ‘laboratory,’ ‘physiological,’ ‘functional
neuroimaging’ and ‘genetic’. At the clinical level, increased diagnostic
precision of MA does not appear to offer any therapeutic advantage. It is
quite unrealistic to expect that significantly distinct pathophysiological
mechanisms or specific therapies will ever be identified for each of the
many subsets of migraine highlighted in either the current or the previous
classification of primary headaches. That currently all preventive
pharmacologic therapies for migraine are empirical is a different issue.
The critical ingredient in migraine research is the need to evolve an
integrative synthesis that:
(i) rationalizes the striking protective
effect of stress; (ii) evolves the conceptual divide between physiological
processes that predispose to a headache or a headache-free state; and
(iii) explains the ability of pharmacotherapeutic agents that do not cross
the blood-brain barrier or critically influence brain neuronal function to
prevent migraine as well as to abort the aura of migraine. [3]
Till then,
the characteristic lateralization (unilateral, bilateral, or side-shift)
of headache of migraine will remain a non-issue. [2]
Based on pure phenomenology, the new diagnostic criteria for MA
constitute a sombre reminder of the limits of our comprehension. [1-4]
Without squarely meeting the challenge of the basic sciences involved in
migraine, such exercises in nosology are likely to ensure that we remain
indefinitely lost in the giant maze of migraine phenomenology.
References
(1). Gupta VK. Migraine: a disease in-waiting. BMJ online response (11
January 2005). Available at:
http://bmj.bmjjournals.com/cgi/eletters/330/7482/54
(2). Gupta VK. Non-lateralizing brain PET changes in migraine:
phenomenology versus pharmacology? Brain 2004;127:E12.
(3). Gupta VK. Stress, adaptation, and traumatic-event headaches:
pathophysiologic and pharmacotherapeutic insights. BMC Neurology 2004.
Available at:
http://www.biomedcentral.com/1471-2377/4/17/comments#106454
(4). Gupta VK. Migraine: searching for pathophysiology in semantics and
nosology. J Neurol Neurosurg Psychiatry online publication (17 January
2005). Available at:
http://jnnp.bmjjournals.com/cgi/eletters/76/1/1-a
Artero and colleagues detected a patterned non-random distribution of
white matter lesions (WML) in the aging brain associated with symptoms and
suggest progression of lesions from frontal through parietal to temporal
and occipital regions.
Since blood pressure is an established risk factor for the presence
and severity of WML, the rheological state of the brain circulation
appears to be the...
Artero and colleagues detected a patterned non-random distribution of
white matter lesions (WML) in the aging brain associated with symptoms and
suggest progression of lesions from frontal through parietal to temporal
and occipital regions.
Since blood pressure is an established risk factor for the presence
and severity of WML, the rheological state of the brain circulation
appears to be the critical factor influencing distribution of such
lesions. Alterations in mental state or cognition are commonly accompanied
by alterations in blood pressure and thereby cranial blood flow; such
alterations in brain neuronal function are unlikely to be causal or
primarily responsible for the appearance of WML. WML are neither age-
specific nor generally heritable, having been found in both sexes in
hypertensive encephalopathy, puerperal eclampsia, migraine, and therapy
with cyclosporin, interferon-alpha, and tacrolimus. [1] In migraine
patients, the occurrence of predominantly posterior circulation territory
infarcts in contrast to anterior circulation infarcts in embolic or
atherosclerotic thrombotic strokes is probably related to rheological
factors; anatomical vulnerability of the posterior cerebral artery renders
it particularly susceptible to vasospastic influences in migraine
patients. [2] Conversely, diffuse, non-lateralizing distribution of deep
WML in migraine patients unaffected by triptan use indicates that these
MRI aberrations do not reflect the outcome of vasospastic ischemia;
sustained vasodilatation and vasogenic cerebal oedema probably underlies
WML in both migraine as well as hypertensive encephalopathy. [2,3]
Mechanistically, there appears to be a fundamental difference in the
pathogenesis of brain infarcts and WML.
