Dear Editor,

Multiple sclerosis is believed to be an autoimmune pathology, yet the mechanisms triggering the disease remain elusive. Therefore, I read with great interest the paper by Zamboni and his team who investigated the venous hemodynamics in patients with multiple sclerosis. His findings that this disease might be attributable to venous refluxes shed new light on the facts that have been known for decades (1), but have been mostly ignored by the scientific community. It should be answered, however, how this pathological outflows in the extra- and intracranial veins could trigger autoimmune reaction.

The loss of integrity of the blood-brain barrier, which is primarily built by tight-junction complexes between adjacent endothelial cells of the cerebrovascular endothelium, is a hallmark of multiple sclerosis. In this context, parallels between multiple sclerosis and chronic venous insufficiency of lower extremities (which is also an endotheliocyte- focused pathology) could be helpful. Yet, it should be remembered that endotheliocytes building the blood-brain barrier highly differ from those in the periphery. Moreover, venous hypertension in cerebral and spinal veins is unlikely to disassemble the cerebrovascular endothelial barrier (2). Indeed, although Zamboni has found increased venous pressure distally of venous stenoses, these pressure gradients were rather small. Thus, it is more likely that not venous hypertension, but pathological pattern of the blood flow-associated forces, decreased level of shear stress in particular, disassembles the blood-brain barrier and increases the transendothelial permeability. It has been found that an enhanced expression of pivotal tight junction proteins: occludin and ZO-1 in the cerebrovascular endothelium was associated with reduced transendothelial permeability and it has been shown, moreover, that an increased shear stress, especially with pulsatile flow characteristics, upregulated these proteins (3). By contrast, loss of shear stress after flow cessation enhanced the blood-brain barrier permeability (4). Therefore, a reduced shear, for instance as a result of the refluxing venous blood flow, could potentially result in the weakening of the blood-brain barrier. This in turn could initiate an autoimmune attack against nervous tissue.

Several questions, though, should have been answered before multiple sclerosis was recognized as a fundamentally hemodynamic disorder. First, if intracranial reflux is indeed the trigger of multiple sclerosis plaques, and not an innocent bystander. This will require additional studies in a much larger cohort of multiple sclerosis patients. Second, if these refluxes only bypass an occlusion and affect exclusively large cerebral and spinal veins, or they extend also into smaller veins (probable, damage of the blood-brain barrier can occur on condition that a decreased shear stress influence the cerebrovascular endothelium in the postcapillary venules). Third, mechanistic links between venous refluxes and cellular and molecular pathways that are responsible for autoimmune reaction should be determined, since such a discovery could result in the development of novel effective pharmacologic agents. Regarding these mechanisms, it should be suspected that the low shear-induced expression of ICAM-1 (adhesion molecule, which is responsible for the firm adhesion of leukocytes to endothelia) by cerebrovascular endothelium, could be a critical point in the initiation of multiple sclerosis plaque, since the crosslinking of ICAM-1 with integrins expressed on the leukocytic surfaces leads to a weakening of the blood-brain barrier and facilitates the transendothelial leukocyte migration (5).

Furthermore, consequently to Zamboni’s findings it may be speculated that at least for some anatomical variants of pathological venous outflow, surgical correction of steno-occlusions can be a therapeutic option in addition to or instead of pharmacotherapy.

In conclusion, investigations of the extra- and intracranial hemodynamic disturbances in multiple sclerosis patients appear to be a challenging avenue and may open a new chapter of therapeutic approach to this debilitating disease.

References

1. Schelling F.
Damaging venous reflux into the skull or spine: relevance to multiple sclerosis.
Med Hypothes 1986;21:141-8.

2. Simka M.
Evidence against the role for dural arteriovenous fistulas in the pathogenesis of multiple sclerosis.
Med Hypothes 2008;71:619.

3. Colgan OC, Ferguson G, Collins NT, et al.
Regulation of bovine brain microvascular endothelial tight junction assembly and barrier function by laminar shear stress.
Am J Physiol Heart Circ Physiol 2007;292:H3190-7.

4. Krizanac-Bengez L, Mayberg MR, Cunningham E, et al.
Loss of shear stress induces leukocyte-mediated cytokine release and blood-brain barrier failure in dynamic in vitro blood-brain barrier model.
J Cell Physiol 2006;206:68-77.

5. Lyck R, Reiss Y, Gerwin N, Greenwood J, Adamson P, Engelhardt B.
T-cell interaction with ICAM-1/ICAM-2 double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells.
Blood 2003;102:3675-83.

