Effects of Spinal Cord Stimulation on Heart Rate Variability in Patients With Failed Back Surgery Syndrome: Comparison Between a 2-lead ECG and a Wearable Device.

OBJECTIVES: Heart rate variability recordings have the potential to examine the role of the autonomic nervous system. Several wearable devices are nowadays readily available. Up until now, no studies explored whether a wearable device is able to reliably measure a treatment response in chronic pain patients. Therefore, the aim of this study is to evaluate the reliability of a Polar V800 (Polar Electro Oy, Finland) wearable device to accurately measure RR intervals in patients with failed back surgery syndrome (FBSS) during spinal cord stimulation (SCS), as compared with an eMotion 2-lead ECG recording. MATERIALS AND METHODS: Twenty-two patients diagnosed with FBSS and treated with SCS participated in this study. HRV was measured with a 2-lead ECG registration tool and a Polar V800 during on and off state of SCS. Intraclass correlation coefficients, correlations, limits of agreement, Cronbach's α, and effect sizes were calculated. RESULTS: Analysis based on the recordings from the ECG and wearable device revealed the same HRV parameters (except for the time-frequency domain) to capture the treatment response of SCS. Parameters that are relevant for measuring the SCS treatment response have strong correlations (r ≥ .82), good ICC values (ICC ≥0.82), acceptable consistency (α ≥ .9), and limited bias. CONCLUSIONS: Similar pre- to posttreatment changes were revealed between a wearable device and 2-lead ECG with reliable HRV estimates for parameters that are able to capture the treatment changes. This suggests that a wearable heart rate monitor might be a reliable wearable tool for the detection of pre- to post treatment changes of SCS, in patients with FBSS.

The Long-Term Response to High-Dose Spinal Cord Stimulation in Patients With Failed Back Surgery Syndrome After Conversion From Standard Spinal Cord Stimulation: An Effectiveness and Prediction Study.

OBJECTIVES: Spinal cord stimulation (SCS) is nowadays available with several stimulation paradigms. New paradigms, such as high dose (HD-)SCS, have shown the possibility to salvage patients who lost their initial pain relief. The first aim of this study is to evaluate the effectiveness of HD-SCS after conversion from standard SCS. The second aim is to develop a model for prediction of long-term response of HD-SCS after unsatisfactory standard SCS. MATERIALS AND METHODS: Seventy-eight patients with failed back surgery syndrome (FBSS) who are treated with standard SCS were enrolled in the study. Self-reporting questionnaires and outcomes were assessed before conversion and at 1, 3, and 12 months of HD-SCS. Longitudinal mixed models were used to determine the effectiveness of HD-SCS. Logistic regression and classification and decision tree analyses were performed to predict responders (NRS decrease ≥2/10) after 12 months of HD-SCS. RESULTS: Significant time effects were found for both low back and leg pain responders, suggesting the effectiveness of HD-SCS after conversion. Logistic regression models revealed the importance of pain intensity scores, medication use, paresthesia coverage (for back pain) and EQ5D (for leg pain) as predictors for being a responder after 12 months of HD-SCS. CONCLUSIONS: Converting patients with unsatisfactory responses from standard SCS to HD-SCS may be an effective strategy to obtain and maintain pain relief in a challenging subgroup of patients with FBSS refractory to standard SCS. The prediction models may guide clinicians in their decision making when considering conversion to HD-SCS in patients with FBSS experiencing inadequate response to standard SCS.

Effects of spinal cord stimulation on heart rate variability in patients with Failed Back Surgery Syndrome.

BACKGROUND: Building on the recent finding that chronic pain patients with impaired functioning of the descending nociceptive inhibitory system (DNIS) present lower resting heart rate variability (HRV), this study aims to investigate the impact of Spinal Cord Stimulation (SCS) on HRV in patients with Failed Back Surgery Syndrome (FBSS). More precisely, we hypothesize that SCS influences the DNIS, with increased parasympathetic tone as a consequence, as measurable by HRV analysis. METHODS: Twenty-two patients diagnosed with FBSS and treated with SCS participated in this study. HRV was measured with a 2-lead ECG registration tool during on and off states of SCS. HRV analysis for time, frequency, time-frequency and nonlinear domain parameters was based on a 5-minute recording segment. RESULTS: The mean heart rate and low frequency power were significantly lower when SCS was activated. HRV, absolute and normalized high frequency power significantly increased during SCS compared to without SCS. The ratio of low frequency/high frequency ratios, as parameter for global sympathetic-parasympathetic equilibrium, significantly decreased when SCS was activated. CONCLUSIONS: When SCS is switched off, patients with FBSS present relatively stronger sympathetic tone and weaker parasympathetic activity. Activation of the SCS, possibly via stimulation of the DNIS, restores this disbalance of autonomic activity.

