Dr. rer. nat. Frank GollnickForschungsgemeinschaft FunkJuutilainen, 1997: Juutilainen J, Lang S: “Genotoxic, carcinogenic and teratogenic effects of electromagnetic fields. Introduction and overview” in: Mutat Res 1997; 387 (3): 165 - 171Brusick, 1998: Brusick D, Albertini R, Mc Ree D, Peterson D, Williams G, Hanawalt P, Preston J: “Genotoxicity of radiofrequency radiation. DNA/Genetox Exp
Vertigocenter.chEuropean Journal of Neurology 2004, 11: 83–89 S P E C I A L A R T I C L E / C M E A R T I C L E EFNS task force – therapy of nystagmus and oscillopsia A. Straubea, R. J. Leighb, A. Bronsteinc, W. Heided, P. Riordan-Evae, C. C. Tijssenf, I. Dehaenegand D. StraumannhaDepartment of Neurology, University of Munich, Munich, Germany; bDepartment of Neurology, Case Western Reserve University, Cleveland, OH, USA; cAcademic Department of Neuro-Otology, Imperial College of Science, Technology and Medicine, London, UK;dDepartment of Neurology, University at Lu¨beck, Lu¨beck, Germany; eDepartment of Ophthalmology, King’s College Hospital, London, UK;fDepartment of Neurology, St Elisabeth Hospital, Tilburg, The Netherlands; gDepartment of Neurology, Algemeen Hospital, Brugge, Belgium; and hDepartment of Neurology, University of Zurich, Zurich, Switzerland An overview of possible treatment options for oculomotor disorders that prevent clear vision is given. Downbeat nystagmus, upbeat nystagmus, seesaw nystagmus, periodic alternating nystagmus, acquired pendular nystagmus, and saccadic oscillations such as opsoclonus/ocular ﬂutter are discussed. In addition, superior oblique myokymia and vestibular paroxysmia are reviewed. All treatment recommendations available in theliterature are classiﬁed as class C only. In general, only some of the patients beneﬁt and pathophysiology of certain distinct ocular motor The ocular motor system serves to hold images steady A large part of this review concerns nystagmus, on the retina (especially the central fovea). Abnormal which is deﬁned as repetitive, to-and-fro involuntary eye movements may cause excessive motion of images eye movements that are initiated by slow drifts of the on the retina, leading to blurred vision and to the illu- eye. Physiological nystagmus that occurs during sion that the seen world is moving (oscillopsia).
rotation of the body in space acts to preserve clear Abnormal eye movements may also interfere with vision. In contrast, pathological nystagmus causes the spatial localization and the ability to make accurate eyes to drift away from the target, thus degrading limb movements. In clinical practice, the identiﬁcation vision. One form, pendular nystagmus, consists of of speciﬁc abnormalities of eye movements is often to-and-fro quasi-sinusoidal oscillations. More com- useful in the topological diagnosis of a broad range of monly, nystagmus consists of an alternation of uni- disorders that aﬀect the brain. Although we now know directional drifts away from the target and their quite a lot about the anatomy, physiology, and phar- correction by fast movements (saccades), which tem- macology of the ocular motor system, our treatment porarily bring the visual target back to the fovea; this options for abnormal eye movements remain fairly is jerk nystagmus. Nystagmus should be distinguished limited. Most drug treatments are based on case from inappropriate saccades that prevent steady ﬁx- reports. Only a few controlled trials have been pub- ation. Saccades are fast movements, and the smeared lished in recent years, and they were all based on a small retinal signal due to these movements is largely number of subjects, and not all patients respond posi- ignored. However, patients in whom abnormal sac- tively to the treatment. Thus, all treatment recommen- cades repeatedly misdirect the fovea often complain dations have to be classiﬁed as class C (Hilgers, 2001).
The goal of the paper is to summarize all publishedtreatment options for nystagmus and oscillopsia as well as to provide a short overview of the deﬁnition One member of the Task Force Panel (AS) searchedthrough all available published information using thedatabase Correspondence: A. Straube, Department of Neurology, KlinikumGrosshadern, Marchioninistrasse 15, 81377 Munich, Germany The search was restricted to papers published in (fax: +49 89 7095 3677; e-mail: email@example.com- English, French, or German. The key words used for the search included the following sequences: Ônystag- This is a Continuing Medical Education paper and can be found with mus and therapyÕ, Ôtreatment of ocular motor disor- corresponding questions on the Internet at: http://www.blackwell- dersÕ, and Ôtreatment of double visionÕ. All published science.com/products/journals/ene/mcqs. Certiﬁcates for correctlyanswering the questions will be issued by the EFNS.
