Efficacy and tolerance of a Neurological Restoration ... - IOS Press

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NeuroRehabilitation 29 (2011) 381–391 DOI 10.3233/NRE-2011-0716 IOS Press

Efficacy and tolerance of a Neurological Restoration Program in stroke patients ´ Liv´an Rodr´ıguez-Mutuberr´ıa, L´azaro Alvarez-Gonz´ alez, Maikel L´opez, Juan E. Bender-del Busto, Elizabeth Fern´andez-Mart´ınez, Susana Mart´ınez-Seg´on and Jorge A. Bergado∗ Internacional Center for Neurological Restoration (CIREN), Havana, Cuba

Abstract. The present paper shows the result of an open prospective study performed to evaluate the tolerance and efficacy of a program for neurological restoration (PRN) in stroke patients. The PRN is organized 4 weeks cycles – 39 hours per week – and applied by a team of physical, occupational, and speech therapists, physiatrists, psychologists, clinicians and nurses; directed by a neurologist. The first phase of treatment aims to increase the physical capacity and tolerance to exercise. The second phase trains specific abilities (balance, posture, gait and handling). Drugs were only used to modulate physical or mood disorders, spasticity, or pain. The study was performed in 80 stroke patients attended in our institution (2005–2007). Only patients with a confirmed diagnosis of stroke in the carotid territories, over 15 years old, and not least than 6 months post-ictal evolution were included. Tolerance to treatment was very good, with only 4 adverse events not related to treatment. The neurological condition was evaluated using the Scandinavian Stroke Scale (SSS), and the functional condition using the Barthel Index (BI). The results show significant improvements both in the neurological (113.45 ± 1.59%) and functional (130.11 ± 5.17%) condition after one treatment cycle, which improved further when therapy continued for a second cycle (233.71 ± 7.76% and 207.62 ± 27.16% respectively). Severity of the impairment was not a negative predictor of the outcome. Age correlated negatively with the initial condition, but does not prevent improvement. Sex, time of evolution, affected hemisphere or interactions among them did not influence the outcome. These results demonstrate that the PRN is well tolerated and effective promoting recovery even in chronic stroke patients. Keywords: Neurological restoration, neurorehabilitation, stroke

1. Introduction Restorative Neurology is a developing field aimed to restore neural functions affected by disease or trauma. Until the last decades of the XX century, the attention of patients suffering sequelae of neurological diseases was based mainly in the control of risk factors to prevent complications, and to provide some self care abilities, mainly though compensation of the lost functions. During the last 20 years, under the influence of the concepts of neural plasticity, this approach has begun to change. Instead of compensate the main goal for Restorative Neurology is the recovery of function [1– 6]. ∗ Corresponding

author: Dr. Jorge A. Bergado, Centro Internacional de Restauraci´on Neurol´ogica (CIREN), Ave. 25 # 15805, 11300 Playa, La Habana, Cuba. Tel.: +53 7 271 6385; Fax: +53 7 273 2420; E-mail: [email protected].

Important in this regard has been the recognition that neural plasticity allows recovery far beyond the temporal limits usually conceived for persons surviving an acute episode; i.e. stroke or trauma [7,8]. The first 6 months seems to be an optimal period for rehabilitation treatment, considering the contribution of a variable degree of spontaneous recovery during that time. There are many reports on early treatments and their efficacy; however studies evaluating strategies aimed for chronic patients are sparse [7,9,10]. The International Center for Neurological Restoration (CIREN) was created to develop, and testing, new therapeutic strategies for chronic neurological diseases. During this time, programs for neurological restoration (PRN) have been developed by our staff for different diseases, combining medical and rehabilitation approaches. The main objective of the present study was to evaluate the tolerance and efficacy of the PRN designed to

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improve the neurological and functional condition of stroke survivors treated in CIREN between the years 2005–2007. We have centered in this pathology considering the high prevalence, which converts stroke in a medical problem of outstanding individual, familiar, and social impact. We have also looked for possible correlations between several factors and the outcome after treatment, as possible predictors that would allow a more accurate planning of the goals and strategies for the intervention.

