Francisco Javier Poblete

Franciso J Poblete

Pablo Corrochano

in the presence of alkaline hexacyanoferrate(III)

Keywords: Ruthenium(VI), Alcohol oxidation, hexacyanoferrate(III)

Alcohol oxidation catalyzed by Ru(VI) in the presence of alkaline hexacyanoferrate(III).

INTRODUCTION

The metal-catalyzed oxidation of organic substrates is a topic of major interest, especially for reactions in which the substrates are not easily oxidized by common oxidants. [1][2][3] One such example is the oxidation in alkaline media of primary and secondary alcohols by hexacyanoferrate(III). The reaction rate is extremely slow, but the presence of ruthenium compounds in catalytic concentrations allows the study of the kinetics in a reasonable time period. 4 The catalytic activity of these ions is attributed to their capacity to exist in more than one oxidation state, their capacity to form complexes and their capacity to change their coordination number. 5 These characteristics justify the use of ruthenium complexes in homogeneous alcohol oxidations. Moreover, the use of a catalyst is compatible with the existence of sensitive linkages in the alcohol molecule. 6 The most frequently used ruthenium catalysts are Ru(III), Ru(VI) and Ru(VIII) species' and numerous kinetic studies have been undertaken using these catalysts. 7- 18 The goal of the work described here was to gain an understanding of the decomposition process of the catalyst-substrate complex with Ru(VI) as catalysts in conjunction with alkaline hexacyanoferrate(III).

With this aim in mind, the results found in this work for different alcohol oxidation reactions, using Ru(VI) as catalyst, are compared with the Taft steric effects and the pK a values of each alcohol in order to predict the reactivity the alcohols.

EXPERIMENTAL

Reactants. The reagents used, i.e. hexacyanoferrate(III), sodium hydroxide, sodium lactate, 2-methyl-2,4-pentanediol, 2,3-butanediol, 2-butanol, 2-propanol and sodium perchlorate were all A.R. grade and were purchased from Merck. The solutions were prepared using deionized water from an OSMO BL-6 deionizer from SETA. Sodium ruthenate solution was prepared according to a literature procedure. [START_REF] Lalitha | Transition Met[END_REF] The purity of stock solutions was assessed by measuring the ratio between the absorbance at 465 nm and 386 nm, which should equal 2.07 for pure ruthenate. General. The oxidation kinetics for the alcohols were followed by measuring the optical absorbance of hexacyanoferrate(III), A, at 420 nm on a Perkin-Elmer Lambda 3B spectrophotometer. The initial rates method was used for the kinetic analysis. The initial rates of disappearance of hexacyanoferrate(III) were obtained as described previously 20 using the expression

) dt / dA ( / 1 v 0 ε - =
, where 1 1 cm M 1000 --= ε at 420 nm. The ionic strength was kept constant at 0.5 M by the addition of sodium perchlorate. The only organic reaction product of the oxidation of the alcohols was the corresponding ketone, which was identified using a Hewlett-Packard 5890 Series II gas chromatograph equipped with a BP-21 polyethylene glycol column (50 m length × 0.22 µm i.d., 25 µm film thickness). The stoichiometry of the reaction was obtained using a concentration excess of hexacyanoferrate(III) in relation to the alcohols. The residual oxidant concentration was measured spectrophotometrically and showed that one mole of alcohol consumed two moles of hexacyanoferrate(III).

RESULTS

The v 0 values for five series' of kinetic runs at different

) 1 ( ] ) ( [ ] ) ( [ 0 3 6 3 2 0 3 6 1 0 - - ′ + ′ ′ = CN Fe k k CN Fe k v
The dependence of v 0 on [alcohol] 0 , while the other parameters are kept constant (

) 3 ( ] ) ( [ ] [ ] ) ( [ ] [ ] ) ( [ ] [ 0 3 6 0 0 3 6 0 0 3 6 0 0 - - - + + + = CN Fe alcohol E CN Fe D alcohol C B CN Fe alcohol A v
A plot of the experimental data shows that the parameter B is negligible in comparison to the other factors (by almost three orders of magnitude), so the equation can be rearranged to:

) 4 ( ] ) ( [ ] [ ] ) ( [ ] [ ] ) ( [ ] [ 0 3 6 0 0 3 6 0 0 3 6 0 0 - - - + + = CN Fe alcohol E CN Fe D alcohol C CN Fe alcohol A v
Equations ( 1) and ( 2) indicate a change of order from one to zero for both hexacyanoferrate(III) and alcohol species upon increasing their concentrations.

The variation of v 0 with [catalyst] 0 is shown in Figure 3 for the oxidation of the different alcohols by hexacyanoferrate(III) using Ru(VI) as a catalyst. The v 0 [catalyst] 0 data were fitted to a linear regression and this gave the following expression:

) 5 ( ] [ 0 0 catalyst k v v c unc + =
These results indicate that the kinetics are first order with respect to catalyst concentration and the rate of the uncatalyzed reaction, v unc , is negligible compared to that of the catalyzed reaction.

For the studied alcohols, the initial rate passes through a maximum as [OH -] is varied, as shown in Figure 4 for the case of sodium lactate. In this figure it can be observed that v 0 does not tend to zero at very low [OH -]. The variation of v 0 with the basicity of the medium is complicated and can obey to the following equation:

F o r P e e r R e v i e w 5 ) 6 ( ] [ ] [ 1 ] [ ] [ 2 2 1 2 2 1 0 0 - - - - + + + + = OH B OH B OH A OH A A v
The v 0 vs. [OH -] data were fitted to equation ( 6) by means of a nonlinear regression program, in order to obtain the parameters A and B. The best average error was obtained when A 2 = 0.

The possible formation of free radicals as intermediates was investigated by the addition of radical scavengers to the reaction mixture. The addition of either 0.01 M acrylonitrile or 1.6 × 10 -4 M 2,4,6-tri-tert-butylphenol (a stronger radical scavenger) did not have any effect on the reaction rate when Ru(VI) was used as the catalyst.

The oxidation of cyclobutanol was carried out because the nature of its oxidation products depends on the reaction mechanism. One-electron oxidation produces acyclic four-carbon compounds, which appear to be derived from the primary free radical ⋅CH 2 CH 2 CH 2 CHO, whereas two-electron oxidation produces cyclobutanone directly. 22,23 The following kinetic conditions were employed in this experiment: [OH -] = 0.1 M, I = 0.5 M and T = 30 ºC. Under these conditions the oxidation of 0.08 M cyclobutanol by 2.0 × 10 -3 M hexacyanoferrate(III) using 2.5 × 10 -6 M catalyst produced cyclobutanone as the major product in the case of Ru(VI).

Although the organic substrates encompass a wide variety of alcohols, including diols, only the 2hydroxyl group will be oxidized, as observed experimentally, because tertiary alcohols (0.1 M tertbutanol) were found to be unreactive under kinetic conditions. 21 The presence of a hydrogen on the αcarbon of the alcohol is therefore necessary for the reaction to progress 24 due to the fact that tertiary alcohols do not react under the experimental conditions employed.

The observed oxidation rate of The relative rates of oxidation of meso-and DL-hydrobenzoin were measured in order to determine if the oxidation proceeds through either an intermediate chelate complex or a complex in which only one hydroxyl group is coordinated with the ruthenium(VI). 25 The experimental data obtained indicate that both isomers were oxidized at comparables rates, so we can conclude that the oxidation of the alcohols involves the coordination of only one hydroxyl group to ruthenium(VI).

DISCUSSION

As previously discussed 7,20,21,26 for Ru(VI), the dependence of the initial rate on

[ 3 CH CHOH R
--] 0 suggests the formation of an intermediate complex,

- 2 1 C , between - 2 4
RuO and the organic substrate:

k 1 k 1 2 2 3 4 1 CH CHOH R RuO C (7) - -→ - ←  - -+
where -2 1 C has the following structure: which decomposes slowly to produce a reduced form of catalyst,

- 3 3 ) OH ( RuO
, and a carbocation as follows:

) 8 ( ) ( 3 3 3 2 1 2 - + - + - - →  OH RuO R OH C CH C k O Ru O C H H R R' 2- F o r P e e r R e v i e w 7
Step 7 involves a hydride transfer from the α-C-H bond of the alcohol to the oxoligand of ruthenium, a process that is favoured by the prior coordination of the organic substrate to the metal through the oxygen of the hydroxy group. 26 The occurrence of this hydride transfer is supported by the following experimental results: (a) a moderate kinetic isotopic effect, which indicates cleavage of a C-H bond and the absence of free radicals in the reaction mixture, (b) oxidation of cyclobutanol produces cyclobutanone as the sole product, and (c) the negative value of the Hammett reaction constant found for the oxidation of benzyl alcohol. 27 The following fast reaction would yield the corresponding ketone:

3 3 2 CH C OH R OH CH C O R H O (9) + - - - +  → - - +
The dependence of v 0 on

+  → +

Step 9 is supported by the previously described fact that the oxidation of alcohols by small quantities of ruthenate proceeds at a similar rate to the reoxidation of the reduced form of the catalyst by

- 3 6 ) CN ( Fe
. 21 Step 9 is fast relative to oxidation of the substrate at high RuO (OH) OH RuO (OH) ( 14)

- -←  -  → +
The existence of these hydroxy-oxy complexes of ruthenium was suggested by Luoma and Brubaker, who studied the reaction between perruthenate and manganate ions in an aqueous alkaline medium. 28 Application of the steady state conditions with respect to RuO (OH) -are equal (for simplicity), gives the following theoretical rate equation for the disappearance of hexacyanoferrate(III): 15) with the experimental rate equation (4) provides the rate constants for intermediate complex decomposition, k 2 , and catalyst regeneration, k 3 . The respective values of k 2 and k 3 for each alcohol are summarized in Table 1.

