Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028738 (nystagmus)
 7,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus. It is hypothesized to occur when physiological inhibitory cerebellar input, namely of the flocculus, to the vestibular nuclei is inhibited. The second most frequent form of acquired nystagmus is upbeat nystagmus (UBN). UBN is probably caused by an imbalance of vertical vestibulo-ocular reflex tone. GABA-ergic substances like baclofen have been used to treat DBN and UBN, but they have had only moderate success. Animal experiments have shown that aminopyridines [3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP)], nonselective blockers of the Kv family of voltage-gated potassium channels, increase Purkinje-cell (PC) excitability. It was assumed that such enhancement of PC activity could restore to normal levels the inhibitory influence of the cerebellar cortex on vertical eye movements. On the basis of these assumptions, we evaluated the efficacy and underlying mechanisms of aminopyridines in DBN and UBN as well as in another cerebellar disorder with an impaired PC function: episodic ataxia type 2 (EA2), which is caused by mutations of the PQ-calcium channel. In a placebo-controlled trial on 17 patients we demonstrated that 3,4-DAP significantly reduces the intensity of DBN. This was confirmed in a recent study with 4-AP, which also showed that 4-AP restores gaze-holding ability independently of fixation in DBN. The efficacy of 4-AP in UBN was demonstrated in single patients. Finally, in an open trial on three patients with EA2 we showed that 4-AP prevents attacks of ataxia. This was also found in an animal model (the tottering mouse) of EA2. The clinical efficacy of 4-AP in EA2 is being further evaluated in an ongoing randomized controlled crossover trial. In conclusion, the use of aminopyridines in DBN, UBN, and EA2 is a new treatment principle for vestibular, cerebellar, and ocular motor disorders.
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PMID:Aminopyridines for the treatment of cerebellar and ocular motor disorders. 1871 50

An overview of the current pharmacotherapy of central vestibular syndromes and the most common forms of central nystagmus as well as cerebellar disorders is given. 4-aminopyridine (4-AP) is recommended for the treatment of downbeat nystagmus, a frequent form of acquired persisting fixation nystagmus, and upbeat nystagmus. Animal studies showed that this non-selective blocker of voltage-gated potassium channels increases Purkinje cell excitability and normalizes the irregular firing rate, so that the inhibitory influence of the cerebellar cortex on vestibular and deep cerebellar nuclei is restored. The efficacy of 4-AP in episodic ataxia type 2, which is most often caused by mutations of the PQ-calcium channel, was demonstrated in a randomized controlled trial. It was also shown in an animal model (the tottering mouse) of episodic ataxia type 2. In a case series, chlorzoxazone, a non-selective activator of small-conductance calcium-activated potassium channels, was shown to reduce the DBN. The efficacy of acetyl-DL-leucine as a potential new symptomatic treatment for cerebellar diseases has been demonstrated in three case series. The ongoing randomized controlled trials on episodic ataxia type 2 (sustained-release form of 4-aminopyridine vs. acetazolamide vs. placebo; EAT2TREAT), vestibular migraine with metoprolol (PROVEMIG-trial), cerebellar gait disorders (sustained-release form of 4-aminopyridine vs. placebo; FACEG) and cerebellar ataxia (acetyl-DL-leucine vs. placebo; ALCAT) will provide new insights into the pharmacotherapy of cerebellar and central vestibular disorders.
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PMID:Update on the pharmacotherapy of cerebellar and central vestibular disorders. 2708 81