2. Subjects and methods 2.1. General design and patient selection

2.3. Evaluation week During the first week all patients were evaluated to confirm the stroke diagnosis. Clinical and neurophysiology studies were always complemented with MRI confirmation, or CAT in cases for which exposure to magnetic fields should be avoided (e.g., external heart pacemaker), The evaluation served as well to establish an individual profile for each patient according to which the PRN was adjusted to his/her capacities and requirements. At the end of the week, and before beginning treatment the functional capacities and the neurological condition of the subjects was evaluated using the Barthel Index (BI) and the Scandinavian Stroke Scale (SSS) respectively. 2.4. Program for Neurological Restoration (PRN)

This open, prospective study was carried out in 80 patients coming for restorative treatment to the CIREN’s Clinic for Brain Static Lesions during the period between January 2005 and January 2007. All patients suffered from neurological impairments as a consequence of stroke affecting the carotid area, and were selected according to inclusion and exclusion criteria (see below). They all formally requested and paid treatment at our institution, and therefore no control group was included. Table 1 summarizes the main characteristics of the final sample. A subgroup of 53 patients performed one treatment cycle (4 weeks, see below) while another group (27) continued for a second cycle (8 weeks of treatment). 2.2. Selection criteria Inclusion: Only patients with a confirmed diagnosis of stroke in the carotid territories, over 15 years old, and not least than 6 months post-ictal evolution were included after obtaining their informed consent to use the data for research purposes with absolute guarantee of their anonymity. Exclusion: Patients showing signs of severe consciousness or mental impairment (e.g., severe dementia, post ictal organic psychosis, major depression), patients with chronic terminal diseases (e.g., cancer, renal failure, caquexia, proteic-caloric malnutrition) or in a very poor physical condition, or patients with more than one infarct area demonstrated by Computer Assited Tomography (CAT) or Magnetic Resonance Imaging (MRI) were excluded.

The PRN combines several conventional methods (traditional-compensatory, Rood’s, Brunnstrom, Bobath, proprioceptice neuromuscular facilitation, taskoriented motor re-learning) following the principles applied in sport training to maximize recovery of function under assumption of the neural plasticity properties of the Nervous System. The program is organized in cycles of 4 weeks each. The minimal option is one cycle; a second cycle is recommended, but the patient and relatives in charge decide whether or not to prolong treatment for a second cycle depending on familiar and financial constraints. As previously mentioned the general program is adjusted to the individual capacities and needs of each patient in an effort to maximize recovery, long-term functional maintenance, reduction of disabilities and improvement in living quality. In each cycle, therapy is applied for 7 hours daily (Monday to Friday) and 4 hours on Saturday, amounting 39 hours a week. The therapy team is composed by a physical therapist, an occupational therapist, a speech therapist, a specialist in physical medicine, a psychologist, a clinician and nurses; all under the direction of a specialized neurologist (see Table 2). The patient’s evolution is followed daily during a visit of the whole team early in the morning, allowing for corrections in the therapeutic strategy according to the outcomes. The first phase of treatment (pre-functional) is aimed to reduce pain and muscle tone, increase the physical fitness and the tolerance to exercise. Physical exercise was a planned and controlled, repetitive movement, organized in long, low intensity trials of aerobic muscle activity. Intense anaerobic exercise was avoided. The

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Table 1 Selected sample of patients and their classifications after initial evaluation Eighty patients enter the program and finished one treatment cycle (left column). From them a subgroup of 27 continued for a second cycle (right column) Age Age in years (mean ± SD)

Sex Functional condition (Barthel Index) Neurological condition (Scandinavian Stroke Scale) (Scandinavian Stroke Scale)

Male Female Severe Moderate Low Very severe Severe Moderate Low

1 treatment cycle (n = 80) 56.9 ± 12.47 (min.20, max.81) 59 73.50% 21 26.25% 37 46.25% 32 40.00% 11 13.75 2 2.50% 24 30.00% 25 31.25% 29 36.25%

2 cycles (n = 27) 57.97 (min.31, max.76) 19 70.37% 8 29.62% 19 70.37 6 22.22% 2 7.40% 1 3.70% 14 51.85% 9 33.33% 3 11.11%