3 6 3 1 2 3 A 6 T 3 3 1 2 A 3 -1 2 B 6 1 3 A 6 d[Fe(CN) ] dt 2 k k k k [Fe(CN) ][diol][Ru(VI)] (15) k k k [diol] k (k k )k [Fe(CN) ] k k k [Fe(CN) ][diol] - - - - - = + + + where k A = 1 + K 1 [OH -] and k B = 1 + K 1 [OH -] + K 1 K 2 [OH -]
On considering the values in Table 1, it can be seen that k 3 , the regeneration of the catalyst, is a constant value that is independent of the nature of the substrate. However, the value of k 2 , the intermediate complex decomposition, varies as a function of the substrate. Considering these facts, a correlation between the structure of a given substrate and oxidation rate can be obtained using the Taft equation. 29

X S H k E Ln (16) k = ′
Taft steric parameters were obtained by the addition of the different molecular fragments in each alcohol [START_REF] Hansch | Substituent Constants for Correlation Analysis in Chemistry and Biology[END_REF] and their values are shown in Table 1. A linear correlation is obtained when Ln k 2 is represented vs. Taft steric parameters, as shown in Figure 5.

The pK a values give a relatively good measure of the nucleophilic nature of molecules. A plot of pK a values and σ steric data is shown in Figure 6 and a good linear correlation is observed. This linear correlation indicates that the higher the pK a value of the alcohol the more nucleophilic it is. If the alcohol is more nucleophilic, the intermediate

- 2 1
C is more stable and, as a result, the complex decomposition rate constant is lower.

CONCLUSION

The kinetics for the oxidation of alcohols by Fe(CN)to regenerate the catalyst. This rate constant for each alcohol studied does not depend of the nature of the alcohol. For the overall alcohol oxidation the rate constants for complex decomposition and catalyst regeneration have been obtained.

Finally, a correlation between the reaction rate of complex decomposition and the inductive and conjugative effects has been established. On considering Figures 5 and6, one can conclude that alcohols with more than one functional group have a higher rate constant. When the alcohol is more nucleophilic, the intermediate

- 2 1
C is more stable and the complex decomposition rate constant is lower. This finding confirms that if the alcohol molecule contains more than one functional group, the intermediate complex decomposition process becomes faster than in single linear alcohols. This effect can be attributed to the inductive and conjugative effect of the "extra" functional groups present in these molecules.

REFERENCES.

1. Hiremath GA, Timmanagoudar PL, Nandibewoor ST. J. Phys. Org. Chem. 1998 Figure 6. Relationship between the pK a of the alcohol and its σ steric .

19

 19

  Figure 1. In each series the concentration values of alcohol, ruthenate, hydroxide ions, temperature and ionic strength were kept constant ([alcohol] = 0.05 M, [NaOH] = 0.15 M, [Ru(VI)] = 6 × 10 -6 M, T = 30 ºC and I = 0.5 M). Analysis of the data obtained shows a good correlation with the expression:

  , [NaOH] = 0.15 M, [Ru(VI)] = 3 × 10 -6 M, T = 30 ºC and I = 0.5 M), is shown in Figure2. The dependence of v 0 on [alcohol] 0 shows a Michaelis-Menten behaviour, as described previously.21 This study led to the following expression:

  ] 0 can be described by the fitted expression:

  order to verify the existence of a kinetic isotope effect. A substantial primary kinetic isotope effect [(v 0,H /v 0,D ) = 5.9] for the catalyst under the following kinetic conditions: [Ru(VI)] ] = 0.5 M, [OH -] = 0.2 M, I = 0.5 M, and T = 30 ºC.

  v 0 on [OH] may be explained by assuming the existence of two active species of catalyst, ) -, which are in equilibrium as follows:

-

  2 and [Ru(VI)] T is the sum of the concentrations of Ru(VI) and Ru(IV), the concentration of Ru(V) would be negligible at any time because such species are involved in fast steps. Equation 15 explains the dependence of v 0 on [OH -], , [alcohol] and [catalyst].

  Ru(VI) as a catalyst, are governed by very similar experimental rate equations. These equations show a change in order from one to zero for both hexacyanoferrate(III) and alcohol upon increasing their concentrations and are first order with catalyst concentration. The reaction mechanism proposed involves alcohol oxidation by Ru(VI) through the formation of a substrate-catalyst complex, which subsequently decomposes to yield Ru(IV). Decomposition of the intermediate complex involves a hydride transfer from the α-C-H bond of the alcohol to the oxoligand of ruthenium and depends on the structure of the substrate (alcohol). The reduced catalyst species are subsequently oxidized by 3 6

  FIGURES

  Figure 2.

  Figure 3.

  Figure 4.

  Figure 5.

  Figure 6.

F

  FIGURE CAPTIONS

Figure 2 .

 2 Figure 2. Plot of v 0 vs. [S] 0 , where [S] = [alcohol] 0 ;

Figure 3 .

 3 Figure 3. Effect of [catalyst] 0 on the initial rate;

Figure 4 .

 4 Figure 4. Variation of v 0 with respect to [NaOH]. [Fe(CN) 6 3-] 0 = 1.2 × 10 -3 M, I = 0.5 M and T = 30 º C.

Figure 5 .

 5 Figure 5. Influence of the steric hidrance on the complex decomposition rate (k 2 ).

  if one accepts that the oxidation of the reduced form of catalyst occurs. In this way, the role of the co-oxidant,

											[	Fe	(	CN	)	3 6 ]	0
																Fe	(	CN	)	3 6	-	, is solely the
	regeneration of the catalyst through steps 10 and 11.
	3 RuO (OH)	3	-	+	Fe(CN)	3 6 -	3  → k	3 RuO (OH)	2	-	+	Fe(CN)	4 6	-	(10)
	3 RuO (OH)	2	-	+	Fe(CN)	3 6	-	 →	3 RuO (OH)	-	+	Fe(CN)	4 6	-	(11)
	3 RuO (OH)	-	OH	-				RuO	2 4	-	2 H O	(12)

can be explained

, 11,: 31

  .2. Panari RG, Chougale RB, Nandibewoor ST. J. Phys. Org.Chem. 1998, 11, 448.

	3. Griffith WP, Suriaatmaja M. Can. J. Chem. 2001, 79, 598.
	4. Kelson EP, Phengsy PP. Int. J. Chem. Kinet. 1999, 13, 901.
	5. Sheturam B. Topics in Chemistry Series 1: Chemical Kinetics and Reaction Mechanism. RBSA
	Publishers: Jaipur, 1991.

6. Griffith WP. Chem. Soc. Rev. 1992, 21, 179.

Table 1 .

 1 Complex decomposition rate (k 2 ) and catalyst regeneration (k 3 ) obtained when experimental data were fitted to expression(15) and values of σ steric and pK a for each alcohol studied.

