I wish to draw your attention to the effect that the title is erroneous. The condition discussed is ONE AND HALF syndrome and not HALF AND HALF syndrome as proposed by the authors. There is no information in the published literature of existence of a condition called Half and Half syndrome. We are currently in process of submitting an interesting case of ONE and HALF SYNDROME and its response to intavenous immunoglobulins at our S...
I wish to draw your attention to the effect that the title is erroneous. The condition discussed is ONE AND HALF syndrome and not HALF AND HALF syndrome as proposed by the authors. There is no information in the published literature of existence of a condition called Half and Half syndrome. We are currently in process of submitting an interesting case of ONE and HALF SYNDROME and its response to intavenous immunoglobulins at our Stroke Unit at Royal Shrewsbury Hospital. The clinical features of our case are almost identical to the case submitted by Randhawa, Shah et al. and it was diagnosed ONE AND HALF SYNDROME.
It was with great interest that we read the article published in the
Journal where rituximab was successfully used to treat myasthenia gravis
refractory cases (1). Here, we describe a case where the drug was
administered in a difficult-to treat-myasthenic crisis. A 65-year-old
woman who suffered from myasthenia gravis since 2006 was admitted to the
intensive care unit (ICU) in severe respiratory distress. The patient was...
It was with great interest that we read the article published in the
Journal where rituximab was successfully used to treat myasthenia gravis
refractory cases (1). Here, we describe a case where the drug was
administered in a difficult-to treat-myasthenic crisis. A 65-year-old
woman who suffered from myasthenia gravis since 2006 was admitted to the
intensive care unit (ICU) in severe respiratory distress. The patient was
well until two weeks before admission, when she was vaccinated against
influenza H1N1. Seven days later, progressive muscle weakness developed
and the patient searched for medical assistance in an emergency situation.
Until then, the disease was well-controlled with pyridostigmine 60 mg qid.
The patient had a previous 40-day ICU admission two months before also due
to a myasthenic crisis triggered at that time by a perforated and infected
cholecystitis, which improved after colecistectomy and resolution of the
infectious process. The disease was positive for anti-acetylcoline
receptor antibodies (titles not available). On admission, orotracheal
intubation and mechanical ventilation were needed. Hydrocortisone (100 mg
IV tid) and neostygmine (0.06 mg/kg/hour under continuous IV infusion)
were started. After two weeks, no improvement on muscle strenght was
observed and the patient remained on mechanical ventilation. Based on
recent literature findings (1) and after a husband's informed consent was
obtained, weekly infusions of rituximab (375 mg per square meter of body
surface) was started. Right before the third infusion, global muscle
strength improvement was observed, allowing weaning from the mechanical
ventilation. One day after the third infusion, the patient was discharged
from the ICU. Rituximab is a chimeric monoclonal antibody against CD20 B-
lymphocytes. It is FDA-approved for the treatment of Hodgkin's lymphoma
and rheumatoid arthritis, but a growing body of evidence supports its use
in several auto-immune diseases where humoral immunity plays a pivotal
role, such as systemic lupus erythematosus and Sjogren syndrome (2).
Recent evidence reveals promissing results for rituximab in refractory
cases of myasthenia gravis. Here, the administration of the drug in an ICU
setting was safe and effective, as previosly reported by Sadnicka and
colleagues (3). Further studies are warranted in order to establish
rituximab as a therapeutic alternative also for severe cases of myasthenic
crisis.
1.Maddison P, McConville J, Farrugia ME et al. The use of rituximab
in myasthenia gravis and Lambert-Eaton myasthenic syndrome. J Neurol
Neurosurg Psychiatry 2010 (Epub ahead of print).
2.Furst DE, Keystone EC, Fleischmann R et al. Updated consensus
statement on biological agents for the treatment of rheumatic diseases,
2009. Ann Rheum Dis 2010;69 Suppl 1:i2-29.
3.Sadnicka A, Reillt MM, Mummery C et al. Rituximab in the treatment
of three coexistent neurological autoimmune diseases: chronic inflammatory
demyelinating polyradiculoneuropathy, Morvan syndrome and myasthenia
gravis. J Neurol Neurosurg Psychiatry 2010 (Epub ahead of print).
Novel descriptions of methodologies , tools and diagnostic devices
have emeerged in the context of diagnosis / treatment of Freezing of gait
( FOG ) in parkinson 's disease.
defined as a sudeen and unpredictable mechanism with the patient ' glued '
to the floor or altered step frorward , which onset may be conditioned by
turning , step initiation , esternal stimuli or spatial constratint . A
plenty of observation tools h...
Novel descriptions of methodologies , tools and diagnostic devices
have emeerged in the context of diagnosis / treatment of Freezing of gait
( FOG ) in parkinson 's disease.
defined as a sudeen and unpredictable mechanism with the patient ' glued '
to the floor or altered step frorward , which onset may be conditioned by
turning , step initiation , esternal stimuli or spatial constratint . A
plenty of observation tools have been studied , considering technologies
in order to elicit and generate FOG-mechanisms.