papers were included, as only a limited number of controlled studies are available. The other members of the task force read the ﬁrst draft of the recom- The most common cause of downbeat nystagmus is mendation and discussed changes (informative con- cerebellar degeneration (hereditary, sporadic, or para- malformation and drug intoxication (especially theanticonvulsants and lithium). Multiple sclerosis (MS) is an uncommon cause, and a congenital form is rare(Halmagyi et al., 1983). In practice cerebellar atrophy, Arnold–Chiari malformation, various cerebellar lesions The vestibulo-ocular reﬂex (VOR) normally generates (MS, vascular, tumors), and idiopathic causes account eye rotations, after a short latency, in the same plane as for approximately one-fourth of the cases each (Bron- the head rotation that elicits them. Disorders of the stein et al., 1987). Downbeat nystagmus occurs in the vestibular periphery cause nystagmus in a direction that channelopathy episodic ataxia type 2, for which a new is determined by the pattern of involved labyrinthine treatment option has recently been developed (Strupp semicircular canals. The complete, unilateral loss of one labyrinth causes a mixed horizontal-torsional nystagmusthat is suppressed by visual ﬁxation. Central vestibular disorders may also cause an imbalance of these reﬂexes, Upbeat nystagmus is present with the eyes close to the leading to upbeat, downbeat, or torsional nystagmus central position and usually increases on upgaze. Ver- (see below). Another consequence of vestibular disease is tical smooth pursuit is usually disrupted by the a change in the size (gain) of the overall dynamic VOR nystagmus. In some patients the upbeat nystagmus response. As a result of this change, patients complain of changes to downbeat nystagmus during convergence.
oscillopsia during rapid head movements. A VOR gainlarger than 1 (eye speed exceeds head speed) results from Etiology Probable causes of upbeat nystagmus are a disinhibition of the brainstem circuits responsible for lesions in the ascending pathways from the anterior the VOR and is caused by vestibulo-cerebellar dysfunc- canals (and/or the otoliths) at the pontomesencephalic tion. Loss of peripheral vestibular function causes im- or pontomedullary junction, near the perihypoglossal paired vision and oscillopsia during locomotion, due to nuclei (Fisher et al., 1983). Upbeat nystagmus is most the inability to compensate for the high-frequency head often seen after medullary lesions (Stahl et al., 2000).
perturbations that occur with each footfall.
The main causes are MS, tumors of the brainstem,Wernicke’s encephalopathy, cerebellar degeneration, Downbeat nystagmus is a central form of vestibularnystagmus that is often present when the eyes are close to the central position; it usually increases on downgaze andespecially on lateral gaze. It also often becomes evident or Downbeat nystagmus No studies on the natural course is increased by placing the patient in a head-hanging of downbeat nystagmus are available. In non-placebo- position, or by tipping the head forward. In patients with controlled studies with a limited number of patients, cerebellar atrophy, some authors found that downbeat administration of the GABA-A agonist clonazepam nystagmus is more prominent in prone than in supine (0.5 mg p.o. three times daily; Currie and Matsuo, 1986), body position (Marti et al., 2002), but this could not be the GABA-B agonist baclofen (10 mg p.o. three times conﬁrmed by others (Bronstein et al., 1987). Visual ﬁx- daily) (Dieterich et al., 1991), and gabapentin (probably ation has little eﬀect on its slow-phase speed; convergence calcium channel blocker) (Averbuch-Heller et al., 1997) may suppress or enhance it in some patients. In general had positive eﬀects and reduced downbeat nystagmus.
the nystagmus is accompanied by a vestibulocerebellar Intravenous injection of the cholinergic drug physostig- ataxia with a tendency to fall backward (Bu¨chele et al., mine (Ach-esterase inhibitor) worsened downbeat ny- 1983). Lesions that cause downbeat nystagmus occur in stagmus in ﬁve patients. This eﬀect was partially reversed the vestibulocerebellum bilaterally and in the underlying in one patient by the anticholinergic drug biperiden, medulla (Leigh and Zee, 1999). The pathophysiological suggesting that anticholinergic drugs might be beneﬁcial, mechanism of downbeat nystagmus appears to be due to as was shown in a double-blind study on intravenous a central imbalance of the vertical VOR (Baloh and scopolamine (Barton et al., 1994). In isolated patients Spooner, 1981) or due to an abnormality of the vertical- with a craniocervical anomaly, a surgical decompression torsional gaze-holding mechanism – the Ôneural integra- by removal of part of the occipital bone in the region of tor for eye movementsÕ (Glasauer et al., 2003).