	TABLES.
	Substrate	k 2 (min -1 )	k 3 (min -1 )	pK a	σ steric
	Sodium lactate	253.81 ± 11.4	(7.08 ± 0.9) × 10 4	--	2.62
	2,3-butanediol	291.12 ± 9.2	(7.10 ± 0.8) × 10 4	14.85	2.1
	2-methyl-2,4-pentanediol	267.23 ± 7.7	(7.13 ± 0.7) × 10 4	14.2	2.5
	2-propanol	58.48 ± 3.6	(7.76 ± 0.4) × 10 4	15.7	1.57
	2-butanol	40.31 ± 2.9	(7.63 ± 0.5) × 10 4	14.93	1.61
	o
		r
		P
		e e r
			R e v i e w
					19

http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry

Journal of Physical Organic Chemistry


MD Anabela Cardoso Pinto
email: anabela.pinto@hsm.min-saude.pt

PhD José Pedro Almeida

MD Susana Candeias Pinto

MD João Pereira

António Oliveira Gouveia

Mamede De Carvalho

António Gouveia Oliveira

PhD ; Mamede De Carvalho

HOME TELEMONITORING OF NON INVASIVE VENTILATION DECREASES HEALTHCARE UTILIZATION IN A PROSPECTIVE CONTROLLED TRIAL OF ALS PATIENTS

Keywords: Amyotrophic lateral sclerosis, healthcare utilization, non-invasive ventilation, survival and telemedicine

établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease in which respiratory insufficiency is the most common terminal event. Non-invasive positive pressure ventilation (NIV) has become the standard management to respiratory impairment by increasing quality of life and reducing the likelihood of resorting to tracheostomy [START_REF] Annane | Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders[END_REF][START_REF] Miller | Examining the evidence about treatment in ALS/MND[END_REF][START_REF] Pinto | Respiratory assistance with a non-invasive ventilator (Bipap) in MND/ALS patients: survival rates in a controlled trial[END_REF][START_REF] Lyall | A prospective study of quality of life in ALS patients treated with noninvasive ventilation[END_REF][START_REF] Heffernan | Management of respiration in MND/ALS patients: an evidence based review[END_REF][START_REF] Annane | Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders[END_REF][START_REF] Servera | Appropriate management of respiratory problems is of utmost importance in the treatment of patients with amyotrophic lateral sclerosis[END_REF][START_REF] Lechtzin | Early use of non-invasive ventilation prolongs survival in subjects with ALS[END_REF][START_REF] Hoglund | Should your hospital implement wireless solutions?[END_REF]. Improved rate of survival and quality of life seem to correlate with the earlier prescription of NIV, before diurnal signs of respiratory failure have been established, with a forced vital capacity (FVC) over 50% of the predicted value, or at detection of early signs of impending nocturnal respiratory insufficiency [START_REF] Lechtzin | Early use of non-invasive ventilation prolongs survival in subjects with ALS[END_REF][START_REF] Pinto | Nocturnal pulse oximetry: a new approach to establish the appropriate time for non-invasive ventilation in ALS patients[END_REF][START_REF] Jackson | A preliminary evaluation of a prospective study of pulmonary function studies and symptoms of hypoventilation in ALS/MND patients[END_REF][START_REF] Lechtzin | Respiratory effects of amyotrophic lateral sclerosis: problems and solutions[END_REF].

NIV requires a dynamic process of adaptation which is achieved in an unknown proportion of patients. Probably, patients with severe bulbar weakness and marked sialorrhea have the highest rate of poor compliance [START_REF] Bach | Amyotrophic lateral sclerosis: prolongation of life by noninvasive respiratory AIDS[END_REF][START_REF] Bach | Oximetry and indications for tracheotomy for amyotrophic lateral sclerosis[END_REF]. In fact, compliance to NIV is a complex issue and a recent matter of debate [START_REF] Pinto | Nocturnal pulse oximetry: a new approach to establish the appropriate time for non-invasive ventilation in ALS patients[END_REF][START_REF] Pinto | Can amyotrophic lateral sclerosis patients with respiratory insufficiency exercise?[END_REF][START_REF] Pinto | Respiratory disorders in ALS: sleep and exercise studies[END_REF][START_REF] Wyatt | British Thoracic Society guidelines on non-invasive ventilation[END_REF][START_REF] Jackson | Factors correlated with NPPV use in ALS[END_REF]. Certainly, improved tolerance and compliance can only be reached by continuous, customized setting of the device that depends on many factors, such as lung mechanics [START_REF] Wyatt | British Thoracic Society guidelines on non-invasive ventilation[END_REF][START_REF] Babu | Non-invasive ventilation in chronic obstructive pulmonary disease[END_REF], inspiratory and expiratory triggers, breathing frequency [START_REF] Baydur | Long term non-invasive ventilation in the community for patients with musculoskeletal disorders: 46 year experience and review[END_REF][START_REF] Aghai | Synchronized nasal intermittent positive pressure ventilation (SNIPPV) decreases work of breathing (WOB) in premature infants with respiratory distress syndrome (RDS) compared to nasal continuous positive airway pressure (NCPAP)[END_REF][START_REF] Achour | Asynchrony and cyclic variability in pressure support noninvasive ventilation[END_REF], effective correction of blood gases [START_REF] Bach | Amyotrophic lateral sclerosis: prolongation of life by noninvasive respiratory AIDS[END_REF][START_REF] Lujan | Non-invasive home mechanical ventilation: effectiveness and efficiency of an outpatient initiation protocol compared with the standard inhospital model[END_REF], and different metabolic demands. The compliance to NIV in ALS has only been evaluated taking into account the number of hours of usage a day, which is very limited information. Nevertheless, most authors have reported longer survival in patients using NIV for more than 4 hours per day [START_REF] Pinto | Respiratory assistance with a non-invasive ventilator (Bipap) in MND/ALS patients: survival rates in a controlled trial[END_REF][START_REF] Lujan | Non-invasive home mechanical ventilation: effectiveness and efficiency of an outpatient initiation protocol compared with the standard inhospital model[END_REF][START_REF] Aboussouan | Objective measures of the efficacy of noninvasive positive-pressure ventilation in amyotrophic lateral sclerosis[END_REF][START_REF] Farrero | Outcome of non-invasive domiciliary ventilation in elderly patients[END_REF].

Recent technology advances allow a more extensive control of the relevant sets in addition to the analysis of the number of hours/day of utilization. It is possible to assess breath pressures and volumes, the percentage of utilization of a predetermined target pressure, respiratory rate, peak flow, number of apneas, percentage of leaks, and oxygen saturation on pulse oximetry. It is also possible to perform online checking and correction via modem connection, hopefully increasing patient comfort, tolerance and compliance [START_REF] Fiorenza | Hospital monitoring, setting and training for home non invasive ventilation[END_REF].

Nonetheless, the advantages of these new technologies have scarcely been evaluated in neuromuscular patients [START_REF] Lucangelo | Lung mechanics at the bedside: make it simple[END_REF].

PATIENTS AND METHODS:

From January 2003 to September 2006, all consecutive ALS patients ventilated with Goodknight 425ST® bi-level device (Tyco Healthcare Group LP, CA) were screened and considered for inclusion in a prospective and controlled trial, if at diagnosis they had no signs or symptoms of respiratory insufficiency with FVC ≥ 75% of the predicted value, PaO 2 ≥80mmHg and PCO 2 ≤45mmHg and age between 18-75 years. Patients with gastrostomy, cognitive impairment, or other significant disorders, were also excluded from this trial.

Patients were randomly assigned to one of two groups according to their residential area.

Patients included in G1 (control) were living in Lisbon, in this group the managing of NIV settings and assessment of compliance was performed through regular office visits at admission, 2-3 weeks later, and then every 3 months. Patients included in G2 (intervention) were living outside Lisbon and the follow-up was performed by weekly modem-tele monitoring, in addition to regular office-visits at each three-month interval. All participants were evaluated with the ALSFRS each 3 months by a physician blind to the study group of the patient. Respiratory functional tests (RFT) were performed each 6 months by a technician unaware of this study. All received a helpline whenever needed, in addition to regular office visits [START_REF]The Amyotrophic Lateral Sclerosis Functional Rating Scale. Assessment of activities of daily living in patients with amyotrophic lateral sclerosis. The ALS CNTF treatment study (ACTS) phase I-II Study Group[END_REF][START_REF] Mendoza | A comparison of maximal inspiratory pressure and forced vital capacity as potential criteria for initiating non-invasive ventilation in amyotrophic lateral sclerosis[END_REF]. The trial duration was established from NIV adaptation to a follow period of 3 years or death. ALS patients were ventilated taking into account a set of criteria that included clinical symptoms, conventional respiratory function tests as recommended by AAN [START_REF] Miller | Examining the evidence about treatment in ALS/MND[END_REF] (including FVC and maximal inspiratory pressure), neurophysiologic studies and nocturnal pulse oximetry [START_REF] Pinto | Nocturnal pulse oximetry: a new approach to establish the appropriate time for non-invasive ventilation in ALS patients[END_REF][START_REF] Jackson | A preliminary evaluation of a prospective study of pulmonary function studies and symptoms of hypoventilation in ALS/MND patients[END_REF]. NIV was indicated as early as patients agreed after the first symptoms and signs of changes, in an office-based setting. NIV is optimized to improve clinical symptoms and nocturnal pulse oxymetric changes. The procedure include slow increments of Inspiratory Positive Air pressure (IPAP) in order to achieve a steady-state with normal breathing patterns, normal pulse rate and SpO2 over 95%, with the back-up rate slightly lower than the patient's own respiratory frequency.