Table 2 A representative example of the daily time distribution and methods employed on patients under treatment in the PRN Therapeutic field Physical therapy

Time 5 h/day

Occupational therapy

1 h/day

Speech therapy

1 h/day

Aphasia

Disartria

Methods Physical condition and muscle strength Movement therapy Inhibition-facilitations techniques Proprioceptive neuromuscular facilitation Relearning of motor skills Passive, assisted, active-assisted and resisted mobilization Manual and mechanical massage Passive, assisted, active-assisted and resisted mobilization Simultaneous and alternative coordination Cognitive stimulation Expressive language: Oral language disinhibition Verbal initiative stimulation Re-establishing articular praxis Improving vocabulary Verbal fluency and rhythm Impressive language: Auditory memory and hearing analysis-synthesis Lexical components of language Logical-grammatical structure Stimulating articular praxis Massage therapy Articular gymnastics

transit to the second (functional) phase depends on the progress during the first phase. The second phase trains and develops specific abilities like balance, posture, gait and hand dexterity, among other. Drugs, when applied, were used to modulate behavioral disorders, mood, memory, attention, muscle spasticity, epilepsy or pain. Drugs with a known plasticity promoting action (amphetamines, citicholine) as well as drugs to correct risk factors for stroke or other systemic diseases were also used as individually required. Rehabilitation in the PRN includes the contribution of experienced therapists in different fields, each with a defined role within the program. Physical therapy was aimed to improve motor functions and the general physical capacities. It was based on conventional re-

habilitation techniques (compensation, repetitive stimulation) combined with the principles of sport training, with particular emphasis in transference and posture, balance, equilibrium and gait. Occupational therapy is used to promote the recovery motor deficits in the upper limbs and cognitive dysfunctions affecting orientation, attention, memory or causing agnosia. Speech and related disorders (dysartria, dysphagia and aphasia) are treated by experienced speech therapists. Psychologists attended the treatment of cognitive, memory, visuospatial, and executive dysfunctions, and collaborate to treat agnosia and aphasia. The physical medicine expert contributes to the normalization of muscle tone and the elimination of pain combin-

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ing methods of hydro-massages, with analgesic physical agents (low intensity electrical currents, magnetic fields, and local laser irradiation). This specialist also indicates, when necessary, the utilization of mechanic stabilizers (bandages, dynamic or static stance supporters). Last, but not least, nursing care contributes to the education of patients and relatives, and the administration of drugs, the vigilance for possible adverse events or collateral undesirable effects and the general care of patients. 2.5. Evaluation of tolerance Tolerance was evaluated using the criteria of adverse events occurring during treatment. All adverse events occurring during this period were recorded and classified according to their possible relationship to treatment (definitively related, most probably related, probably related, posibly related, not related, unknown) following international criteria [11]. In every case of an adverse event, related or not to treatment, all efforts were done to eliminate or minimize it, including the interruption of treatment if necessary. 2.6. Evaluation of efficacy To evaluate the effects of treatment on the neurological condition the Scandinavian Stroke Scale (SSS) was employed. The functional condition was evaluated by means of the Barthel Index (BI). These evaluations were performed at the end of the evaluation week, before starting the treatment, and at the end of the first cycle (day 30) and at day 60 in those patients that took a second treatment cycle. According to the results of the first SSS patient’s affection in neurological condition was classified in: very severe (0–14 points) severe (15–29 points) moderate (30–44 points) or mild (45–58 points) after Jorgensen [12]. The functional condition according the BI was considered severe ( 59 points), moderate (60–90 points) or mild (> 90 points) following Wallace [13]. 2.7. Data collection and statistics Data were collected in the individual clinical history of the patients. This information was then organized in a data base to allow statistical testing. Paired samples Student’s t test were performed to compare the absolute values of the scores before and after treatment. To analyze the relative change after treatment an ANOVA,

