In their recent paper Chung and colleagues[1] describe 3 cases of cerebral amyloid angiopathy related inflammation (CAA-I) all confirmed by brain biopsy and review the scientific literature, proposing the criteria for probable and definite diagnosis.
CAA-I is a rare and treatable encephalopathy affecting a subgroup of CAA patients, in which a predisposing condition is represented by the APOE ?4/?4 genotype in the majority of pati...
In their recent paper Chung and colleagues[1] describe 3 cases of cerebral amyloid angiopathy related inflammation (CAA-I) all confirmed by brain biopsy and review the scientific literature, proposing the criteria for probable and definite diagnosis.
CAA-I is a rare and treatable encephalopathy affecting a subgroup of CAA patients, in which a predisposing condition is represented by the APOE ?4/?4 genotype in the majority of patients. CAA-I generally presents with subacute headaches, cognitive and behavioral changes, seizures and focal neurological deficits[2]. Radiological features of CAA-I are mainly represented by bilateral, generally asymmetric, swollen white matter lesions in the cerebral hemispheres, hyperintense in T2-weighted images, possibly exerting mass effect, usually without contrast enhancement. Appropriate MR Gradient Echo sequences may show multiple microhemorrhages that strongly suggest CAA.
The pathogenesis of CAA-I is still unknown, but it is probably due to an autoimmune reaction against amyloid-beta (A?) deposits in the wall of blood vessels, leading to an acute inflammatory response known as vasogenic edema (VE). The recognition of this rare condition is important, in order to rapidly initiate a treatment with high-dose steroid and immunosuppressive agents, with a significant clinical improvement in the majority of patients.
We have recently described one patient with probable CAA-I, according to Kinnecom diagnostic criteria[3], in whom we showed a specific increase of anti-A? 1-40 and 1-42 autoantibodies in the CSF of the patient before steroid treatment, and their reduction to normal levels following dexamethasone 24 mg/day IV for 20 days[4].
These results, even if assessed on a single case, seem to be of striking importance in order to understand the pathogenetic mechanism of CAA-I[5]. Anti-A? autoantibodies may in fact represent the mediators of the autoimmune reaction against A? protein located in brain vessels, leading to the inflammatory reaction occurring in CAA-I.
We believe that these results should also be confirmed in other cases of CAA-I and the role of anti-A? autoantibodies in the pathogenesis of the disease should be clarified. At present, there is no clinical/radiological investigation, other than brain and leptomeningeal biopsy, that could be considered specific for the diagnosis of CAA-I. If the role of the anti-A? autoantibodies will be confirmed in the pathogenesis of CAA-I, their dosage in the CSF of supposed CAA-I patients could be proposed as one of the diagnostic criteria for the disease.
Finally, a better understanding of the role of anti-A? autoantibodies might have possible implications also in the field of Alzheimer's disease immunotherapy. In fact, VE has been consistently documented as one major side effect of passive immunotherapy (especially in ?4 carriers)[6], and early active A? vaccination trials had to be stopped because of severe meningoencephalitis strictly resembling CAA-I, as pointed out by Chung and colleagues[1].
REFERENCES
1. Chung KK, Anderson NE, Hutchinson D, et al. Cerebral amyloid angiopathy related inflammation: three case reports and a review. J Neurol Neurosurg Psychiatry. 2011 Jan;82(1):20-6.
2. Eng JA, Frosch MP, Choi K, et al. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 2004;55: 250 -256.
3. Kinnecom C, Lev MH, Wendell L, et al. Course of cerebral amyloid angiopathy-related inflammation. Neurology 2007;68:1411-1416.
4. DiFrancesco JC, Brioschi M, Brighina L, et al. Anti-A? autoantibodies in the CSF of a patient with CAA-related inflammation: a case report. Neurology. 2011 Mar 1;76(9):842-4.
5. Greenberg SM, Frosch MP. Life imitates art: anti-amyloid antibodies and inflammatory cerebral amyloid angiopathy. Neurology. 2011 Mar 1;76(9):772-3.
6. Panza F, Frisardi V, Imbimbo BP, et al. Anti-?-Amyloid Immunotherapy for Alzheimer's Disease: Focus on Bapineuzumab. Curr Alzheimer Res. 2011 May 18. [Epub ahead of print]
Dementia and depression are frequently comorbid among older adult
patients. Depression is related to cognitive decrement and can even
represent the first signs of a neurodegenerative process. It can be
difficult to distinguish depressed patients exhibiting the first signs of
dementia from those whose cognition will improve with treatment. Studies
from the neuropsychological reported that there is relationship between
de...