For NIV compliance follow-up and flexible parameter settings changes, all participants received a helpline to clarify any doubts or to seek medical advice whenever difficulties were felt. Patients in G1 were, in addition, re-observed 2-3 weeks after entry, and patients in G2 had a modem pre-installation programmed to communicate every week.

Anticipating difficulties and constraints imposed by continuously monitoring and data storing, patients in G2 were further instructed to activate the system once a week or whenever they felt uncomfortable with the device, after giving a phone call to the physician in charge, and instructed to be in touch with the helpline in case of need.

A crucial element of the telemedicine instrument functionality is the remote transmission of data. The instrument is equipped with an internal modem, allowing direct access to the Internet via TCP/IP protocol along with data storing at the patient's home. The bi-directionality of the system allowed us not only to register compliance data but also to introduce modifications in parameter settings, thus permitting real-time evaluation of its impact on ventilatory mechanics. Regarding the device used in this study the bi-level instrument included backup rate/assist control as well as patented FlowSens technology that allow the physician to customize the inspiratory and expiratory settings for greater patient comfort and synchronicity.

In addition, an intermediate level of care was set up to detect and flag alarm signs requiring an immediate revision of settings. This monitoring was performed by one of us (JP) who, after reviewing the synthesis report or night calendar, was instructed to send a message to the physician who decided on possible setting change, to schedule an office visit, a phone call or a real-time communication. Since, there are no published or established alert signs for home ventilation, in rapidly progressive neuromuscular disorders, we considered all data that were ±1SD of the mean values of IPAP, expiratory positive air pressure (EPAP), Inspiratory/expiratory ratio (I: E), back-up rate, inspiratory sensivity (IS), expiratpry sensivity (ES) and rise time (rT), as alert signs. These limits were defined by data analysis of 67 ALS with regular NIV use ≥ 6 hours a day followed in our Unit (unpublished data). In addition, we also considered as an alert sign all data conflicting with the preceding ventilation profile of the patient.

Primary Outcome

We considered 2 primary outcomes measurements. First, the number of office and emergency room visits, and hospital admissions during the entire span of NIV use; second, the number of parameter setting changes during the period (number of days, DTC) needed to achieve full compliance (defined as NIV use >6 hours) and throughout all period of NIV use.

Secondary Outcomes

As secondary outcome measures we considered the clinical and functional disease progression as defined by ALSFRS total score, respiratory, spinal and bulbar sub-score (every 3 months) , RFT (very six months), the total survival (total number of days from symptoms onset to death or the end of the study), survival from first visit (total number of days from diagnosis to death or end of study) and survival with NIV (total number of days from NIV adaptation to death or end of the study). In addition, we also recorded the type of parameter setting change and the compliance, assessed by the number of hours of usage a day; the percentage of spontaneous breathing; back-up respiratory rate; average, minimum and maximal respiratory rates; and the percentage of attained predetermined pressures.

In this study, all patients gave written informed consent, after protocol approval by the local Ethics Committee and since this is a pilot study, sample size considerations were not based on a predefined clinical significant difference in health resource utilization and survival probability, but rather on studying the minimal number of subjects (20 per group) that would allow the application of large sample statistical methods.

Statistical Analysis

Demographic and baseline clinical and respiratory function data were analysed for homogeneity between groups with two-sample t-tests and Fisher's exact test. Event count data, such as health care utilization data (number of office visits, hospital admissions and emergency room admissions, the number of parameters changes and number of DTC were analysed with the person-years method and reported as incidence rate ratios with exact Poisson confidence intervals and significance tests. Repeated measurements data (panel data) on parameters settings and patient compliance were analyzed with random effects regression.

Survival was analysed with the Kaplan-Meier method and survivor functions were compared with the log rank test. Student's t-tests and the Fisher's exact test were used throughout as appropriate. Differences were considered statistically significant at the p<0.05 level. All tests are two-tailed. Statistical analysis was performed with STATA 10 (Stata Corporation, College Station, TX, USA).

RESULTS:

Out of 155 consecutive home-ventilated ALS patients, 51 were excluded because they were ventilated with devices that did not allow compliance analysis through modem communication. A group of 62 additional patients were excluded because had FVC lower than 75% of the predicted value. Among the 42 eligible patients, two patients refused to participate and were excluded. The final analysis set consisted of 20 patients in the control group (G1) and 20 patients in the intervention group (G2), but one patient in G2 was lost for follow-up and excluded from analysis. (Figure 1) No difference was found regarding demographic data, clinical characteristics and respiratory function tests between groups both at diagnosis and at NIV adaptation, except for FVC that was significantly higher in G1 at diagnosis (p=0.04) -Tables 1 and2. Moreover, mean values of the initial parameter settings of NIV at the time of non-invasive ventilation onset were not different, showing that the procedure was the similar in both groups.

Primary outcome

Table 3 shows incidence data regarding the number of office and emergency room visits and in-hospital admissions. The incidence rate was three to six times lower in G2 patients (p< 0.0001). Random-effects regression analysis of the overall difference in the type of parameter settings changes throughout the ventilation period showed no differences between groups. The same negative results were observed in the comparison of compliance data, although a trend towards a greater number of daily hours of NIV use in Group 2 was observed (p= 0.17).

Secondary outcomes

The incidence rate of the number of changes in parameter settings during DTC and over the entire period of NIV showed a slightly higher incidence rate in G2 during the initial period of adaption (20%, p < 0.01%) but a clearly lower rate over the entire period of NIV (50%, p < 0.0001) -table 4.

The clinical progression rate prior to NIV adaption showed no differences between groups for the total ALSFRS score, as well as for bulbar and spinal subscores. Respiratory subscore tended to progress faster in G1 (p=0.04). However, after NIV adaptation, the random-effects general linear model regression analysis did not show statistically significant differences in the clinical progression, despite of a trend for slower progression of spinal subscore in G2 (p=0.15).

Considering survival evaluation, at study finish 12 patients were still alive in each group and differences did not reach statistical significance at the 5% level. However, patients included in G2 tended to have a longer survival (table 5 and figure 2).

DISCUSSION:

ALS is a dreadful neurological condition with a low incidence of 2-4/100.000 inhabitants, short survival and low prevalence of 5-7/100000 according to different epidemiological studies [START_REF] Wijesekera | Amyotrophic lateral sclerosis[END_REF]. The relatively small number of patients supports some difficulties in the randomization of patients based on computer generation in a single centre in our country. Thus, the present study is a prospective single-blinded quasi-randomized clinical trial that included consecutive patients, aimed to test the feasibility, efficacy and efficiency of telemedicine for home monitoring NIV. In addition, the patient selection based on geographical residence was not considered biased and, probably, appropriated to our purpose.

The feasibility of telemedicine for home monitoring patients with chronic respiratory failure (CRF) discharged from hospital in COPD patients within a mean follow-up time of 176 days has been assessed and showed that home monitoring was feasible, and useful for titration of ventilation settings [START_REF] Vitacca | A pilot study of nurse-led, home monitoring for patients with chronic respiratory failure and with mechanical ventilation assistance[END_REF].

To the best of our knowledge the present study is the first trial of NIV compliance evaluation with the new technical solution that enabled us to monitor at distance the registered data in the equipment software.

Before the present trial, in the run-in period, we had an exploratory phase to test safety, acceptance and accuracy. The system was suitable worked well and served our investigational purposes. Main limitations were related to the need of a fixed telephone line and the speed of data extraction.

Our study supports the role and utility of tele-monitoring in eliminating difficulties imposed by geographical distances and the lack of resources. We observed objective gains in terms of health care utilization (table 3) reflecting the efficiency of the system. Cost analysis is underway, but our preliminary data indicates significant cost reduction using telemonitoring (approximately 50%), as expected from the lower number of hospital visits and admissions. Therefore, in view of the limited resources of health systems [START_REF] De Lusignan | A pilot study of radiotelemetry for continuous cardiopulmonary monitoring of patients at home[END_REF][START_REF] Pfeifer | Telecare of patients with chronic obstructive airway diseases[END_REF],

this study strongly supports that the frequent virtual visits to the patients by modem communications may become current practice, as an alternative to the office-based control of compliance to NIV. Indeed the control of compliance is a critical issue because, despite recommendations, the rate of NIV use is poor and highly variable (range 0-70%) in European and American ALS centers. Chiò and co-workers showed that the use of NIV ranged from 50-70% depending on the size of the ALS clinics. More recently, Jackson reported 36% use in ALS patients with FVC lower than 50% of the predicted value, and correlated tolerance to respiratory symptoms. Other factors like age, race, type of insurance, forced vital capacity, disease duration, ALSFRS, caregiver burden or quality of life were not predictors of compliance [START_REF] Jackson | Factors correlated with NPPV use in ALS[END_REF][START_REF] Bourke | Noninvasive ventilation in ALS: indications and effect on quality of life[END_REF][START_REF] Bradley | Changes in the management of ALS since the publication of the AAN ALS practice parameter 1999[END_REF][START_REF] Miller | Outcomes research in amyotrophic lateral sclerosis: lessons learned from the amyotrophic lateral sclerosis clinical assessment, research, and education database[END_REF][START_REF] Chio | Amyotrophic lateral sclerosis care in Italy: a nationwide study in neurological centers[END_REF].