the foramen magnum was beneﬁcial (Pedersen et al., Ó 2004 EFNS European Journal of Neurology 11, 83–89 1980; Spooner and Baloh, 1981; personal observation).
disrupts visual ﬁxation, being present also during nor- Recent placebo-controlled studies (Strupp et al., 2003) mal viewing. These observations and animal experi- have suggested that the potassium channel blocker ments support the idea that this type if nystagmus is 3,4-diaminopyridine may be eﬀective in downbeat caused by lesions of the inferior cerebellar vermis nystagmus. As downbeat nystagmus is generally less (nodulus and uvula), leading to a disinhibition of the pronounced in upward gaze, base-down prisms some- GABA-ergic velocity-storage mechanism, which is times help to reduce oscillopsia during reading.
mediated in the vestibular nuclei (Waespe et al., 1985;Furman et al., 1990). The underlying etiologies are craniocervical anomalies, MS, cerebellar degenerations Treatment with baclofen (5–10 mg p.o. three times or tumors, brainstem infarction, anticonvulsant ther- daily) resulted in an improvement in several patients In general, periodic alternating nystagmus does not Seesaw nystagmus is a rare pendular or jerk oscillation.
improve spontaneously. Several case reports describe a One half cycle consists of elevation and intorsion of one positive eﬀect of baclofen, a GABA-B agonist, in a dose eye with synchronous depression and extorsion of the of 5–10 mg p.o. three times daily (Halmagyi et al., other eye. During the next half cycle there is a reversal 1980; Larmande and Larmande, 1983; Isago et al., of the vertical and torsional movements. The frequency 1985; Carlow, 1986; Nuti et al., 1986). Furthermore, is lower in the pendular (2–4 Hz) than in the jerk phenothiazine and barbiturates have been found to be eﬀective in single cases (Nathanson et al., 1953; Isagoet al., 1985). Periodic alternating nystagmus due to bilateral visual loss resolves if vision is restored (Cross Jerk hemi-seesaw nystagmus has been attributed to unilateral meso-diencephalic lesions (Halmagyi et al.,1994), aﬀecting the interstitial nucleus of Cajal and its Non-vestibular supranuclear oculomotor disorders vestibular aﬀerents from the vertical semicircular canals(Endres et al., 1996; Rambold et al., 1999). The pen- dular form is associated with lesions aﬀecting the optic Acquired pendular nystagmus (APN) is a quasi-sinu- chiasm. Loss of crossed visual input seems to be the soidal oscillation that may have a predominantly hori- crucial element in the pathophysiology of pendular zontal, vertical, or mixed trajectory (i.e. circular, seesaw nystagmus (Stahl et al., 2000).
elliptical, or diagonal); it can predominantly be eithermonocular or binocular (Gresty et al., 1982; Traccis et al., 1990; Leigh et al., 1992; Lopez et al., 1996). The Alcohol had a beneﬁcial eﬀect (1.2 g/kg body weight) in frequency of this type of nystagmus is 2–7 Hz (Zee, two patients (Frise`n and Wikkelso, 1986; Lepore, 1985), and often the nystagmus is associated with head 1987), as was clonazepam (Carlow, 1986). Recently, titubation (not synchronized with the nystagmus), Averbruch-Heller et al. (1997) reported on three trunk and limb ataxia, or visual impairment.
patients with a seesaw component to their pendularnystagmus, who improved on gabapentin.
EtiologyAcquired pendular nystagmus occurs with several disorders of myelin (MS, toluene abuse, Pelizaeus– Periodic alternating nystagmus is a spontaneous hori- Merzbacher disease), as a component of the syndrome zontal beating nystagmus, the direction of which of oculopalatal tremor (myoclonus), in Whipple’s dis- changes periodically. Periods of oscillation range from ease (Leigh and Zee, 1999); the two more common 1 s to 4 min, typically 1–2 min. When the nystagmus etiologies in the adult are MS and brainstem stroke amplitude gradually decreases, the nystagmus reverses (Lopez et al., 1996). On the basis of observations that its direction, and then the amplitude increases again.
the nystagmus is often dissociated and that eye move- During the nystagmus patients often complain of ments other than optokinetic nystagmus and voluntary saccades are also disturbed, a lesion in the brainstemnear the oculomotor nuclei has been suggested (Gresty et al., 1982). Alternatively, an inhibition of the inferior Patients with periodic alternating nystagmus commonly olive due to lesions of the ÔMollaret triangleÕ (Lopez have vestibulocerebellar lesions. Their nystagmus also et al., 1996) or an instability of the gaze-holding Ó 2004 EFNS European Journal of Neurology 11, 83–89 network (neural integrator) has been proposed; this (0.5–1.0 mg p.o. three times daily) can be tried. Further suggestion has received experimental modeling support possibilities are scopolamine patches or trihexyphen- (Das et al., 2000) and has led to the proposal of idyl. However, side eﬀects are a major limitation of potential therapies (Stahl et al., 2000).