Dementia and depression are frequently comorbid among older adult
patients. Depression is related to cognitive decrement and can even
represent the first signs of a neurodegenerative process. It can be
difficult to distinguish depressed patients exhibiting the first signs of
dementia from those whose cognition will improve with treatment. Studies
from the neuropsychological reported that there is relationship between
depression and dementia shown by examining potential neurobiological
mechanisms that may potentiate both syndromes in the context of the
ongoing debate on depression as a prodrome and/or a risk factor for
dementia. Other article concluded with suggestions for clinicians when
deciding who to refer for neuropsychological assessment and with ideas for
further research that might promote a better understanding of the complex
association between depression and dementia during old age. In series of
research studies it was found that Geriatric depression has been
associated with cognitive impairments, but whether suboptimal effort
contributes to these deficits is unknown. One study investigated
differences in cognitive functioning between depressed and nondepressed
elderly veterans, before and after excluding patients who provided
suboptimal effort on testing at a memory disorders clinic. Patients
diagnosed with a depressive disorder performed more poorly than non
depressed patients on almost all Repeatable Battery for the Assessment of
Neuropsychological Status indices, but these differences became
nonstatistically significant after excluding patients who provided
suboptimal effort. However, when patients were classified as normal,
mildly, or severely depressed based on Geriatric Depression Scale scores,
these groups were not significantly different on Repeatable Battery for
the Assessment of Neuropsychological Status indices, regardless of whether
patients who provided suboptimal effort were included or excluded from
analyses. The findings suggest that cognitive deficits in depression
reported in previous research may be attributable to suboptimal effort and
that identifying depression via clinical diagnosis or psychometric data
may affect this trend.
General speaking ,low mood and dementia even in early cognitive
impairments remains a prominent co morbid factors among older adult
patients more researchers are in need to explore more about other co
morbid factors associated with early and progressive dementia process
Espay and colleagues report a detailed clinical and pathological
study of two unrelated individuals with rapidly progressive atypical
parkinsonism (similar to progressive supranuclear palsy, PSP), and
additional frontotemporal and motor neuron involvement, in whom TDP-43
inclusion pathology was demonstrated. (1) Sequencing of PGRN and TARDBP
gene coding regions was negative, and therefore no genetic cause...
Espay and colleagues report a detailed clinical and pathological
study of two unrelated individuals with rapidly progressive atypical
parkinsonism (similar to progressive supranuclear palsy, PSP), and
additional frontotemporal and motor neuron involvement, in whom TDP-43
inclusion pathology was demonstrated. (1) Sequencing of PGRN and TARDBP
gene coding regions was negative, and therefore no genetic cause was
identified. An additional gene that needs to be considered, however, in
light of important very recent evidence, is ATXN2, in which pure CAG
expansions (range 34-59 repeats) lead to spinocerebellar ataxia (SCA2).
The encoded protein ataxin-2 was shown to interact with TDP-43, which
plays a key role in motor neuron disease (MND), and modulate its toxicity,
with intermediate CAG expansions in ATXN2 (27-33 repeats) appearing to be
risk factors for MND. (2) This has already been confirmed in other
studies, 3-4 and importantly a clear association with PSP was also shown,
(3) with the risk highest for both MND and PSP for repeats >30. Rather
than the pure CAG repeats which occur in the typical SCA2 phenotype, CAA
interruptions of the CAG expansion repeats are found in motor neuron
disease and PSP. (3-4)
It is therefore plausible that the unexplained PSP / MND overlap
phenotype with TDP-43 inclusions may have been associated with interrupted
intermediate size expansions in ATXN2, and confirmation of this would
advance understanding of the pathology of this novel type of
neurodegeneration. Testing of DNA from different tissues and brain regions
available would also allow the investigation of possible mosaicism, which
has been previously reported in SCA2 (5) and could help explain the
phenotypic variation of this type of ATXN2 mutation.
1. Espay AJ, Spina S, Houghton DJ, Murrell JR, de Courten-Myers GM,
Ghetti B, et al. Rapidly progressive atypical parkinsonism associated with
frontotemporal lobar degeneration and motor neuron disease. J Neurol
Neurosurg Psychiatry 2011;82:751-3.
2. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, et al.
Ataxin-2 intermediate-length polyglutamine expansions are associated with
increased risk for ALS. Nature 2010;466:1069-75.
3. Ross OA, Rutherford NJ, Baker M, Soto-Ortolaza AI, Carrasquillo MM,
Dejesus-Hernandez M, et al. Ataxin-2 repeat-length variation and
neurodegeneration. Hum Mol Genet 2011. doi:10.1093/hmg/ddr227
4. Yu Z, Zhu Y, Chen-Plotkin AS, Clay-Falcone D, McCluskey L, Elman L, et
al. PolyQ repeat expansions in ATXN2 associated with ALS are CAA
interrupted repeats. PLoS One 2011;6:e17951.
5. Matsuura T, Sasaki H, Yabe I, Hamada K, Hamada T, Shitara M, et al.
Mosaicism of unstable CAG repeats in the brain of spinocerebellar ataxia
type 2. J Neurol 1999;246:835-9.