Other reasons may implicate the possible relationship of compliance to settings of the ventilators. The possible role of setting changes through modem communications in increasing compliance was not confirmed in the present study, probably due to the identical procedures that took place in both groups, all performed by one of the authors (AP) or due to the small sample size. However, our results showed a trend towards a greater number of hours of NIV use in G2, suggesting a marginal effect on compliance. Probably associated with this marginal effect, we observed a trend toward a survival benefit (p=0.17) in G2, table 5.

In addition, in G2 we were able to show 50% reduction in the number of parameter setting changes during the survival period with NIV, but 20% increase during the DTC period (exact Poisson p< 0.001. This result represents a tighter follow-up during the initial period of NIV adaptation, thus driving a reduction of the total time need to adjust settings over the whole period of ventilation.

Regarding the functional and survival outcome measures, the median survival with NIV was 334 days in G1 versus 865 days in G2 (p=0.13). Considering the survival from symptoms onset, the benefit in the median survival time was over 1500 days (figure 2).

Further calculations of the sample needed to achieve 90% of statistical power resulted in a number of 40 patients in each arm to show a significant survival impact. Moreover, a trend was also observed toward an improved functional outcomes in G2 patients, regarding ALSFRS spinal sub score (p = 0.15). This was not anticipated, as ALS patients in G1 had a closer follow-up provided by physiotherapy in our specialized centre.

Exercise was suggested to all patients included to the limits of perceived fatigue (Borg scale), simultaneously with NIV if needed [START_REF] Pinto | Can amyotrophic lateral sclerosis patients with respiratory insufficiency exercise?[END_REF], but patients in G1 were supervised by physiotherapists with special training in ALS. We hypothesise that timed and adequate intervention due to early detection of alert signs might allow patients to perform more daily physical activities. Ventilation subtleties may be not fully understood without quantifying measurements related to lung mechanics, meaning that clinical judgment may not be sensitive enough to early detect deviations from a ventilation profile otherwise detected by the regular observation of the night calendar. The increased speed of these communications with faster data transmission and improved alarm signs would certainly reassure patients, caregivers and physicians with benefits to all [START_REF] Tura | A telemedicine instrument for home monitoring of patients with chronic respiratory diseases[END_REF].

Whether our positive results are related to closer vigilance and faster correction of respiratory changes or to other undisclosed factor remains to be clarified. Future studies should evaluate impact of telemonitoring on the quality of life of patients and caregivers.

Figure 1 :

 1 Figure 1: Population and methods (flow chart)

Figure 2 :

 2 Figure 2: Kaplan-Meier survival estimate curves

Table 1 :

 1 Demographic and baseline clinical characteristics at diagnosis

	Assessed for eligibility: Consecutive ALS
	pats. with NIV(n= 105 )
	2003-2006
	Excluded (n= 51 )ventilated with
	other equipments : Harmony ST II
	® (n=49); VIVO 30 (n=3)
	Not meeting inclusion criteria:
	FVC < 75% act.pred.(n= 12 )
	Refused to participate: (n=2 )

ALS-FRS -ALS functional rating scale (B sc -bulbar subscore, Sp sc -spinal subscore, ALSFRS-R (R) -respiratory subscore of ALS-FRS-R); FVC (forced vital capacity), MIP (maximal inspiratory pressure), MEP (maximal expiratory pressure) and P01 (mouth occlusion pressure at 100ms) are expressed in percentage of the predicted value; sd -standard deviation.

Table 2 :

 2 Respiratory evaluation at NIV adaptation See abbreviations in table 1 footnote.

		Group 1	Group 2
		(m ± sd); range (min-max)	(m ± sd); range (min-max) p-value
	FVC (%)	(76±23);(55-122)	(85±20);(54-119)	0.32
	MIP (%)	(42±28);(10-89)	(50±20);(13-89)	0.40
	MEP (%)	(44±24);(13-98)	(54±21);(15-86)	0.24
	P0.1 (%)	(101±39);(51-196)	(91±54);(39-231)	0.61
	PaCO2 (mmHg)	(42±7);(35-59)	(40±5);(35-52)	0.46
	PaO2 (mmHg)	(83±15);(55-106)	(84±8);(71-95)	0.88

Table 3 :

 3 Results of Primary Outcome, health care utilization It is represented the confidence intervals (CI) and p values by applying exact Poisson statistics.

		Incidence density (% person-days)	Incidence rate ratio	95% C. I	p-value
		Group 1 Group 2
	Office visits	9.01	3.02	0.336	0.293-0.384 <0.0001
	Emergency room	0.58	0.11	0.194	0.099-0.373 <0.0001
	visits
	Hospital admissions	0.37	0.06	0.173	0.066-0.407 <0.001

Table 4 :

 4 Secondary outcome, incidence rate of parameters settings number of changes Incidence density is the person-time incidence rate. Incidence rate ratio is the ratio of the incidence density G1/G2. Changes/ NIV relates to the total period of NIV; Changes/DTC concerns the period from NIV onset to full compliance (>6 hours/day). It is represented the confidence intervals (CI) and p values by applying exact Poisson statistics. I, hereby sign disclose any personal or financial support or involvement with organizations with financial interest with the subject matter or any actual or potential conflict of interests Lisboa, 15th December 2009 Susana Pinto I, hereby sign disclose any personal or financial support or involvement with organizations with financial interest with the subject matter or any actual or potential conflict of interests Lisboa, 15th December 2009

		Incidence density	Incidence	95% CI	p-value
		(% person-days)	rate ratio
		Group 1	Group 2
	Changes/ NIV	1.70	0.91	0.533	0.401-0.711	<0.0001
	Changes/DTC	7.69	9.52	1.238	0.930-1.651	<0.001

To the best of our knowledge, only one study has compared the effectiveness of an outpatient initiation protocol with the standard in-hospital model for NIV[START_REF] Lujan | Non-invasive home mechanical ventilation: effectiveness and efficiency of an outpatient initiation protocol compared with the standard inhospital model[END_REF]. No study has yet evaluated the impact on compliance, function, survival and healthcare utilization of ALS patients submitted to wireless telemetry to control NIV settings, compared with the officevisit approach. We aimed to investigate this relevant problem

Acknowledgment:

This work was supported by "Fundação para a Ciência e Tecnologia" -PIC/IC/82765/2007.

The authors are grateful to Linde Sogas Co. for technical support.

Acknowledgment:

This work was supported by "Fundação para a Ciência e Tecnologia" -PIC/IC/82765/2007. The authors are grateful to Linde Sogas Co. for technical support.

Competing interests

The authors disclose any personal or financial support or involvement with organizations with financial interest with the subject matter or any actual or potential conflict of interests


PT Francesco Ferrarello
email: francescoferrarello@tiscali.it.

Marco Baccini

PT Lucio Antonio Rinaldi

Maria Chiara Cavallini

MD, PhD Enrico Mossello

PhD Giulio Masotti

MD Niccolò Marchionni

MD Mauro Di Bari

EFFICACY OF PHYSIOTHERAPY INTERVENTIONS LATE AFTER STROKE: A META-ANALYSIS

Keywords: Stroke, Clinical trials, Meta-analysis, Rehabilitation

Objective. Physiotherapy is usually provided only in the first few months after stroke, while its effectiveness and appropriateness in the chronic phase are uncertain. We conducted a systematic review and meta-analysis of randomized clinical trials (RCT) to evaluate the efficacy of physiotherapy interventions on motor and functional outcomes late after stroke. Methods. We searched published studies where participants were randomized to an active physiotherapy intervention, compared to placebo or no intervention, at least 6 months after stroke. Outcome was change in mobility and activities of daily living (ADL) independence. Quality of trials was evaluated using the PEDro scale. Findings were summarized across studies as effect size (ES) or, whenever possible, weighted mean difference (WMD) with 95% confidence interval (CI) in random effects models. Results. Fifteen RCT were included, enrolling 700 participants with follow-up data. The meta-analysis of primary outcomes from the original studies showed a significant effect of the intervention (ES 0.29, 95% CI 0.14-0.45). Efficacy of the intervention was particularly evident when short-and long-distance walking (SDW, LDW) were considered as separate outcomes, with WMD of 0.05 m/sec (95% CI 0.008-0.088) and 20 m (95% CI 3.6-36.0), respectively. Also ADL improvement was greater, though non-significantly, in the intervention group. No significant heterogeneity was found. Interpretation. A variety of physiotherapy interventions improve functional outcomes even when applied late after stroke. These findings challenge the concept of a plateau in functional recovery of patients that had experienced stroke and should be valued in planning community rehabilitation services.