While Artero et al allude to a particular ‘vulnerability’ of frontal
areas to WML that transcends disease entities but appears linked to
symptoms, disease symptomatology cannot logically be dissociated from the
disease process. The general susceptibility of the frontal regions to
develop WML earlier than other brain regions probably reflects the outcome
of a regional variation in density of autonomic innervation of the cranial
circulation. By virtue of the tonic vasoconstrictive influence on
posterior cranial circulation, [2,4] the occipital region appear to be
least susceptible to surges in cranial blood flow and, therefore, are
least likely to develop WML.
The proposal to study longitudinally the distribution of WML in the
general population, as suggested by these investigators, is complicated by
the intrinsic reversibility of such lesions. [1,3] In such a situation,
there is little to distinguish whether any location-specific WML detected
at MRI at two different points in time, say five years apart, represents
the same or a different newer lesion – the previous lesion at the same
site having resolved completely. All investigative modalities have their
limitations; issues primarily related to natural variations in the index
disease have to be addressed through conceptual groundwork rather than the
accretion of more ‘hard evidence’.
References
(1). Gupta VK. White matter hyperintensities: pearls and pitfalls in
interpretation of MRI abnormalities. Stroke 2004; 35: 2756-2757.
(2). 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.
While Pearce analyses the paper of Furman, Balaban, Jacob, and Marcus
[1] with precision [2] insofar as migraine is concerned no suffix carries
any pathophysiological import or diminishes the mystery of migraine. With
both migraine [3] and dizziness having been around since antiquity,
restraint is the key watchword that determines - or should determine -
use of the term ‘new’ in describing any migraine...
While Pearce analyses the paper of Furman, Balaban, Jacob, and Marcus
[1] with precision [2] insofar as migraine is concerned no suffix carries
any pathophysiological import or diminishes the mystery of migraine. With
both migraine [3] and dizziness having been around since antiquity,
restraint is the key watchword that determines - or should determine -
use of the term ‘new’ in describing any migraine related symptom-complex.
The available description of migraine by patients is already inexhaustive.
Conversely, the cerebral spur that the term ‘condition’ offers is a
powerful goad [4]. The only pre-condition required to stimulate lateral
thinking in primary headache research is to be able to place the
disconnect between clinical phenomenology and the basic sciences in the
centrestage [5].
Whereas the concept of spreading depression remains nebulous and
misleading [6], certain neglected aspects of pharmacotherapy help to
demystify the Gordian knot of migraine. If drugs like atenolol and
verapamil – that do not freely cross the blood-brain barrier or critically
influence brain neuronal function – [7] and both serotonin agonists
(antidepressants) and antagonists (cyproheptadine) can prevent migraine
headache [8], much of perceived wisdom in migraine pathophysiology
requires modification [4]. Complex flow charts implicating noradrenergic
or serotonergic brain neuronal systems in the pathogenesis of migraine are
attractive but deceptive.
The hidden gem in the paper of Furman et al. is the elucidation of
the link between visual cues and migraine symptoms, including space and
motion discomfort (SMD). Optokinetic-reflex related nystagmus may well
prove to be the pathophysiological basis of motion sickness as well as the
link between SMD and migraine; scopolamine, dimenhydrinate, and
promethazine reduce motion-related nystagmus [9]. Rapid-to-sudden
augmentation of proprioceptive and nociceptive ocular trigeminal nerve
traffic by optokinetic and/or vestibulo-ocular nystagmus might underlie
the bidirectional link between migraine and motion sickness.
References
(1). J M Furman, C D Balaban, R G Jacob, and D A Marcus
Migraine–anxiety related dizziness (MARD): a new disorder?
J Neurol Neurosurg Psychiatry 2005; 76: 1--8.
(2). Pearce JMS. Migraine–anxiety related dizziness (MARD): a non-
diagnosis? J Neurol Neurosurg Psychiatry 2005 (Online response) (7 January
2005)
It is my hypothesis (1985) that Alzheimer's disease
results from low DHEA. This has since been
supported. HRT reduces DHEA production (Metabolism.
2001 Apr;50(4):488-93). This may be why HRT has
recently been found to increase the onset of
Alzheimer's disease. I suggest the past support of
positive effects of HRT are due to a stimulus of DHEA
production followed by loss of DHEA production with...