followed by a Tukey post hoc test, was used. Correlations between relevant variables and treatment outcome were also analyzed. In every case differences or relationships were considered significant only if p < 0.05. Data are presented in graph bars (mean ± standard error of the mean) 2.8. Bioethics The protocol for this study was revised and approved by the institutional Bioethics Committee taking into consideration the statements of the Helsinki’s Declaration (1996 version) and the Cuban regulations for research with patients. Measures to protect the confidentiality of the patient’s identity were taken, and no data allowing the identification of the patients will be published. 3. Results 3.1. Tolerance to treatment The tolerance to treatment was very good. Only 4 adverse events were recorded in 4 different patients that lead to the interruption of treatment before finishing the first cycle. Two events were falls (one of them with rib fracture) during the rest period while the patient was under care of relatives and were classified as non-related. The other 2 were patients with a very poor physical condition, obese and with a history of heart failure that were unable to sustain training showing disnea in response to physical exercise which were classified as possibly related (the adverse event can be explained based on the clinical status of the patient). None of the patients died during treatment. The final number of 80 patients in the study was reached after excluding these 4 cases. 3.2. Efficacy of treatment 3.2.1. First cycle The neurological condition was evaluated using the SSS before starting treatment and at the end of the first 4 weeks cycle. Figure 1A shows the averaged scores (mean ± SEM, n = 80) in both moments. An improvement in the patient’s neurological condition is proven by the statistically significant higher score in the evaluation after the first cycle. A more detailed analysis considering the scores obtained in each item of the SSS showed significant im-

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Fig. 1. Results of the patient’s evaluation after PRN. A) Averaged (mean ± standard error of the mean) total score in the evaluation of the neurological condition using the Scandinavia Stroke Scale (SSS) before and after treatment. B) Averaged (mean ± standard error of the mean) total score in the evaluation of the functional condition using the Barthel Index (BI) before and after treatment. C) Averaged (mean ± standard error of the mean) total score in the evaluation of the neurological condition using the Scandinavian Stroke Scale (SSS) before and after one or two cycles of treatment. D) Averaged (mean ± standard error of the mean) total score in the evaluation of the functional condition using the Barthel Index (BI) before and after one or two cycles of treatment. D) Averaged (mean ± standard error of the mean) scores in the items composing BI before (white bars) after the first cycle (light gray bars) and the second cycle (dark gray bars). *Significant differences between groups (p < 0.05, paired samples t-test). E) Averaged (mean ± standard error of the mean) relative change in the evaluation of the neurological condition using the Scandinavian Stroke Scale (SSS) after one or two cycles of treatment. E) Averaged (mean ± standard error of the mean) relative change in the evaluation of the functional condition using the Barthel Index (BI) after one or two cycles of treatment.

provements for items: Orientation, Speech, Gait, Arm Motor Power, Hand Motor Power, and Leg Motor Power (Fig. 2A). No changes were observed in items: Facial Palsy, and Foot Paresis. Items Consciousness, and Eye Movement, did not change, but these showed no

initial deficits (see inclusion and exclusion criteria). The patient’s functional condition was evaluated by means of the BI. Figure 1B shows the scores of this index before and after the first treatment cycle. A significantly higher score after treatment indicates an

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Fig. 2. Itemized breakdown of scales. A) Punctuation per Item in the Scandinavian Stroke Scale before (white bars) and after (gray bars) the first cycle of treatment. B) Punctuation per Item in the Scandinavian Stroke Scale before (white bars) after the first cycle (gray bars) and after the second cycle of treatment (dark gray bars). * Significant difference (t-test, p < 0.05) with respect to the values before treatment, # significant differences with respect to the values before treatment and after one cycle of treatment. C: consciousness; O: orientation; S: speech; EM: eye movement; FP: facial palsy; G: gait; A: arm motor power; H: hand motor power; L: leg motor power; F: foot paresis. C) A) Punctuation per Item in the Barthel Index before (white bars) and after (gray bars) the first cycle of treatment. D) Punctuation per Item in the Barthel Index before (white bars) after the first cycle (gray bars) and after the second cycle of treatment (dark gray bars). * Significant difference (t-test, p < 0.05) with respect to the values before treatment, # significant differences with respect to the values before treatment and after one cycle of treatment. F: feeding; Ba: bathing; D: dressing; G: grooming; Bo: bowels; Bl: bladder; TU: toilet use; T: transfers; M: mobility; S: stairs. Bars show mean ± standard error of the mean.

