Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study.

Cladribine is currently registered as a 10-milligram tablet formulation with a fixed cumulative dosage of 3.5 mg/kg over 2 years. It is important to investigate if an increased dosage may lead to further clinical stability with preserved safety. This study used an off-label subcutaneous (s.c.) formulation of cladribine and compared outcomes (Expanded Disability Status Scale (EDSS) scores and disease progression) between 52 relapsing multiple sclerosis (RMS) patients receiving different s.c. dosing regimens with up to 20 years of follow-up. The study group received induction therapy with s.c. cladribine (1.8 mg/kg cumulative dose; consistent with 3.5 mg/kg of cladribine tablets). Patients were subsequently offered maintenance therapy (repeated courses of 0.3 mg/kg s.c. cladribine during 5-20-year follow-up). Forty-one patients received an increased cumulative dose (higher than the induction dose of 1.8 mg/kg); 11 received the standard induction dose. Risk of progression on the EDSS correlated with lower cumulative dose (p < 0.05) and more advanced disability at treatment initiation (p < 0.05) as assessed by EDSS change between year 1 and years 5 and 10 as the last follow-up. Maintenance treatment was safe and well-tolerated, based on limited source data. Subcutaneous cladribine with increased cumulative maintenance dosage was associated with disease stability and favorable safety over a prolonged period of follow-up (up to 20 years) in RMS patients.

Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies.

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was -1.0 (interquartile range -2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].

Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study.

BACKGROUND: There has been long-term interest in cladribine as a drug for the treatment of MS. The current study focused on the effect of cladribine on oligoclonal bands (OCB) expression in the CSF in relapsing-remitting MS (RRMS) patients observed over 10 years. METHODS: 29 treatment-naive subjects with RRMS were prospectively enrolled and received induction therapy with subcutaneous parenteral cladribine (at a cumulative dose of 1.8 mg/kg; divided into 6 courses every 5 weeks given for 4-6 days, depending on patients' body weight). Selected patients received maintenance doses in the follow-up period. RESULTS: Isoelectric focusing revealed that 55% of patients did not have OCB in CSF after cladribine treatment as compared to baseline testing when 100% of patients were positive for OCB. There were no significant differences in Expanded Disability Status Scale scores at baseline and at the end of treatment cycle between OCB-positive vs. OCB-negative subgroups. At the last follow-up, OCB-negative patients had lower disability compared to OCB-positive patients (p = 0.03). CONCLUSION: Cladribine-induced immune reconstitution leads to long lasting suppression of intrathecal humoral response, which might be an additional mechanism that enhances the therapeutic effect on disease progression in RRMS patients.

Standards in neurosonology. Part III.

The paper presents standards related to ultrasound imaging of the cerebral vasculature and structures. The aim of this paper is to standardize both the performance and description of ultrasound imaging of the extracranial and intracranial cerebral arteries as well as a study of a specific brain structure, i.e. substantia nigra hyperechogenicity. The following aspects are included in the description of standards for each ultrasonographic method: equipment requirements, patient preparation, study technique and documentation as well as the required elements of ultrasound description. Practical criteria for the diagnosis of certain pathologies in accordance with the latest literature were also presented. Furthermore, additional comments were included in some of the sections. Part I discusses standards for the performance, documentation and description of different ultrasound methods (Duplex, Doppler). Part II and III are devoted to standards for specific clinical situations (vasospasm, monitoring after the acute stage of stroke, detection of a right-to-left shunts, confirmation of the arrest of the cerebral circulation, an assessment of the functional efficiency of circle of Willis, an assessment of the cerebrovascular vasomotor reserve as well as the measurement of substantia nigra hyperechogenicity).

Standards in neurosonology. Part II.