Association Between Spinal Cord Stimulation and Top-Down Nociceptive Inhibition in People With Failed Back Surgery Syndrome: A Cohort Study.

BACKGROUND: Descending nociceptive inhibitory pathways often malfunction in people with chronic pain. Conditioned pain modulation (CPM) is an experimental evaluation tool for assessing the functioning of these pathways. Spinal cord stimulation (SCS), a well-known treatment option for people with failed back surgery syndrome (FBSS), probably exerts its pain-relieving effect through a complex interplay of segmental and higher-order structures. OBJECTIVE: To the best of our knowledge, no clinical studies have thoroughly investigated the associations between SCS and CPM. DESIGN: This was a prospective cohort study in people with FBSS. METHODS: Seventeen people who had FBSS and were scheduled for SCS were enrolled in this study. The CPM model was evaluated at both sural nerves and was induced by electrical stimulation as the test stimulus and the cold pressor test as the conditioning stimulus. RESULTS: Before SCS, less than 30% of the participants with FBSS showed a CPM effect. Significant increases in the electrical detection threshold on the symptomatic side and the nonsymptomatic side were found. On the symptomatic side, no differences in the numbers of CPM responders before and after SCS could be found. On the nonsymptomatic side, more participants showed a CPM effect during SCS. Additionally, there were significant differences for CPM activation and SCS treatment. LIMITATIONS: Limitations were the small sample size and the subjective outcome parameters in the CPM model. CONCLUSIONS: This study revealed a bilateral effect of SCS that suggests the involvement of higher-order structures, such as the periaqueductal gray matter and rostroventromedial medulla (key regions in the descending pathways), as previously suggested by animal research.

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

BACKGROUND: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. AIMS: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. METHODS: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. RESULTS: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. CONCLUSIONS: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.

Cerebral Blood Flow and Heart Rate Variability in Chronic Fatigue Syndrome: A Randomized Cross-Over Study.

BACKGROUND: Pain, fatigue, and concentration difficulties are typical features of chronic fatigue syndrome (CFS). The exact underlying mechanisms of these symptoms are still unknown, but available evidence suggests an important role for impaired pain modulation. As evidence also suggests that pain modulation is related to cardiovascular mechanisms, it seems logical to investigate whether cerebral blood flow (CBF) and heart rate variability (HRV) are altered in these patients. OBJECTIVES: We aimed to investigate the role of the cardiovascular system in pain modulation and symptoms of CFS; the response of CBF and HRV to physical stress and their relation to the change in temporal summation (TS) of pressure pain and self-reported symptoms was evaluated. STUDY DESIGN: A controlled, randomized cross-over trial. SETTING: University Hospital Brussels. METHODS: Twenty CFS patients and 20 sedentary healthy controls were included in this study. In both of the groups, the change in TS of pressure pain, CBF (using transcranial Doppler), and HRV (using finger plethysmography) was examined during physical and emotional stress (to control for potential bias), as well as their association mutually and with self-reported symptoms of pain, fatigue, and concentrations difficulties. RESULTS: There was no significant interaction or group (F-values ranging from .100 to 1.862, P-values ranging from .754 to .181) effect in CBF or HRV parameters. HRV and CBF did change during physical exercise, but the changes did not differ between patients and controls. While pain scores during TS at the trapezius site reduced in the control group after the physical exercise protocol (P = .037), they did not change in the CFS group (P = .108), suggesting impaired pain modulation. There were no significant correlations between CBF, HRV, TS, and self-reported symptoms (all P-values of correlation analyses > .01). LIMITATIONS: Although effect sizes were medium to large, the study sample was relatively low. Also, the mild nature of the exercise bout is discussable. Nonetheless, this mild exercise was able to provoke endogenous pain modulation in the control group, which endorsed a proper execution of the cycling exercise. Moreover, mild exercises are more applicable to daily physical activities in CFS patients than vigorous exercises. CONCLUSION: These results seem to refute the previously suggested alterations of CBF/HRV in CFS patients. These cardiovascular parameters appear not to explain pain before, during, and following exercise. KEY WORDS: Chronic pain, physical exercise, emotional stress, pain modulation, cardiovascular systems, temporal summation, pain pressure thresholds, transcranial Doppler, plethysmography.

Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke.