Most reports (case reports or case series) state that Opsoclonus consists of repetitive bursts of conjugate sacc- anticholinergic treatment with trihexyphenidyl (20– adic oscillations, which have horizontal, vertical, and 40 mg p.o. daily) is eﬀective (Herishanu and Louzoun, torsional components. During each burst of these high- 1986; Jabbari et al., 1987), but in a double-blind study by frequency oscillations, the movement is continuous, with- Leigh et al. (1991a) only one of six patients showed out any intersaccadic interval. These oscillations are often improvement from this oral treatment, whereas three triggered by eye closure, convergence, pursuit, and sac- patients showed a decrease in nystagmus and improve- cades; amplitudes range up to 2–15°; (overview in Leigh and ment of visual acuity during treatment with tridihexethyl Zee, 1999). In ocular ﬂutter the same pattern is restricted chloride (a quaternary anticholinergic that does not cross to the horizontal plane. The ocular symptoms are often the blood–brain barrier). In contrast, Barton et al. (1994) accompanied by cerebellar signs, such as gait and limb found in a double-blind trial that scopolamine (0.4 mg myoclonus (the Ôdancing feet, dancing eyes syndromeÕ).
i.v.) decreased the nystagmus in all ﬁve tested patientswith acquired pendular nystagmus. However, there are even observations that scopolamine may make the pen- A functional disturbance of active saccadic suppression by dular nystagmus worse in some patients (Kim et al., the pontine omnipause neurons is the most probable 2001). In three other patients the combination with lid- pathophysiological mechanism. As histological abnor- ocaine (100 mg i.v.) decreased nystagmus (Ell et al., malities of these neurons have not been shown (Ridley 1982; Gresty et al., 1982). Recently, Starck et al. (1997) et al., 1987), a functional lesion of the glutaminergic reported an improvement in three of 10 patients who cerebellar projections from the fastigial nuclei to the om- received a scopolamine patch (containing 1.5 mg sco- nipause cells is a likely cause for their disinhibition.
polamine, released at a rate of 0.5 mg per day). The same Opsoclonus can be observed in benign cerebellar authors failed to observe further improvement when encephalitis (post-viral, e.g. coxsackie B37; post-vaccinal), scopolamine and mexiletine (400–600 mg p.o. daily) or as a paraneoplastic symptom (infants, neuroblastoma; were given in combination. The most eﬀective substance adults, carcinoma of the lung, breast, ovary, or uterus).
in their study was memantine, a glutamate antagonist,which signiﬁcantly improved the nystagmus in all nine tested patients (15–60 mg p.o. daily). Two patients In addition to therapy for any underlying process such responded to clonazepam (3 · 0.5–1.0 mg p.o. daily), a as tumor or encephalitis, treatment with immunoglob- GABA-A agonist (Starck et al., 1997). Two other groups ulins or prednisolone may be occasionally eﬀective have reported beneﬁt with GABA-ergic drugs. Traccis (Pless and Ronthal, 1996). Four of ﬁve patients with et al. (1990) showed improvement in one of three patients square-wave oscillations, probably a related ﬁxation with APN and cerebellar ataxia due to MS when treated disturbance, showed an improvement on therapy with with isoniazid (800–1000 mg p.o. daily) and glasses with valproic acid (Traccis et al., 1997). In single cases an prisms that induced convergence. This observation was improvement has been observed during treatment with not conﬁrmed by other investigators (Leigh et al., 1994).
propranolol (40–80 mg p.o. three times daily), nitraze- Gabapentin substantially improved the nystagmus (and pam (15–30 mg p.o. daily), and clonazepam (0.5– visual acuity) in 10 of 15 patients (Averbruch-Heller 2.0 mg p.o. three times daily) (overview in Leopold, et al., 1997). Gabapentin was superior to vigabatrin in a 1985; Carlow, 1986). Nausieda et al. (1981) reported a small series of patients (Bandini et al., 2001). Interest- dramatic improvement in one patient after the admin- ingly Mossman et al. (1993) described two patients who istration of 200 mg thiamine i.v.; no further descrip- beneﬁted from intake of alcohol but not from other tions of the patient are given in the paper.
substances. The necessary blood levels were 20–35 mmol/l. Recently, a beneﬁcial eﬀect of cannabis was Nuclear and infranuclear ocular disorders also reported (Schon et al., 1999; DellÔOsso, 2000).