There is no conflict of interest regarding this letter.

Dear Editor,

I have read with great interest the article by Edison et al about the amyloid load in patients with Parkinson´s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) (1). Authors hypothesised that amyloid pathology would be uncommon in PD without dementia, an occasional feature of PDD and present in the majority of DLB cases. This hypothesis was clearly demonstrated (1). However, there are some points which are at variance with previous imaging and pathological data. I am going to focus in two of them which can be considered as paradigmatic of similar studies. The first study used [11C]PIB scan and showed that 22% of cognitively normal people had amyloid deposition in their brains (2) (This percentage was of 15% in another study including 20 subjects after adjusting for age (3)). These subjects were comparable in terms of age and MMSE scores, to the ones included in the study by Edison et al. However, [11C]PIB scans were normal in all the 41 control individuals and 10 PD patients without dementia studied. The second one refers to the pathological analysis of the brains of patients of the Sidney cohort (4). In this study, between 50 and 80% of the patients with a clinical diagnosis of PDD showed amyloid plaques in their brains. The shorter the duration of PD, the higher the percentage of plaques. Amyloid plaques were also found in 83% of patients dead with a clinical diagnosis of DLB (4).

The purpose of this letter is not to discuss the psysiopathological basis of dementia associated with PD, the position of DLB in the clinical spectrum of Lewy body disorders or the value of [11C]PIB scanning for the preclinical detection of AD, but to point out the fact that these results do not fit with previous imaging data obtained in a similar way, as well as with pathological studies. These discordant aspects are not discussed by Edison et al yet they have been used to raise some conclusions quite relevant to the concepts of AD and PD, such as the possibility of preclinical diagnosis and the contribution of aging and AD-like pathology to the development of dementia in PD. Moreover, one of the authors took part in one of the prior studies with [11C]PIB imaging (2). How to reconcile these data? Is this a diagnostic problem or a technical issue? Is [11C]PIB imaging useful to diagnose amyloid deposition in cognitively normal subjects? Is [11C]PIB deposition the reflection of the presence of amyloid plaques? Was the diagnosis of DLB or PDD incorrect? Are the conclusions of the Sidney study valid or more than 50% of the patients included in this cohort actually had DLB instead of PD or PDD? It is necessary to clarify the relationships between symptomatology, imaging and pathology in degenerative diseases to avoid misinterpretations.

References

1. Edison P, Rowe CC, Rinne JO, et al.
Amyloid load in Parkinson’s disease dementia and Lewy Body dementia measured with [11C]PIB PET.
J Neurol Neurosurg Psychiatry 2008; doi:10.1136/jnnp.2007.127878

2. Rowe CC, Ng S, Ackermann U et al.
Imaging beta-amyloid burden in aging and dementia.
Neurology 2007;68:1718-1725

3. Mintun MA, Larossa GN, Sheline YI et al.
[11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease.
Neurology 2006;67:446-452

4. Halliday G, Hely M, Reid W, Morris J.
The progression of pathology in longitudinally followed patients with Parkinson’s disease.
Acta Neuropathol 2008; 115:409–415

Dear Editor,

The authors report that "those taking antidepressants had a higher median (interquartile range) body mass ratio (25.0 (21.4-27.6) versus 22.0 (20.0-25.2) (p=0.03) and a shorter median (interquartile range) time on the treadmill (8.6 (6-11) versus 11.0 (8-12) minutes) (p=0.02). They also had a significantly lower mean (SD) peak VO2 (27.9 (9.0) versus 32.8 (7.0) ml/kg/min) (p=0.02)." In the discussion section, the authors then say, "body mass index has been previously noted in subjects reporting fatigue. This particular association, when combined with both the known and this study's association between antidepressants and body mass index, suggests that weight reduction might be a useful treatment strategy in some patients with CFS."

Given in particular, the mention of weight reduction, I find it strange that at this stage the authors don't comment that their results might influence prescribing patterns with regards to some CFS patients i.e. the corollary of the sentence above would be that avoiding antidepressants "might be a useful treatment strategy in some patients with CFS". So I'm doing it now.

In my experience, antidepressants are being prescribed for all sorts of symptoms in CFS patients: pain, sleep, IBS-type symptoms, mental fatigue/cognitive problems, low blood pressure/orthostatic issues, depression to name a few. Following the reasoning above, it would suggest that other methods may be preferable.

Since this study was published, a study by Welsh researchers[1] had some intereresting things to say on the use of antidepressants in CFS patients.