BACKGROUND: While neurogranin has no value as plasma biomarker for Alzheimer's disease, it may be a potential blood biomarker for traumatic brain injury. This evokes the question whether there are changes in neurogranin levels in blood in other conditions of brain injury, such as acute ischemic stroke (AIS). METHODS: We therefore explored neurogranin in paired cerebrospinal fluid (CSF)/plasma samples of AIS patients (n = 50) from a well-described prospective study. In parallel, we investigated another neuronal protein, i.e. tau, which has already been suggested as potential AIS biomarker in CSF and blood. ELISA as well as Single Molecule Array (Simoa) technology were used for the biochemical analyses. Statistical analyses included Shapiro-Wilk testing, Mann-Whitney analyses and Pearson's correlation analysis. RESULTS: In contrast to tau, of which high levels in both CSF and plasma were related to stroke characteristics like severity and long-term outcome, plasma neurogranin levels were only correlated with infarct volume. Likewise, CSF neurogranin levels were significantly higher in patients with an infarct volume > 5 mL than in patients with smaller infarct volumes. Finally, neurogranin and tau were significantly correlated in CSF, whereas a weaker relationship was observed in plasma. CONCLUSIONS: These findings indicate that although plasma and CSF neurogranin may reflect the volume of acute cerebral ischemia, this synaptic protein is less likely to be a potential AIS biomarker. Levels of tau correlated with severity and outcome of stroke in both plasma and CSF, in the present study as well as previous reports, confirming the potential of tau as an AIS biomarker.

Twiddler's Syndrome and Neuromodulation-Devices: A Troubled Marriage.

OBJECTIVE: The occurrence of Twiddler's syndrome in subjects with neurostimulator devices is poorly understood and might be influenced by age, sex, BMI, use of medication or psychologic disorders. METHODS: Two hundred thiry-five patients who received a neuromodulator were included in this retrospective study in a period between 2008 and 2015. The subjects were divided into a group of Twiddler's syndrome patients (TS) and a group of non-Twiddler's patients (NTS). Outcome measures were gender, age at implantation, type of neuromodulation, use of antipsychotics, antidepressants and opioids, the presence of other psychologic disorders and BMI. RESULTS: Both groups differ significantly in age (p = 0.024), weight (p = 0.001) and BMI (p = 0.001). No statistical difference was found in the type of neuromodulation (p = 0.537), gender (p = 0.368), the use of antipsychotics (p = 0.071), antidepressants (p = 0.097), and opioids (p = 1). Forward stepwise logistic regression of all variables showed that age of implementation (p = 0.029), the use of antipsychotics (p = 0.022) and BMI (p = 0.001) were statistically significant for predicting Twiddler's syndrome. CONCLUSION: Twiddler's syndrome is an uncommon complication of neuromodulation implantable devices. Younger age, use of antipsychotics, and high BMI are risk factors that can be used to facilitate rapid diagnosis and treatment.

Acute Ischemic Stroke Severity, Progression, and Outcome Relate to Changes in Dipeptidyl Peptidase IV and Fibroblast Activation Protein Activity.

Dipeptidyl peptidase IV (DPPIV) inhibition may be a promising therapeutic strategy for acute stroke treatment, given its potential to prolong the biological half-life of neuroprotective substrates. A related protease, fibroblast activation protein (FAP), was recently shown to inactivate the same substrates. Therefore, it should also be investigated as a potential target in stroke. The study aimed to investigate whether stroke severity and outcome correlate with DPPIV and FAP activities and their kinetics shortly after acute ischemic stroke. DPPIV and FAP activities were analyzed in the serum of 50 hyperacute stroke patients at admission, 1 day, 3 days, and 7 days after stroke onset and in 50 age-matched healthy controls. This was done as part of the Middelheim's Interdisciplinary Stroke Study. DPPIV activity tended to increase shortly after stroke compared to the control population. DPPIV and FAP activities steadily decreased in the first week after stroke onset. Higher infarct volumes (≥5 ml) and a more severe stroke (NIHSS >7) at admission were correlated with a stronger decrease in the activities of both enzymes. Moreover, these patients more often developed a progressive stroke, were more often institutionalized. Patients with a stronger increase in DPPIV activity at admission and decrease in the activity of both DPPIV and FAP during the first week after stroke onset had a more severe stroke and worse short-term outcomes.

High-Density in Spinal Cord stimulation: Virtual Expert Registry (DISCOVER): Study Protocol for a Prospective Observational Trial.

