Alexander G. Munts

Intrathecal baclofen for dystonia of complex regional pain syndrome.

ABSTRACT Dystonia in complex regional pain syndrome (CRPS) responds poorly to treatment. Intrathecal baclofen (ITB) may improve this type of dystonia, but information on its efficacy and safety is limited. A single‐blind, placebo‐run‐in, dose‐escalation study was carried out in 42 CRPS patients to evaluate whether dystonia responds to ITB. Thirty‐six of the 38 patients, who met the responder criteria received a pump for continuous ITB administration, and were followed up for 12 months to assess long‐term efficacy and safety (open‐label study). Primary outcome measures were global dystonia severity (both studies) and dystonia‐related functional limitations (open‐label study). The dose‐escalation study showed a dose‐effect of baclofen on dystonia severity in 31 patients in doses up to 450 μg/day. One patient did not respond to treatment in the dose‐escalation study and three patients dropped out. Thirty‐six patients entered the open‐label study. Intention‐to‐treat analysis revealed a substantial improvement in patient and assessor‐rated dystonia scores, pain, disability and quality‐of‐life (Qol) at 12 months. The response in the dose‐escalation study did not predict the response to ITB in the open‐label study. Eighty‐nine adverse events occurred in 26 patients and were related to baclofen (n = 19), pump/catheter system defects (n = 52), or could not be specified (n = 18). The pump was explanted in six patients during the follow‐up phase. Dystonia, pain, disability and Qol all improved on ITB and remained efficacious over a period of one year. However, ITB is associated with a high complication rate in this patient group, and methods to improve patient selection and catheter‐pump integrity are warranted.

Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome.

Activated immune cells in the spinal cord may play an important role in the development and maintenance of neuropathic pain, such as occurs in response to peripheral inflammation or tissue injury. Immune activation may therefore serve as a therapeutic target for immune modulating drugs like corticosteroids. This double‐blind randomized placebo‐controlled parallel‐group trial aimed to investigate the efficacy and safety of a single intrathecal administration of 60 mg methylprednisolone (ITM) in chronic patients with complex regional pain syndrome (CRPS). The primary outcome measure was change in pain (pain intensity numeric rating scale; range 0–10) after 6 weeks. With 21 subjects per group the study had a 90% power to detect a clinically relevant difference (≥2 points). After 21 patients (10 on ITM) were included, the trial was stopped prematurely after the interim analysis had shown that ITM had no effect on pain (difference in mean pain intensity numeric rating scale at 6 weeks 0.3, 95% confidence interval −0.7 to 1.3) or any other outcome measure. We did not find any difference in treatment‐emergent adverse events between the ITM and placebo group. We conclude that a single bolus administration of ITM is not efficacious in chronic CRPS patients, which may indicate that spinal immune activation does not play an important role in this phase of the syndrome.

Fixed Dystonia in Complex Regional Pain Syndrome: a Descriptive and Computational Modeling Approach

BackgroundComplex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback.MethodsWe systematically characterized the pattern of dystonia in 85 CRPS-patients with dystonia according to the posture held at each joint of the affected limb. We compared the patterns with a neuromuscular computer model simulating aberrations of proprioceptive reflexes. The computer model consists of an antagonistic muscle pair with explicit contributions of the musculotendinous system and reflex pathways originating from muscle spindles and Golgi tendon organs, with time delays reflective of neural latencies. Three scenarios were simulated with the model: (i) increased reflex sensitivity (increased sensitivity of the agonistic and antagonistic reflex loops); (ii) imbalanced reflex sensitivity (increased sensitivity of the agonistic reflex loop); (iii) imbalanced reflex offset (an offset to the reflex output of the agonistic proprioceptors).ResultsFor the arm, fixed postures were present in 123 arms of 77 patients. The dominant pattern involved flexion of the fingers (116/123), the wrists (41/123) and elbows (38/123). For the leg, fixed postures were present in 114 legs of 77 patients. The dominant pattern was plantar flexion of the toes (55/114 legs), plantar flexion and inversion of the ankle (73/114) and flexion of the knee (55/114).Only the computer simulations of imbalanced reflex sensitivity to muscle force from Golgi tendon organs caused patterns that closely resembled the observed patient characteristics. In parallel experiments using robot manipulators we have shown that patients with dystonia were less able to adapt their force feedback strength.ConclusionsFindings derived from a neuromuscular model suggest that aberrant force feedback regulation from Golgi tendon organs involving an inhibitory interneuron may underpin the typical fixed flexion postures in CRPS patients with dystonia.