In a study of 23 patients and 42 healthy controls, they found that: "The serum [free Trp]/[CAA] ratio was 43% higher in CFS patients, due to a 48% higher [free Trp]. [Total Trp] was also significantly higher (by 19%) in CFS patients, and, although the [total Trp]/[CAA] ratio did not differ significantly between the control and patient groups, the difference became significant when the results were co-varied with age and gender. [CAA] was not significantly different between groups, but was significantly lower in females, compared to males, of the CFS patient group." The authors go on to say: "We have provisionally identified two subgroups of CFS patients, one with normal serotonin and the other with a high serotonin status."

The discussion section of the paper explains the relevance of some of the findings. It also re-iterates my point that antidepressants are often used to try to treat various symptoms associated with CFS: "If the present results are confirmed, our proposals should have important implications for the pharmacotherapy of the CFS. Serotonin-modifying and other antidepressants are prescribed to CFS patients to treat depression (if present), pain and/or fatigue. However, CFS patients with serotonin excess should not be exposed to, and are unlikely to benefit from, serotonin-modifying antidepressants, particularly selective serotonin-re- uptake inhibitors (SSRIs), to avoid a potential excessive serotonin hyperactivity. Similarly, in view of the well known Trp-SSRI interaction, the latter should not be prescribed to CFS patients with high Trp levels or increased availability to the brain. By contrast, as suggested by a meta-analysis of previous pharmacological trials (O'Malley et al., 1999) and a survey of psychiatrists (Hickie et al., 1999), tricyclic antidepressants have a greater likelihood of efficacy than SSRIs, are preferred by patients with chronic pain, and have superior antinociceptive properties in fibromyalgia (McQuay et al., 1996). Also, our clinical impression suggests that tricyclic antidepressants improve sleep disturbances in, and are better tolerated than SSRIs by, CFS patients."

An alternative explanation could be read into the association between exercise tolerance and body mass index: the more severely affected patients are with CFS, because of some (as yet unknown) disease process associated with some or all cases of CFS, the less able they are to exercise and so the harder it is for them to keep their weight to optimum levels. (Or alternatively the disease process increases their weight by some other means.)

Similarly muscle weakness (which also featured in regression models of exercise tolerance) could be a marker of the severity of the disease process in some or all cases of CFS - I say "some or all cases" because, as Lane points out in the accompanying editorial[2], "it is increasingly recognised that chronic fatigue syndrome (CFS) is heterogeneous... Failure to recognise this heterogeneity prejudices attempts to understand CFS in cross sectional studies." He pointed out that some research that had been published at that time suggested "some patients with CFS have a form of metabolic myopathy". He subsequently published a paper[3] which found that "there is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients." This was found by combining a subanaerobic threshold exercise test (SATET) and a RT-NPCR test for viruses: "Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus."

An empirically derived definition for "ME/CFS"[4] has included "generalized muscle weakness". "Muscle Weakness" has also been used in other definitions of ME[5]. (CFS and ME are terms that are sometimes used interchangeably).

It would have been interesting if information on the results of those who had done graded exercise therapy had been included in this study, both at the end of the 12 week intervention and at follow-up. There are a lot of references to the trial but the paper itself[6] only gives bits and pieces of the data of measures included in the current study.

It is interesting to note that the trial[6] did not prove graded exercise therapy was a panacea for CFS, which has been demonstrated numerically in a recent meta-analysis[7], which analysed the data (the authors of the meta-analysis reported that they contacted authors of the studies for missing data so they may have had access to data we are not given).

For the studies under review, the Cohen's d value (an effect measure) was calculated using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self- rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study."

Malouff et al[7] calculated the d value for the study[6] as 0.46 (95% CI: 0.03-0.95). For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[7].

That Graded Exercise Therapy is not a panacea for CFS is not surprising given the aforementioned association Lane found[3] between enteroviruses and abnormalities on exercise testing in some CFS patients.

REFERENCES

[1] Badawy AA, Morgan CJ, Llewelyn MB, Albuquerque SR, Farmer A.
Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome. J Psychopharmacol.
2005 Dec;19(4):385-91.

[2] Lane R.
Chronic fatigue syndrome: is it physical?
J Neurol Neurosurg Psychiatry. 2000 Sep;69(3):289.

[3] Lane RJ, Soteriou BA, Zhang H, Archard LC
Enterovirus related metabolic myopathy: a postviral fatigue syndrome.
J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1382-6.