Practically, treatment should start with memantine in a dosage of 15–60 mg p.o. or alternatively 300–400 mggabapentin three times daily. If there is no or only Superior oblique myokymia consists of paroxysmal monocular high-frequency oscillations. In the primary Ó 2004 EFNS European Journal of Neurology 11, 83–89 gaze position and in abduction these oscillations are attacks may reveal signs of permanent vestibular deﬁcit, mainly torsional, but when the eyes are in adduction the hypoacusis, or facial paresis on the aﬀected side (Brandt oscillations have a vertical component. Voluntary eye and Dieterich, 1994; Straube et al., 1994).
movements, as when looking down, can provokethe oscillations. The patients usually complain of oscillopsia during these paroxysmal attacks.
High-resolution magnetic resonance imaging may showthe compression of the VIIth nerve by an artery (most often AICA) or seldom a vein in the region of the root The pathophysiology of this condition is not totally entry zone of the vestibular nerve in some patients, but clear. Analogous to hemifacial spasm and trigeminal this can also be seen in subjects without symptoms.
neuralgia, vascular compression of the IVth nerve (Lee, The neuropathological mechanism may be peripheral 1984; Hashimoto et al., 2001; Yousry et al., 2002), or ephaptic transmission that takes place in the part of the alternatively spontaneous discharges in the IVth nerve cranial nerve still containing central myelin (derived nucleus (Hoyt and Keane, 1962) or of the superior from oligodendroglia), if the nerve has direct contact oblique muscle may be responsible (Leigh et al., 1991b).
with a blood vessel. This hypothesis is supported by theanalysis of epidemiological data which show a corre- lation of the incidence of the syndrome with the ana- Spontaneous remissions, which can last for days up to tomical length of the central myelin (De Ridder et al., years, are typical of superior oblique myokymia but 2002). Another theory is that the pulsation of the blood there are several reports that anticonvulsants, especially vessel causes an aﬀerent sensory inﬂow that then causes carbamazepine, have a therapeutic eﬀect. Carbamaze- pine (200–400 mg p.o. three or four times daily) or, lessoften, phenytoin (250–400 mg p.o. daily) are recom- mended (Susac et al., 1973; Rosenberg and Glaser, As initial therapy, an anticonvulsant [carbamazepine 1983). Gabapentin has also been reported to be eﬀective (slow release formulation) 2 · 200–800 mg p.o. daily; (Tomsak et al., 2002). Long-term studies on the con- phenytoin 250–400 mg p.o. daily, lamotrigine 100– tinued eﬀectiveness of these drugs are not available.
400 mg p.o. daily] should be given (Brandt, 1999). In Rosenberg and Glaser (1983) described a decrease in general, a positive response to antiepileptic drugs can be the eﬃcacy of the treatment after a month in some achieved with low dosages. If the symptoms do not patients. Beta-blockers, even topically, have been cease, a surgical approach may be considered (Jannetta reported to be eﬀective (Tyler and Ruiz, 1990; Bibby et al., 1984). There are no satisfactory follow-up stud- ies, and the diagnostic criteria have not yet been fully In chronic cases that did not improve with anticon- vulsants, tenotomy of the superior oblique musclehas been performed, but usually it necessitates inferior oblique surgery as well (Palmer and Shults, 1984; Braziset al., 1994). Surgical decompression of the IVth nerve Averbuch-Heller L, Tusa RJ, Fuhry L et al. (1997). A double- blind controlled study of gabapentin and baclofen as has also been reported to be beneﬁcial but may result in treatment for acquired nystagmus. Ann Neurol 41:818–825.
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Proper Usage of Drugs, Chemicals and Feed Additives in Show Market Animals Floron (Buddy) C. Faries, Jr., DVM, MS Texas A&M AgriLife Extension Service Definition of a Drug: Based on Usage Any compound administered or applied with the intent: Approved Drug Types Vaccines Antibiotics/Antibacterials Chemicals Hormones/Steroids Food Animal Residue Av