We read with interest the article "Dangers of bone graft substitutes:
lessons from using Genex" (Saadoun, MacDonald, Bell and Papadopoulos, JNNP
published online March 8, 2011), notably as it purported the potential for
Genex putty to "cause soft tissue inflammation and destruction".
All three patients in the article were reported to have wound related
adverse reactions. Since initial certification, in excess of 5,0...
We read with interest the article "Dangers of bone graft substitutes:
lessons from using Genex" (Saadoun, MacDonald, Bell and Papadopoulos, JNNP
published online March 8, 2011), notably as it purported the potential for
Genex putty to "cause soft tissue inflammation and destruction".
All three patients in the article were reported to have wound related
adverse reactions. Since initial certification, in excess of 5,000 packs
of Genex have been distributed worldwide and, as a percentage of Genex
released in 2010, there were fewer than 0.4% reported complaints. None of
the reports were related to soft tissue damage.
The article presents a hypothesis that Genex putty "produces sterile
pus which destroys adjacent soft tissues"; a mouse study is used to test
this hypothesis.
All manufacturers of bone graft substitutes are required to conduct
extensive testing of both the raw materials used in the manufacture of
their products and the finished device itself in order to show that their
devices are biocompatible with respect to the intended application and
duration of contact.
Testing to ISO 10993 Biological evaluation of medical devices is
advised, not only to ensure patient safety, but also to comply with the
demanding international regulatory requirements that apply to the medical
device industry.
It should be noted that allograft, such as cadaver tissue and
demineralised bone matrix, is not regulated as a medical device either in
Europe or the USA. As such it is not subject to the same strict regulatory
demands as synthetic bone void fillers.
All bone void fillers (often referred to as bone graft substitutes)
are indicated for use in bony voids or gaps in the skeletal system that
are not intrinsic to the stability of the bony structure and should not be
used where infection is present. They should not be used to overfill or
pressurise the defect site.
Any implanted material has the potential to elicit a foreign-body
reaction. This reaction depends upon the property of the material itself
and also upon the patient and the site of implantation.
As part of the essential requirements for the regulatory approval of
Genex putty an implantation study was performed utilizing the Boden
model.[1] This involves an intertransverse process spinal fusion procedure
in a rabbit. The graft material is placed adjacent to the decorticated
vertebral body and between the transverse processes. Macroscopic,
radiographic and histologic appearance of the fusion was performed at 4, 8
and 12 weeks following surgery, 6 animals per time point (total 18
rabbits).
In this model, Genex was shown to be safe and efficacious and
promoted increasing fusion with implantation time. At no time point (4
weeks minimum) was there evidence of neutrophil infiltrate, either in the
graft bed or within adjacent tissue.
Although it is appreciated that this model does not specifically
assess an acute soft tissue response, no adverse events or tissue
reactions were reported in this study.
The article mentions bone morphogenic proteins. It is now well known
that BMP usage in the cervical spine has been associated with soft tissue
inflammation and significant adverse events, but has not shown these
reactions when used in other sites. This serves to indicate that adverse
events can be indication (and patient) specific.
Medical devices in Europe must be CE marked in accordance with the
Medical Devices Directive 93/42/EEC (as amended). This signifies
compliance to the Essential Requirements (Annex I), including safety and
biocompatibility requirements. All approved bone graft substitutes,
including Genex (Biocomposites, UK), have been certified as meeting the
requirements for class III resorbable devices in the EEC.
Similarly, Genex has been cleared as a Class II medical device by the
US Food & Drug Administration (FDA) and is recognised internationally
by other regulatory agencies as a medical device.
Finally, being classified as a medical device does not make adverse
incident reporting difficult. On the contrary, the homepage of the
Medicines and Healthcare products Regulatory Agency (MHRA website:
www.mhra.gov.uk), has a clear selection button to "Report Medical Device
Adverse Incidents" taking the user directly to the online reporting
system.
Synthetic bone void fillers have a long and safe history of clinical
use, when used appropriately. The first reported use of calcium sulphate
as a bone void filler was by Dreesmann in 1892.[2] The use of tricalcium
phosphate as a bone void filler was first reported by Albee in 1920.[3]
Their advantages over autograft and allograft tissue have been well
documented.
Based on our knowledge of global use, Genex is a safe and effective
bone void filler when used in accordance with the Instructions for Use.
References
1. Boden S, Schimandle J, Hutton W. An experimental lumbar
intertransverse process spinal fusion model. Radiographic, histologic and
biomechanical healing characteristics. Spine 1995;20:412-20.
2. Dreesmann H, Ueber Knochenplombierung. Beitr Klin Chir 1892;9:804-810.
3. Albee FH, Studies in bone growth: Triple calcium phosphate as a
stimulus to osteogenesis. Ann Surg 1920;71:32.