Current diagnostic methods employed in FOG descriptives include motorized
treadmill with specific paradigms , with periods between obstacle release
until the obstacle left the treadmill ( obstacle avoidance ) or ' baseline
treadmill walking '( obstacle leaving the treadmill until latent strides )
Nowadays subjects samples , show , in Movement Disorders Clinics an
overall proportion of freezers around 60-70 % with long distance
conditions and turning , but with absence of correspondence between
overgroung FOG episodes between freezers with or without FOG on the
treadmill.
Previous results show highly significative linear correlation coefficients
( r= 0.94-0.98 ) between ambulatory gait monitors with pressure-sensitive
walkways.
A positive linear correlation would be obtained in step time , with nearly
fitted results in the rest of parameters.
Thus , briefly , we could say that external rhythms ( mainly based on time
cues ) would origin a motor paardigm , added to spatial hillmarks , as it
is observed in synthetic aperture magnetometry ( SAM ) results.
References
-Buma F.External cueing and activity in the Parkinson brain :
development of a motor paardigm.Park & realted disorders.2007 ; 52:
Vol 13
-Snijders A ; Weerdesteyn V , Hagen Y , Duysens J , Giladi N , Bloem B .
Obstacle avoidance to Elicit Freezing of Gait during Treadmill Walking .
Mov Disord 2010 ; 25 : 57-63
- Boonstra T , van der Kooij H , Munneke M , Bloem B. Gait disorders and
balance disturbances in PD : Clinical update and patophysiology . Curr
Opin Neurol 2008 ; 21 : 461-471
I have read with the greatest interest the large investigation on the
mutated superoxide dismutase (SOD) frequency in the Dutch amyotrophic
lateral sclerosis patients (1). The results seem to show that is very rare
in the Netherlands, or it may be only an epiphenomenon from the point of
view of the disease pathogenesis.
This conclusion could be reconciled with the circumstance that a
large...
I have read with the greatest interest the large investigation on the
mutated superoxide dismutase (SOD) frequency in the Dutch amyotrophic
lateral sclerosis patients (1). The results seem to show that is very rare
in the Netherlands, or it may be only an epiphenomenon from the point of
view of the disease pathogenesis.
This conclusion could be reconciled with the circumstance that a
large part of brain SOD is due to the enzyme activity in glia (2).
Increased brain SOD has been induced in rats by chlorophenols contaminated
with TCDD (3).
Furthermore, a peculiar protein species has been detected in the
myelin fraction isolated from patients (4). Its characteristics do not
correspond to those of SOD.
1 van Es, MA, Dahlberg C, Veldink JH, et al. Large-scale SOD 1
mutation screening provides evidence for genetic heterogeneity in
amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2010; 81: 562
-566.
2 Savolainen H. Superoxide dismutase and glutathione peroxidase
activities in rat brain. Res Commun Chem Pathol Pharmacol 1978; 21: 173-
176.
3 Savolainen H, Pekari K. Neurochemical effects of peroral
administration of technical pentachlorophenol. Res Commun Chem Pathol
Pharmacol 1979; 23: 97-105
4 Palo J, Savolainen H, Kivalo E. Comparison between the proteins of
human brain myelin in subacute sclerosing panencephalitis, amyotrophic
lateral sclerosis and malignant diseases. J Neurol Sci 1973; 18: 175-181
Vestibular paroxysmia has been defined classically by series of
rotational to-and-fro vertigo, precipitated or modulated by head
position.Then , descriptional basis of the clinical picture may be
disclosed if vertigo may be associated to hipoacusis and tinitus or not.
In the case of pure tinnitus description , the loud / low pitch
sound of the tinnitus may be defined as paroxysmal tinnitus.
Ethilogical purposes...
Vestibular paroxysmia has been defined classically by series of
rotational to-and-fro vertigo, precipitated or modulated by head
position.Then , descriptional basis of the clinical picture may be
disclosed if vertigo may be associated to hipoacusis and tinitus or not.
In the case of pure tinnitus description , the loud / low pitch
sound of the tinnitus may be defined as paroxysmal tinnitus.
Ethilogical purposes have been described considering neurovascular
compression : a vascular compression of the eight cranial nerve , defined
in up to 65 % of samples ( vascualr loops in the internal auditory canal )
. Mechanisms have been proposed , such as ectopic discharges / conduction
block ( vestibular hypofunction / excitation ).
Recent findings enhance the role of amygdalohippocampal , cochlear and
temporal cortex in tinnitus pathogenesis .What should be discerned is the
concurrent importance of ephaptic transmission in a solely description /
plus or not central mechanisms derived of such condition.
References:
-Strupp M et al. Acute vestibulopathy. Curr Opin neurol 2001 ; 14: 11-20.
