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.

Conflict of Interest:

None declared

Most authorities, from Samuel Johnson's to the current Oxford University Dictionary, define "progression" as a change for the better stemming from the Latin "prograde" to improve continuously and "deterioration" as a change for the worse (Latin "deteriore"). Yet most neurological journals appear to accept "disease progression" (as in secondary progressive multiple sclerosis and progressive supranuclear palsy) to indicate that the natural history of an illness is deteriorating in character; most patients and their families would not agree. The most insensitive of neurologists would hardly tell an anxious family that their dear one's terminal illness was progressing. While lexicographers emphasise the dynamic flexibility of language, I doubt whether they would favour contrary ambiguity. Nor would they agree with a definition expressed in "Alice through the looking glass". "When I use a word "Humpty Dumpty said in a rather scornful tone, "it means just what I choose it to mean - neither more nor less". It seems legitimate to propose that "progression" should be applied to the disease process and hopefully to its elucidation, and that "deterioration" should apply to the history of a patient's illness. Perhaps the author's conventional confessions at the end of a submitted article, such as competing interests, provenance and particularly patient's consent should also indicate whose side they are on: the disease or the patient?

Gerald Stern

University College Hospitals, Queen Square, London WC1

Conflict of Interest:

None declared

Dear Sirs,

we read with great interest the paper by Cruz de Souza et al (1) , since we conducted a similar clinical experience, with slightly different findings In order to achieve data regarding the usability and reliability in the "real world" of CSF biomarkers in the early differentiation of Alzheimer Disease (AD) from frontal variant of Fronto-Temporal Dementia (fvFTD) , we designed a prospective study in which patients with initial doubtful diagnoses underwent lumbar puncture besides usual clinical, neuropsychological and neuroimaging tools. These patients were then followed up for at least 3 years, in order to confirm their diagnoses: the accuracy of the initial CSF diagnosis was assessed by comparison with the final clinical diagnosis The CSF samples have been collected by lumbar puncture in the morning, immediately centrifuged and stored at -80? until analysis. Beta-amyloid peptide 1-42 (bA) , tau and Ptau (phosphorilated at 181 Thr) were measured with ELISA kits (Innogenetics, Ghent, Belgium) in a laboratory where the operators were blinded to clinical information. The typical CSF AD profile was defined as a score below 1 calculated with the formula: bA/ 240+1.18 tau, which is known to distinguish AD from controls and from other dementias with optimal sensitivity and specificity (2) This prospective study started on January 2006. All consecutive patients admitted to our tertiary Memory Clinic with a doubtful diagnosis of AD or fvFTD according to current research criteria underwent lumbar puncture as a diagnostic tool. On the basis of full clinical, neuropsychological and bioimaging evaluations, they were initially classified as AD or fvFTD independently from CSF metabolites levels.. Afterwards, they were evaluated at six months intervals by two expert neurologists (MF and MZ), blind to the CSF results, who had to confirm or discard the previous diagnosis. Thirty nine patients with AD and 37 patients with fvFTD showed significantly different CSF levels of tau and Ptau (increased in AD, p= 0.0004 and p= 0.009, respectively), bA (reduced in AD, p = 0.018), and ratios of tau and Ptau to bA (p = 0.0009 and p = 0.014, respectively). Seventy-seven per cent of AD and 30% of fvFTD patients showed the typical AD CSF pattern, with a K-index of concordance of CSF and clinical diagnoses of 47% . The not negligible prevalence of CSF AD pattern in fvFTD was unexpected but coherent with the findings of Visser et al (3) who found a typical AD CSF pattern in 31% of their 89 healthy controls. The sensitivity and the specificity of typical CSF AD pattern were 77%; the positive predictive value (PPV) was 73% and negative predictive value (NPV) was 80% When we tried to correlate CSF metabolites with main clinical and demographic features, only the ratio tau/bA negatively correlated with MMSE scores, both in AD (r = - 0.33; p = 0.022) and fvFTD (r = - 0.34; p = 0.030) These results are similar to those of Pijnenburg et al (4) who studied CSF tau and bA of 35 FTD and 51 AD patients, clinically defined but not followed up. They found significant differences in the comparison of the two groups, but concluded that the "measurement of tau and bA is not useful for the diagnosis of FTD" Notwithstanding similarities in sizes of AD and fvFTD groups, methological design, diagnostic criteria and biochemical measurements, our findings are less optimistic than those of Cruz de Sousa et al. A major limitation of both studies is the lack of pathological confirmation of the diagnoses. Until now there is only one paper (5) in which the diagnoses were definite neuropathologically or genetically. The CSF biomarkers of 19 AD were compared with those of 30 FTD patients and, using ROC analysis, the ratio tau/bA at a cut-off value of 1.06 had a sensitivity of 79% and a specificity of 97% at distinguishing AD from FTD. We suggest that until there will be a convincingly ample study comparing CSF markers from autopsy-verified AD and FTD patients, the CSF analysis must be considered useful but not definite diagnostic criteria