Intrathecal glycine for pain and dystonia in complex regional pain syndrome

ABSTRACT Since glycinergic neurotransmission plays an important inhibitory role in the processing of sensory and motor information, intrathecal glycine (ITG) administration may be a potential therapy for both pain and movement disorders in patients with complex regional pain syndrome (CRPS). Aims of the current study, which is the first report on ITG in humans, were to evaluate its safety and efficacy. ITG treatment during 4 weeks was studied in CRPS patients with dystonia in the period before they received intrathecal baclofen treatment. Twenty patients were assessed and after exclusion of one patient, the remaining 19 patients were randomized in a double‐blind placebo‐controlled crossover study. Safety was assessed by clinical evaluation, blood examinations and electrocardiograms. Efficacy measures involved pain (numeric rating scale, McGill pain questionnaire), movement disorders (Burke–Fahn–Marsden dystonia rating scale, unified myoclonus rating scale, tremor research group rating scale), activity (Radboud skills questionnaire, walking ability questionnaire), and a clinical global impression (CGI) and patients global impression score (PGI). Treatment‐emergent adverse events were generally mild to moderate and not different from placebo treatment. During ITG treatment growth hormone levels were slightly increased. Although there was a trend to worsening on the CGI and PGI during ITG treatment, there were no significant differences between ITG and placebo treatment in any of the outcomes. ITG given over 4 weeks was ineffective for pain or dystonia in CRPS. Although no serious adverse events occurred, further studies are required to rule out potential neurotoxicity of ITG.

Analysis of cerebrospinal fluid inflammatory mediators in chronic complex regional pain syndrome related dystonia.

Objectives There is compelling evidence of central nervous system involvement in neuropathic pain and movement disorders in patients with complex regional pain syndrome (CRPS). Previously, elevated cerebrospinal fluid (CSF) levels of interleukin-1β and interleukin-6 were found in CRPS patients with and without movement disorders. The aim of the present study was to replicate these findings and to search for additional CSF biomarkers in chronic CRPS patients with dystonia. Methods CSF samples of 20 patients and 29 controls who underwent spinal anesthesia for surgical interventions participated. We measured interleukin-1β, interleukin-6, interferon-γ inducible protein-10, RANTES (regulated upon activation, normal T-cell expressed and secreted), complement C3, mannose-binding lectin, complement C1q, soluble intercellular adhesion molecule-1, endothelin-1, nitric oxide, human lactoferrin, and hypocretin-1 levels in these samples. Results No differences in the CSF levels of these effector mediators between patients and controls were found. Conclusion Our CSF findings do not support a role of a variety of inflammatory mediators or hypocretin-1 in chronic CRPS patients with dystonia.

Clinical and neurophysiological characterization of myoclonus in complex regional pain syndrome

The origin of myoclonus in patients with complex regional pain syndrome (CRPS) is unknown. Eight patients with CRPS related myoclonus were clinically evaluated and studied with intermuscular and corticomuscular coherence analysis. Jerks were present at rest, aggravated during action and were frequently associated with tremulousness or dystonia. Electromyography demonstrated a burst duration ranging from 25 to 240 ms with burst frequencies varying from <1 jerk/s during rest to 20 Hz during action. Coherence studies showed increased intermuscular coherence in 4 patients in the 6 to 12 Hz band, as reported in patients with enhanced physiological tremor. In 2 patients side‐to‐side coherence was observed, pointing to a central oscillatory drive. Significant coherence entrainment was detected in 5 patients. We conclude that the characteristics of myoclonus in CRPS are different from other forms of myoclonus.

