Jörg Wissel

Recommendations for the use of botulinum toxin type A in the management of cerebral palsy

Botulinum toxin type A (BTX-A) is increasingly being used for the treatment of childhood spasticity, particularly cerebral palsy. However, until very recently, all such use in this indication has been unapproved with no generally accepted treatment protocols, resulting in considerable uncertainty and variation in its use as a therapeutic agent. In view of the increasing awareness of, and interest in, this approach to the treatment of spasticity, and also the recent licensing in a number of countries of a BTX-A preparation for treating equinus deformity in children, it would seem timely to establish a framework of guidelines for the safe and efficacious use of BTX-A for treating spasticity in children. This paper represents an attempt, by a group of 15 experienced clinicians and scientists from a variety of disciplines, to arrive at a consensus and produce detailed recommendations as to appropriate patient selection and assessment, dosage, injection technique and outcome measurement. The importance of adjunctive physiotherapy, orthoses and casting is also stressed.

Management of spasticity associated pain with botulinum toxin A.

Lesions of the central nervous system often result in an upper motor neuron syndrome including spasticity, paresis with pyramidal signs, and painful spasms. Pharmacological treatment with oral antispasticity drugs is frequently associated with systemic side effects which limit their clinical use. Botulinum Toxin A (BtxA) injected in spastic muscles has been shown to be effective in reducing muscle tone, but only few studies have reported pain relief as additional benefit. Therefore, we investigated the effects of local BtxA injections in 60 patients with acute (< 12 months) and chronic spasticity and pain in a prospective multicenter study. Target muscles for BtxA were selected on the basis of clinical examination. Intramuscular BtxA injections were placed in muscles exhibiting increased muscle tone in combination with pain during passive joint movement. Patients received a mean total dose of 165.7 +/- 108.2 [30-400] units BOTOX((R)) per treatment session in a mean 3.4 +/- 1.5 muscles. Baseline and follow-up (mean 5.9 weeks) measures included a patient self-assessment of pain and function on a five-level scale, a physicians evaluation of function, and a global rating of response to BtxA. Fifty-four of sixty patients experienced improvement in pain without subjective functional improvement. The effects were comparable in acute (n = 17) and chronic (n = 43) spasticity. Physicians assessment of gain in function increased significantly (p < 0.05) only in patients with chronic spasticity. No serious adverse event was observed. Mild reversible side effects (local pain, hematoma, edema, mild weakness) were observed in four patients. In conclusion, we found that intramuscular BtxA injections are a potent, well-tolerated treatment modality to significantly reduce spasticity-related local pain. This problem may be a main indication, especially in patients with poor response or intolerable side effects to oral medication.

Survival with full neurologic recovery and no cerebral pathology after prolonged cardiopulmonary resuscitation with vasopressin in pigs

OBJECTIVES We sought to determine the effects of vasopressin and saline placebo in comparison with epinephrine on neurologic recovery and possible cerebral pathology in an established porcine model of prolonged cardiopulmonary resuscitation (CPR). BACKGROUND It is unknown whether increased cerebral blood flow during CPR with vasopressin is beneficial with regard to neurologic recovery or detrimental owing to complications such as cerebral edema after return of spontaneous circulation. METHODS After 4 min of cardiac arrest, followed by 3 min of basic life support CPR, 17 animals were randomly assigned to receive every 5 min either vasopressin (0.4, 0.4 and 0.8 U/kg; n = 6), epinephrine (45, 45 and 200 microg/kg; n = 6) or saline placebo (n = 5). The mean value +/- SEM of aortic diastolic pressure was significantly (p < 0.05) higher 90 s after each of three vasopressin versus epinephrine versus saline placebo injections (60 +/- 3 vs. 45 +/- 3 vs. 29 +/- 2 mm Hg; 49 +/- 5 vs. 27 +/- 3 vs. 23 +/- 1 mm Hg; and 50 +/- 6 vs. 21 +/- 3 vs. 16 +/- 3 mm Hg, respectively). After 22 min of cardiac arrest, including 18 min of CPR, defibrillation was attempted to achieve return of spontaneous circulation. RESULTS All the pigs that received epinephrine and saline placebo died, whereas all pigs on vasopressin survived (p < 0.05). Neurologic evaluation 24 h after successful resuscitation revealed only an unsteady gait in all vasopressin-treated animals; after 96 h, magnetic resonance imaging revealed no cerebral pathology. CONCLUSIONS During prolonged CPR, repeated vasopressin administration, but not epinephrine or saline placebo, ensured long-term survival with full neurologic recovery and no cerebral pathology in this porcine CPR model.