improved functional condition. The BI is also composed by the punctuation of several items. A significant improvement was found for items (Fig. 2C): Feeding, Dressing, Grooming, Toilet Use, Transfers, Mobility and Stairs. The item Bathing and those related to vegetative functions (Bowels, and Bladder) did not change. These results confirm that the treatment strategy designed and applied in this PRN can induce significant improvements in both, the neurological and functional condition of the patient, and contribute to increase their independence and living quality. 3.2.2. Second cycle As previously mentioned, a subgroup of patients (n = 27) continued treatment for a second 4 weeks cycle. The scores of the SSS after each cycle are compared in figure 1C. This subgroup also shows a positive increase in the neurological condition after the first cycle, although the major improvement was mea-

sured after the second one, which resulted statistically significant not only against the initial value, but compared to the results after the first cycle as well. Notice that, within this subgroup a lower starting value was averaged, indicating a more severe compromise of their neurological condition before starting treatment. The itemized analysis showed significant differences for the results of the second cycle in items Orientation only compared to the pretreatment values, while items Speech, Gait, Arm Motor Power and Leg Motor Power significant differences were statistically proven when compared both to the initial values, and those after the first cycle (Fig. 2B). Similar results were seen in the evaluation of the BI. Figure 1D shows the averaged scores before treatment compared to those after the first or the second cycle. Significant improvements were obtained after the second cycle compared to the pretreatment values and those after the first cycle. A lower initial score was also present in this subgroup. The itemized analy-

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sis showed significant improvements in the scores after finishing the second cycle (compared to the initial values and those after the first cycle) for items: Feeding, Bathing, Dressing, Grooming, Transfers, Mobility, and Stairs. Toilet use resulted significant only against the initial value, while items Bowels and Bladder showed no improvement (Fig. 2D). It is evident from these results that the functional capacity of the patients benefits from a second cycle of treatment, showing further increases in the functional and neurological indexes, even in one item that did not improve after one cycle (Bathing). However, vegetative functions (Bowels and Bladder) did not improve. This is an aspect that should be attended in the future development of the PRN. 3.2.3. The relative change The results presented so far show the absolute values of the scales after each cycle. It is however, interesting to consider results in relative terms: how much has the patient gained (or lost) after treatment? For that purpose, we have calculated the percent values of the scores after treatment using as baseline (100%) the score before treatment. Figure 1E shows the results of the SSS after each cycle. As can be seen the relative improvement after the second cycle (n = 27) is higher than that after the first cycle (n = 80). A very similar result was obtained for the BI (Fig. 1F). No statistical comparison between groups was performed due to big difference in the number of subjects in each group, however a one way ANOVA showed that the factor CYCLES (1 or 2) influence significantly the relative change in the BI (F1,25 = 8.03184, p < 0.05). Our results show that restorative and rehabilitation treatments, as applied in the PRN are beneficial for patients suffering sequels of stroke, even in chronic patients. They show further that prolonging treatment can add value to the therapeutic effects on both the neurological and functional condition of the patients. 3.3. Factors influencing the response to treatment Defining factors that influence the outcome of treatment with PRN, might be of great value for the selection of patients, and the more precise definition of goals and objectives. One of these possible factors is the degree of initial impairment. Both the BI and the SSS classify patients in categories of severity. The SSS considers 4 categories: very severe, severe, moderate and mild (see Methods). The relative change