We read with interest the article written by de Seze et al(de Seze,
Blanc et al. 2010), published on the April 2010 issue of the Journal of
Neurology, Neurosurgery and Psychiatry. The authors describe a transversal
investigational research comparing magnetic resonance spectroscopy (MRS)
of NAWM and NAGM of 24 patients with NMO, 46% of whom had brain
abnormalities, and 12 healthy subjects. In this st...
We read with interest the article written by de Seze et al(de Seze,
Blanc et al. 2010), published on the April 2010 issue of the Journal of
Neurology, Neurosurgery and Psychiatry. The authors describe a transversal
investigational research comparing magnetic resonance spectroscopy (MRS)
of NAWM and NAGM of 24 patients with NMO, 46% of whom had brain
abnormalities, and 12 healthy subjects. In this study, the authors found
no difference on Naa/Cr of NAWM and NAGM in patients with NMO comparing to
healthy controls, an information that corroborates the idea that there is
no silent and continuous degenerative process in the SNC tissues of
patients with NMO(Wingerchuk, Pittock et al. 2007).
The authors state that they had no previous knowledge of MRS studies
on NMO, so we would like to share our experience evaluating the NAWM of 16
patients with NMO and 16 age matched healthy control subjects. We
described similar results, i.e., there was no difference in NAWM of
patients and healthy volunteers(Bichuetti, Rivero et al. 2008). We also
included patients with brain abnormalities and cautiously positioned the
voxel away from brain lesions to avoid changes in the metabolic pattern of
the spectrum in this region. We further evaluated 41 patients with
relapsing NMO in order to clarify if the brain abnormalities seen on
recent studies(Pittock, Lennon et al. 2006; Bichuetti, Rivero et al. 2008)
correlate with a worse prognosis, and found that there is no different on
annualized relapse rate and progression index between patients with or
without brain abnormalities, in our cohort.(Bichuetti, Oliveira et al.
2009). We were not able to evaluate the impact of NMO-IgG positivity in
our cohort since the test was not available in Brazil during the period we
conducted the study.
We congratulate de Seze et al for their very interesting work and
would like to encourage them and other investigators to look for their
clinical data in order to search for clinical marker of disease severity,
as well as MRI/clinical correlations.
Aboul-Enein, F., M. Krssak, et al. (2010). "Diffuse white matter
damage is absent in neuromyelitis optica." AJNR Am J Neuroradiol 31(1): 76
-79.
Bichuetti, D., E. Oliveira, et al. (2009). "Neuromyelitis optica in
Brazil: a study on clinical and prognostic factors." Mult Scler 15(5): 613
-619.
Bichuetti, D. B., R. L. Rivero, et al. (2008). "White matter
spectroscopy in neuromyelitis optica: a case control study." J Neurol
255(12): 1895-1899.
Bichuetti, D. B., R. L. Rivero, et al. (2008). "Neuromyelitis optica:
brain abnormalities in a Brazilian cohort." Arq Neuropsiquiatr 66(1): 1-4.
de Seze, J., F. Blanc, et al. (2010). "Magnetic resonance
spectroscopy evaluation in patients with neuromyelitis optica." J Neurol
Neurosurg Psychiatry 81(4): 409-411.
Pittock, S. J., V. A. Lennon, et al. (2006). "Brain abnormalities in
neuromyelitis optica." Arch Neurol 63(3): 390-396.
Wingerchuk, D. M., S. J. Pittock, et al. (2007). "A secondary
progressive clinical course is uncommon in neuromyelitis optica."
Neurology 68(8): 603-605.
I thank Dr. Civardi and his group, who have demonstrated a large
experience with the practical use of Motor Evoked Potentials, for their
interest in our article describing a patient with presumed psychogenic
left hemiparalysis and abnormal transcranial magnetic stimulation (TMS)
(1). Our initial aim in performing TMS to our patient was exactly to prove
that MEPs were normal, as suggested by other authors (including Dr.
C...
I thank Dr. Civardi and his group, who have demonstrated a large
experience with the practical use of Motor Evoked Potentials, for their
interest in our article describing a patient with presumed psychogenic
left hemiparalysis and abnormal transcranial magnetic stimulation (TMS)
(1). Our initial aim in performing TMS to our patient was exactly to prove
that MEPs were normal, as suggested by other authors (including Dr.
Civardi and coworkers). However, in our patient, there was a non-
significant difference between left and right hemisphere MEP amplitudes,
but the cortico-motor threshold was 170% higher in the right hemisphere.
The similar F-waves size between sides excluded a difference in lower
motor neuron excitability. These changes reverted after the patient has
recovered and the diagnosis of conversive disorder has been explained. Dr.
Civardi refers to an important retrospective study on TMS in psychogenic
paralysis, since it shows that normal TMS can reassure the neurologist
regarding the absence of a structural CNS dysfunction (2). In this work a
single evaluation was made in 21 patients, 15 of which had a
unilateral/asymmetric paralysis. From this group only 9 patients had the
final diagnosis of conversive disorder. Although Dr. Civardi states, in
his letter, that no differences between hemispheres were found, this is
not reported in the referred paper (only mean values are shown).