It is my hypothesis (1985) that Alzheimer's disease
results from low DHEA. This has since been
supported. HRT reduces DHEA production (Metabolism.
2001 Apr;50(4):488-93). This may be why HRT has
recently been found to increase the onset of
Alzheimer's disease. I suggest the past support of
positive effects of HRT are due to a stimulus of DHEA
production followed by loss of DHEA production with
time. The reason is that DHEA is naturally reduced in
the elderly, reaching very low levels. It is this
ultimate loss of DHEA to which I attribute the
negative effects of prolonged HRT use. That is, I
think all tissues act optimally when DHEA levels are
high. The ultimate loss of DHEA from extended use of
HRT by the elderly results in problems caused by low
DHEA.
Now, I suggest the findings of Henderson, et al,
represent the effects of HRT on the early stimulus of
DHEA production in still relatively young subjects.
These individuals are still able to produce a
stimulated production of DHEA so you saw positive
results regarding Alzheimer's disease. My caveat is
that this early positive result may eventually
increase the onset of Alzheimer's disease in this
cohort.
We read with interest the paper of Chaudhuri et al. [1] on long
duration asymmetrical postural tremor. Like all thought-provoking
research, the paper raises many questions that lend themselves to further
research and thought.
The issue of the relationship between ET and parkinsonism is
complicated and this study underscores the need for further longitudinal
research to clarify dise...
We read with interest the paper of Chaudhuri et al. [1] on long
duration asymmetrical postural tremor. Like all thought-provoking
research, the paper raises many questions that lend themselves to further
research and thought.
The issue of the relationship between ET and parkinsonism is
complicated and this study underscores the need for further longitudinal
research to clarify disease progression and diagnosis. Broadly speaking,
in a given cohort of patients with postural or kinetic tremor, what
clinical features would most strongly predict the future development of
parkinsonism? To give just one example, the authors have suggested
asymmetry of the arm tremor as one such factor. Since arm tremor in ET may
be mildly asymmetric [2], one avenue of inquiry might be to attempt to
quantify the extent of this asymmetry that might reliably predict the
later development of parkinsonism.
A second related issue is the pathology of the two conditions and its
relationship to the clinical diagnosis. ET probably represents a family of
diseases united by the presence of action tremor, in the same way that
Parkinsonism is a family of disorders united by a common set of clinical
findings [3]. While we have some understanding of the subtypes of
Parkinsonism, we do not have the same level of understanding of ET. Some
subtypes of ET might in fact represent forms of Lewy body (LB) disease. We
reported a patient with a clinical diagnosis of ET for more than forty
years whose postmortem brain examination revealed a very focal presence of
Lewy bodies in the locus ceruleus (not in the substantia nigra)
representing an anatomically-restricted form of LB disease [4].
Another possibility, given the clinical heterogeneity of ET is that,
perhaps none of Chaudhuri’s patients had PD but rather, a form of ET whose
pathology had eventually spread to the basal ganglia [5], resulting in
clinical features of Parkinsonism (i.e., neither ET-PD or PD but a
subtype of ET).
Finally, we would like to end with a minor quibble. In an otherwise
interesting and thought provoking paper the authors have concluded that
asymmetric postural tremor may predict PD. While the authors clearly have
shown that some patients with postural tremor go on to develop PD, their
study design does not lend itself to the conclusion that asymmetric
postural tremor predicts the development of PD. To determine risk (i.e., A
“is likely to predict” B), one would have to start with a cohort with
asymmetric postural tremor to see how many developed PD over time,
comparing them to a cohort without this type of postural tremor. Future
research using a prospective cohort of patients with tremor is indicated
to confirm this clinical observation.
References
(1). Chaudhuri KR, Buxton-Thomas M, Dhawan V, Peng R, Meilak C, Brooks
DJ. Long duration asymmetrical postural tremor is likely to predict
development of Parkinson’s disease and not essential tremor: clinical
follow up study of 13 cases. J Neurol Neurosurg Psychiatry 2005;76:115-
117.
(2). Louis ED, Wendt KJ, Pullman SL, Ford B. Is essential tremor
symmetric? Observational data from a community-based study of essential
tremor. Arch Neurol 1998;55:1553-1559.