The paper presents standards related to ultrasound imaging of the cerebral vasculature and structures. The aim of this paper is to standardize both the performance and description of ultrasound imaging of the extracranial and intracranial cerebral arteries as well as a study of a specific brain structure, i.e. substantia nigra hyperechogenicity. The following aspects are included in the description of standards for each ultrasonographic method: equipment requirements, patient preparation, study technique and documentation as well as the required elements of ultrasound description. Practical criteria for the diagnosis of certain pathologies in accordance with the latest literature were also presented. Furthermore, additional comments were included in some of the sections. Part I discusses standards for the performance, documentation and description of different ultrasound methods (Duplex, Doppler). Part II and III are devoted to standards for specific clinical situations (vasospasm, monitoring after the acute stage of stroke, detection of a right-to-left shunts, confirmation of the arrest of the cerebral circulation, an assessment of the functional efficiency of circle of Willis, an assessment of the cerebrovascular vasomotor reserve as well as the measurement of substantia nigra hyperechogenicity).

Standards in neurosonology. Part I.

The paper presents standards related to ultrasound imaging of the cerebral vasculature and structures. The aim of this paper is to standardize both the performance and description of ultrasound imaging of the extracranial and intracranial cerebral arteries as well as a study of a specific brain structure, i.e. substantia nigra hyperechogenicity. The following aspects are included in the description of standards for each ultrasonographic method: equipment requirements, patient preparation, study technique and documentation as well as the required elements of ultrasound description. Practical criteria for the diagnosis of certain pathologies in accordance with the latest literature were also presented. Furthermore, additional comments were included in some of the sections. Part I discusses standards for the performance, documentation and description of different ultrasound methods (Duplex, Doppler). Part II and III are devoted to standards for specific clinical situations (vasospasm, monitoring after the acute stage of stroke, detection of a right-toleft shunts, confirmation of the arrest of the cerebral circulation, an assessment of the functional efficiency of circle of Willis, an assessment of the cerebrovascular vasomotor reserve as well as the measurement of substantia nigra hyperechogenicity).

Aggressive behavior as a rare side effect of subthalamic stimulation in Parkinson's disease.

Although deep brain stimulation (DBS) has a well-established position in the treatment of Parkinson's disease (PD), it may be accompanied by different side effects including behavioral changes. We present a patient with advanced PD after bilateral stimulation of the subthalamic nucleus (STN) who developed attacks of aggressive behavior. The patient with a 12 year history of PD underwent the procedure of DBS with one-stage bilateral stereotactic approach using the Leksel G stereotactic frame. For STN identification microrecording technique was applied (5 microelectrodes). Four weeks after surgery STN stimulation was switched on. With increasing the amplitude of stimulation on the right (active contacts 1 and 2) the patient experienced transient episodes of aggression. Change of stimulation mode led to withdrawal of all side effects. We hypothesize that aggression episodes in the patient were caused by stimulation of limbic circuit probable within STN although we cannot exclude simultaneous stimulation of neighboring structures. Aggression episodes are rare side effect of STN-DBS, nevertheless they may be expected in more posteromedial placement of the electrode within STN. The presented case extends the evidence for non-motor functions of STN and highlights its role as an integrating structure within the basal ganglia system.

[Evaluation of the effectiveness of add-on therapy with tiagabine and evaluation of cognitive functions after application of this therapy in patients with drug-resistant focal epilepsy - an observational study (GABI-EPI)]. / Ocena skutecznosci terapii dodanej tiagabina oraz ocena funkcji poznawczych po zastosowaniu tej terapii u pacjentów z ogniskowa padaczka lekoodporna - badanie obserwacyjne (GABI-EPI).