By the time of our report, only a few papers addressed changes on MEPs
related to immobilization and reports on voluntary inhibition of movement
mainly analysed the ability to inhibit prepared movements and did not
specifically analysed MEP thresholds (3,4). As previously stated,
conclusions from a single case should be cautious; especially when we now
know that cognitive processes such as motor imagering may influence the
results (5). Studies making comparisons between normal controls and
patients with conversive paresis should clearly state controls test
conditions (was there an indication to be quiet, to think of movement and
inhibiting it, etc), otherwise subtle differences may be neglected. We
recently had another patient with conversive hemiparesis in whom the
affected hemisphere showed a strikingly increased cortico-motor threshold
in the involved hemisphere. This fact may be conflicting with the existing
literature, however it fits with the functional imaging data, and should
be further investigated, namely with well defined task protocols.
1. Geraldes R, Coelho M, Rosa MM, Severino L, Castro J, de Carvalho
M. Abnormal transcranial magnetic stimulation in a patient with presumed
psychogenic paralysis. JNNP; 2008; 79:1412-1413
2. Cantello R, Boccagni C, Civardi C, Monaco F. Diagnosis of psychogenic
paralysis: the role of motor evoked potentials. J Neurol; 2001; 248:889-
897
3. Crews RT, Kamen G. Motor-evoked potentials following imagery and limb
disuse. Int J Neurosci.2006;116(5):639-513.
4. Cocon JP, Stinear CM, Byblow WD. Intracortical inhibition during
volitional inhibition of prepared action. J Neurophysiol. 2006; 95(6):3371
-83
5. Liepert J, Hassa T, Tuscher O, Schmidt R. Abnormal motor
excitability in patients with psychogenic paresis. A TMS study. J Neurol.
2009; 256(1):121-6.
Metabolic Syndrome and Alzheimer's Disease:
Contrasting Epidemiological Evidence and Possible Underlying Mechanisms
We thank Giannopoulos and colleagues for their interesting Letter. At
present, cumulative evidence suggested that metabolic syndrome (MetS), a
constellation of interrelated metabolic derangements increasing the risk
of cerebrovascular disease (CVD) and diabetes, has been shown to be
in...
Metabolic Syndrome and Alzheimer's Disease:
Contrasting Epidemiological Evidence and Possible Underlying Mechanisms
We thank Giannopoulos and colleagues for their interesting Letter. At
present, cumulative evidence suggested that metabolic syndrome (MetS), a
constellation of interrelated metabolic derangements increasing the risk
of cerebrovascular disease (CVD) and diabetes, has been shown to be
independently associated with predementia and dementia syndromes. In
particular, MetS appeared to increase the risk for age-related cognitive
decline (ARCD), while for mild cognitive impairment (MCI) and its
progression to dementia the findings were too limited to draw any
conclusion [1-3]. Furthermore, several studies suggested that MetS may be
linked to the risk of developing dementia and VaD [4-7], while contrasting
findings existed of the possible role of MetS in developing AD [5-10].
Several individual components of MetS have been linked to risk of
developing dementia and cognitive impairment. Among the five MetS
components, hyperglycemia, lower high density lipoprotein (HDL) levels,
and elevated triglyceride levels were the components with increased risk
for predementia syndromes. Furthermore, hypertriglyceridemia was the
component with increased risk of dementia syndromes, particularly VaD [6].
However, the suggested association between MetS and AD was not
confirmed by four large longitudinal and population-based studies, the
Honolulu-Asia Aging Study , the Three-City Study, the Italian Longitudinal
Study on Aging, and the cohort of Medicare recipients residing in northern
Manhattan, in which no association between MetS and AD was found [5-8].
These results did not support those from population-based and case-control
studies in which MetS appeared to increase the risk of AD [9, 10].
However, the Kuopio Study was only cross-sectional and, consequently,
cannot address the question of whether MetS predicts AD [9], while the
case-control study demonstrated a link between MetS and AD, but important
limitations were the relatively small sample and the design of the study
[10]. In fact, it was not possible to distinguish between those factors
that may precede the development of AD and have a causal role and those
factors that may have been altered as a consequence of the disease. There
was also a selection bias because AD patients were selected from memory
clinics; therefore, there could be a spurious identification of risk
factors associated with clinic attendance rather than the disease itself
[10].