REFERENCES

1) Cruz de Sousa L, Lamari F, Belliard S, Jardel C, Houillier C, de Paz R, Dubois B, Sarazin M. Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer's disease from other cortical dementias. JNNP 2011;82:240-246 2) Riemenschneider M, Lautenschlager N, Wagenspfeil S, Diehl J, Drzezga A, Kurz A Cerebrospinal fluid tau and bA proteins identify Alzheimer's disease in subjects with mild cognitive impairment. Arch Neurol 2002; 59: 1729-1734. 3) Visser PJ, Verhej F, Knol DL, et al. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study : a prospective cohort study. Lancet Neurol 2009; 8: 619-627. 4) Pijnenburg YAL, Schoonenboom NSM, Rosso SM, et al. CSF tau and bA are not useful in the diagnosis of frontotemporal lobe degeneration. Neurol 2004; 62:1649 5) Bian H, van Swieten JC, Leight S, et al. CSF biomarkers in frontotemporal lobar degeneration with known pathology Neurol 2008; 70: 1827-1835.

Conflict of Interest:

None declared

In 2002, we reported in this journal a patient with corticosteroid- responsive oculopharyngeal myopathy and an absence of chondroitin sulfate in muscle biopsies [1]. In recent years, the patient was found to have antibodies against muscle-specific kinase (MuSK). This female patient presented in 1993 at the age of 42 years with proximal muscle weakness in the neck and difficulty in swallowing, followed by blepharoptosis and double vision. The symptoms showed no obvious diurnal variation with normal repetitive stimulation tests and a negative Tensilon test, and there was no thymoma. The patient developed respiratory failure associated with hypercapnia and had to receive artificial respiration, but eventually showed a dramatic recovery with oral corticosteroid therapy. The initial diagnosis remained undetermined. Reports in the medical literature describing corticosteroid-responsive myopathic cases with similar clinical symptoms and signs associated with deficient chondroitin sulfate prompted us to examine chondroitin sulfate in stored muscle specimens from the patient and the results provided evidence for deficient chondroitin sulfate [1,2]

In 2004, the patient had a worsening of her respiratory function while given predonisolone orally at a dose of 12 mg/day. An increase of predonisolone to 60 mg/day resulted in a marked resolution of the serious symptoms, and this was followed by a gradual tapering of corticosteroids. In 2008, a similar serious episode also induced a respiratory problem when the patient was given predonisolone at a dose of 20 mg/day, in which an increase of the dose to 60 mg/day again improved the symptoms. Thereafter, predonisolone was gradually tapered to 30 mg/day as a maintenance dose.

Given the presence of similar symptoms in cases that were positive for antibodies against MuSK [3], we examined the levels of these antibodies in the patient's serum in 2008. We observed anti-MuSK antibodies at a concentration of 10.0 nM (less than 0.01 nM in controls). This high antibody titer led to a diagnosis of anti-MuSK antibody-positive oculopharyngeal myopathy, although the patient did not have the clinical features of myasthenia gravis. To the best of our knowledge, there are only 2 cases, our current case and a previously reported case, characterized by chondroitin sulfate-deficient myopathy [1,2].

The pathogenic relationship between deficient chondroitin sulfate and anti-MuSK antibodies remains to be defined. It is possible that the absence of chondroitin sulfate may involve an event that is secondary to the myopathy associated with the presence of anti-MuSK antibodies. MuSK forms a complex with several factors such as Dok7 [4]. Further studies are necessary to examine whether chondroitin sulfate interacts with one of these factors.

References 1. Yabe I, Kikuchi S, Higashi T, et al. A Japanese case of steroid responsive myopathy with deficient chondroitin sulphate. J Neurol Neurosurg Psychiatry 2002; 73: 89-90. 2. al-Lozi MT, Hemelt VB, Pestronk A. Steroid-responsive myopathy with deficient chondroitin sulfate C in skeletal muscle connective tissue. Neurology 1998; 50: 526-9. 3. Ohta K, Shigemoto K, Fujinami A, et al. Clinical and experimental features of MuSK antibody positive MG in Japan. Eur J Neurol 2007; 14: 1029-34. 4. Bergamin E, Hallock PT, Burden SJ, et al. The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell 2010; 39: 100-9.

Conflict of Interest:

None declared