Laryngorhinootologie 2018; 97(01): 14-23
DOI: 10.1055/s-0043-123487
Übersicht
Georg Thieme Verlag KG Stuttgart · New York

Medikamentöse Therapiemöglichkeiten bei vestibulären Störungen, Nystagmus und zerebellären Ataxien

Pharmacotherapy of Vestibular Disorders, Nystagmus and Cerebellar Disorders
K. Feil
1   Neurologische Klinik und Deutsches Zentrum für Schwindel- und Gleichgewichtsstörungen, Klinikum der Universität München
,
N. Böttcher
1   Neurologische Klinik und Deutsches Zentrum für Schwindel- und Gleichgewichtsstörungen, Klinikum der Universität München
,
O. Kremmyda
1   Neurologische Klinik und Deutsches Zentrum für Schwindel- und Gleichgewichtsstörungen, Klinikum der Universität München
,
C. Muth
2   Deutsches Zentrum für Schwindel- und Gleichgewichtsstörungen, Klinikum der Universität München
,
J. Teufel
1   Neurologische Klinik und Deutsches Zentrum für Schwindel- und Gleichgewichtsstörungen, Klinikum der Universität München
,
A. Zwergal
1   Neurologische Klinik und Deutsches Zentrum für Schwindel- und Gleichgewichtsstörungen, Klinikum der Universität München
,
T. Brandt
2   Deutsches Zentrum für Schwindel- und Gleichgewichtsstörungen, Klinikum der Universität München
,
M. Strupp
1   Neurologische Klinik und Deutsches Zentrum für Schwindel- und Gleichgewichtsstörungen, Klinikum der Universität München
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2018 (online)

Zusammenfassung

Zur Pharmakotherapie von vestibulären Erkrankungen kommen im Wesentlichen folgende Wirkstoffgruppen zum Einsatz: Antivertiginosa, Antikonvulsiva, Antidepressiva, Antiphlogistika, Anti-Menière-wirksame Substanzen, Migräneprophylaktika, Aminopyridine (Kaliumkanalblocker) und Acetyl-DL-Leucin (eine modifizierte essenzielle Aminosäure). Die Behandlung des Symptoms Schwindel und der begleitenden vegetativen Beschwerden wie Übelkeit, Brechreiz oder Erbrechen sollte zeitlich stets begrenzt werden. Bei einem akuten einseitigen Vestibularisausfall verbessern Kortikosteroide die Erholung der peripher vestibulären Funktion, ohne ausreichende Evidenz für eine allgemeine Empfehlung.

Für die Wirksamkeit von Betahistin (16 mg dreimal täglich oder 48 mg dreimal täglich) bei Morbus Menière gibt es bislang keine ausreichende Evidenz, ggf. sollten hierbei höhere Dosierungen angestrebt werden – insbesondere, da in tierexperimentellen Studien eine Verbesserung der Durchblutung des Innenohrs nachgewiesen wurde. Bei der Vestibularisparoxysmie sind Carbamazepin/Oxcarbazepin wahrscheinlich wirksam, es fehlen aber noch randomisierte kontrollierte Studien (RCTs) dazu. Bei der vestibulären Migräne gibt es bislang keine RCTs zur Wirksamkeit von Betablockern oder Topiramat, so dass hier aufgrund von klinischen Erfahrungen die Therapie in Analogie zur Migräne ohne Aura empfohlen wird.

Aminopyridine werden für die Behandlung von Patienten mit Downbeat-Nystagmus (2 RCTs) und der episodischen Ataxie Typ 2 (EA2, 1 RCT) empfohlen. Die Wirksamkeit von Aminopyridinen wurde in tierexperimentellen und funktionellen Bildgebungsstudien evaluiert. Acetyl-DL-Leucin, eine modifizierte essenzielle Aminosäure, verbessert die klinischen Symptome der zerebellären Ataxie (bisher 3 Beobachtungsstudien). Nach tierexperimentellen Studien beschleunigt es auch die zentrale Kompensation vestibulärer Störungen; randomisierte klinische Studien dazu waren negativ. Derzeit werden die folgenden klinischen RCTs zu verschiedenen Erkrankungen durchgeführt: Vestibularisparoxysmie (Carbamazepin, VesPa), akute einseitige Vestibulopathie/Neuritis vestibularis (Betahistin, BETAVEST), vestibuläre Migräne (Metoprolol, PROVEMIG), BPPV (Vitamin D, VitD@BPPV), EA2 (Aminopyridin vs. Acetazolamid, EAT-2-TREAT) und zerebelläre Ataxien (Acetyl-DL-Leucin, ALCAT).