INTRODUCTION

Beside being the third leading cause of death, stroke is the main cause of severe disability in the aging populations of industrialized countries. [START_REF] Lopez | Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data[END_REF] The dynamics of the disabling process after stroke is complex. Although most stroke survivors show some neurological recovery in the initial post-acute phase, usually within the first three months, [START_REF] Hankey | Rate, degree, and predictors of recovery from disability following ischemic stroke[END_REF] improvement may continue well beyond this time. As many as 40% to 60% of patients will recover functional independence in the domains of mobility and ADL from three months to 10 years after a stroke [START_REF] Hankey | Rate, degree, and predictors of recovery from disability following ischemic stroke[END_REF] and at a widely variable pace. [START_REF] Hankey | Long-term disability after first-ever stroke and related prognostic factors in the Perth Community Stroke Study, 1989-1990[END_REF] Conversely, once a given level of independence is reached, it can be hardly maintained long term, as functional status generally tends to deteriorate slowly over time. [START_REF] Langhammer | Bobath or motor relearning programme? A follow-up one and four years post stroke[END_REF][START_REF] Van De Port | Susceptibility to deterioration of mobility long-term after stroke: a prospective cohort study[END_REF] In general, rehabilitation services are designed without fully taking into account the complexity in functional evolution of stroke survivors. Although a variety of in-hospital or out-of-hospital multidisciplinary interventions may be proposed to promote motor function recovery, [START_REF] Duncan | Management of Adult Stroke Rehabilitation Care: a clinical practice guideline[END_REF] physiotherapy usually is deemed appropriate only within weeks or a few months after stroke. [START_REF] Jorgensen | Outcome and Time-Course of Recovery in Stroke .2. Time-Course of Recovery -the Copenhagen Stroke Study[END_REF] Thus, it is unusual that patients with "chronic" stroke are offered any form of rehabilitation. [START_REF] Langhammer | Bobath or motor relearning programme? A follow-up one and four years post stroke[END_REF] This is due to the limited availability of resources as well as to the paucity of high quality evidence of the efficacy of late rehabilitation. In view of scarce and inconclusive findings from RCT, the concept prevails that there is a limit to late functional recovery after a stroke and doubts are cast upon the effectiveness of late motor rehabilitation interventions.

As a result evidence-based practice guidelines generally agree that stroke survivors with persistent disabilities should be periodically assessed for further possible interventions, whereas agreement is scarce on the strength of recommendations on late rehabilitation. [START_REF] Duncan | Management of Adult Stroke Rehabilitation Care: a clinical practice guideline[END_REF][START_REF]The Intercollegiate Stroke Working Party. National clinical guidelines for stroke[END_REF][START_REF]Management of patient with stroke. Rehabilitation, prevention and management of complications, and discharge planning. A national clinical guideline[END_REF][START_REF]Clinical Guidelines for Stroke Rehabilitation and Recovery[END_REF][START_REF]Guidelines for management of ischaemic stroke and transient ischaemic attack 2008[END_REF] The present systematic review and meta-analysis of RCT was performed to evaluate the efficacy of motor rehabilitation and physiotherapy interventions conducted late after stroke.

METHODS

In accordance with the meta-analysis of randomized controlled trials (QUOROM) statement, [START_REF] Moher | Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses[END_REF] we conducted an extensive search for published RCT performed at least 6 months after stroke onset, enrolling five or more adults in each group, randomized to an active physiotherapy intervention aimed either at improving mobility and ADL independence, or at controlling treatment (placebo or no intervention). Active treatment had to be represented by conventional rehabilitation (including neuromuscular interventions, practicing functional activities, muscle strengthening and application of assistive equipments), and had to be provided or supervised by qualified physiotherapists (alone or within a multidisciplinary team).

This selection focused on physiotherapy interventions that are considered standard practice in stroke rehabilitation, [START_REF] Wit | Stroke rehabilitation in Europe -What do physiotherapists and occupational therapists actually do?[END_REF][START_REF] Hale | Exploring the content of physiotherapeutic home-based stroke rehabilitation in New Zealand[END_REF][START_REF] Dejong | Toward a taxonomy of rehabilitation interventions: Using an inductive approach to examine the "Black box" of rehabilitation[END_REF] excluding techniques which are highly innovative (e.g. robotic therapy) or poorly used in most community-based rehabilitation services (e.g. treadmill training with partial body weight support).

Because we focused on outcomes represented by functional abilities mostly involving lower extremities, we also excluded studies where active treatment targeted upper extremities (e.g. constraint induced movement therapy).

We performed an electronic search of original papers, published in English or Italian, indexed in MEDLINE, PEDro, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINHAL, ISI Web of Science, and EMBASE, with no temporal limits up to January 2010, using the following combination of keywords: (stroke OR cerebrovascular accident OR cerebrovascular disorders) AND (rehabilitation OR physical therapy OR physiotherapy OR occupational therapy OR exercise OR exercise therapy OR training) AND (randomized controlled trial OR meta-analysis). To ensure retrieval of all potentially relevant RCT, we scanned reference lists of pertinent articles, and performed handsearch of major journals. Reference lists of articles retrieved were evaluated for relevant publications. Setting, duration of intervention and of follow-up were recorded, but not used as selection criteria. Full texts of all articles judged to be of possible interest on the basis of title and abstract were retrieved. Two reviewers (FF, MDB) independently evaluated the studies selected for final inclusion; disagreement was resolved by consensus.

Outcome of the study was difference between groups at the end of the treatment period in mobility and ADL independence, measured with previously validated tools. Relevant data were extracted using a standard data recording spreadsheet, including characteristics of the population involved (age, gender, time elapsed from stroke), sample size, number of participants completing the study, characteristics of the intervention (therapeutic approach, setting, duration and professionals involved), primary and secondary objectives, results related to all the outcomes assessed, and other characteristics useful for quality evaluation (see below).

Where information was not available in the published material, details were requested from the authors.

The PEDro database, [START_REF]PEDro-the Physiotherapy Evidence Database[END_REF] which scores published RCT on rehabilitation, was consulted for quality evaluation. The PEDro score, developed by the Centre for Evidence-Based Physiotherapy, has been shown to be reliable [START_REF] Maher | Reliability of the PEDro scale for rating quality of randomized controlled trials[END_REF] and particularly useful for assessing the quality of studies in stroke rehabilitation. [START_REF] Olivo | Scales to Assess the Quality of Randomized Controlled Trials: A Systematic Review[END_REF] Criteria for quality assessment are represented by randomness and concealment of allocation, baseline comparability between groups, blinding of participants, therapists, and assessors, adequacy of follow-up assessments, intention-to-treat analysis, betweengroup comparisons, point estimates and variability. The total PEDro score ranges from 0 (poor quality) to 10 (excellent quality); a score of 6 is conventionally considered as a threshold to identify high quality studies. [START_REF]PEDro-the Physiotherapy Evidence Database[END_REF] The same criteria were applied to evaluate the quality of the two most recent studies, [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF] not found in the PEDro database.

Analytic procedures

To obtain the same data format for as many outcome measures as possible, preliminary data manipulation was performed as follows. In one study [21] mean and pooled standard deviation (SD) were calculated to create a single intervention group from data originally divided into three experimental groups, which differed only in the specific care setting (outpatient, home, and mixed). Missing SD values for the end of treatment Functional Independence Measure (FIM) scale were substituted with baseline values in one study [START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF] or were calculated from reported standard error of the mean in another. [START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF] Finally, mean and SD data were obtained directly from the authors of a study, [23] where most outcome data had been originally reported as median and interquartile range. Original values of outcome measures which decrease with improving performance were reverted into corresponding negative values. [24,25] Three studies, in which a cross-over design was used, [24,26,27] were analyzed as parallel group RCT, by calculating effects before the point of cross-over. In one study, [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF] data pertinent to the present meta-analysis were represented only by those collected in one of three intervention arms and to controls.

A variety of different outcome measures were found, sometimes also in the same study, within the broad category of mobility and ADL independence. The primary outcome of each original study was chosen as the primary measure of interest of this meta-analysis. When a primary outcome had not been explicitly declared, the first outcome reported in the area of mobility and ADL independence was selected.