Conflict of Interest:
Simon Fitzer and John Cooper are both employees of Biocomposites Ltd (JS is Technical Research Director)
Vivekananda et al(1)report that when controlled for sex, cases of
sporadic amyotrophic lateral sclerosis (ALS) have a lower mean finger
length ratio R [where R = (2D / 4D) and 2D and 4D are the lengths of the
2nd and 4th digits respectively] than healthy controls. These authors
interpret their finding as indicating prenatal involvement of high
concentrations of intrauterine testosterone, T. However, their
interpretation...
Vivekananda et al(1)report that when controlled for sex, cases of
sporadic amyotrophic lateral sclerosis (ALS) have a lower mean finger
length ratio R [where R = (2D / 4D) and 2D and 4D are the lengths of the
2nd and 4th digits respectively] than healthy controls. These authors
interpret their finding as indicating prenatal involvement of high
concentrations of intrauterine testosterone, T. However, their
interpretation is not the only one : another possibility arises from the
reported variation of R with adult sex hormone levels(2). So (some cases
of) ALS may arise either as a consequence of high maternal T levels, or of
high levels of the patient's own postnatal T (or both). Here I offer a
means of discriminating between these two hypotheses.
I have adduced substantial quantities of data to support the
hypothesis that mammalian (including human) offspring sex ratios at birth
are partially controlled by parental hormone levels around the time of
conception(3-5). Ex hypothesi, high levels of T are associated with the
subsequent births of sons. So if my hypothesis and that of Vivekananda et
al(1) were both correct, that would explain why probands with ALS contain
an excess of males(6,7). Moreover, if both hypotheses were correct, then
ALS probands should have a statistical excess of brothers. The point
should be tested.
An illustrative use of this form of argument provided support for
Baron-Cohen's hypothesis(8) that one cause of autism is high intrauterine
T concentrations. If his hypothesis and mine were both correct, then
autistic probands should have an excess of brothers. This has been
reported(9) and twice replicated(10,11), giving strong support to Baron-
Cohen's hypothesis. So it would be interesting to see data on the sib sex
ratio of ALS probands.
Another approach to the present problem may be via the variable of
parity or birth order. First-borns, as contrasted with later-borns, are
reportedly exposed to higher levels of testosterone in early(12), and
late(13) pregnancy. So if the hypothesis of Vivekananda et al(1) were
correct, there should be a statistical excess of first-borns among ALS
probands. This point has been tested, also by Vivekananda and co-
workers(14), and they reported a non-significant result. However this
latter conclusion may be indecisive : there are pitfalls in the
interpretation of birth order studies.
1. In the first place, Vivekananda et al(14) were testing for a
positive birth order effect (viz one in which the risk correlates
positively with birth order). So they omitted a substantial quantity of
their data viz : all their affected sibships of size less than 4 because
these sibships might have been incomplete and thus be uninformative about
the effect. However the purpose at present is to test for a negative birth
order effect : viz one in which the risk correlates negatively with birth
order and which may therefore be manifest in incomplete sibships of size
2+. So I suggest that these workers should test their complete material
without omitting the shorter sibships.
2. In the second place, these workers give no explanation for their
choice of statistical test : in particular, and in the absence of a
control group, it is not clear that it is as powerful as other more
conventional tests e.g. that of Haldane and Smith(15). So I suggest that
their entire material should be submitted to that test. If a significant
birth order effect is indicated, that will give strong support to the
hypothesis of Vivekananda et al(1) that one cause of amyotrophic lateral
sclerosis is high intrauterine levels of testosterone.
References
1. Vivekananda U, Manjalay ZR, Garesalingam J et al. Low index to
ring finger length in sporadic ALS supports prenatally defined motor
neuronal vulnerability. J Neurol Neurosurg Psychiatr 2011;82:635-637
2. Manning JT, Scutt D, Wilson J et al. The ratio of 2nd to 4th digit
lengths : a prediction of sperm numbers and concentrations of
testosterone, luteinizing hormone and oestrogen. Hum Reprod 1998;13:3000-
3004
3. James WH. Evidence that mammalian sex ratios at birth are
partially controlled by parental hormone levels at the time of conception.