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after the first cycle showed a significant influence of Severity on the outcomes (ANOVA F3,76 = 7.265, p < 0.05). As can be seen in Fig. 3A the severe cases show greater improvements, confirmed by the post hoc Tukey test showing significant differences between severe patients and moderate or mild impaired. The very severe group comprised only two cases, and was not statistically different from any other severity group, probably due to the reduced n value. After the second cycle the ANOVA showed Severity again as a significant factor (F2,24 = 5.7689, p < 0.05, see Fig. 3B). In this analysis we have excluded the very severe group because only one patient followed for a second cycle. The Tukey test showed significant differences between severe and mild groups, but the moderate group does not differ from the mildly impaired one. Similar relationships were observed in the functional condition. In this case, 3 conditions are distinguished according the results of the BI: severe, moderate, and mild (see Methods). A one way ANOVA showed that the severity of impairment influenced significantly the outcome after the first cycle (F2,77 = 14.3673, p < 0.05). The relative change in the scores of the patients in these categories is shown in Fig. 3C. However, also with this index, the major improvements were found within the group showing the worst initial functional condition, as confirmed with the post hoc Tukey test: the severe group differs significantly from the moderate and mild group, while these do not differ from each other. When the results after the second cycle (a subgroup of 27 patients) were analyzed (Fig. 3D), the factor severity resulted not significant (F2,24 = 2.46998). This can be a consequence of the lower number of cases in this subgroup, but can also mean that with a longer treatment severity reduces its influence, a positive rather than negative fact. The severity of the impairment appears as a significant factor influencing results, but the prognosis is not pessimistic. Instead, it seems to mean simply that the most impaired patients have the opportunity of a greater progress. We have also analyzed other possible predictors of the outcome. A regression study, confirmed also by ANOVA and Linear General Models, showed Age as the only factor influencing the results, while neither sex, time of evolution, the affected hemisphere, nor any interaction between them showed a significant relationship. Age correlates with the results of the BI, both after the first (r = 0.27, p < 0.05, see Fig. 4A) or the second cycle (r = 0.40, data not shown); but not with the results of the SSS (data not shown). In a first approach

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Fig. 3. Influence of the initial severity on the outcome of PRN. A) Averaged (mean ± standard error of the mean) relative change in the evaluation of the neurological condition using the Scandinavian Stroke Scale (SSS) after one cycle of treatment separating patients according to the initial severity of impairment (number of patients in each group in parenthesis). B) Averaged (mean ± standard error of the mean) relative change in the evaluation of the neurological condition using the Scandinavian Stroke Scale (SSS) after two cycles of treatment separating patients according to the initial severity of impairment (the very severe group is omitted because only one patient in this category continued treatment for a second cycle) . C) Averaged (mean ± standard error of the mean) relative change in the evaluation of the neurological condition using the Barthel Index (BI) after one cycle of treatment separating patients according to the initial severity of impairment (number of patients in each group in parenthesis). C) Averaged (mean ± standard error of the mean) relative change in the evaluation of the neurological condition using the Barthel Index (BI) after two cycles of treatment separating patients according to the initial severity of impairment (number of patients in each group in parenthesis). *Significant differences, p < 0.05 ANOVA, and Tukey post hoc test.

this seems to suggest that older people improve more than younger ones, an idea which contradicts general believes on the adaptive abilities of the aged brain. We have therefore analyzed also whether there exists a relationship between age and the score in the pretreatment evaluation with the BI. The results show a negative correlation between both variables (r = − 0.37, p < 0.05, Fig. 4B). One should also keep in mind that a low initial score permits greater increases than higher ones; in fact a completely healthy person can not improve at all.

4. Discussion The results presented in the previous section show that the PRN is a well tolerated therapy, able to promote

neurological and functional recovery in stroke patients after the post-acute phase, in which spontaneous recovery is very limited or completely absent. This might partially compensate for one of the main limitations in our design: the absence of a placebo or untreated control group. All patients that finished at least one cycle improved both in their neurological and functional condition. The improvement increases with the duration of therapy, and there appear to be no age limits, provided a minimal physical condition to sustain exercise. The PRN has several distinctive characteristics: intensity (more than 7 hours daily), duration (4 weeks cycles), multidisciplinary team under the leadership of a neurologist, and the combination of drug and rehabilitation therapies. There are a great number of papers reporting results of different rehabilitation strategies;

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A

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B

Fig. 4. Impact of age on the outcome of the PRN. A) Scatterplot and regression line between age and change in the BI after the first treatment cycle. B) Scatterplot and regression line between age and initial severity in the Barthel Index.