The impact of blepharospasm and cervical dystonia on health-related quality of life and depression

Abstract. The aim of the study was to evaluate and compare health-related quality of life (HR-QoL) and depression in essential blepharospasm (BSP) and idiopathic cervical dystonia (CD), to identify the clinical and demographic factors associated with poor HR-QoL in both disorders and to analyse the effect of Botulinum Toxin A (BtxA) therapy. Two hundred-twenty consecutive patients with BSP (N = 89, 62 % women, mean age 64 years, mean disease duration 7 years) and CD (N = 131, 64 % women, mean age 53 years, mean disease duration 8 years) recruited from routine referrals to eight Austrian dystonia clinics were included. HR-QoL was measured by the Short Form 36 (SF-36) and depression by the Beck Depression Inventory (BDI). At baseline, patients with CD and BSP scored significantly worse in all eight SF-36 domains compared with an age-matched community sample. In addition, 47 % of patients with CD and 37 % of those with BSP were depressed. Women with BSP scored significantly lower in all SF-36 domains and were more depressed than male patients. In contrast, there was no significant effect of gender on HR-QoL and depression in CD. Neck pain had a significant impact on all SF-36 domains and represented the main determinant of depression in CD. Although BtxA therapy resulted in a significant improvement of clinical symptoms in BSP and CD, HR-QoL did not improve in BSP and only two of the eight SF-36 domains improved significantly in patients with CD. The present study for the first time demonstrated that BSP has a substantial impact on health status emphasizing the need for psychological support with interventions aimed at treating depression in these patients. Our results provide further evidence for the profound impact of CD on HR-QoL and indicate the importance of an adequate management of neck pain in addition to reducing the severity of dystonia in CD. The mismatch between objective BtxA derived improvement of dystonia and lack of change of HR-QoL as determined by the SF-36 illustrates the need for optimized disease specific quality of life rating scales in patients with craniocervical dystonia.

A study of the paravertebral anatomy for ultrasound-guided posterior lumbar plexus block.

IMPLICATIONS We investigated the feasibility of posterior paravertebral sonography as a basis for ultrasound-guided posterior lumbar plexus blockades. Posterior paravertebral sonography proved to be a reliable as well as accurate imaging procedure for visualization of the lumbar paravertebral region except the lumbar plexus.

Impaired dopaminergic neurotransmission in patients with traumatic brain injury: a SPET study using 123I-β-CIT and 123I-IBZM

Abstract. Structural imaging suggests that traumatic brain injury (TBI) may be associated with disruption of neuronal networks, including the nigrostriatal dopaminergic pathway. However, to date deficits in pre- and/or postsynaptic dopaminergic neurotransmission have not been demonstrated in TBI using functional imaging. We therefore assessed dopaminergic function in ten TBI patients using [123I]2-β-carbomethoxy-3-β-(4-iodophenyl)tropane (β-CIT) and [123I]iodobenzamide (IBZM) single-photon emission tomography (SPET). Average Glasgow Coma Scale score (±SD) at the time of head trauma was 5.8±4.2. SPET was performed on average 141 days (SD ±92) after TBI. The SPET images were compared with structural images using cranial computerised tomography (CCT) and magnetic resonance imaging (MRI). SPET was performed with an ADAC Vertex dual-head camera. The activity ratios of striatal to cerebellar uptake were used as a semiquantitative parameter of striatal dopamine transporter (DAT) and D2 receptor (D2R) binding. Compared with age-matched controls, patients with TBI had significantly lower striatal/cerebellar β-CIT and IBZM binding ratios (P≤0.01). Overall, the DAT deficit was more marked than the D2R loss. CCT and MRI studies revealed varying cortical and subcortical lesions, with the frontal lobe being most frequently affected whereas the striatum appeared structurally normal in all but one patient. Our findings suggest that nigrostriatal dysfunction may be detected using SPET following TBI despite relative structural preservation of the striatum. Further investigations of possible clinical correlates and efficacy of dopaminergic therapy in patients with TBI seem justified.

Treatment of adductor spasticity with BTX-A in children with CP: a randomized, double-blind, placebo-controlled study

Adductor spasticity in children with cerebral palsy (CP) impairs motor function and development. In a placebo‐controlled, double‐blind, randomized multicentre study, we evaluated the effects of botulinum toxin A(BTX‐A) in 61 children (37 males, 24 females; mean age 6 years 1 month [SD 3y 1mo]) with CP (leg‐dominated tetraparesis, n=39; tetraparesis, n=22; GMFCS level I, n=3; II, n=6; III, n=17; IV, n=29; V, n=6). Four weeks after treatment, a significant superiority of BTX‐A was observed in the primary outcome measure (knee‐knee distance ‘fast catch’, p=0.002), the Ash worth scale (p=0.001), and the Goal Attainment Scale (p=0.037).

