Causes of Flapping

Motivation: Look - the hands are flapping.  One of the useful tests in a confused patients is to ask them to stop traffic with outstretched hands.  If the hands start flapping in a non-rhythmic way ('asterixis'), that is interpreted as proof of generalized toxic-metabolic encephalopathy.  But, then again, there is probably a neural pathway underlying this mechanism.  We often dismiss asterixis in a blase way, but can there be focal brain lesions underlying asterixis?

Paper: Degos, J-D., Verroust, J., Bouchareine, A., et. al. "Asterixis in Focal Brain Lesions"  Arch Neurol. (1979); 36: 705-707

Methods: At Henri Mondor Hospital (Creteil, France), one of the authors documented twenty cases of asterixis with focal brain lesions.  EMG was available for nine patients.

Results:
Midbrain Lesions: Four patients ranging from 38 to 62 years presenting with unilateral asterixis after abrupt onset weakness in the affected side.

Parietal Lesions: Seven cases of asterixis with pathologic proof in four occurred from parietal lesions.  These lesions could occurred on contralateral side from the asterixis and could be from mass lesions (glioblastoma, abscess, metastatic lesion) or from stroke (hemorrhagic or ischemic).

Suspected Midbrain and Parietal Lesions: Six cases with suspected lesions.  One of these cases was a right temporal glioblastoma invading the lenticular nuclei with left sided asterixis and another had an expanding right thalamic tumor with left sided asterixis.

Unclear lesions: Three cases of unilateral asterixis with accompanying unilateral weakness or numbness of unclear etiology.

EMG Recordings: During episodes of asterixis, there were 50-100 ms periods of electrical silence in both agonist and antagonist.

Discussion: This old paper shows that true asterixis is not purely a toxic-metabolic phenomenon.  Apparently, parietal, midbrain, and thalamic lesions can result in contralateral asterixis.  While this paper certainly does not suggest a pathophysiological explanation of asterixis, some important points are that: (1) asterixis appeared contralateral to the lesion meaning that usually the side with asterixis is the one that is weak or numb, (2) both cortical and deep lesions can result in asterixis,.  I think that this account provides a cautionary note of dismissing asterixis as purely toxic phenomenon.

Interfering with RNA

Motivation: In medical school, while watching cartoons depicting disease pathophysiology pathways, I have thought many times that if we could just somehow block that damaged protein, we will cure that disease.  In mice, of course, multiple techniques exist including creating mutant breeds, transfecting with viruses, or injecting short RNA interfering sequences.  I was thrilled to read last month that such magic has for the first time been tried successfully in human beings.  Given the momentous significance of the recent trial testing RNA interference in transthyretin amyloidosis, we will cover the technique and consequences.

Paper: Coelho, T., Adams, D., Silva, A., et. al. "Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis" NEJM (2013); 369: 819-29.

Methods: This Phase I study consisted of two parts.  In the first portion, eligible patients were older than 18 years with biopsy proven transthyretin amyloidosis with mild-to-moderate neuropathy.  Patients were excluded if they had liver, renal, or thyroid dysfunction.  These patients were injected in a blinded way with lipid nanoparticles containing RNA interfering (RNAi) sequences or with placebo.  In the second part, seventeen healthy patients were injected with a second generation lipid nanoparticle containing RNAi sequences testing for safety.

The lipid nanoparticles consisted of ionizable lipid components with RNA sequence that targets a conserved sequence at the 3' untranslated region of mRNA of Transthyretin protein (TTR).

Results:
Cohort: In the cohort with disease, there were 32 patients with 56% male and median age of 37.  Majority of participants were recruited from Portugal (23/32 patients).  The healthy volunteer cohort were all 17 male subjects with mean age of 27 (all were from England).

Amyloidosis Cohort: Patients with TTR amyloidosis treated with placebo did not have change in serum transthyretin levels.  In the group receiving 1mg/kg lipid nanoparticle dose, there was a mean reduction of 38% in serum transthyretin levels with recovery to close to baseline levels by day 28.

Healthy Volunteers: Using the second generation lipid nanoparticles, peak reduction of serum transthyretin level was reached at approximately day 10.  At 0.3 mg/kg and 0.5 mg/kg doses, the mean levels of suppression were 82.3% and 86.8%.  The serum transthyretin levels remained suppressed even at day 28.

Safety: There were no drug related serious adverse events or study drug discontinuation.  No significant changes in hematologic, liver, or renal measurements were seen.  Mild to moderate infusion reactions occurred in 7 to 20% of reactions responding to temporary interruption of infusion or administration of glucocorticosteroids.  Antibodies to pegylated lipid components were not seen.

Discussion: This trial demonstrated successful use of lipid nanoparticle RNAi to suppress transthyretin levels.   In the four week follow-up, there were remarkably no drug related side effects.  This Phase I trial, while promising, does not show efficacy of treatment on important clinical variables.  Transthyretin is primarily synthesized by the liver but is also synthesized to a smaller extent in the retina and choroid plexus.  The hepatic suppression may still leave the patient vulnerable to retinal and CNS side-effects.  In normal physiology, transthyretin is associated with retinol binding protein levels and Vitamin A levels.  Long term suppression of transthyretin may also interfere with Vitamin A metabolism.  Also, it is unclear whether repeated administration of lipid nanoparticles will generate an immunologic response.  Nonetheless, the trial is an encouraging start on selective suppression of hepatic protein synthesis.