Abstract

There are currently different groups of drugs for the pharmacotherapy of vertigo, nystagmus and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications and antidepressants, anticonvulsants, aminopyridines as well as acetyl-DL-leucine. In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but currently there is not sufficient evidence for a general recommendation. There is insufficient evidence to support the view that 16 mg t. i. d. or 48 mg t. i. d. betahistine has an effect in Menière’s disease. Therefore, higher dosages are recommended. In animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There has been no RCT on the efficacy of beta-blockers or topiramate but one RCT on flunarizine in vestibular migraine. Based on clinical experience, a treatment analogous to that for migraine without aura can be recommended. Acetyl-DL-leucine improved cerebellar ataxia (two observational studies); it also accelerated central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on treatment of vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT).

 
  • Literatur

  • 1 Strupp M, Thurtell MJ, Shaikh AG. et al. Pharmacotherapy of vestibular and ocular motor disorders, including nystagmus. J Neurol 2011; 258: 1207-1222
  • 2 Strupp M, Kremmyda O, Brandt T. Pharmacotherapy of vestibular disorders and nystagmus. Semin Neurol 2013; 33: 286-296
  • 3 Brandt T, Dieterich M, Strupp M. Vertigo – Leitsymptom Schwindel. 2. Auflage. Heidelberg: Springer-Verlag; 2012
  • 4 Beck R, Gunther L, Xiong G. et al. The mixed blessing of treating symptoms in acute vestibular failure-evidence from a 4-aminopyridine experiment. Exp Neurol 2014; 261: 638-645
  • 5 Shaia WT, Diaz RC. Evolution in surgical management of superior canal dehiscence syndrome. Curr Opin Otolaryngol Head Neck Surg 2013; 21: 497-502
  • 6 McDonnell MN, Hillier SL. Vestibular rehabilitation for unilateral peripheral vestibular dysfunction. Cochrane Database Syst Rev. 2015 CD005397 1
  • 7 Baloh RW. Clinical practice. Vestibular neuritis. N Eng J Med 2003; 348: 1027-1032
  • 8 Baloh RW, Ishyama A, Wackym PA. et al. Vestibular neuritis: clinicalpathologic correlation. Otolaryngol Head Neck Surg 1996; 114: 586-592
  • 9 Schuknecht HF, Gacek MR. The three faces of vestibular ganglionitis. Ann Otol Rhinol Laryngol 2002; 111: 103-114
  • 10 Gacek RR, Schuknecht HF. Pathology of the ear. 2 ed. Phildelphia: Lea & Febinger; 1993
  • 11 Nadol Jr JB. Vestibular neuritis. Otolaryngol Head Neck Surg 1995; 112: 162-172
  • 12 Schuknecht HF, Kitamura K. Second Louis H. Clerf Lecture. Vestibular neuritis. The Annals of otology, rhinology & laryngology Supplement 1981; 90: 1-19
  • 13 Arbusow V, Derfuss T, Held K. et al. Latency of herpes simplex virus type-1 in human geniculate and vestibular ganglia is associated with infiltration of CD8+ T cells. J Med Virol 2010; 82: 1917-1920
  • 14 Arbusow V, Schulz P, Strupp M. et al. Distribution of herpes simplex virus type 1 in human geniculate and vestibular ganglia: implications for vestibular neuritis. Ann Neurol 1999; 46: 416-419
  • 15 Arbusow V, Theil D, Strupp M. et al. HSV-1 not only in human vestibular ganglia but also in the vestibular labyrinth. Audiol Neurootol 2001; 6: 259-262
  • 16 Theil D, Arbusow V, Derfuss T. et al. Prevalence of HSV-1 LAT in human trigeminal, geniculate, and vestibular ganglia and its implication for cranial nerve syndromes. Brain Pathol 2001; 11: 408-413
  • 17 Bisdorff A, Von Brevern M, Lempert T. et al. Classification of vestibular symptoms: towards an international classification of vestibular disorders. J Vestib Res 2009; 19: 1-13