[4] Osoba T, Pheby D, Gray S, Nacul L.
The Development of an Epidemiological Definition for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Journal of Chronic Fatigue Syndrome, Vol. 14(4), 2007

[5] Goudsmit EM, Stouten B, Howes S.
Fatigue in Myalgic Encephalomyelitis.
Bulletin of the IACFS/ME - Volume 16, Issue 3. http://www.iacfsme.org/BULLETINFALL2008/Fall08GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx

[6] Fulcher KY, White PD
Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome.
BMJ 1997, 314:1647 -1652.

[7] Malouff, J. M., et al.
Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis.
Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004

[8] Cohen J
Statistical power analysis for the behavioural sciences.
Edited by: 2. New Jersey: Lawrence Erlbaum; 1988.

Dear Editor I am pleased to read the comments by Dr. Derakhshan of 27 August, 2008. I would like to reply some questions in following paragraphs.

First, Dr. Derakhshan wrote that it was hard to understand that the sensory defects of our patient were detected on the right side of the body by the callosal infarction, and this might have been a typographical or clerical error. If you mentioned the somaesthetic transfer defect, I�fm afraid that you might misunderstand the method of its evaluation. This method requires no verbal answer. As shown in the paper, I touched a point on the patient�fs hand with a pen while the patient�fs eyes were closed, and then asked him to touch the corresponding place on the ipsilateral and contralateral hand using his thumb. When I touched the patient�fs left hand, the patient correctly identified 16/16 on the left hand, namely on the ipsilateral hand to the stimulated hand, and 6/16 on the right hand, namely on the contralateral hand to the stimulated hand.
When the patient replied by his left hand to the stimulus on his left hand, the sensory input to right hemisphere was connected to the motor area in the same, right hemisphere. But, when the patient replied by his right hand to the stimulus on his left hand, the information of the touch by a pen on the patient�fs left hand must be transferred from right to left hemisphere, in order to touch corresponding place using his thumb of his right hand. The results were significantly lowered in the latter case (left stim./left reply 16/16, left stim./right reply 6/16, p=0.0002).
This means the sensory input to right hemisphere could not be transferred to left hemisphere, due to the callosal infarction. So, we may say that the patient revealed the somaesthetic transfer defect.

Second, Dr. Derakhshan stated that, in violin playing, the right hand also played a critical role to produce the sounds. I completely agree this opinion, but, in our patient, I suppose that the impairment of violin playing was due to the impairment of the movements of his left fingers.
As written in the paper, the patient complained that, after his cerebrovascular event, he could not play violin as well as before, because his left fingers could not move with their previous accuracy. For example, when he pressed the string by his index finger of left hand, the middle finger also moved involuntarily and touched the string, so the sound became very vague. Then, he complained that independent movements of his left fingers were damaged after the cerebrovascular event. At the same time, he told that he felt no abnormal change about the bowing by right hand, compared to before the infarction. We suppose that the impairment of the movement of left fingers was caused by the callosal apraxia. It is generally considered that left hemisphere is also dominant about voluntary movements, so the callosal apraxia appears only in the left hand, because the disconnection between the praxic center of left hemisphere and the motor area of right hemisphere. Though the subtle disorder of bowing movement might also participate, I suppose that it is reasonably conclude that, as the patient stated by himself, the impairment of his violin playing was mainly caused by the disturbance of the movement of his left fingers due to the callosal apraxia.

Third, Dr. Derakhshan wrote that the patient�fs left hemianopia for musical symbols which was displayed in tachistoscopic examinations was due to the difficulty in moving his eyes to the left in the time allowed. I wonder if Dr. Derakhshan might misunderstand the meaning of tachistoscopic examination. As shown in our paper, in tachistoscope, the visual stimuli were presented for 70ms in each visual hemifield, beside a yellow spot 3 degrees in visual angle. As you know, the tachistoscopic examination is carried out in order to measure the responses of each cerebral hemisphere independently. The duration of 70ms is set in order NOT to allow the time to move eyes. So, if the patient has the enough time to move his eyes as Dr. Derakhshan said, the visual stimuli are input to both hemispheres.
Therefore, we may say that our tachistoscopic examination was methodologically adequate and its results were reliable.

Dr. Derakhshan also wrote that the splenium of corpus callosum seemed intact. As far as we identified the series of MRI images of the patient, we can state that the anterior half of the splenium was damaged.

I am afraid that I could not understand your useful questions correctly, because of my poor English. If so, I'll be happy if you point out my mistakes, again.