Trick maneuvers in cervical dystonia: Investigation of movement‐ and touch‐related changes in polymyographic activity

Antagonistic gestures or trick maneuvers are well‐known clinical features to reduce or abolish dystonic posturing in cervical dystonia (CD). The maneuvers typically consist of a finger touch to the facial skin but their physiology remains unknown. To determine the temporal profile of geste maneuver performance, 25 patients with idiopathic CD were studied by means of polymyography of six cervical muscles prior to any botulinum toxin treatment. Two piezoelectric elements fixed to a fingertip of the hand involved in the trick maneuver and to the facial target region, respectively, were used to relate the essential points of the trick maneuver time course (start of geste‐arm movement, facial contact, end of contact, end of movement) to changes in polymyographic activity. Thirteen patients (52%) showed marked reductions of electromyographic (EMG) activity (≥50% in at least one muscle) during arm movement, definitely prior to contact between fingers and facial target area; in the remaining 12 patients (48%), geste‐related EMG effects were confined to facial–finger contact. These results might indicate different physiological mechanisms in clinically indistinguishable antagonistic gestures.

Botulinum toxin treatment in atypical parkinsonian disorders associated with disabling focal dystonia.

Abstract We investigated the efficacy of botulinum toxin A (BtxA) therapy in patients with atypical parkinsonian disorders (APD) exhibiting different types of disabling focal dystonia unresponsive to oral drug therapy. Eight patients with functionally disabling focal dystonia out of a series of 60 consecutive patients with APDs regularly treated at our outpatient movement disorders clinic were included. Patients were diagnosed according to established criteria and had disabling limb dystonia (n=4) or craniocervical dystonia (n=4) unresponsive to oral pharmacological treatment. Localization and dose of BtxA injections was determined individually based on clinical examination as well as EMG in patients with limb dystonia. BtxA reduced dystonic symptoms in all patients; only one developed a transient local side-effect. BtxA was particularly effective in the long-term treatment (up to 50 months) of blepharospasm associated with progressive supranuclear palsy (PSP). BtxA also alleviated PSP-associated retrocollis and orofacial dystonia with lower lip retraction associated with PSP and multiple system atrophy. BtxA treatment of limb dystonia in corticobasal degeneration (CBD) temporarily improved hand and arm function in early disease stages while treatment in advanced stages reduced pain, facilitated hygiene and prevented secondary contractures. Limb dystonia was also alleviated by BtxA therapy in one patient with neuronal multisystem degeneration of undetermined cause. The results suggest that BtxA therapy may represent an effective means of alleviating disabling focal dystonia in different APDs. Particularly in early stage APD with disabling limb dystonia local BtxA injections may result in functional improvement.

Quantification of sensory trick impact on tremor amplitude and frequency in 60 patients with head tremor

Head tremor with an obvious head deviation is the typical clinical picture of tremulous cervical dystonia (TCD), whereas head tremor without any significant head deviation allows for the differential diagnosis of dystonic head tremor (DHT) as well as essential head tremor (EHT). Clinical and polyelectromyographic (poly‐EMG) studies have shown a suppression of dystonic muscle activity in patients with TCD performing a maneuver called geste antagonistique. The effect of these trick maneuvers on head tremor has not been investigated in patients with DHT and EHT. We studied the impact of sensory trick maneuvers on head tremor amplitude and frequency clinically by using the tremor subscore of the Tsui scale and by means of computer‐based accelerometry in 60 patients with head tremor as their major disorder. Based on clinical data (modified Tsui scale: rating of spontaneous head deviation [rotation + lateroflexion + ante‐/retroflexion]), pharmacologic response of tremor (propranolol, primidone, or alcohol), family history (postural hand tremor in first‐degree relatives), and poly‐EMG findings (reciprocal inhibition in neck muscles during voluntary head rotation), 34 patients were diagnosed as having TCD, 14 were classified as having DHT, and 12 patients were diagnosed as having EHT. Using a clinical rating scale, head tremor amplitudes showed a significant decrease compared with baseline during the performance of sensory trick maneuvers in patients with TCD and DHT, but not in patients with EHT. This clinically observed effect was accompanied by a significant reduction in the mean peak power of the dominant frequency in patients with TCD (decrease by 83%, p = 0.0001) and DHT (decrease by 90%, p = 0.01), but not in patients with EHT (decrease by 6%, p = 0.6). Head tremor frequencies showed no significant changes in relation to the trick maneuvers. We conclude that a significant reduction of head tremor amplitude during a sensory trick maneuver is a useful quantitative criterion to distinguish TCD and DHT from EHT.