  • 18 Strupp M, Zingler VC, Arbusow V. et al. Methylprednisolone, valacyclovir, or the combination for vestibular neuritis. N Engl J Med 2004; 351: 354-361
  • 19 Goudakos JK, Markou KD, Franco-Vidal V. et al. Corticosteroids in the treatment of vestibular neuritis: a systematic review and meta-analysis. Otol Neurotol 2010; 31: 183-189
  • 20 Karlberg ML, Magnusson M. Treatment of acute vestibular neuronitis with glucocorticoids. Otol Neurotol 2011; 32: 1140-1143
  • 21 Goudakos JK, Markou KD, Psillas G. et al. Corticosteroids and vestibular exercises in vestibular neuritis. Single-blind randomized clinical trial. JAMA Otolaryngol Head Neck Surg 2014; 140: 434-440
  • 22 Fishman JM, Burgess C, Waddell A. Corticosteroids for the treatment of idiopathic acute vestibular dysfunction (vestibular neuritis). Cochrane Database Syst Rev. 2011 DOI: 10.1002/14651858.CD008607 pub2: CD008607
  • 23 Wegner I, van Benthem PP, Aarts MC. et al. Insufficient evidence for the effect of corticosteroid treatment on recovery of vestibular neuritis. Otolaryngol Head Neck Surg 2012; 147: 826-831
  • 24 Dutia MB. Mechanisms of vestibular compensation: recent advances. Curr Opin Otolaryngol Head Neck Surg 2010; 18: 420-424
  • 25 Vibert N, Vidal PP. In vitro effects of acetyl-DL-leucine (tanganil) on central vestibular neurons and vestibulo-ocular networks of the guinea-pig. Eur J Neurosci 2001; 13: 735-748
  • 26 Strupp M, Arbusow V, Maag KP. et al. Vestibular exercises improve central vestibulospinal compensation after vestibular neuritis. Neurology 1998; 51: 838-844
  • 27 Herdman SJ. Vestibular rehabilitation. Curr Opin Neurol 2013; 26: 96-101
  • 28 Minor LB, Schessel DA, Carey JP. Menière’s disease. Curr Opin Neurol 2004; 17: 9-16
  • 29 Semaan MT, Alagramam KN, Megerian CA. The basic science of Menière’s disease and endolymphatic hydrops. Curr Opin Otolaryngol Head Neck Surg 2005; 13: 301-307
  • 30 Sajjadi H, Paparella MM. Menière’s disease. Lancet 2008; 372: 406-414
  • 31 Merchant SN, Adams JC, Nadol JB. et al. Pathophysiology of Menière’s syndrome: are symptoms caused by endolymphatic hydrops?. Otol Neurotol 2005; 26: 74-81
  • 32 Yeh TH, Herman P, Tsai MC. et al. A cationic nonselective stretch-activated channel in the Reissner’s membrane of the guinea pig cochlea. Am J Physiol 1998; 274: C566-C576
  • 33 Thirlwall AS, Kundu S. et al. Diuretics for Menière’s disease or syndrome. Cochrane Database Syst Rev. 2006 DOI: 10.1002/14651858.CD003599. pub2: CD003599
  • 34 Pullens B, Verschuur HP, van Benthem PP. Surgery for Menière’s disease. Cochrane Database Syst Rev. 2013 CD005395 2.
  • 35 Arrang JM, Garbarg M, Quach TT. et al. Actions of betahistine at histamine receptors in the brain. Eur J Pharmacol 1985; 111: 73-84
  • 36 Gbahou F, Davenas E, Morisset S. et al. Effects of betahistine at histamine H3 receptors: mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo. J Pharmacol Exp Thers 2010; 334: 945-954
  • 37 Dziadziola JK, Laurikainen EL, Rachel JD. et al. Betahistine increases vestibular blood flow. Otolaryngol Head Neck Surg 1999; 120: 400-405
  • 38 Bertlich M, Ihler F, Sharaf K. et al. Betahistine metabolites, Aminoethylpyridine, and Hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo. Int J Audiol 2014; 53: 753-759
  • 39 Strupp M, Hupert D, Frenzel C. et al. Long-term prophylactic treatment of attacks of vertigo in Menière’s disease-comparison of a high with a low dosage of betahistine in an open trial. Acta Otolaryngol 2008; 128: 520-524
  • 40 Lezius F, Adrion C, Mansmann U. et al. High-dosage betahistine dihydrochloride between 288 and 480 mg/day in patients with severe Menière’s disease: a case series. Eur Arch Otorhinolaryngol 2011; 268: 1237-1240