OBJECTIVE: To assess the efficacy of add-on therapy with tiagabine and cognitive functions in patients with drug-resistant focal epilepsy, when used in everyday clinical practice. MATERIALS AND METHODS: The total number of 437 patients with drug-resistant epilepsy with focal seizures were observed; 436 patients were treated with tiagabine as add-on therapy at a dose of 5-50 mg per day. During the study a number visits were secheduled: Visit V0 - upon enrolment of tiagabine-treated patients into the observational study, visit V1 - four weeks after reaching the initial dose of tiagabine, visit V2 - four weeks after reaching the target dose of tiagabine. The type and number of epileptic seizures, antiepileptic therapy used, concomitant treatment and adverse events were analysed. Analyses were performed using McNemar's, Wilcoxon's, Mann-Whitney's and Fisher's tests. The patients'cognitive functions were assessed using the MM SE scale. RESULTS: The mean observation time was 90 days. Men accounted for 48.3% of the study population and their average age was 41,5±14,0 and women accounted for 51.7% and their average age was 43.4±13.9. About 80% of the patients received valproic acid or carbamazepine before administration of tiagabine. Other most commonly used drugs included acetylsalicylic acid and ramipril. In the group of 185 patients who used drugs inducing liver enzymes before administration of tiagabine, 13% received a dose below 30 mg of tiagabine and 87% above 30 mg. In the group of patients treated with drugs which do not induce liver enzymes, 91.6% received tiagabine in a dose below 30 mg and 8.4% in a dose above 30 mg. The percentage of patients experiencing epileptic seizures was reduced from 72.2% between visits V0-V1 to 58.7% between visits V1-V2 (p<0.001). A decrease in the population of patients who experienced seizures and a reduction of the number of seizures were observed in all age groups. In the youngest age group, the number of seizures since the last visit went down from 5.4 to 3.7 (the average difference amounted to 1.7), in the 40-59 years age group, the number of seizures went down from 4.0 to 3.1 (the average difference amounted to 0.9) and in patients above the age of 60, from 3.0 to 2.1 (the average difference amounted to 0.9) (p<0.001; p=0.001 and p<0.001, respectively). Adverse events occurred in 4 (i.e. 0.9%) patients, dizziness being the most common. The Mini Mental State Examination (MM SE) was performed in 25% of patients. Cognitive functions did not deteriorate. The average MM SE score corresponded to a mild level of cognitive impairment. CONCLUSIONS: Tiagabine is a well tolerated drug providing effective control of focal seizures and in a sub-population of 25% patients whose cognitive functions were evaluated using MM SE, no significant adverse effect of the drug on such functions was observed.

Disappearance of white matter lesions on MRI and clinical recovery after initiating antiretroviral therapy in a case of HIV infection presenting as spastic paraparesis.

We present a case of a 30-year-old Polish female who presented with increasing for about 2 years spastic paraparesis and urinary incontinence. She denied any risky sexual behaviors, drug abuse, there was no history of surgery or blood transfusions. MRI of the brain showed diffuse, hyperintensive in T2, poorly defined lesions in the white matter. About 3 months later paraparesis increased and control MRI showed progression of previously described lesions. She was then diagnosed with HIV infection. There was a suspicion of progressive multifocal leucoencephalopathy (PML) or vacuolar myelopathy in the course of HIV infection. Antiretroviral treatment was initiated leading, together with rehabilitation, to a progressive improvement of symptoms. Pathological lesions on brain MRI completely disappeared. In conclusion, HIV test should be done in every patient with neurological signs of unknown cause.

Quality of life in Polish patients with multiple sclerosis.

PURPOSE: This study is a pilot evaluation of the quality of life (QoL) in Polish patients with multiple sclerosis (MS). MATERIAL/METHODS: Data from 21 centers in Poland were collected from May 2008 to January 2009. QoL was assessed using the questionnaire Euro Quality of Life (EQ-5D), with Polish population norms. Demographic profile of patients, duration/form/relapsing activity of the disease, disability and comorbidity were also analyzed. RESULTS: Data from 3521 patients (F/M ratio 2.4:1) were collected. The average EQ-5D index was 0.8 ± 0.27 and the mean score in a visual analog scale (EQ-VAS) was 65.6 ± 21.5. There was a highly significant positive correlation between both indices (r=0.7334, p<0.0001). The mean patient age was 40.7 years (11.2-92.3 years) and disease duration was 10.3 ± 8.8 years (0.04-53 years). 74.2% of subjects had relapsing-remitting form of MS, while 17.2% were classified as secondary progressive and 8.6% as primary progressive. In the group of relapsing-remitting MS subjects there were 2.5% patients with "benign MS". The average degree of disability on EDSS scale was 3.6 ± 2.2, while disability ≥6 was observed in 20.3% of patients. Most patients did not have other diseases besides MS. CONCLUSIONS: This is the first large study of QoL in patients with MS in Poland (approximately 18% of all patients). Our results confirm a reduction in QoL compared with the general population. Further studies are indicated to identify the modifiable risk factors (e.g. type of treatment) that may affect QoL.