Notwithstanding the association between MetS an AD should be confirmed in
other larger studies with longer follow-up periods, we are completely
agree with Giannopoulos and colleagues on the growing evidence of a series
of underlying mechanisms related to this suggested association. These
suggestions proposed in a particular group of patients the presence of a "metabolic-cognitive
syndrome", i.e. a MetS plus cognitive
impairment of degenerative or vascular origin. This could represent a
pathophysiological model in which to study in depth the mechanisms linking
MetS and MetS components with dementia, particularly AD, and predementia
syndromes (ARCD or MCI), suggesting a possible integrating view of the
MetS components and their influence on cognitive decline. The potential
mechanisms linking the continuum of obesity, hyperinsulinemia,
hypertension, hyperlipidemia, and type 2 diabetes mellitus are multiple,
overlapping, and highly correlated. Therefore, it has been suggested a
role of these factors in the development of cognitive decline and
dementia, including underlying mechanisms, supporting their influence on ß-amyloid (A ß) peptide
metabolism and tau protein hyperphosphorylation, the principal
neuropathological hallmarks of AD. For example, recent work reveals that
leptin may be linked to AD through modulation of
A ß production and clearance [11]. Leptin was
found to reduce production of A ß, apparently through a reduction in ß-secretas activity, as well as to increase apolipoprotein E (APOE)-mediated clearance of Aß fibrils.
Recently, findings from the Health ABC study confirmed the neuroprotective role of leptin levels in the elderly individuals, against cognitive
decline, but also suggested that leptin resistance may play a role in the cognitive impairment [12]. Moreover, once established a leptin resistance
status, this influenced negatively not only cognitive performances but
also the metabolic response. In fact, leptin has been shown to have an
antidiabetic function through control of intracellular fatty acid
metabolism, maintenance of glucose sensitivity, and prevention of islet
lipotoxicity [13]. This double action of leptin on cognitive performances
and metabolism suggested not only the link but also the complexity of
mechanisms subtending to a metabolic-cognitive syndrome.
Furthermore, among MetS components, peripheral insulin resistance could be
the primary pathophysiological mechanism of MetS, although the definitions
of MetS and its components do not include any reference to insulin
resistance or hyperinsulinemia. In AD, an age-related desynchronization of
biological systems may result, involving cortisol and noradrenaline axes
associated with stress components, reactive oxygen species, and membrane
damage, and causing an insulin resistant brain state with decreased
glucose/energy metabolism and the increased formation of
hyperphosphorylated tau protein and A ß[14]. These interactive effects may provide clues to shared etiologies among metabolic
disorders [15]. For example, weight loss through lifestyle interventions
or medications may alter adipokine activity, improve hyperinsulinemia,
inflammation, glucose tolerance, blood pressure, lipids, and the risk of
CVD. Considerable interest has also arisen regarding the effects of
lifestyle interventions such as exercise and dietary/nutraceutical
manipulations. Pharmacological interventions currently under study include
statins, antihypertensive therapies, and insulin-sensitizing drugs. If
MetS and its components are associated with increased risk of developing
cognitive impairment, then early identification and treatment of these
individuals might offer avenues for disease course modification.
References
1. Roberts RO, Geda YE, Knopman DS, et al. Metabolic syndrome,
inflammation, and nonamnestic mild cognitive impairment in older persons:
a population-based study. Alzheimer Dis Assoc Disord 2009; [post author
corrections] DOI: 10.1097/WAD.0b013e3181a4485c.
2. Solfrizzi V, Scafato E, Capurso C, et al; Italian Longitudinal Study on
Aging Working Group Metabolic syndrome, mild cognitive impairment, and
progression to dementia. The Italian Longitudinal Study on Aging.
Neurobiol Aging 2009; [Epub ahead of print]
DOI:10.1016/j.neurobiolaging.2009.12.012.
3. Yaffe K, Weston AL, Blackwell T, Krueger KA The metabolic syndrome and
development of cognitive impairment among older women. Arch Neurol 66: 324
-328 (2009).
4. Roriz-Cruz M, Rosset I, Wada T, et al. Cognitive impairment and frontal
-subcortical geriatric syndrome are associated with metabolic syndrome in
a stroke-free population. Neurobiol Aging 2007;28:1723-36.
5. Kalmijn S, Foley D, White L, et al. Metabolic cardiovascular syndrome
and risk of dementia in Japanese-American elderly men: the Honolulu-Asia
aging study. Arterioscler Thromb Vasc Biol
2000;20:2255-60.
6. Raffaitin C, Gin H, Empana JP, et al. Metabolic syndrome and risk for
incident Alzheimer's disease or vascular dementia: the Three-City Study.
Diabetes Care 2009;32:169-74.
7. Solfrizzi V, Scafato E, Capurso C, et al.; Italian Longitudinal Study
on Aging Working Group. Metabolic syndrome and the risk of vascular
dementia. The Italian Longitudinal Study on Aging. J Neurol Neurosurg.
Psychiatry 2009; [Epub ahead of print] DOI: 10.1136/jnnp.2009.181743.
8. Muller M, Tang MX, Schupf N, et al. Metabolic syndrome and dementia
risk in a multiethnic elderly cohort. Dement Geriatr Cogn Disord
2007;24:185-92.
9. Vanhanen M, Koivisto K, Moilanen L, et al. Association of metabolic
syndrome with Alzheimer disease: a population-based study. Neurology
2006;67:843-47.
10. Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and
Alzheimer disease. Arch Neurol 2007;64:93-6.