J Theor Biol 1996;180:271-286
4. James WH. Further evidence that mammalian sex ratios are partially
controlled by parental hormone levels around the time of conception. Hum
Reprod 2004;19:1250-1256
5. James WH. Evidence that mammalian sex ratios at birth are
partially controlled by parental hormone levels around the time of
conception. J Endocrinol 2008;198:3-15
6. McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral
sclerosis. Gender Med 2010;7:557-570
7. Logroscino G. Incidence of amyotrophic laternal sclerosis in
Europe. J Neurol Neurosurg Psychiatr 2010;81:385-390
8. Baron-Cohen S. The extreme male brain theory of autism. Trends
Cogn Sci 2002;6:248-254
9. James WH. Further evidence that some male-based neurodevelopmental
disorders are associated with high intrauterine testosterone
concentrations. Dev Med Child Neurol 2008;50:15-18
10. Mouridsen SE, Hauschild KM. The sex ratio of siblings of
individuals with a history of developmental language disorder. Logoped
Phoniatr Vocol 2010;35:144-148
11. Mouridsen SE, Rich B, Isager T. Sibling sex ratio of individuals
diagnosed with autism spectrum disorder as children. Dev Med Child Neurol
2010;52:289-292
12. Troisi E, Hoover RN, Thadhani R. et al. Maternal, prenatal and
perinatal characteristics and first trimester maternal serum hormone
concentrations. Br J Cancer 2008;99:1161-1164
13. Maccoby EE, Doering CH, Jacklin CN et al. Concentration of sex
hormones in umbilical cord blood and their relation to sex and birth order
of infants. Child Dev 1979;50:632-642
14. Vivekananda U, Johnston C, McKenna-Yasek D et al. Birth order and
the genetics of amyotrophic lateral sclerosis. J Neurol 2008;255:99-102
15. Haldane JBS, Smith CAB. A simple exact test for birth order
effect. Ann Eugen (Lond)1947;14: 117-124
Regarding your Cochrane review "Antidepressants for neuropathic pain"
which was published in J Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1372
-3, we would like to point out an inconsistency.
Our comment refers to the statement made on page 11: : "Six placebo-
controlled studies were found in postherpetic neuralgia. All demonstrated
superiority of a...
Regarding your Cochrane review "Antidepressants for neuropathic pain"
which was published in J Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1372
-3, we would like to point out an inconsistency.
Our comment refers to the statement made on page 11: : "Six placebo-
controlled studies were found in postherpetic neuralgia. All demonstrated
superiority of antidepressants over placebo. Four of them included data of
global improvementor pain relief with risk ratio of effectiveness NNT 2.7
(95% CI 2to 4), RR 2.3 (95%CI 1.7 to 3.2) (Bowsher 1997;Kishore-Kumar
1990; Max 1988; Watson 1982).
Our comment also refers to the figure "Analysis 3.1 Comparison 3
Postherpetic neuralgia- number of patients with moderate pain relief or
better, Outcome 1 Antidepressant vs placebo."
We feel that the trial by Bowsher in 1997, which contributes 72% of
the weight in the point-estimate calculation, in fact examines a
preventive rather than therapeutic effect, in patients with acute herpes
zoster rather than postherpetic neuralgia.
This trial's population does therefore not consist of patients with
postherpetic neuralgia, but rather of patients with acute herpes zoster.
They are treated with a 90-day course of amitryptilline in order to
prevent postherpetic neuralgia in the future. In contrast, the other
trials mentioned in the review examine the therapeutic effect of
amitryptilline as a pain killer once post-herpetic neuralgia has
developed.
These are essentially distinct study-populations, with essentialy distinct
treatment goals. In the first case the goal is to prevent postherpetic
pain, while in the latter the goal is to treat it.
In our opinion, this distinction should be made explicit in the
Cochrane review and these trials should not be meta-analyzed in one pooled
point-estimate.
Yours sincerely,
JMI Vos, MD, internist-hematologist in training
Prof. Dr. S. Middeldorp, internist
Corresponding author
JMI Vos
Dept. of Hematology, F4-224
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
The Netherlands
Tel. (31)205665785
j.m.vos@amc.uva.nl
We were interested to read the meta-analysis by Handel and
Ramagopalan,1 summarising the body of evidence which points towards a
reduction of cancer risk in patients with multiple sclerosis.
We performed a study investigating the same question, using our
hospital's clinical coding database to compare the frequency of cancer in
all multiple sclerosis patients admitted over a 10 year period (1090
patients), with...
We were interested to read the meta-analysis by Handel and
Ramagopalan,1 summarising the body of evidence which points towards a
reduction of cancer risk in patients with multiple sclerosis.
We performed a study investigating the same question, using our
hospital's clinical coding database to compare the frequency of cancer in
all multiple sclerosis patients admitted over a 10 year period (1090
patients), with a control group constituting all patients admitted with
epilepsy or migraine over the same time period (5596 patients).
Our results add weight to the meta-analysis' findings with a
significant reduction in risk seen with regards to solid tumours (RR 0.42,
p= 0.05).2
This relationship suggests that the hyperactive immune system
associated with multiple sclerosis might have a protective value; this may
have implications both for understanding tumour genesis and the
pathophysiology of multiple sclerosis, and in the need for vigilance in
our patients treated with an increasingly wide range of immunomodulatory
therapies.