Impact of cladribine therapy on changes in circulating dendritic cell subsets, T cells and B cells in patients with multiple sclerosis.

BACKGROUND: Cladribine causes sustained reduction in peripheral T and B cell populations while sparing other immune cells. We determined two populations of dendritic cells (DCs): namely CD1c(+)/CD19(-) (myeloid DCs) and CD303(+)/CD123(+) (plasmacytoid DCs), CD19(+) B lymphocytes, CD3(+) T lymphocytes and CD4(+) or CD8(+) subpopulations in patients with multiple sclerosis after cladribine therapy. METHODS: We examined 50 patients with secondary progressive multiple sclerosis (SP MS) according to McDonalds et al.'s criteria, 2001 [15]. Blood samples were collected before the initiation of cladribine therapy and after 1st, 2nd, 3th, 4th and 5th courses of treatment. DC subsets, T and B cells were analyzed by flow cytometry. RESULTS: During cladribine treatment the myeloid DCs CD1c(+)/CD19(-) did not change (p=0.73175), and the plasmacytoid DCs CD303(+)/CD123(+) significantly increased (p=0.00034) which resulted in significant changes in the ratio of myeloid DCs to plasmacytoid DCs (p=0.00273). During therapy, B lymphocyte CD19(+) significantly decreased (p=0.00005) and significant changes in CD4(+) cells (p=0.00191), changes in CD8(+) cells (p=0.05760) and significant changes in CD3(+) (p=0.01822) were found. CONCLUSIONS: We noticed significant trend to increase the CD303(+) circulating the dendritic cells. This population produces large amounts of IFN-alfa. We found significant and rapid decrease in B cells and CD4(+) Th cells. Our results suggest two possible ways of beneficial cladribine influence on immune system in MS. Induction of IFN-alfa producing cells and their predominance over BDCA-1(+) DCs, which are associated with cytotoxic response. Additionally, cladribine could influence two populations of lymphocytes: B cells and Th lymphocytes responsible for induction of immune response against myelin antigens.

Efficacy and safety of Privigen(®) in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, open-label Phase III study (the PRIMA study).

This prospective, multicenter, single-arm, open-label Phase III study aimed to evaluate the efficacy and safety of Privigen(®) (10% liquid human intravenous immunoglobulin [IVIG], stabilized with L-proline) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients received one induction dose of Privigen (2 g/kg body weight [bw]) and up to seven maintenance doses (1 g/kg bw) at 3-week intervals. The primary efficacy endpoint was the responder rate at completion, defined as improvement of ≥1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The preset success criterion was the responder rate being ≥35%. Of the 31 screened patients, 28 patients were enrolled including 13 (46.4%) IVIG-pretreated patients. The overall responder rate at completion was 60.7% (95% confidence interval [CI]: 42.41%-76.43%). IVIG-pretreated patients demonstrated a higher responder rate than IVIG-naïve patients (76.9% vs. 46.7%). The median (25%-75% quantile) INCAT score improved from 3.5 (3.0-4.5) points at baseline to 2.5 (1.0-3.0) points at completion, as did the mean (standard deviation [SD]) maximum grip strength (66.7 [37.24] kPa vs. 80.9 [31.06] kPa) and the median Medical Research Council sum score (67.0 [61.5-72.0] points vs. 75.5 [71.5-79.5] points). Of 108 adverse events (AEs; 0.417 AEs per infusion), 95 AEs (88.0%) were mild or moderate in intensity and resolved by the end of study. Two serious AEs of hemolysis were reported that resolved after discontinuation of treatment. Thus, Privigen provided efficacious and well-tolerated induction and maintenance treatment in patients with CIDP.

Reduction of thalamic tremor with deep brain stimulation performed for post stroke chronic central pain.

