Adam Czaplinski

Predictability of disease progression in amyotrophic lateral sclerosis

The aim of this study was to determine the predictors of disease progression in a group of 832 patients with the diagnosis of definite or probable amyotrophic lateral sclerosis (ALS). Disease progression was defined as the time to 20‐point change in Appel ALS (AALS) score. The effects of individual prognostic factors on disease progression were assessed with the Kaplan–Meier life‐table method. In addition, the prognostic value of each factor was estimated using both univariate and multivariate Cox proportional hazard analyses. The median time to a 20‐point change in AALS score in our patient population was 9 months. Age, site of symptom onset, time between first symptom and first examination, total AALS score at first examination, and AALS preslope (rate of disease progression between first symptom and first examination) were significant and independent covariates of disease progression in our population. Identification of predictors of disease progression will facilitate better design of therapeutic trials, permitting the use of disease progression as a primary endpoint and improving baseline stratification of patient populations. Muscle Nerve, 2006

ALSFRS AND APPEL ALS SCORES : DISCORDANCE WITH DISEASE PROGRESSION

Progression of disease and effectiveness of therapy in patients with amyotrophic lateral sclerosis (ALS) are determined by both questionnaire‐ and examination‐based measures. To determine whether both types of measurement tools are equally predictive at all stages of disease, we compared questionnaire‐based ALS Functional Rating Scale (ALSFRS) scores to the examination‐based Appel ALS (AALS) scores at different stages of disease. Same‐day scores were obtained during 174 visits in 62 patients with definite or probable ALS. Using normalized scores, correlation between the scales and predictability were best in mildly affected patients. Predictions of ALSFRS based on AALS scores were less than half as precise in the later stages of disease. Both scales showed significant change with disease progression, but ALSFRS consistently underestimated disease severity defined by AALS (P < 0.001). Questionnaire‐based measurements should be compared against objective scales at all stages of disease severity before they are accepted as primary endpoint measures. Muscle Nerve, 2008

Ice pack test for myasthenia gravis. A simple, noninvasive and safe diagnostic method.

Sirs: Intravenous injection of the acetylcholinesterase inhibitor edrophonium (tensilon) is commonly used in the diagnosis of myasthenia gravis (MG), because of rapid onset and short duration of its effects. The estimated sensitivity of tensilon testing in myasthenia gravis is high; however, false-negative responses have been reported. Tensilon, however, may produce serious side effects, including significant bradycardia, loss of consciousness and death [4]. Consequently its use has been restricted in Switzerland and in other European countries. According to previous publications local cooling improves neuromuscular transmission, whereas warming has the opposite effect [1]. However, the precise mechanism of this effect is unclear. Reduction or inhibition of the activity of acetylcholinesterase by lowering temperature is a possible mechanism [8]. The purpose of the present article is to be a reminder of an alternate method to tensilon testing that is simple and safe but seems to have fallen into oblivion in the neurological literature. Design/Methods: Five patients with ptosis from previously undiagnosed myasthenia gravis and five with non-myasthenic ptosis were studied with the use of tensilon testing, orbital cooling, and other tests for MG such as repetitive nerve stimulation and determination of antiacetylcholine receptor antibody (AchR-ab) levels. Each patient was photographed before ice or tensilon testing. In the ice test, the patient was asked to hold an ice pack (ice cube wrapped in a surgical glove) over the closed eye with ptosis. If ptosis was bilateral, we cooled the more affected eye. The ice pack was then removed after 2 minutes. After 10 minutes, three i. v. injections, one containing 10 mg edrophonium and two placebo, were administered in a double blinded fashion by a nurse. Photographs were taken immediately after cooling or 1 minute after injection. All pictures were reviewed by a blinded observer. Outcome measure was the effect of ice or edrophonium on ptosis. Results: Five subjects improved with the ice test; however, in one of them the edrophonium test was negative. All subjects with positive response to orbital cooling were subsequently shown to have myasthenia gravis by other tests (elevated titers of anti-acetylcholine receptor antibody and compound muscle action potential (CMAP) amplitude decrement to repetitive stimulation greater than 20 %). Patients with non-myasthenic ptosis (negative anti-acetylcholine receptor antibody titer and no decremental response in repetitive nerve stimulation tests) did not improve in either ice or edrophonium test. LETTER TO THE EDITORS

Prolonged-release fampridine in multiple sclerosis: Improved ambulation effected by changes in walking pattern