11. Fewlass DC, Noboa K, Pi-Sunyer FX, ey al. Obesity-related leptin
regulates Alzeimer's Abeta. FASEB J
2004;18:1870-8.
12. Holden KF, Lindquist K, Tylavsky FA, et al; Health ABC study. Serum
leptin level and cognition in the elderly: Findings from the Health ABC
Study. Neurobiol Aging 2009;30:1483-9.
13. Shimabukuro M, Koyama K, Chen G, et al. Direct antidiabetic effect of
leptin through triglyceride depletion of tissues. Proc Natl Acad Sci USA
1997;94:4637-4641.
14. Salkovic-Petrisica M, Osmanovica J, Grunblattb E, et al. Insulin
resistant brain state generates multiple long-term morphobiological
abnormalities including hyperphosphorylated tau protein and amyloid- ß. J Alzheimer Dis 2009;18:729-50.
15. Craft S. The role of metabolic disorders in Alzheimer disease and
vascular dementia: two roads converged. Arch Neurol 2009;66:300-5.
We wish to thank Dr. Morrish for his comments to our review. He argues in his letter that for diagnostic purposes a technique needs to be sensitive to the disease and reproducible and that DAT-SPECT unfortunately falls down on each. Sensitivity is poor, he says, since DAT-SPECT imaging has been found to be normal in about 5 to 15% of individuals with parkinsonism. Such individuals ( SWEDDs ("scans without evidence of dopaminergic...
We wish to thank Dr. Morrish for his comments to our review. He argues in his letter that for diagnostic purposes a technique needs to be sensitive to the disease and reproducible and that DAT-SPECT unfortunately falls down on each. Sensitivity is poor, he says, since DAT-SPECT imaging has been found to be normal in about 5 to 15% of individuals with parkinsonism. Such individuals ( SWEDDs ("scans without evidence of dopaminergic dysfunction") or false negatives scans), he believes, exist not because of failure of diagnosis but because of failure in the technique. These false negative cases may well have Parkinson`s disease (PD) , probably tremor dominant forms that have less abnormality in DAT-SPECT imaging. However, we maintain that available information strongly suggests that most if not all SWEDDs in fact do not have involvement of the nigrostriatal pathway and do not suffer from PD. Poor response to levodopa and lack of progression on sequential dopaminergic imaging (1), indicate that PD is an unlikely diagnosis in most cases of SWEDDs . Furthermore, withdrawal of anti-parkinsonian drug therapy in patients with parkinsonism with normal FP-CIT SPECT without any deleterious effects would not be possible in individuals with true PD, tremor dominant or not.(2) Support for this interpretation also comes from a recent study by Schwingenschuh et al. who has shown that SWEDDs share electrophysiological characteristics similar to patients with segmental dystonia and can clearly be separated from patients with PD and from patients with essential tremor.(3) We believe that the bulk of evidence suggests that the issue with the "false negative" cases (SWEDDs) is not a problem of sensitivity of the DAT-SPECT but rather an issue of an alternative diagnosis. We agree with Morrish that neuropathological studies of SWEDDs cases are needed to clarify this issue.
Morrish also feels DAT-SPECT falls down on reproducibility since in his opinion the result of a scan can vary by 40% from day to day (4), an issue he has previously highlighted in a letter to the JNNP in 2003.(5) The study by Booij et al (6) analyzing variability of [123I] FP-CIT SPECT showed an absolute variability of 7.25 ± 3.22% (ROI method) and 7.47 ± 6.35% (VOI method) in normal volunteers and 7.90 ± 6.89% (ROI method) and 7.36 ± 6.16% (VOI method) in PD patients . The use by Morrish of absolute means may not be appropriate way to calculate the range of variability . In contrast the above mentioned study by Booij et al reported a high test-retest reliability with FP-CIT (intraclass correlation coefficient close to 1) which indicates that with some tracers reproducibility is adequate for diagnostic use and potentially for disease progression studies, where the major issue is the demonstration of sensitivity to clinical change.