Deep brain stimulation (DBS) of the sensory thalamus and the periventricular/ peri-aqueductal grey area complex may be applied for the treatment of intractable neuropathic pain syndrome. The presented study concerns a patient who experienced ischemic stroke within the posterolateral part of the left hypothalamus, with subsequent severe burning pain localized in the right upper limb, predominantly within the hand, and thalamic tremor which occurred 4 months after the stroke. After 2 years of ineffective pain treatment, the patient was offered implantation of electrodes to the periventricular grey matter (PVG)/periaqueductal grey matter (PAG), as well as implantation of an electrode to the ventroposterolateral thalamic nucleus (VPL). Soon after starting simultaneous PAG/PVG and PVL stimulation, significant alleviation of the patient's thalamic tremor in the hand was observed, which persisted over subsequent months. The presented study discusses possible mechanism underlying tremor suppression in the patient concerned, probably at the level of the cerebellar outflow pathways. The study highlights the fact that DBS provide more insight into the functional anatomy of the thalamus, which used to be available only from animal studies.

Bilateral paramedian thalamic infarction with hypothalamic dysfunction.

Unilateral thalamic lesions cause transient or permanent behavioral, sensory and oculomotor disturbances; bilateral lesions of thalamus result in more severe and longer lasting symptoms. We present an atypical case of bilateral paramedian thalamic infarct with concomitant hypothalamic dysfunction. The only risk factor of ischaemic stroke found in the patient was a short lasting episode of atrial fibrillation. Bilateral paramedian thalamic infarcts may result from occlusion of one paramedian thalamic artery, which arises from the posterior cerebral artery, either with separated or with a common trunk, thus supplying the thalamus bilaterally. Independently of anatomical variants of thalamus blood supply, the most probable cause of infarct in our patient was unilateral or bilateral occlusion of the posterior cerebral artery by cardioembolism, probably in the course of basilar artery occlusion. Hypothalamic dysfunction may accompany thalamic infarcts; thus hypothalamo-pituitary function should be routinely assessed in bithalamic infarcts.

Neurofilament heavy chain and heat shock protein 70 as markers of seizure-related brain injury.

PURPOSE: Status epilepticus (SE) has deleterious effects on brain tissue, but whether brief recurrent seizures may also damage neurons represents a matter of controversy. Therefore, it remains a central area of epilepsy research to identify individuals at risk where disease progression can be potentially prevented. Biomarkers may serve as tools for such identification. Thus the present study aimed at analyzing the levels of heat shock protein 70 (HSP-70, also designated as HSPA1A) and neurofilament heavy chain protein (NfH(SMI35) ) in cerebrospinal fluid (CSF) of patients with seizures of different severity. METHODS: Forty-one patients were included, of whom 20 patients had a single generalized tonic-clonic seizure (GTCS) episode (SS), 11 had repetitive GTCS (RS), and 10 experienced convulsive SE. The control group consisted of 18 subjects. HSP-70 levels were measured using a conventional enzyme-linked immunosorbent assay (ELISA), whereas the NfH(SMI35) protein levels were detected by an electrochemiluminescence (ECL) immunoassay. KEY FINDINGS: Patients with SE (p < 0.001) and RS (p < 0.05) had significantly higher NfH(SMI35) levels than controls, and SE was associated with increased concentrations when compared with SS (p < 0.001). NfH(SMI35) levels in SS did not differ from controls. Patients with SE had significantly raised HSP-70 levels compared to RS (p < 0.05), SS (p < 0.05), and controls (p < 0.001). SS and RS did not differ from each or from controls. Levels of NfH(SMI35) and HSP-70 showed a significant correlation (r = 0.34; p = 0.007) in the group of all study subjects, which was not apparent when controls and patients with seizures were considered separately. The correlation between NfH(SMI35) and HSP-70 tended to be inverse in patients with SE, but it did not reach statistical significance (r = -0.3; p > 0.05). SIGNIFICANCE: Studying biochemical markers as additional quantitative tools for the measurement of neuronal damage (especially subclinical), complementary to available techniques of imaging, and clinical assessment might prove useful for identifying patients at risk of accumulating neuronal injury resulting from uncontrolled seizures. NfH(SMI35) and HSP-70 are of potential value as sensitive and specific biomarkers of seizure-related pathologic events. Future longitudinal studies are needed to monitor such patients by correlating biochemical, neuroimaging, and clinical methods of assessment.

Factors predicting quality of life in a group of Polish subjects with multiple sclerosis: accounting for functional state, socio-demographic and clinical factors.

