ILSA #14 (Italian Edition)

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A study in 31 patients with type 1 Gaucher disease revealed three patients with polyneuropathy confirmed by electrophysiological assessment. Electrophysiological assessment was carried out in only half of the studied patients 15 out of 31 , and the selection criteria for patients to have this test were not made clear Capablo et al. Thus, contrary to the classical non-neuronopathic phenotypical description, peripheral nervous system manifestations appear to be of particular relevance in type 1 Gaucher disease, but available data do not permit a reliable estimate of the prevalence and incidence of peripheral neuropathy in type 1 Gaucher disease.

The occurrence of peripheral neuropathy in type 1 Gaucher disease is of specific interest following observations of two cases during a clinical trial with the substrate reduction therapy, miglustat Zavesca TM , Actelion Pharmaceuticals, Basel, Switzerland Cox et al.

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As part of a post-marketing surveillance commitment of Actelion to the European Medicines Evaluation Agency in relation to the registration of miglustat, a multicentre study was undertaken to investigate comorbidities in type 1 Gaucher disease, with a special focus on peripheral neuropathy.

Here, we report baseline and 2-year follow-up data from this study, with the principal aim of determining the prevalence and incidence of polyneuropathy in type 1 Gaucher disease. Additional aims were to evaluate the prevalence and incidence of mononeuropathy, other neurological or electrophysiological abnormalities not fulfilling the criteria for a mono- or polyneuropathy, and standard type 1 Gaucher disease manifestations. Finally, a literature search was performed on the prevalence and incidence of polyneuropathy in the general population, for comparison with the study data.

This 2-year prospective, longitudinal, observational cohort study was conducted in eight centres across seven countries in Europe.

The primary outcome parameters were the prevalence and incidence of polyneuropathy, evaluated by standardized assessments of neurological symptoms and signs in conjunction with standardized electrophysiological assessment. Additional outcomes included the prevalence and incidence of mononeuropathy, other neurological or electrophysiological abnormalities not fulfilling the criteria for a mono- or polyneuropathy, general type 1 Gaucher disease symptoms and assessments of associated conditions.

All diagnoses of peripheral neuropathy were adjudicated centrally. The data from the observational cohort study were compared with data obtained from 25 healthy subjects who were assessed using identical methodology to the current study including equally standardized electrophysiological assessment at the Academic Medical Centre in Amsterdam. A comparison was also made with data obtained after a systematic review of the literature.

To this end, Medline and Embase were searched to identify all studies reporting on prevalence and incidence of polyneuropathy in the general population between and Those with a history of oculomotor gaze palsies, ataxia or other manifestations associated with type-3 disease were excluded.

Patients were also excluded if they were undergoing or had undergone treatment with miglustat or an investigational agent. All patients provided written informed consent before participation. The study protocol was approved by independent local ethics committees and was conducted in accordance with the Declaration of Helsinki and subsequent revisions. Patients were initially screened for entry by the assessment of medical history including Gaucher disease history and concurrent medical conditions and comorbidities.

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Special attention was given to conditions and comorbidities that are related to, or may cause, polyneuropathies, such as diabetes and alcohol use. Concomitant therapies were fully documented. In addition, all patients underwent laboratory investigations including vitamin B 12 , vitamin B 1 , folic acid, creatinin, total protein and electrophoresis. Homocysteine and methylmalonic acid were measured in a central laboratory. Glucose levels were measured in all patients diagnosed with polyneuropathy, eventually followed by glucose and HbA1c during fasting.

Chitotriosidase levels were measured in a central laboratory. On study entry, and every 6 months thereafter, all patients underwent a systematic neurological assessment of symptoms and signs. In addition, all patients underwent standardized electrophysiological assessment at baseline. Furthermore, all patients diagnosed with a polyneuropathy at baseline underwent a repeated electrophysiological assessment at 24 months.

Clinical neurological symptoms were assessed using a neurological symptom survey, a questionnaire-based evaluation used to assess symptoms according to a standardized protocol. Patients were asked whether they had experienced the following symptoms for periods of at least 1 week either unilaterally or bilaterally in the hands, arms, legs and feet: This extensive questionnaire was used with the aim of detecting all patients with potential peripheral nerve disease, accepting that many would turn out not to have peripheral nerve involvement high sensitivity, low specificity.

Clinical neurological signs were evaluated by examination of muscle strength, deep tendon reflexes and sensation. Muscle strength was assessed using the standard Medical Research Council scale Kleyweg et al. Symptoms and signs were assessed by certified neurologists who were trained by the central assessor before study site initiation and were considered to be due to polyneuropathy only if they were present in a symmetrical distribution with a proximal-to-distal gradient and confirmed by electrophysiological abnormalities.