  • 41 James AL, Burton MJ. et al. Betahistine for Menière’s disease or syndrome. Cochrane Database Syst Rev. 2001 DOI: 10.1002/14651858.CD001873: CD001873
  • 42 Nauta JJ. Meta-analysis of clinical studies with betahistine in Menière’s disease and vestibular vertigo. Eur Arch Otorhinolaryngol 2014; 271: 887-897
  • 43 Postema RJ, Kingma CM, Wit HP. et al. Intratympanic gentamicin therapy for control of vertigo in unilateral Menière’s disease: a prospective, double-blind, randomized, placebo-controlled trial. Acta Otolaryngol 2008; 128: 876-880
  • 44 Stokroos R, Kingma H. Selective vestibular ablation by intratympanic gentamicin in patients with unilateral active Menière’s disease: a prospective, double-blind, placebo-controlled, randomized clinical trial. Acta Otolaryngol 2004; 124: 172-175
  • 45 Diamond C, O’Connell DA, Hornig JD. et al. Systematic review of intratympanic gentamicin in Menière’s disease. J Otolaryngol 2003; 32: 351-361
  • 46 Huon LK, Fang TY, Wang PC. Outcomes of intratympanic gentamicin injection to treat Menière’s disease. Otol Neurotol 2012; 33: 706-714
  • 47 Colletti V, Carner M, Colletti L. Auditory results after vestibular nerve section and intratympanic gentamicin for Menière’s disease. Otol Neurotol 2007; 28: 145-151
  • 48 Huppert D, Strupp M, Brandt T. Long-term course of Menière’s disease revisited. Acta Otolaryngol 2010; 130: 644-651
  • 49 Phillips JS, Westerberg B. Intratympanic steroids for Menière’s disease or syndrome. Cochrane Database Syst Rev. 2011 DOI: 10.1002/14651858. CD008514.pub2: CD008514
  • 50 Garduno-Anaya MA, Couthino De Toledo H, Hinojosa-Gonzalez R. et al. Dexamethasone inner ear perfusion by intratympanic injection in unilateral Menière’s disease: a two-year prospective, placebo-controlled, double-blind, randomized trial. Otolaryngol Head Neck Surg 2005; 133: 285-294
  • 51 Gabra N, Saliba I. The effect of intratympanic methylprednisolone and gentamicin injection on Menière’s disease. Otolaryngol Head Neck Surg 2013; 148: 642-647
  • 52 Brandt T, Dieterich M. Vestibular paroxysmia: vascular compression of the eighth nerve?. Lancet 1994; 343: 798-799
  • 53 Hufner K, Barresi D, Glaser M. et al. Vestibular paroxysmia: diagnostic features and medical treatment. Neurology 2008; 71: 1006-1014
  • 54 Moller MB, Moller AR, Jannetta PJ. et al. Diagnosis and surgical treatment of disabling positional vertigo. Journal of neurosurgery 1986; 64: 21-28
  • 55 Strupp M, von Stuckrad-Barre S, Brandt T. et al. Teaching neuroimages: Compression of the eighth cranial nerve causes vestibular paroxysmia. Neurology 2013; 80: e77
  • 56 Brandt T, Dieterich M. VIIIth nerve vascular compression syndrome: vestibular paroxysmia. Bailliere’s clinical neurology 1994; 3: 565-575
  • 57 Ilg W, Bastian AJ, Boesch S. et al. Consensus paper: management of degenerative cerebellar disorders. Cerebellum 2014; 13: 248-268
  • 58 Neuhauser HK. Epidemiology of vertigo. Curr Opin Neurol 2007; 20: 40-46
  • 59 Neuhauser HK. Epidemiology of dizziness and vertigo. Nervenarzt 2009; 80: 887-894
  • 60 Lempert T, Olesen J, Furman J. et al. Vestibular migraine: diagnostic criteria. Consensus document of the Barany Society and the International headache society. Rev Neurol (Paris) 2014; 170: 401-406
  • 61 Lepcha A, Amalanathan S, Augustine AM. et al. Flunarizine in the prophylaxis of migrainous vertigo: a randomized controlled trial. Eur Arch Otorhinolaryngol 2014; 271: 2931-2936
  • 62 Maldonado Fernandez M, Birdi JS, Irving GJ. et al. Pharmacological agents for the prevention of vestibular migraine. Cochrane Database Syst Rev. 2015 CD010600 6