1. Handel AE, Ramagopalan SV, Multiple Sclerosis and Risk of Cancer:
A Meta-Analysis J Neurol Neurosurg Psychiatry 2010;81:1413-1414
2. Needham E, Lee M, The Hyperactive Immune System of Multiple
Sclerosis - An Evolutionary Benefit? Multiple Sclerosis 2009;15:S191
We write in relation to the editorial commentary from Khan et Tselis
(1) who rightly suggest caution to consider chronic cerebrospinal venous
insufficiency (CCSVI) as a pathological entity and cast serious doubt on
its relevance to multiple sclerosis (MS); they forecast properly designed
studies to investigate the relevance of CCSVI to MS, in order to carry out
interventional procedures.
The absence of extracranial venous...
We write in relation to the editorial commentary from Khan et Tselis
(1) who rightly suggest caution to consider chronic cerebrospinal venous
insufficiency (CCSVI) as a pathological entity and cast serious doubt on
its relevance to multiple sclerosis (MS); they forecast properly designed
studies to investigate the relevance of CCSVI to MS, in order to carry out
interventional procedures.
The absence of extracranial venous stenosis at the earliest stage of MS
makes it an unlikely cause of the disease (2). The idea of venous
congestion as a possible contributor to the pathogenesis of MS has been
discussed for the past 40 years, but remained widely unappreciated by the
scientific community.
In contrast with other authors, Zamboni et al (3) defined CCSVI as a
vascular condition associated with MS; it is characterized by multiple
intraluminal stenosing malformations of the principal pathways of
extracranial venous drainage, particularly in the internal jugular veins
(IJVs) and the azygous vein (AZY), that restrict the normal outflow of
blood from the brain.
In the study of Zamboni et al there was significant extracranial venous
stenosis localised at the principal level of the cerebrospinal venous
segments as detected by selective venography and anomalies of venous
outflow at color Doppler high resolution examination. The pathological
consequences of CCSVI have been hypothesised to emanate from chronic
venous reflux and hypertension leading to increased iron deposition in the
brain and subsequent MS pathology, including inflammation and
neurodegeneration. Other recent reports found no differences in
cerebrospinal venous drainage using transcranial and extracranial Doppler
imaging (4-5).
The discrepancies in the results may be explained with the absence of
standardized internationally accepted criteria for normal Doppler venous
flow parameters (2).
We performed complete post-mortem examination of two patients with MS,
died for different causes. One patient, a 74 year-old-woman, was
hospitalized for acute respiratory illness and died because of bacterial
pneumonia; the other one, a 35 year-old-woman, died for otogenic bacterial
meningitis complicated with internal jugular thrombosis as demonstrated on
MR venography.
Postmortem examination demonstrated in both patients a marked stenosis of
left internal jugular vein at the apex of the angle formed by the two
heads of the sternocleidomastoid muscle where the IJV overlie the carotid
artery with ectasia and congestion of the intracranial veins. Venous flow
slowing, caused by the stenosis, had predisposed to IJV thrombosis,
histologically demonstrated in the second case.
Severe inflammatory disease may be a risk factor for deep venous
thrombosis but also chronic cerebrospinal venous insufficiency.
We demonstrate, for the first time as far as we are aware, the presence
of anatomical alteration in the veins of the neck with impaired venous
drainage from the central nervous system in two patients with multiple
sclerosis who died from other causes. We do not know the exact
implications in MS pathology and certainly there is no doubt that this
area warrants a great deal more study. Clinical trials for evaluating new
therapeutic agents and other clinical experimental protocols may be
required.
References
1. Khan O, Tselis A.
Chronic cerebrospinal venous insufficiency and multiple sclerosis: science
or science
fiction?
J Neurol Neurosurg Psychiatry 2011;82:355.
2. Yamout B, Herlopian A, Issa Z
Extracranial venous stenosis is an unlikely cause of multiple sclerosis
Mult Scler 2010 16: 1341-9
3. Zamboni P, Galeotti R, Menegatti E, et al
Chronic cerebrospinal venous insuffiency in patients with multiple
sclerosis.
J Neurol Neurosurg Psychiatry 2009;80:392-9.
4. Doepp F, Paul F, Valdueza JM, et al
No cerebrocervical venous congestion in patients with multiple sclerosis.
Ann Neurol 2010, 68:173-183.
5. Sundstrom P, Wahlin A, Ambarki K, et al
Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control
study.
Ann Neurol 2010, 68:255-259.
We read with interest the meta-analysis with the focus on
physiotherapy interventions late after stroke and we would like to thank
the authors for their effort to shed light on this subject. Interventions
late after stroke are an important area of rehabilitation that has been
neglected. There most certainly is a need for rehabilitation and exercise
tailored for stroke survivors late after onset. As the authors point out...