Background: Prolonged-release fampridine (PR-fampridine, 4-aminopyridine) increases walking speed in the timed 25-foot walk test (T25FW) in some patients (timed-walk responders) with multiple sclerosis (MS). Objective: To explore the effects of PR-fampridine on different aspects of walking function and to identify associated gait modifications in subjects with MS. Methods: In this prospective, randomized, placebo-controlled, double-blind, phase II study (FAMPKIN; clinicaltrials.gov, NCT01576354), subjects received a 6-week course of oral placebo or PR-fampridine treatment (10 mg, twice daily) before crossing over. Using 3D-motion-analysis, kinematic and kinetic parameters were assessed during treadmill walking (primary endpoint). Clinical outcome measures included T25FW, 6-minute walk test (6MWT), and balance scales. Physical activity in everyday life was measured with an accelerometer device. Results: Data from 55 patients were suitable for analysis. Seventeen subjects were timed-walk responders under PR-fampridine. For the total study population and for responders, a significant increase in walking speed (T25FW) and distance (6MWT) was observed. Gait pattern changes were found at the single-subject level and correlated with improvements in the T25FW and 6MWT. Physical activity was increased in responders. Conclusion: PR-fampridine improves walking speed, endurance, and everyday physical activity in a subset of subjects with MS and leads to individual modifications of the gait pattern.

The value of database controls in pilot or futility studies in ALS

Objective: To evaluate the use and reliability of database controls in place of a placebo group in pilot or “futility” ALS trials. Methods: We compared the rates of disease progression in the placebo arm of the clinical phase III US Insulin-like Growth Factor-I Trial (n = 90) with the rates of disease progression of 207 patients with ALS selected from 1,600 ALS database patients using the same inclusion criteria. Results: The mean rates of change in the Appel ALS (AALS) score were nearly identical in the placebo group (4.70 points/month) and in the database group (4.79 points/month). In addition, there was no significant difference in the median time to achieving a 20-point progression in AALS score: 143 days for database match vs 146 days for the placebo group (log rank p = 0.88). Furthermore, in the multivariate Cox analysis, both the rate at which the disease had progressed prior to first exam (preslope) (p < 0.001) and first exam AALS total score (p = 0.01) were shown to be covariates of subsequent rate of disease progression. Conclusion: The similarity in disease progression between placebo arm of clinical phase III trial and matched database group suggests the value of historical databases in futility trials. However, the proposed study design requires appropriate matching of study patients with database controls. Based on our results, we suggest matching by stage of the disease and rate of clinical decline in a contemporaneous ALS population.

Inflammatory demyelinating neuropathies and neuropathies associated with monoclonal gammopathies: Treatment update

SummaryThis review focuses on recent data regarding inflammatory demyelinating neuropathies and neuropathies associated with monoclonal gammopathies. We describe both acute and chronic inflammatory neuropathies, and we discuss conditions ranging from mostly cell-mediated to antibody-mediated disorders. These diseases are characterized by proximal and distal sensory motor involvement. Treatments are based on immune-modulation and/or immune-suppression. Work-up sequence and therapeutical modes are discussed in the light of recently published data, with a special interest on new treatment modalities.

Cranial and peripheral neuropathy due to leptomeningeal infiltration in a patient with Waldenstrom's macroglobulinemia