Electrophysiological assessment consisted of nerve conduction studies and electromyography according to standardized methodology being conducted by certified neurophysiologists at each centre Donofrio and Albers, Electrophysiological data for each patient were compared with normative and cut-off values from the laboratory at which the measurement took place to ascertain if findings were normal or abnormal, and if abnormal findings were compatible with the definition of a polyneuropathy.

Further standardization between laboratories was not judged to be necessary, as the data were not required for use in any statistical calculations. Electrophysiological abnormalities confined to one nerve, especially nerve conduction slowing or compound muscle action potential reduction over common entrapment sites, were considered to be compatible with a mononeuropathy. An electrophysiological diagnosis of polyneuropathy required more or less symmetric abnormalities in more than two nerves with the legs being more affected than the arms, i.

American Academy for Emergency Medicine criteria for demyelination were used to distinguish between axonal and demyelinating polyneuropathy Olney, All results of electrophysiological studies were evaluated centrally in a two-step process. First, copies of the full reports were assessed in a blinded fashion i. This resulted in four categories: Secondly, the central reviewer evaluated these findings in the context of all available clinical data and formulated a final diagnosis.

This resulted in the following six categories: First, a cohort of 25 healthy subjects was assessed using identical methodology to the current study including equally standardized electrophysiological assessment both conducted and reviewed in a blinded manner by the same assessor as for the observational cohort study at the Academic Medical Centre in Amsterdam. These subjects were investigated during the past 5 years as part of a natural history study in hereditary motor and sensory neuropathy type 1a patients, and hence were not formally part of the protocol of the cohort study Verhamme et al.

Secondly, a literature search was performed to identify all studies reporting on prevalence and incidence of polyneuropathy in the population. References listed in eligible papers and in review articles were searched. Papers that met the following criteria were selected:. In the latter case, the most strict definition possible was used;. The cohort study is an observational study in a rare disease, and as such the sample size was chosen on pragmatic grounds.

The prevalence of mono- and polyneuropathy was determined from all patients who underwent both clinical neurological examinations and electrophysiological assessment. The incidence was calculated as the number of new cases divided by the calculated sum of follow-up years of all included patients. All other results are expressed by median and ranges. Characteristics of patients with polyneuropathy were compared with those of patients without polyneuropathy. Data were collected by Actelion Pharmaceuticals Ltd, sponsor of the study. The full-study database was released by Actelion to three of the authors M.

To generate from the selected literature a pooled estimate of the prevalence of polyneuropathy in the general population, the numbers of polyneuropathy cases were extracted from each eligible study. All patients with a confirmed diagnosis of type 1 Gaucher disease were asked to participate in this study. From a total of patients screened for inclusion, patients were enrolled; one patient withdrew after screening due to an inability to commit to follow-up assessments. Patient characteristics are summarized in Table 1.

One hundred and two patients attended at least one follow-up visit. Two patients withdrew due to starting treatment with miglustat, one patient was non-compliant and the other four patients requested withdrawal from the study. Demographics, type 1 Gaucher disease characteristics, genotype and enzyme replacement therapy use all-enrolled data set. The healthy comparator subjects had a median range age of 48 33—72 years, and this cohort consisted of 11 males and 14 females. At baseline, a total of 11 patients Details of the results of neurological screening for each of the 11 patients with polyneuropathy are given in Table 2.

Mononeuropathy of the ulnar nerve at the elbow was found in two patients 1. One of these two patients was a frequent tennis player; the other patient did not have a history of trauma, arthritis or repetitive strain injury that could explain his mononeuropathy. Shoulder abduction, elbow flexion, wrist extension, finger ab- and adduction, hip flexion, knee extension, foot flexion and foot extension were assessed. Sum score ranges from 0 completely paralysed to 80 full strength.

The NSS consists of 15 sensory items, 10 motor items and 2 pain items with a maximum score of 27 if all items are present. A total of 22 patients Conversely, electrophysiological abnormalities were recorded in a total of 23 patients Of these 23 patients, 19 had only minor abnormalities but 4 3. The conclusions of electrophysiological studies did not change during the two-step assessment of peripheral nerve disease. Follow-up studies revealed six new cases 2. Details of the results of neurological assessments are given in Table 2. No new cases of mononeuropathy were found.

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The electrophysiological test results of the remaining 7 patients remained unchanged during the follow-up period. Only 1 of the 4 patients who were considered to be in the sub-clinical phase of developing a polyneuropathy had follow-up electrophysiological studies. This patient did not develop a polyneuropathy. Amazon Advertising Find, attract, and engage customers. Amazon Drive Cloud storage from Amazon. Alexa Actionable Analytics for the Web.

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