Due to variability of outcome measures, standardized ES and 95% CI were calculated for this outcome, using Cohen's d estimator, as the difference between post-test values in the intervention and control groups, divided by the pooled SD. A second set of comparisons was performed, by separately pooling measures of ADL independence, SDW (usually 10 meters), and LDW (6 min walking). For the first of these comparisons, ES was calculated, whereas for SDW and LDW WMD and 95% CI, as clinically meaningful outcome measures, were compared between intervention and control groups. For this purpose, the original SDW measure units were converted into m/sec as a common unit; a study [21] which reported SDW speed in terms of relative velocity was excluded from this specific analysis. Results were pooled across studies with DerSimonian-Laird random effects models, [START_REF] Dersimonian | Meta-analysis in clinical trials[END_REF] anticipating possible heterogeneous effects among different treatment strategies.

StatsDirect® (version 2.7.2) was used to perform statistical analysis. A p value <0.05 was assumed to represent a significant result.

RESULTS

Of 200 titles retrieved, 121 were excluded because they did not meet the inclusion criteria. Of the remaining 79 titles, 76 were found in full text and were evaluated by two independent investigators, who eventually included only 15 studies, [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF][21][START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF][23][24][25][26][27][START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF][30][31][32][33][START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] fulfilling the selection criteria. The two main causes of exclusion were when stroke onset was less than 6 months before enrollment and if experimental interventions were not coherent with our inclusion criteria (Figure 1).

<Insert Figure 1

here>

Participants

The sample size of selected trials ranged from 13 to 170 participants, totaling 730 randomized participants, 700 of whom were reassessed at follow-up. The proportion of participants reassessed at follow-up was similar (p=0.506) between active treatment (n=370, 96%) and controls (n=330, 95%). All studies except one [21] detailed demographic and clinical characteristics of the sample. Age was 40 years or above (weighted mean age: 70.3 years) and 59% of participants were males. The proportion of the side affected was comparable between treatment groups. Major comorbidities and, in particular, other neuromuscular and skeletal diseases or dementia were exclusion criteria in all RCT but two. [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF][21][START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF][23][24][25][26][START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF][30][31][32][START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] Eleven studies [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF]21,[START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF][25][26][27][START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF][30][31]33,[START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] did not include participants with severe cognitive or sensory deficits, and four [21,[32][33][START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] specified that participants had to be clinically stable. Stroke occurred at least 6 months before enrolment in five studies, [START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF]23,[START_REF] Dersimonian | Meta-analysis in clinical trials[END_REF][START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF][30] 9 months in one study, [26] and at least 12 months in the others [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][21][START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF][23][24]27,[32][33][START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] (weighted mean: 4 years).

Baseline functional level ranged widely. Authors, with one exception, [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF] specified various functional inclusion criteria: moderate to severe disability, [START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF][23][24]27] being able to walk without [START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] or else with or without assistive devices, [START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF]21,25,26,[START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF]30,32,33] a minimum walking capacity (15 minutes [26,32] or a given distance [25,[START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF]30,33,[START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF]), minimum [START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] or maximum [30] walking speed, a minimum activity tolerance of 45 minutes. [26,[START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF]31] Most studies allowed classifying participants at baseline according to Perry's Ambulation Classification: [START_REF] Perry | Classification of Walking Handicap in the Stroke Population[END_REF] 15.4% of participants were household ambulators, 60.7% were limited community ambulators, and 15.6% were full community ambulators, whereas this classification could not be obtained for the remaining 8.3%, whose functional level was of severe-to-moderate disability as an inclusion criterion. [START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF]27] As reported in nine out of 15 articles, studies differed for duration and kind of off-protocol treatment delivered. Three RCT specified that all [21,[START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF] or 13 out of 19 [27] participants had received inpatient rehabilitation in the acute phase. One study reported that 50 out of 63 participants had received inpatient rehabilitation after the initial hospital stay, and 41 had outpatient rehabilitation after discharge home. [32] In two articles, participants had completed rehabilitation; [START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF]30] three studies required the absence of physical therapy treatments four to six months before enrollment, [START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF]23,27] and three others clarified that no other type of rehabilitation was delivered in the period of the study. [21,25,33]

Intervention

The duration of a single treatment session ranged between 10 and 120 minutes.

The intervention lasted from 4 to 26 weeks (with a frequency from less than one up to 5 sessions per week) and was delivered at home in three cases, [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF]24,27] in an outpatient setting in ten cases [START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF][START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF]25,26,[START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF][30][31][32][33][START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] (three of which were in groups of 8 to 12 participants [START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF][START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF]32]), and in a mixed out-patient and home-based setting in the remaining two [21,23] (Table 1).

In most studies, conventional therapeutic approaches (neuromuscular interventions, practicing functional activities, muscle strengthening and application of assistive equipments), were combined, with the aim of improving mobility or independence. As illustrated in studies, or specified by authors on request, [START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF]31,[START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] active intervention was practiced or supervised by physical therapists, alone, within a multidisciplinary staff (which might include occupational therapists, exercise physiologists, or instructors), or in collaboration with the family (Table 1).

Outcome measures

A variety of outcome measures had been used in the original studies (Table 1).

The FIM-motor scale [START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF] and the Rivermead Mobility Index [23] were indicated as primary outcomes. First mobility or ADL independence outcome measures reported were the Barthel Index, [27] the Timed-Up-and-Go-Test, [25] SDW speed, [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF][21]24,26,[START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF]30,33,[START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] and the 6-minute walking test (6MWT). [31,32] Overall, four studies had measures of ADL independence, [START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF][23][24]27] whereas measures of walking ability, either on SDW or LDW, were reported in 13, [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF][21][23][24][25][26][START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF][30][31][32][33][START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] out of 15 studies, of which six [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF]25,30,31,33] had both SDW and LDW measures.

Quality evaluation

Following PEDro criteria, [START_REF]PEDro-the Physiotherapy Evidence Database[END_REF] trials selected for this meta-analysis had a quality score ranging from three to eight (mean 6.3). Randomization was concealed in seven trials; [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF]23,30,[32][33][START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] assessors were blinded in all studies but two, [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF][START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF][23][24][25]27,[START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF][30][31][32][33][START_REF] Yang | Dual-task exercise improves walking ability in chronic stroke: a randomized controlled trial[END_REF] whereas both participants and therapists could never be blinded to group assignment. All studies except one [26] reported baseline data by randomization group.

Based on the original description, analysis was by intention-to-treat in six cases. [START_REF] Ng | Does the use of TENS increase the effectiveness of exercise for improving walking after stroke? A randomized controlled clinical trial[END_REF][START_REF] Mudge | Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial[END_REF][21][START_REF] Kim | Effects of isokinetic strength training on walking in persons with stroke: a double-blind controlled pilot study[END_REF]31,32] One article [START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF] was not accurate in reporting variability of follow-up data (Table 2). Table 2. PEDro quality score of the studies included.

Random allocation

Concealment of allocation

Comparability of groups at baseline

Blinding of patients

Blinding of therapists

Blinding of assessors

Adequacy of follow-up

Analysis by intention to treat

Between-group statistical comparisons

Reports of point estimates and measures of variability

Meta-analysis

The meta-analysis of all outcome measures showed a pooled ES of 0.29 (95% CI 0.14-0.45; p <0.001) in favour of the intervention, with no heterogeneity (Figure 2).

<Insert Figure 2 here>

In terms of ADL independence, a trend in favour of the intervention did not reach statistical significance, with a pooled ES of 0.08 (95% CI -0.21-0.37; p=0.583)

and no heterogeneity (Figure 3).

<Insert Figure 3 here> Active treatment significantly improved both SDW and LDW ability, as shown by WMD of 0.05 m/sec (95% CI 0.008-0.088; p=0.017) (Figure 4) and 20 m (95% CI 3.6-36.0; p=0.017) (Figure 5), respectively, with no significant heterogeneity. These figures represented an 8% gain over baseline values of SDW and LDW.

<Insert Figures 4 and5 here>

DISCUSSION

This study provides evidence, drawn from systematic search and meta-analysis of RCT, that a variety of conventional motor rehabilitation and physiotherapy interventions, applied late after stroke, improve motor and functional outcomes, compared to no treatment or placebo. Specifically, SDW and LDW ability improved substantially.