  • 63 Ophoff RA, Terwindt GM, Vergouwe MN. et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87: 543-552
  • 64 Jen JC. Hereditary episodic ataxias. Ann N Y Acad Sci 2008; 1142: 250-253
  • 65 Strupp M, Zwergal A, Brandt T. Episodic ataxia type 2. Neurotherapeutics 2007; 4: 267-273
  • 66 Jen JC, Baloh RW. Familial episodic ataxia: a model for migrainous vertigo. Ann N Y Acad Sci 2009; 1164: 252-256
  • 67 Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurology 2004; 62: 17-22
  • 68 Alvina K, Khodakhah K. The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia. J Neurosci 2010; 30: 7258-7268
  • 69 Strupp M, Kalla R, Dichgans M. et al. Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 2004; 62: 1623-1625
  • 70 Strupp M, Kalla R, Claassen J. et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology 2011; 77: 269-275
  • 71 Claassen J, Teufel J, Kalla R. et al. Effects of dalfampridine on attacks in patients with episodic ataxia type 2: an observational study. J Neurol 2013; 260: 668-669
  • 72 Wagner JN, Glaser M, Brandt T. et al. Downbeat nystagmus: aetiology and comorbidity in 117 patients. J Neurol Neurosurg Psychiatry 2008; 79: 672-677
  • 73 Kalla R, Deutschlander A, Hufner K. et al. Detection of floccular hypometabolism in downbeat nystagmus by fMRI. Neurology 2006; 66: 281-283
  • 74 Sprenger A, Zils E, Rambold H. et al. Effect of 3,4-diaminopyridine on the postural control in patients with downbeat nystagmus. Ann N Y Acad Sci 2005; 1039: 395-403
  • 75 trupp M, Schuler O, Krafczyk S. et al. Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study. Neurology 2003; 61: 165-170
  • 76 Helmchen C, Gottschalk S, Sander T. et al. Beneficial effects of 3,4-diaminopyridine on positioning downbeat nystagmus in a circumscribed uvulo-nodular lesion. J Neurol 2007; 254: 1126-1128
  • 77 Kalla R, Spiegel R, Claassen J. et al. Comparison of 10-mg doses of 4-aminopyridine and 3,4-diaminopyridine for the treatment of downbeat nystagmus. J Neuroophthalmol 2011; 31: 320-325
  • 78 Claassen J, Spiegel R, Kalla R. et al. A randomised double-blind, crossover trial of 4-aminopyridine for downbeat nystagmus-effects on slowphase eye velocity, postural stability, locomotion and symptoms. J Neurol Neurosurg Psychiatry 2013; 84: 1392-1399
  • 79 Feil KCJ, Bardins S, Teufel J. et al. Effect of chlorzoxazone in patients with downbeat nystagmus: a pilot-trial. Neurology 2013; 81: 1152-1158
  • 80 Glasauer S, Kalla R, Buttner U. et al. 4-aminopyridine restores visual ocular motor function in upbeat nystagmus. J Neurol Neurosurg Psychiatry 2005; 76: 451-453
  • 81 Dieterich M, Straube A, Brandt T. et al. The effects of baclofen and cholinergic drugs on upbeat and downbeat nystagmus. J Neurol Neurosurg Psychiatry 1991; 54: 627-632
  • 82 Kremmyda O, Zwergal A, la Fougere C. et al. 4-Aminopyridine suppresses positional nystagmus caused by cerebellar vermis lesion. J Neurol 2013; 260: 321-323
  • 83 Ilg W, Synofzik M, Brotz D. et al. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology 2009; 73: 1823-1830
  • 84 Schniepp R, Wuehr M, Ackl N. et al. 4-Aminopyridine improves gait variability in cerebellar ataxia due to CACNA 1A mutation. J Neurol 2011; 258: 1708-1711
  • 85 Strupp M, Teufel J, Habs M. et al. Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J Neurol 2013; 260: 2556-2561
  • 86 Bremova TMV, Amraoui Y, Mengel E. et al. Acetyl-DL-leucine in Niemann-Pick type C: a case series. Neurology. 2015 In press
  • 87 Pelz JO, Fricke C, Saur D. et al. Failure to confirm benefit of acetyl-DL-leucine in degenerative cerebellar ataxia: a case series. J Neurol 2015; 262: 1373-1375