Modeling movement disorders¿CRPS-related dystonia explained by abnormal proprioceptive reflexes

Humans control their movements using adaptive proprioceptive feedback from muscle afferents. The interaction between proprioceptive reflexes and biomechanical properties of the limb is essential in understanding the etiology of movement disorders. A non-linear neuromuscular model of the wrist incorporating muscle dynamics and neural control was developed to test hypotheses on fixed dystonia. Dystonia entails sustained muscle contractions resulting in abnormal postures. Lack of inhibition is often hypothesized to result in hyperreflexia (exaggerated reflexes), which may cause fixed dystonia. In this study the model-simulated behavior in case of several abnormal reflex settings was compared to the clinical features of dystonia: abnormal posture, sustained muscle contraction, increased stiffness, diminished voluntary control and activity-aggravation. The simulation results were rated to criteria based on characteristic features of dystonia. Three abnormal reflex scenarios were tested: (1) increased reflex sensitivity-increased sensitivity of both the agonistic and antagonistic reflex pathways; (2) imbalanced reflex offset-a static offset to the reflex pathways on the agonistic side only; and (3) imbalanced reflex sensitivity-increased sensitivity of only the agonistic reflex pathways. Increased reflex sensitivity did not fully account for the features of dystonia, despite distinct motor dysfunction, since no abnormal postures occurred. Although imbalanced reflex offset did result in an abnormal posture, it could not satisfy other criteria. Nevertheless, imbalanced reflex sensitivity with unstable force feedback in one of the antagonists closely resembled all features of dystonia. The developed neuromuscular model is an effective tool to test hypotheses on the underlying pathophysiology of movement disorders.

Postdural Puncture Headache in Complex Regional Pain Syndrome: A Retrospective Observational Study

OBJECTIVE To describe the unusual course of postdural puncture headache (PDPH) after pump implantation for intrathecal baclofen (ITB) administration in patients with complex regional pain syndrome (CRPS)-related dystonia. DESIGN Case series based on data collected from 1996 to 2005. Setting. Movement disorders clinic, university hospital. PATIENTS A total of 54 patients with CRPS-related dystonia who were treated with ITB. RESULTS A high incidence (76%) and prolonged course (median 18 days, range 2 days to 36 months) of PDPH was found. Radionuclide studies performed in two patients with long-lasting symptoms (12-16 months) did not reveal cerebrospinal fluid (CSF) leakage. In patients without signs of CSF leakage (N = 38), epidural blood patches administered in 24 patients were effective in 54%, while ketamine infusions administered in six patients were effective in 67%. CONCLUSIONS Our observations may suggest that other mechanisms besides intracranial hypotension play a role in the initiation and maintenance of PDPH in CRPS and stimulate new directions of research on this topic.

Acute-onset chronic inflammatory demyelinating polyneuropathy after Zika virus infection

In December 2016, a 69-year-old man with a history of hypertension, hypercholesterolaemia and knee operations developed an erythematous pruritic rash on his trunk, cold shivers and swollen hands and feet with paraesthesias and numbness while on holiday in Curacao. Eight days later he developed pain in his right leg and back, provoked by walking and stretching. This pain slowly increased over the next 5 weeks to the point that it became difficult to walk. He was admitted to the neurology ward of a regional hospital in The Netherlands, and neurological examination showed an antalgic gait, hypaesthesia of fingertips and feet and normal muscle strength and tendon reflexes. MRI of the cervical, thoracic and lumbar spine without gadolinium was normal. Eight days after admission he developed a progressive weakness of the legs starting in the right leg. Neurological examination showed a proximal and distal flaccid paraparesis with absent reflexes of the legs and normal reflexes of the arms. Cerebrospinal fluid (CSF) examination 3 days after admission showed a leucocyte count of 1/10 E6/L and a protein level of 620 mg/L. Electrolytes, liver and kidney function and inflammatory parameters were normal. Nerve conduction studies (NCS) 5 days after admission showed slightly prolonged distal motor latencies of the peroneal and tibial nerves, mildly prolonged F-wave latencies of the ulnar and tibial …

Foot Drop Dystonia Resulting from parkin (PARK2) Mutation

Mutations in the parkin gene (PRKN, PARK2) cause autosomal-recessive early-onset Parkinson’s disease (PD). Reported parkin mutation frequencies vary across studies, but percentages up to 49% of familial and 20% of sporadic cases of early-onset PD have been reported on. It is difficult to clinically distinguish parkin mutations from other causes of PD. Clinical clues for mutations in the parkin gene are symmetrical onset, dystonia, hyperreflexia, slower disease progression, and a good response to levodopa. In this report, we describe a 35-year-old Dutch man with “foot drop dystonia” resulting from a parkin mutation.