Morrish also refers to an earlier study in patients with clinically uncertain parkinsonism in which 6 scans changed over a period of 2 years.(7) As discussed in the paper, the changes in visual assessment were the result of over-interpretation of the images in a small subgroup of patients in whom a mismatch occurred between visual evaluation of the DAT-SPECT and the clinical diagnosis. When independent investigators were asked to read those images there was total consensus about that the images were normal and the same reading was obtained at 2 years follow up. The problem was not reproducibility but over-interpretation in a study done in an unusual subset of individuals with uncertain parkinsonism. We agree with Dr. Morrish that all efforts should be made to reduce variability of DAT SPECT imaging if this technique has to be used successfully in longitudinal studies of disease progression or neuroprotection and that these studies have to take into account variations due to the technique when decisions are taken about endpoints and sample size calculation (8)
Morrish indicates that DAT-SPECT has been validated as a screen for persons at risk of developing PD. While recent evidence shows that DAT-SPECT abnormalities can antedate the development of parkinsonism we do not know the predictive value of positive results in a normal population or even in a population at high risk for PD such as non manifesting carriers of genetic mutation causing autosomal dominant PD and therefore we reaffirm our opinion that DAT-SPECT has indeed not been validated yet as a useful premotor marker of PD.(9)
Morrish mentions in his letter that we write that "its (DAT-SPECT) use in longitudinal monitoring has not been considered; in 2002 a large US review group did just that". We wrote that "DAT-SPECT has also been used as a potential biomarker for disease progression in PD and has shown a progressive decline of striatal DAT binding with increasing disease duration of PD and with increasing disease severity also in agreement with [18F]dopa PET studies." Our statement is in line with the comments of the review of Ravina et al (10) quoted by Morrish in which the authors indicate, referring to studies using F-dopa PET and beta CIT SPECT, that "Natural history studies for each radiotracer have had small sample sizes, but the results are consistent. This suggests that these tracers measure biologic processes that are related to the duration and severity of PD as measured by motor rating scales in the practically defined "off" state". Whether the extra information obtained from these studies may not have justified the radiation exposure of so many patients on two or more occasions, as he states in his letter, is a difficult statement to support. These studies, like the ones he and others have conducted in the past which involve radiation exposure have been performed with the hopes that the information would indeed outweigh the possible risks of this technique.
We obviously agree with Morrish that a good clinician may prefer, instead of ordering a DAT-SPECT, to rely on their own judgment and the fullness of time. However, as it often happens, in the appropriate cases good clinicians may decide that ordering a DAT-SPECT may be a better course to follow than waiting that time may provide clarification of a diagnosis.
Finally Dr Morrish indicates that one of us (ET) did not declare as a conflict of interest in our Review being the principal investigator of a large study on DAT SPECT in parkinsonism 7 funded by GE Healthcare. I want to thank him for bringing this to my and the readership attention and for giving me the opportunity of declaring this now (see below Disclosure).
Reference List
1 Marek K, Jennings DL, Seibyl JP. Long-Term Follow-Up of Patients with Scans
without Evidence of Dopaminergic Deficit (SWEDD) in the ELLDOPA Study.
Neurology64 (Suppl 1):(Abstract).
2 Marshall VL, Patterson J, Hadley DM, Grosset KA, Grosset DG. Successful
antiparkinsonian medication withdrawal in patients with Parkinsonism and normal
FP-CIT SPECT. Mov Disord. 2006;21:2247-50.
3 Schwingenschuh P, Ruge D, Edwards MJ, Terranova C, Katschnig P, Carrillo F, Silveira-
Moriyama L, Schneider SA, Kagi G, Palomar FJ, Talelli P, Dickson J, Lees AJ, Quinn N,
Mir P, Rothwell JC, Bhatia KP. Distinguishing SWEDDs patients with asymmetric resting
tremor from Parkinson's disease: A clinical and electrophysiological study. Mov Disord.
DOI 10.1002/mds.23019 2010.4.
4 Morrish P. Controversies in Neuroimaging. Parkinson's disease: Diagnosis and
Clinical Management 2nd edition. 2008,Eds Factor and Weiner. Demos Publishing.
28;317-326.
5 . Morrish PK. The harsh realities facing the use of SPECT imaging in monitoring disease
progression in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003;74:1447
6 Booij J, Habraken JB, Bergmans P, Tissingh G, Winogrodzka A, Wolters EC, Janssen AG,Stoof JC, van Royen EA. Imaging of dopamine transporters with iodine-123-FP-CIT SPECT in healthy controls and patients with Parkinson's disease. J Nucl.Med 1998;39:1879-84.
7. Tolosa E, Borght TV, Moreno E. Accuracy of DaTSCAN (123I-Ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2-year follow-up of an open-label study. Mov Disord. 2007;22:2346-51.
8. Winogrodzka A, Bergmans P, Booij J, van Royen EA, Janssen AG, Wolters EC. [123I]FP- CIT SPECT is a useful method to monitor the rate of dopaminergic degeneration in early- stage Parkinson's disease. J Neural Transm 2001; 108(8-9):1011-1019.
9 Tolosa E, Gaig C, Santamaria J, Compta Y. Diagnosis and the premotor phase of Parkinson disease . Neurology 2009;72 (suppl 2) :S12-S20.
10 Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M, Dhawan V, Feigin A,
Fahn S, Guttman M, Gwinn-Hardy K, McFarland H, Innis R, Katz RG, Kieburtz K, Kish
SJ, Lange N, Langston JW, Marek K, Morin L, Moy C, Murphy D, Oertel WH, Oliver G,
Palesch Y, Powers W, Seibyl J, Sethi KD, Shults CW, Sheehy P, Stoessl AJ, Holloway R .
The role of radiotracer imaging in Parkinson's disease. Neurology 2005; 64(2) 208-15.