however they differ greatly in their design, intensity, duration and the methods to evaluate efficacy [14–16]. It is therefore difficult to find adequate references to compare our results. Wallace [13] and Indredavik [18] have shown the value of a multidisciplinary approach, while other authors [19,20] demonstrate the benefits of an intensive treatment, in agreement with our results. These benefits can increase if the intensive treatment is prolonged as evidenced when the results of the first and second cycle in our study were compared. Our results demonstrate that neither severity, nor chronicity of the sequels are excluding factors. Taken together, these arguments are a strong argument to justify a therapeutic intervention in stroke patients, even in chronic and severely affected ones, and to justify the approach developed in the PRN. The analysis of separate items, allowed us to distinguish, at least preliminarily, those aspects that reacted positively from those showing little or no response. In our study, the best responses were seen in cognitive (orientation, speech) and motor items (gait, arm and foot mobility) which according to Pyoria [21] is important to activate functional recovery. Facial palsy does not improve after treatment, but, fortunately this is not a highly impairing factor. The improvements in the patient’s neurological condition expresses also in an improvement in their functional capacities, as shown also by Aprile [22]. The functional evaluation showed no significant improvement in vegetative functions. In part this might be simply a consequence of the fact that bowel and bladder dysfunctions are not frequent after carotid stroke. Only

17 out of 80 patients in our series showed some degree of sphincter dysfunction. Nevertheless, this is a factor to be taken into consideration in future developments of the PRN to warrant a more successful recovery of daily life activities [23,24]. Evidently, the response to any therapeutic intervention depends also of individual characteristics of the patients. Several studies have addressed that issue in acute patients [25–27]. The Copenhagen Stroke Study identified severity as the main negative prognosis factor in acute stroke patients [25]. However, correlative studies are sparse beyond 6 months post-stroke. Chronic patients remain in a kind of neurological “steady state”, showing no spontaneous progress and no further deterioration. This might explain that severity, in our study, behaves as a positive, rather than negative predictor. The measured change in the neurological and functional condition is higher in severely impaired patients. This might not be surprising considering that in our case we evaluate the response to a treatment and not the natural course of a disease. However, a relevant contention to keep in mind comes from the so called “ceiling effect” of scales that limits the gain for mildly impaired patients. The influence of this arithmetical factor is reduced when one considers the relative change rather than the absolute values, an approach that normalizes values. This normalization, on the other hand, can exaggerate some apparent effects, especially when the initial values are low. In this report we show that factors like age, sex or time of evolution do not correlate with the response to

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treatment, and constitute no limiting factors to enter a restorative intervention. Although the PRN consists of several therapeutic elements it is certain that one essential component is multifactor rehabilitation. The most plausible interpretation to the improvement shown by patients is based on neural plasticity processes elicited by therapy that may include synaptic potentiation [28–30], sprouting and reactive synaptogenesis [31]. G´omez [7] have provided evidences of cortical plasticity after PRN by mapping the motor cortex using transcraneal magnetic stimulation before and after the first 4 weeks cycle in stroke patients. The results show an expansion of the motor cortex representation in the affected hemisphere, even in cases showing no response in the initial evaluation. Interestingly, an expansion was also seen in the contralateral motor cortex. This was a controlled study. No spontaneous change was measured in any of the paired control patients that remained untreated. While specific training might induce specific neuroplastic changes in specific brain areas, we believe also that the physical activity that precedes the training of abilities in the Prefunctional Phase, and continues during the Functional Phase has effects beyond increasing in the aerobic capacities of patients. Recent evidence shows that physical exercise promotes and stimulates relevant processes within the brain like neurotrophin secretion [32–34], synaptic plasticity [35], neurogenesis [36] as well as angiogenesis and blood flow [37] creating in the brain a “plasticity promoting environment” which facilitates the changes induced by training specific abilities [2]. One is tempted to speculate that similar mechanisms, in a wider time range, may explain the improvements observed after a second treatment cycle. Future studies should contribute to a more precise and effective use of the therapies included in the PRN, and their possible combination with other techniques. We have recently published results of a preliminary study to test safety and tolerance of the transplantation of stem cells from the bone marrow in stroke patients [38]. A combination of both appears as a logical next step, but the present results confirm that hope and hard work are irreplaceable tools in the way to recover after stroke.

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