Systematic reviews show that organized multidisciplinary care and rehabilitation are effective in the early phase of a stroke, improving survival and independence, and reducing length of hospital stay and need for institutionalization. [START_REF] Perry | Classification of Walking Handicap in the Stroke Population[END_REF][START_REF]Organised inpatient (stroke unit) care for stroke[END_REF][START_REF] Bettger | Effectiveness of multidisciplinary rehabilitation services in postacute care: state-of-the-science. A review[END_REF][START_REF] Foley | Specialized stroke services: a meta-analysis comparing three models of care[END_REF][START_REF] Langhorne | Does the organization of postacute stroke care really matter?[END_REF] A meta-analysis of RCT demonstrates that therapy-based rehabilitation services, targeting community-dwelling patients within one year of stroke, improve ADL independence and reduce the risk of further functional deterioration. [START_REF] Legg | Rehabilitation therapy services for stroke patients living at home: systematic review of randomised trials[END_REF] Another meta-analysis of RCT [START_REF] Kwakkel | Effects of augmented exercise therapy time after stroke: a meta-analysis[END_REF] reports that augmented exercise therapy time of at least 16 hours within the first 6 months after stroke obtains a measurable improvement in ADL and, to a lesser degree, in instrumental ADL and gait speed. A Cochrane systematic review reports that, compared to no treatment or placebo, a mix of conventional rehabilitation approaches significantly improves the recovery of postural control and lower limb function following stroke, thus enhancing independence. [START_REF] Pollock | Physiotherapy treatment approaches for the recovery of postural control and lower limb function following stroke[END_REF] Finally, an RCT reports that older patients that had had a stroke benefit on a short-term basis from a higher intensity of community-based rehabilitation, especially in the domains of social participation and health-related quality of life. [START_REF] Ryan | A randomized controlled trial to evaluate intensity of community-based rehabilitation provision following stroke or hip fracture in old age[END_REF] Solid scientific evidence supports the practice of physiotherapy early after a stroke, while evidence is more controversial for physiotherapy interventions applied after six months or more from the acute phase. A Cochrane review [START_REF] Aziz | Therapy-based rehabilitation services for patients living at home more than one year after stroke[END_REF] analyzed five RCT with 487 participants that had suffered stroke, at least 75% of whom were recruited one year after the event. They were randomized to receive a therapy-based rehabilitation intervention or conventional care. Primary outcome was the proportion of participants who deteriorated or were dependent in ADL at the end of the follow up. Although no conclusive evidence was found that therapy-based rehabilitation improves ADL independence, [START_REF] Aziz | Therapy-based rehabilitation services for patients living at home more than one year after stroke[END_REF] the sensitivity to interventions of such a hard outcome is limited. Another recent Cochrane review that investigated the effectiveness of overground gait training for improving overall measures of gait function in people who had suffered a stroke, found limited evidence of benefits for variables such as gait speed or 6MWT. [START_REF] States | Overground physical therapy gait training for chronic stroke patients with mobility deficits[END_REF] Gait speed and mobility measures, such as those considered in the present meta-analysis, have robust metric properties, [START_REF] Tyson | The psychometric properties and clinical utility of measures of walking and mobility in neurological conditions: a systematic review[END_REF] are more sensitive to change and represent major, clinically relevant endpoints. [START_REF] Schmid | Improvements in speed-based gait classifications are meaningful[END_REF] Notably, in the only included study reporting a favourable effect of active treatment on ADL, number and cumulative duration of treatment sessions were substantially greater than in other studies. [START_REF] Werner | Effectiveness of an intensive outpatient rehabilitation program for postacute stroke patients[END_REF] Consequently, we might speculate that, as in early stroke rehabilitation, [START_REF] Kwakkel | Effects of augmented exercise therapy time after stroke: a meta-analysis[END_REF] late rehabilitation effects on ADL may well be a matter of treatment intensity and duration.

Using mobility measures as an outcome, the present meta-analysis shows favourable effects of physiotherapy late after stroke, thus contributing to fill an important knowledge gap. However, we are aware of the limitations of the evidence provided, stemming from the small number of participants enrolled, as well as from differences in type, frequency, and intensity of interventions delivered and outcomes assessed. All these characteristics usually increase heterogeneity and threaten validity.

Nevertheless, no statistical evidence of heterogeneity was detected. Moreover, the rehabilitation interventions applied were similar to those routinely used in clinical practice, and study outcomes were represented by simple, previously validated functional measures. Furthermore, it should be noted that almost all the outcome measures selected have been identified as core measures in stroke rehabilitation. [START_REF] Van Peppen | The development of a clinical practice stroke guideline for physiotherapists in The Netherlands: A systematic review of available evidence[END_REF] Thus, we believe that the present meta-analysis reflects stroke rehabilitation as practiced in most community services. As evaluated according to PEDro methodology, [START_REF]PEDro-the Physiotherapy Evidence Database[END_REF] the quality of the studies included was satisfactory: since blinding of participants and therapists cannot be obtained in this kind of trials, the mean score of 6.3 (Table 2) should be weighed against a maximum score of only 8, not 10, points obtainable. [START_REF] Maher | A systematic review of workplace interventions to prevent low back pain[END_REF] When strengths and limitations of the RCT contributing to this metaanalysis are carefully balanced, we feel that the findings obtained are valid, clinically meaningful, and generalizable.

The clinical and public health implications of this study deserve further attention. In general, rehabilitation services for stroke survivors are available and deliver more intensive interventions in the initial phase after the stroke, gradually decreasing thereafter. [START_REF] Langhammer | Bobath or motor relearning programme? A follow-up one and four years post stroke[END_REF] Six to 12 months after the acute phase, physical therapy is usually no longer provided, especially when patients appear to reach a plateau and fail to improve further with prolonged treatment. [START_REF] Page | Reconsidering the motor recovery plateau in stroke rehabilitation[END_REF] Yet, our findings suggest that a significant functional recovery can be observed after a stroke later than usually believed. The improvement observed was small, below what is usually considered clinically meaningful, [START_REF] Tyson | The psychometric properties and clinical utility of measures of walking and mobility in neurological conditions: a systematic review[END_REF] but it possibly challenges the concept itself of a plateau, which might rather stem from the delivery of less intensive therapy. [START_REF] Demain | Recovery plateau following stroke: fact or fiction?[END_REF] Before existing practices are definitively changed, further studies are required to corroborate our findings and to clarify areas of uncertainty they cannot solve. First of all, it would be interesting to make clear if delivering higher doses of physiotherapy, or targeting patients more accurately, would lead to greater improvement. Likewise, the potential economic implications of our results deserve careful consideration and further investigation. Most healthcare systems cannot afford allocation of additional resources to physiotherapy programs, extended several months to years after stroke onset. However, scientific evidence of clinical efficacy should not be overlooked in the face of pure economic constraints: cost-effectiveness analyses, as well as studies on predictors of recovery, should be performed to help clinicians and politicians make informed decisions on this issue. Pooled ES: 0.29 (0.14 -0.45), p= <0.001

Favours treatment Favours control

Cochran Q= 12.9, p= 0.535 I 2 = 0%

Figure 1 .

 1 Figure 1. Literature search flow chart, and main exclusion criteria.

Figure 2 .

 2 Figure 2. Plot of random effects meta-analysis of effect size for all the outcomes

Figure 3 .

 3 Figure 3. Plot of random effects meta-analysis of effect size for the outcomes of ADL

Figure 4 .

 4 Figure 4. Plot of random effects meta-analysis of weighted mean differences for the

Figure 5 .

 5 Figure 5. Plot of random effects meta-analysis of weighted mean differences for the

Figure 1 -

 1 Figure 1

Figure 2 Pooled

 2 Figure 2

Table 1 .

 1 Characteristics of the studies included * Data are reported as mean (SD) or range † Main outcome was represented by the primary outcome, when explicitly declared, or by the first mobility and ADL independence outcome reported. ‡ In groups of 8 to 12 persons.

	Providers	Setting

Abbreviations. 6MWT: Six-Minute Walk Test, AE: Application Of Assistive Equipments, BI: Barthel Index, Ctr: Control group, EI: Exercise Instructor, EP: Exercise Physiologist, FA: Practicing Functional Activities, FIM-mm: Functional Independence Measures -motor measure, FU: follow-up, Int: Intervention group, MS: Muscle Strengthening, NA: Not Available, NI: Neuromuscular Interventions, OT: Occupational Therapist, PT: Physiotherapist, RMI: Rivermead Mobility Index, SDW: Short Distance Walk, TUG: Timed Up and Go Test.

ACKNOWLEDGMENT

We are greatly indebted to Mrs. Rossella Del Bianco and Mrs. Rossella Stefanini for their precious secretarial assistance.

COMPETING INTEREST

The authors report no conflicts of interest.

FUNDING

The study was financed with institutional funds of the University of Florence.

COPYRIGHT LICENCE STATEMENT

I Ferrarello Francesco, the Corresponding Author of this article, has the right to grant on behalf of all authors and does grant on behalf of all authors, a licence to the BMJ Publishing Group Ltd and its licensees, to permit this Contribution (if accepted) to be published in Journal of Neurology, Neurosurgery and Psychiatry (JNNP) and any other BMJ Group products and to exploit all subsidiary rights, as set out in our licence set out at: (http://jnnp.bmj.com//ifora/licence.pdf).