We read with interest the meta-analysis with the focus on
physiotherapy interventions late after stroke and we would like to thank
the authors for their effort to shed light on this subject. Interventions
late after stroke are an important area of rehabilitation that has been
neglected. There most certainly is a need for rehabilitation and exercise
tailored for stroke survivors late after onset. As the authors point out
the disabling process after stroke is complex and resources to maintain
physical functions, after the first months of primary rehabilitation are
scarce. It is not an area prioritized by administrators and health
politicians in any country and we applaud the authors' genuine wish to
forward this need of maintenance and need for exercise late after stroke.
However, the authors do not distinguish between the different underlying
mechanisms in early and late motor function recovery in this meta-
analysis. Most studies are either in the acute scenario OR, as the ones
presented in this meta-analysis late after stroke. Several studies
provided evidence that patients with stroke reach a plateau after 3-6
months and functional improvements seem to stabilize on a "peak
performance" (1-3).
So, the early rehabilitation seems to be very important in regaining
as much function as possible. How successful this is depends on many
factors. But, if treated in a stroke unit with multidisciplinary care and
with proper early rehabilitation all stroke survivors get a functional
profit to some degree. Some of the stroke survivors perform on a higher
level and some on lower levels in accordance with the initial lesion and
the damage that was imposed. Basically, one can speak of a therapeutic
window up till approximately 6 months to regain the function of the lost
bodily motor functions. This does by no means indicate that rehabilitation
after 6 months is futile. For one thing can patients with stroke at any
later stage learn to exploit their obtained motor potential to a larger
extent, and for another thing can patients with stroke like everybody else
gain strength and endurance with the help of training.
There are few studies that have followed stroke patients continuously from
the acute to the chronic stages, with or without interventions. However,
the few that exist indicate an interesting development: If treatment and
exercise is abandoned functions deteriorate, but if treatment and exercise
persist, functions are maintained(4-7).
In the acute early stage of rehabilitation focus is on regaining bodily
functions. After 3-6 months, it seems, you will not see any significant
difference in the RECOVERY of function, as to less paresis, but if
maintained they will be preserved at that level. Some patients may even be
able to improve functional abilities due to practice, but usually on the
basis of the motor function regained early after stroke (8).
However, if this new and improved function is not maintained with exercise
or physical activity the motor functions may and will deteriorate...and
rapidly so. And many stroke survivors are less active and sometimes
overprotected by their kind relatives so performance often DOES
deteriorate (9).
So people with stroke, like the general population, have a need for
maintenance of capacity and function (10).
And this is we would like to argue, that these studies in this meta-
analysis have focused on: maintenance of capacity. So the beauty of it all
is that stroke patients can enhance their capacity like endurance and
strength and thereby their functioning in daily life activities, on line
with healthy people BUT nevertheless seems genuine motor recovery to be
limited to the first 3 - 6 months post stroke.
Thank you once again for bringing this topic to attention!
Birgitta Langhammer, Associate Professor, PhD, Oslo University
College, Norway
Iris Brunner, Research Fellow, MSc, University of Bergen, Norway
References
1. Kwakkel G, van Peppen R, Wagenaar RC, Wood Dauphinee S, Richards
C, Ashburn A, Miller K, Lincoln N, Partridge C, Wellwood I, Langhorne P.
Effects of augmented exercise therapy time after stroke: a meta-analysis.
Stroke 2004;35(11):2529-39.
2. Kollen B, van de Port I, Lindeman E, Twisk J, Kwakkel G.Predicting
improvement in gait after stroke: a longitudinal prospective study. Stroke
2005;36(12):2676-80.
3. Verheyden G, Nieuwboer A, De Wit L, Thijs V, Dobbelaere J, Devos
H, Severijns D, Vanbeveren S, De Weerdt W. Time course of trunk, arm, leg,
and functional recovery after ischemic stroke. Neurorehabilitation And
Neural Repair 2008;22(2):173-9.
4. Van de Port IG, Kwakkel G, van Wijk I, Lindeman E. Susceptibility
to deterioration of mobility long-term after stroke: a prospective cohort
study. Stroke 2006 Jan;37(1):167-71.
5. Langhammer B, Stanghelle JK, Lindmark B.An evaluation of two
different exercise regimes during the first year following stroke: a
randomised controlled trial. Physiotherapy Theory And Practice
2009;25(2):55-68.
6. Langhammer B, Stanghelle JK, Lindmark B. Exercise and health-
related quality of life during the first year following acute stroke. A
randomized controlled trial. Brain Injury 2008;22(2):135-45.
7. Langhammer B, Lindmark B, Stanghelle JK. Stroke patients and long-
term training: is it worthwhile? A randomized comparison of two different
training strategies after rehabilitation. Clinical Rehabilitation
2007;21(6):495-510.