BACKGROUND: Spinal cord stimulation (SCS) is a proven and effective treatment for neuropathic pain conditions such as failed back surgery syndrome (FBSS). The hypothesis that different settings for SCS parameters activate unique, pain-relieving mechanisms has boosted the development of various SCS paradigms. High density spinal cord stimulation (HD-SCS) is one of those promising, novel stimulation forms characterized by subthreshold stimulation, delivering more pulses per second and a higher pulse density to the spinal cord than conventional SCS. OBJECTIVES: The aim of DISCOVER is to gather evidence about the effectiveness, feasibility, and (possible) side effects of HD stimulation. METHODS: The prospective, non-interventional, multi-center, clinical study, DISCOVER, is currently restricted to Belgium where 19 neuromodulation centers were selected. Patient recruitment started in October 2016 and is expected to end in October 2017. Subjects included are (1) patients with insufficient pain relief from conventional SCS or (2) neurostimulation-naïve patients suited for SCS. Patients will be assessed 1 month, 3 months, and 12 months after conversion to HD-SCS settings. Each patient's visit will include: a numerical rating scale (NRS), Oswestry disability index (ODI), Pittsburgh sleep quality index (PSQI), EQ-5D, a pain map, registration of SCS settings, and a list of used pain medication. CONCLUSIONS: Although promising results have been reported, adequate registration of its effectiveness and (possible) side-effects remains an unmet need. Main results are expected in 2019.

Disc Fragment Herniectomy Through a Facet Joint Quadrantectomy for Extraforaminal Lumbar Herniation: Technique and Results.

BACKGROUND: Extraforaminal lumbar disc herniation (EFLDH) accounts for 7%-12% of all lumbar disc herniations. We report on a surgical technique for EFLDH, which requires only minimal resection of the facet joint and also allows access to the preforaminal space, if necessary. METHODS: The medical records of 61 consecutive patients treated with disc fragment herniectomy through a facet joint quadrantectomy for EFLDH at the Universitair Ziekenhuis Brussel were critically evaluated with respect to preoperative clinical signs and symptoms, surgery-related complications and outcome at 6 weeks after intervention. Patient satisfaction after the surgery was evaluated using the MacNab classification. RESULTS: The prevalence of leg pain decreased from 100% before the intervention to 19.7% at follow-up. Only 9 patients (14.8%) suffered from residual motor deficit at follow-up, compared with 37 patients (60.7%) in the preoperative situation. The postoperative improvement was highly significant for all parameters (P < 0.0001) and this evolution is also reflected in the MacNab classification showing 62.3% excellent, 23.0% good, 13.1% fair, and only 1.6% poor satisfaction. Using logistic regression analysis, only the presence of a preoperative sensory deficit was found to be an independent predictor for excellent patient satisfaction on the MacNab classification. CONCLUSIONS: Disc fragment herniectomy through a facet joint quadrantectomy for EFLDH is a safe and minimal invasive technique resulting in very satisfactory results. Preservation of facet joint stability and the possibility to convert to a classic approach to reach for preforaminal components, if necessary, are major advantages of this technique.

Spinal cord stimulation modulates cerebral neurobiology: a proton magnetic resonance spectroscopy study.

INTRODUCTION: Although spinal cord stimulation (SCS) is a widely used treatment for chronic neuropathic pain secondary to spinal surgery, little is known about the underlying physiological mechanisms. METHODS: The primary aim of this study is to investigate the neural substrate underlying short-term SCS by means of (1)H MR spectroscopy with short echo time, in 20 patients with failed back surgery syndrome. RESULTS: Marked increase of γ-aminobutyric acid (GABA) and decrease in glucose in the ipsilateral thalamus were found between baseline situation without SCS and after 9' of SCS, indicating the key role of the ipsilateral thalamus as a mediator of chronic neuropathic pain. In addition, this study also showed a progressive decrease in glucose in the ipsilateral thalamus over time, which is in line with the findings of previous studies reporting deactivation in the ipsilateral thalamic region. CONCLUSIONS: The observation of GABA increase and glucose decrease over time in the ipsilateral thalamus may be the causal mechanism of the pain relief due to SCS or an epiphenomenon.

Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young.

OBJECTIVE: In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with α-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population. METHODS: Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed. RESULTS: Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot α-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. CONCLUSIONS: We could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants.

Feasibility of cerebral magnetic resonance imaging in patients with externalised spinal cord stimulator.