Sirs: Lymphoplasmacytic lymphoma or Waldenstrom’s macroglobulinemia (WM) is a chronic mature B-cell lymphoproliferative disorder of plasmacytoid lymphocytes usually involving bone marrow, lymph nodes and spleen. A serum monoclonal immunoglobulin M (IgM) may be present and may be associated with hyperviscosity and/ or cryoglobulinemia. We present the case of a 70 year old male who was diagnosed with WM. Bone marrow infiltration at time of diagnosis was 40%, the monoclonal IgM kappa in peripheral blood was 11.5g/l, and cryoglobulines were present. A therapy with four cycles of R-CHOP (rituximab, cyclophosphamid, doxorubicin, vincristin, and prednison) was administered. The patient responded well to therapy and achieved a good partial remission with only a residual bone marrow infiltration of 5–10% and the monoclonal IgM kappa in peripheral blood was 0.7 g/l. Six months later the patient gradually developed persistent headaches, nuchal rigidity, double vision, dysphagia and dysarthria. The clinical examination at admission showed meningism and severe bulbar paralysis along with symptoms of sensori-motor polyneuropathy. Examination of cerebrospinal fluid disclosed 106 cells/mm3, elevated protein level (3160 mg/l) and elevated beta-2-microglobulin (6.35 mg/l). Cytological analyses revealed atypical lymphocytes and flow cytometry analysis showed a kappa monoclonal CD19 positive B-cell population. Bone marrow examination showed a persistent multifocal infiltration with lymphoplasmacytic lymphoma (15% of nucleated cells). Transformation in a diffuse large B cell lymphoma was excluded. The serum monoclonal IgM kappa was 0.4 g/l, cryoglobulines were low, and serum antiMAG (myelin associated glycoprotein) antibodies were negative. The brain MRI showed a mild thickening of leptomeninges without tumor mass or meningeal enhancement. In addition the MRI of the lumbar spinal cord after gadolinium injection showed an increased signal in perimedullary and cauda equina roots regions, as well as enlargement of the latter (Fig. 1 and 2). We interpreted the symptoms as cranial and peripheral neuropathy due to leptomeningeal and nerve root infiltration and the patient was given a palliative radiation-therapy of the brain and the cauda with simultaneous steroid therapy. The patient’s condition improved with a clear decrease of bulbar and polyneuropathic symptoms. Although these therapeutic interventions were established, the patient died eleven weeks after diagnosis. Sensori-motor neuropathy related to the antibody activity of the monoclonal IgM to the MAG is a well-known neurological complication of WM [2, 3]. However, involvement of the peripheral nervous system due to leptomeningeal infiltration by neoplastic cells is very rare and has been reported in few cases only [1, 4–6]. Remarkably, in contrast to other non-Hodgkin’s lymphomas where meningeal involvement develops in the setting of progressive disease, in our patient meningeal infiltration occurred in a stable partial remission phase of the WM. In conclusion, we hypothesize that WM may progress in the nervous system without transformation into a more malignant Bcell-lymphoma (Richter syndrome) even if the initial chemotherapy leads to significant remission of the disease. Dr. R. Sutter (&) Æ A.J. Steck Æ A. Czaplinski Dept. of Neurology University of Basel Patersgraben 4 4031 Basel, Switzerland E-Mail: sutte r@uhbs.ch

Recommendations for the use of prolonged-release fampridine in patients with multiple sclerosis (MS).

Prolonged‐release fampridine (fampridine PR) is a potassium channel blocker that improves conductivity of signal on demyelinated axons in central nervous system. Fampridine PR has been approved to improve speed of walking in patients with multiple sclerosis. This statement provides a brief summary of data on fampridine PR and recommendations on practical use of the medication in clinical practice, prediction, and evaluation of response to treatment and patient management.

Slower disease progression and prolonged survival in contemporary patients with amyotrophic lateral sclerosis.

BACKGROUND In recent years, considerable effort has been made to improve the treatment of patients with amyotrophic lateral sclerosis (ALS). However, despite the increased use of supportive measures, controversy still exists about overall trends in disease progression and survival. OBJECTIVE To analyze whether survival and disease progression in patients with ALS have changed during the past 20 years. DESIGN By using the Kaplan-Meier life-table method, we compared disease progression (measured as time to a 20-point increase in the Appel ALS score) and survival in 1041 patients diagnosed as having ALS between January 1, 1984, and January 1, 1999 (historical group, n = 647), and between January 2, 1999, and November 1, 2004 (contemporary group, n = 394). The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS The median survival from symptom onset was 4.32 years (95% confidence interval [CI], 3.81-4.84 years) in the contemporary group compared with 3.22 years (95% CI, 3.04-3.41 years) in the historical group (P<.001). The contemporary patients progressed more slowly (10 months to a 20-point increase; 95% CI, 9-13 months) compared with patients in the historical group (9 months to a 20-point increase; 95% CI, 8-9 months) (P<.001). In the multivariate Cox proportional hazards model, the observed outcome improvement over time was independent of confounding factors, such as age, sex, diagnostic delay, site of symptom onset, baseline forced vital capacity, and baseline Appel ALS score, and independent of the use of potentially outcome-modifying therapies (riluzole, noninvasive ventilation, and percutaneous gastrostomy). CONCLUSIONS Contemporary patients had significantly prolonged survival and slower disease progression compared with patients from the historical group. The improved outcome seemed independent of specific ALS outcome-modifying therapies, but we cannot rule out an effect of comorbid conditions, which could have influenced medical treatment and survival. Nevertheless, our observations suggest the possibility that disease course has changed and that ALS is becoming less aggressive over time. Further studies are needed to determine whether there has been a fundamental change in the natural history of the disease or whether our results are because of other unmeasured aspects of improved multidisciplinary care.