(3). Louis ED. Essential tremor. The Lancet Neurology (In Press).
(4). Louis ED, Honig LS, Vonsattel JPG, Maraganore DM, Borden S,
Moskowitz CB. Essential tremor associated with focal non-nigral Lewy
bodies: A clinical-pathological study. Arch Neurol (In Press).
(5). Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest tremor in
essential tremor patients: Prevalence, clinical correlates, and
electrophysiological characteristics. Arch Neurol 2003;60:405-410.
Dear Editor,
Nagayama and colleagues report on the greatest number of patients with Parkinsonian syndromes undergoing MIBG scintigraphy sofar. They calculated a sensitivity of 87.7% and a specificity of 37.4% to correctly detect 122 patients with idiopathic Parkinson´s disease (PD) in relation to patients with MSA (n=14), dementia of Lewy body type (DLB) (5), PSP (7), senile dementia of Alzheimer type (SDAT) (...
Dear Editor,
The ultimate aims and objectives of the neurologist immersed in clinical work are no different from those of the academic: put simply, we all like to understand why we make certain management decisions, investigative or therapeutic, and yearn for scientific validity and logical defensibility of our medical or surgical practices and procedures. By placing great emphasis on nosologic sophistication in...
Dear Editor,
I read with interest the article by Nedeltchev et al. [1]. Using their standard protocol, thrombophilia screen only managed to identify 2 patients with Factor V Leiden deficiency and 1 patient with Protein C deficiency. Thrombophilia is well known to cause venous thrombosis but only very rarely associated with arterial occlusive disease in adulthood. In contrast, thrombophilia is significant...
Dear Editor,
Donnet, Valade and Régis did not find gamma knife radiosurgery clinically useful in the intermediate or long-term management of patients with severe cluster headache (CH) refractory to other therapies; intriguingly, immediate / short-term results are dramatic and definitely encouraging but rather unpredictable. [1] The disconnect between these two set of results remains unexplained but may hold the vi...
Dear Editor,
We read with interest the article “Wilson’s disease: diagnostic errors and clinical implications”, written by Prasanth et al, in your journal, 2004;75:907-909. [1]
We would like to thank the authors for bringing to light the difficulties in diagnosing Wilson’s disease (WD) and the protean manifestations that often masquerade as other diseases in India. We would like to share our expe...
Dear Editor,
Eriksen, Thomsen and Olesen present data underpinning the new criteria for migraine with aura (MA) in the International Headache Society -2 Classification. The research as well as clinical utility of being able to delineate a more homogeneous sample of MA patients or the evolution of a system that can be used at different levels of specialisation is debatable. At the research level, increasing nosolog...
Dear Editor,
Artero and colleagues detected a patterned non-random distribution of white matter lesions (WML) in the aging brain associated with symptoms and suggest progression of lesions from frontal through parietal to temporal and occipital regions.
Since blood pressure is an established risk factor for the presence and severity of WML, the rheological state of the brain circulation appears to be the...
Dear Editor,
While Pearce analyses the paper of Furman, Balaban, Jacob, and Marcus [1] with precision [2] insofar as migraine is concerned no suffix carries any pathophysiological import or diminishes the mystery of migraine. With both migraine [3] and dizziness having been around since antiquity, restraint is the key watchword that determines - or should determine - use of the term ‘new’ in describing any migraine...
Dear Editor,
It is my hypothesis (1985) that Alzheimer's disease results from low DHEA. This has since been supported. HRT reduces DHEA production (Metabolism. 2001 Apr;50(4):488-93). This may be why HRT has recently been found to increase the onset of Alzheimer's disease. I suggest the past support of positive effects of HRT are due to a stimulus of DHEA production followed by loss of DHEA production with...
Dear Editor,
We read with interest the paper of Chaudhuri et al. [1] on long duration asymmetrical postural tremor. Like all thought-provoking research, the paper raises many questions that lend themselves to further research and thought.
The issue of the relationship between ET and parkinsonism is complicated and this study underscores the need for further longitudinal research to clarify dise...
Pages