OBJECT: Spinal cord stimulation (SCS) is a well-known treatment option for intractable neuropathic pain after spinal surgery, but its pathophysiological mechanisms are poorly stated. The goal of this study is to analyse the feasibility of using brain MRI, functional MRI (fMRI) and Magnetic Resonance Spectroscopy (MRS) as tools to analyse these mechanisms in patients with externalised neurostimulators during trial period. METHODS: The authors conducted in an in vitro and in vivo study analysing safety issues when performing brain MRI, fMRI and MRS investigations in human subjects with externalised SCS. Temperature measurements in vitro were performed simulating SCS during MRI sequences using head transmit-receive coils in 1.5 and 3 T MRI systems. 40 Patients with externalised SCS were included in the in vivo study. 20 patients underwent brain MRI, fMRI and another 20 patients underwent brain MRI and MRS. RESULTS: A maximal temperature increase of 0.2°C was measured and neither electrode displacements nor hardware failures were observed. None of the patients undergoing the MRS sequences at the 1.5 or 3 T MRI scanners described any discomfort or unusual sensations. CONCLUSION: We can conclude that brain MRI, fMRI and MRS studies performed in patients with externalised SCS can be safely executed.

Retrograde C0-C1 insertion of cervical plate electrode for chronic intractable neck and arm pain.

OBJECTIVE: Spinal cord stimulation is an effective treatment for chronic neuropathic pain after spinal surgery. In addition to the most common placement of electrodes at the thoracic level for low back and leg pain, electrodes can also be placed on a cervical level in patients with chronic neck and upper limb pain. Surgical insertion of plate electrodes via an orthodromal direction requires a partial laminectomy. Therefore, the authors describe a surgical technique using retrograde insertion of a plate electrode to avoid laminectomy. METHODS: Six patients with uncontrolled neck and upper limb pain despite optimal analgesic medication were treated with a surgical electrode placed at the C1-C2 level via a retrograde placement technique without laminectomy. RESULTS: All patients received stimulation paresthesias at the desired regions and reported significant pain reduction in the neck and arm regions. CONCLUSION: This retrograde placement of plate electrodes enables cervical lordosis to be overcome and results in adequate stimulation of the upper cervical region, which is mandatory to reduce neck and shoulder pain without laminectomy.

Belgian Fabry study: prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease.

BACKGROUND AND PURPOSE: Data on the prevalence of Fabry disease in patients with central nervous system pathology are limited and controversial. In this study, we assessed the prevalence of Fabry disease in young patients presenting with cerebrovascular disease in Belgium. METHODS: In this national, prospective, multicenter study, we screened for Fabry disease in 1000 patients presenting with ischemic stroke, transient ischemic attack, or intracranial hemorrhage; unexplained white matter lesions; or vertebrobasilar dolichoectasia. In male patients, we measured alpha-galactosidase A (alpha-GAL A) activity in dried blood spots. Female patients were screened for mutations by exonic DNA sequencing of the alpha-GAL A gene. RESULTS: alpha-GAL A activity was deficient in 19 men (3.5%), although all had normal alpha-GAL A gene sequences. Enzymatic deficiency was confirmed on repeat assessment in 2 male patients (0.4%). We identified missense mutations in 8 unrelated female patients (1.8%): Asp313Tyr (n=5), Ala143Thr (n=2), and Ser126Gly (n=1). The pathogenicity of the 2 former missense mutations is controversial. Ser126Gly is a novel mutation that can be linked to late-onset Fabry disease. CONCLUSIONS: alpha-GAL A deficiency may play a role in up to 1% of young patients presenting with cerebrovascular disease. These findings suggest that atypical variants of Fabry disease with late-onset cerebrovascular disease exist, although the clinical relevance is unclear in all cases.

Middelheim Fabry Study (MiFaS): a retrospective Belgian study on the prevalence of Fabry disease in young patients with cryptogenic stroke.

OBJECTIVE: To assess the prevalence of Fabry disease in young patients with cryptogenic stroke. PATIENTS AND METHODS: We retrospectively assessed the prevalence of Fabry disease in patients aged 16-60 years that were admitted to ZNA Middelheim Hospital from January 1, 2000 to December 31, 2004 for cryptogenic stroke. We screened for Fabry disease by measurement of alpha-galactosidase A and beta-glucuronidase activity on blood spot. In all patients with abnormal enzymatic activity and in all female patients with low normal values, genetic sequencing of the alpha-GAL-gene was performed. RESULTS: In a population of 103 young patients with cryptogenic stroke that met the in- and exclusion criteria, we were unable to identify any patient with Fabry disease. CONCLUSION: Based on the results of alpha-galactosidase A and beta-glucuronidase activity, genetic sequencing and the low prevalence of clinical signs and symptoms of Fabry disease in this population, we believe that the true prevalence of Fabry disease in patients with cryptogenic stroke may be less than currently accepted in literature.