Conflict of Interest:
Eduardo Tolosa was the principal investigator on an international trial on the value of DaTSCAN SPECT in parkinsonism 7 . For this he received no personal compensation. He has in the past received honoraria for lecturing in symposia on imaging in Parkinson disease sponsored by GE Healthcare
Kagi and colleagues (1) provide a review but not a critique of a
controversial technique. For a technique to have diagnostic utility it
needs sensitivity to the disease and reproducibility; DAT-SPECT
unfortunately falls down on each.
The review describes the test as around 100% sensitive as a diagnostic
tool in detecting PD. The authors conclude that the normal scans in 5-15%
of patients with de-novo PD are normal becau...
Kagi and colleagues (1) provide a review but not a critique of a
controversial technique. For a technique to have diagnostic utility it
needs sensitivity to the disease and reproducibility; DAT-SPECT
unfortunately falls down on each.
The review describes the test as around 100% sensitive as a diagnostic
tool in detecting PD. The authors conclude that the normal scans in 5-15%
of patients with de-novo PD are normal because
"some patients with dystonic tremor are
misdiagnosed as PD" rather than that the test
itself may not be perfect. The gold standard is not clinical opinion, DAT
scan or PET scan, but post mortem. It can be shown, from knowledge and
understanding of the technique's parameters
(2), that DAT-SPECT has both false negatives and false positives, the
predictive value of a result varying according to the composition of the
population being tested. We know that tremor-dominant patients may have
slow progression (3), and that their DAT-SPECT scan may be less abnormal
than the akinetic-rigid patient (4). Many of the
SWEDD's (though I prefer the term false-
negative) may be tremor-dominant and slowly progressing. Only a very long
time (not the one or two years quoted here) and a post-mortem will provide
the evidence that they do or do not have idiopathic
Parkinson's disease.
The authors do not consider the issue of reproducibility, a key problem in
DAT-SPECT (2). How useful is a technique in which a result can vary by
40% from day to day (2)? Some SWEDD's will
undoubtedly be due to technical error.
Tolosa has undermined the confidence in the technique that he expresses in
this review by an earlier publication (5). In 2007 he reported 6
"uncertain
parkinsonism" patients in whom the DAT-scan
changed between first and second scan, over a two year period. Five went
from abnormal to normal; presumably either the first scan was falsely
positive or the second scan was falsely negative. In the sixth patient
the scan changed from normal to abnormal; presumably, the first was a
false negative.
The authors write that DAT-SPECT has not been validated as a screen for
persons at risk of developing PD. It has, and its limitations
(particularly the low predictive value of positive results in a normal
population) mean that it will not be useful (2). They also write that its
use in longitudinal monitoring of disease progression has not been
considered; in 2002 a large US review group did just that (6). Despite
this, many SPECT progression studies have been carried out in
Parkinson's disease (eg CALM, ELLDOPA,CEP-
1347). The extra information that has been gained by this addition to
clinical progression studies may not have justified the radiation exposure
of so many patients on two or more occasions.
Despite my misgivings over the technique there may be one clinical
application. Falsely positive DAT-SPECT scans are relatively uncommon in
a de-novo Parkinsonian population (2) and so the scan, if reproducible,
could be helpful in distinguishing the organic from the non-organic. A
good clinician may instead prefer to rely on their own judgement and the
fullness of time.
Finally it should be noted that Dr Tolosa was chief investigator on a
large recent study (5) funded by GE Healthcare, a manufacturer of a DAT-
SPECT pharmaceutical agent. Its omission as a possible conflict of
interest may have been an oversight but, if not, it might have been better
for him to declare this so that the reader could make their own judgement.
1. Kagi G, Bhatia KP, Tolosa E . The role of DAT-SPECT in
movement disorders. J Neurol Neurosurg Psychiatry. 2010 Jan;81(1):5-12.
2. Morrish P. Controversies in Neuroimaging.
Parkinson's disease: Diagnosis and Clinical
Management 2nd edition. 2008,Eds Factor and Weiner. Demos Publishing.
28;317-326.
3. Hoehn MM, Yahr MD. Parkinsonism:onset, progression and mortality.
Neurology 1967, 17; 427-42.
4. Spiegel J, Hellwig D, Samnick S et al. Striatal FP-CIT uptake differs
in the subtypes of early Parkinson's disease.
J Neural Transm 2007, 114(3):331-5.
5. Tolosa E, Borght TV, Moreno E et al. Accuracy of DaTSCAN([123]I-
Ioflupane) SPECT in diagnosis of patients with clinically uncertain
parkinsonism: 2 year follow-up of an open label study. Mov Disord
2007;22:2346-51
6. Ravina B, Eidelberg D, Ahlskog JE et al. The role of radiotracer
imaging in Parkinson's disease. Neurology 2002;
64(2) 208-15
Conflict of Interest:
In 2002 I received payment from Amersham International, manufacturers of a DAT-SPECT product, (via a grant from the Movement Disorders Society)for an article appearing as a supplement in Movement Disorders
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