OBJECTIVES: Quality of life (QoL) has presently a firmly established position as an important endpoint in medical care. Multiple sclerosis (MS) is a chronic neurological disease with considerable effect on patients' QoL. QoL of MS patients from many European countries has already been assessed but little is known on health-related QoL of Polish subjects with MS. Few studies have taken into consideration multiple predictors of QoL. The aim of this study was to elicit the most relevant factors that determine QoL of Polish group of MS patients. Socio-demographic and clinical factors as well as the influence of disability level were analyzed in this study. PATIENTS AND METHODS: 173 MS patients and 86 healthy controls underwent assessment using the Mini Mental Status Examination, WHOQOL-100, Beck Depression Inventory and Fatigue Severity Scale. Data were analyzed by a stepwise linear regression analysis. RESULTS: MS patients had significantly worse global QoL and worse QoL in physical and psychological health domains, lower level of independence, worse social relations and were less satisfied with the surrounding environment they lived in compared with healthy controls (p<0.05). MS subjects had also higher level of depression and fatigue compared to healthy controls (p<0.05). CONCLUSIONS: The study determined that the strongest predictors of global QoL of Polish MS patients were depression, disability level and fatigue.

Some markers of neuronal damage in cerebrospinal fluid of multiple sclerosis patients in relapse.

In this paper the performance of cerebrospinal fluid (CSF) protein biomarkers important for monitoring damage of brain astrocytes and neurons for MS is reviewed. We estimated neurofilament, tau and phospho-tau proteins, ß-APP, Aß, S-100B and neuron-specific enolase in CSF of MS patients during relapse. We noted elevation of neurofilament, tau and phospho-tau proteins, S-100B, neuron-specific enolase and c-terminal epitopes of ß-APP; concomitantly decrease of Aß was observed. These CSF biomarkers for MS relapse should reflect the central pathogenic processes in the brain, i.e., axonal and neuronal degeneration.

[Efficacy and tolerability of dose-escalation with generic gabapentin--a multicenter, non-interventional study]. / Skutecznosc i bezpieczenstwo zwiekszania dawek generycznej gabapentyny--wieloosrodkowe badanie nieinterwencyjne.

The aim of this study was to determine the efficacy and tolerability of 1800-2400 mg/day of generic gabapentin (Gabapentin Teva) as add-on treatment for refractory partial - onset epilepsy. This was a multicenter, open-label, dose-escalation study of patients with refractory epilepsy (median age of 45.5 years [41-50; 25-75% percentile range], male 45.6%, female 47.8%). The inclusion criteria were insufficient partial-onset epilepsy control, defined as at least 1 seizure per month, while on adjunctive therapy with gabapentin used on daily doses below 1200 mg. The baseline seizure number was assessed over 3 months of observation in patients being on stable doses of their AED therapy and those subjects who met the inclusion criteria were enrolled into the study by their neurologist (Visit 0). Subsequently, patients were seen, and their data were evaluated at Visit I i.e. after the target dose of 1800 mg per day was achieved (mean duration of 3.6 [0.1-28.3] weeks) and 4 weeks later at Visit II, after the target dose up to 2400 mg per day. Primary efficacy was assessed by seizure frequency (number/month). Tolerability was assessed by adverse events and clinical evaluations. All the study periods were completed by 916 patients. A substantially lower median seizure frequency was observed at all gabapentin dosing periods (visit I - 2.0 [0-40] seizures per month and visit II - 1.0 [0-13] seizures per month; median and range) compared with the baseline period (3.0 [1-20] seizures per month) (Wilcoxon test p<0.001). In addition, the gradual increase of GBP dose led to raising proportion of patients rendered seizure free (Visit I - 1.1% and Visit II - 28.5%) compared with the baseline period 0.0% (McNemar test p<0.001). The dose escalation with GBP was well tolerated by the majority of patients. The most common adverse events during visit II were somnolence (2.8%) and dizziness (1.8%). In conclusion, gabapentin dose escalation to a dose range of 1800-2400 mg/d over 8 [1-32] week period proved to be an effective and well tolerated in patients with insufficient seizure control on lower doses with partial-onset epilepsy.