8. Langhammer B, Stanghelle JK. Exercise on a treadmill or walking
outdoors? A randomized controlled trial comparing effectiveness of two
walking exercise programmes late after stroke.Clinical Rehabilitation
2010;24(1):46-54.
9. Michael KM, Allen JK, Macko RF. Reduced ambulatory activity after
stroke: the role of balance, gait, and cardiovascular fitness.Archives Of
Physical Medicine And Rehabilitation 2005;86(8):1552-6.
10. Pang MY, Eng JJ, Dawson AS, Gylfad?ttir S. The use of aerobic
exercise training in improving aerobic capacity in individuals with
stroke: a meta-analysis.Clinical Rehabilitation 2006; 20(2):97-111.
We have read with great interest the work of Dhollander et al. [1]
and express our congratulation for their wonderful work, but we would like
to add some considerations.
The authors describe two patients presenting clinically transient
neurological deficit and radiologically with a focal cortical subarachnoid
haemorrhage in the brain CT and multifocal cortical siderosis in brain MR.
They compare their patients with the clas...
We have read with great interest the work of Dhollander et al. [1]
and express our congratulation for their wonderful work, but we would like
to add some considerations.
The authors describe two patients presenting clinically transient
neurological deficit and radiologically with a focal cortical subarachnoid
haemorrhage in the brain CT and multifocal cortical siderosis in brain MR.
They compare their patients with the classical diagnosis of superficial
siderosis but remark the differences with that diagnosis and propose the
term of cortical superficial siderosis.
We think from a radiological point of view it is better to consider these
patients as having suffered a focal cortical convexity subarachnoid
haemorrhage (cSAH), a term previously proposed in the literature [2;3]. In
this way there are some works showing a wide differential diagnosis
between the different aetiologies of cSHA including vasculitic, toxic,
pharmacological, vascular and amyloid angiopathy related causes. In an
interesting manner some reviews have shown how, in the older group of age,
all the cases were associated with amyloid angiopathy [3].
And, secondly, when cSAH appears in the elderly, the clinical
manifestations of transient neurological deficit are repeatedly described
and the hypotheses about its physiopathology have been related to cortical
spreading depression [4;5].
For these reasons we think this clinico-radiological picture of a
cSAH in the brain CT of an elderly patient presenting with neurological
transient deficitary manifestations is emerging as one of the
manifestations of cerebral amiloyd angiopathy, aside from lobar
haemathoma.
It is remarkable the elegant demonstration of Dhollander et al. [1]
of beta-amyloid deposition, in their patients, in the regions of the brain
usually involved in Alzheimer disease and, especially, in the areas
previously affected of a focal cortical subarachnoid bleeding. In our
knowledge this has not previously been reported as a demonstration of
amyloid pathology in cSAH.
1. Dhollander I, Nelissen N, Van Laere K, Peeters D, Demaerel P, Van
Paesschen W, Thijs V, Vandenberghe R. In vivo amyloid imaging in cortical
superficial siderosis. J Neurol Neurosurg Psychiatry 2011;82:469-71.
2. Spitzer C, Mull M, Rohde V, Kosinski CM. Non-traumatic cortical
subarachnoid haemorrhage: diagnostic work-up and aetiological background.
Neuroradiology 2005;47:525-31.
3. Kumar S, Goddeau RP, Jr., Selim MH, Thomas A, Schlaug G,
Alhazzani A, Searls DE, Caplan LR. Atraumatic convexal subarachnoid
hemorrhage: clinical presentation, imaging patterns, and etiologies.
Neurology 2010;74:893-9.
4. Izenberg A, Aviv RI, Demaerschalk BM, Dodick DW, Hopyan J, Black
SE, Gladstone DJ. Crescendo transient Aura attacks: a transient ischemic
attack mimic caused by focal subarachnoid hemorrhage. Stroke 2009;40:3725-
9.
5. Brunot S, Osseby GV, Rouaud O, Kazemi A, Ricolfi F, Couvreur G,
Catteau A, Hervieu M, Moreau T, Giroud M, Bejot Y. Transient Ischaemic
Attack Mimics Revealing Focal Subarachnoid Haemorrhage. Cerebrovasc Dis
2010;30:597-601.
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Sir
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We read with interest the meta-analysis with the focus on physiotherapy interventions late after stroke and we would like to thank the authors for their effort to shed light on this subject. Interventions late after stroke are an important area of rehabilitation that has been neglected. There most certainly is a need for rehabilitation and exercise tailored for stroke survivors late after onset. As the authors point out...
We have read with great interest the work of Dhollander et al. [1] and express our congratulation for their wonderful work, but we would like to add some considerations. The authors describe two patients presenting clinically transient neurological deficit and radiologically with a focal cortical subarachnoid haemorrhage in the brain CT and multifocal cortical siderosis in brain MR. They compare their patients with the clas...
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