Neurology 2017 Jul 14

Authors: Arnold WD, Kline D, Sanderson A, Hawash AA, Bartlett A, Novak KR, Rich MM, Kissel JT

Abstract
To determine open-label, pilot study whether ranolazine could improve signs and symptoms of myotonia and muscle stiffness in patients with myotonia congenita (MC).
Thirteen participants were assessed at baseline and 2, 4, and 5 weeks. Ranolazine was started after baseline assessment (500 mg twice daily), increased as tolerated after week 2 (1,000 mg twice daily), and maintained until week 4. Outcomes included change from baseline to week 4 in self-reported severity of symptoms (stiffness, weakness, and pain), Timed Up and Go (TUG), hand grip and eyelid myotonia, and myotonia on EMG.
Self-reported severity of stiffness (p < 0.0001) and weakness (p < 0.01) was significantly improved compared with baseline. TUG and grip myotonia times were reduced (p = 0.03, p = 0.01). EMG of the abductor digiti minimi and tibialis anterior showed significantly reduced myotonia duration (p < 0.001, p < 0.01) at week 4. No participant discontinued ranolazine because of side effects.
Ranolazine appeared to be well tolerated over a period of 4 weeks in individuals with MC, and ranolazine resulted in improvement of signs and symptoms of muscle stiffness. The findings of this study suggest that ranolazine should be investigated in a larger controlled study.
This study provides Class IV evidence that ranolazine improves myotonia in myotonia congenita.

PMID: 28710329 [PubMed - as supplied by publisher]

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 2017 Apr

Authors: Sindelar B, Shinners M, Sherman S, Novak K, Erickson K, Patel V, Kubilis P, Smith D, Finan J, Bailes JE

Abstract
Internal jugular vein (IJV) compression before blast injury will lead to reduced risk of traumatic hearing injury following exposure to a blast injury.
IJV compression and its effects on not only intracranial, but also intracochlear pressure may potentiate blast induced hearing injury, therefore, precluding its use as a prophylactic therapy for blast induced traumatic brain injury.
Twenty Sprague Dawley rats were exposed to a 17.9 ± 0.4 PSI (195.8 dB SPL) right sided shock wave in which 10 had application of a custom IJV compression collar before injury. All rodents received baseline and post blast injury otoacoustic emission (OAE) and auditory brainstem response (ABR) testing followed by cochlear histology.
IJV compression was shown to significantly reduce ABR and OAE threshold shifts in comparison to the non-intervention group by: 14.9 ± 4.8 dB (right ear ABR 0.5 kHz Day 1 post blast, p = 0.01), 13.1 ± 4.9 dB (right ear ABR 4 kHz Day 1 post blast, p = 0.04), 16.5 ± 4.5 dB (right ear ABR click Day 1 post blast, p = 0.003), 12.1 ± 4.6 dB (right ear ABR click Day 6 post blast, p = 0.04), and 14.0 ± 3.2 dB (both ears OAE 3.2-10 kHz, p < 0.0001). Also, those animals with collar application had a greater number of total hair cells per mm from 70 to 100% distance from the cochlear apex following blast injury in comparison to those without intervention (blast: 211.8 ± 27.5 versus blast+collar: 355.5 ± 39.5 [p = 0.0002]).
This study supports the use of IJV compression in a pre-clinical model as a new prophylactic mechanism to combat blast induced hearing injury.

PMID: 28079681 [PubMed - as supplied by publisher]

Annals of neurology 2015 Feb

Authors: Novak KR, Norman J, Mitchell JR, Pinter MJ, Rich MM

Abstract
Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warmup phenomenon. Our goal was to identify the mechanism underlying warmup and to use this information to guide development of novel therapy.
To determine the mechanism underlying warmup, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warmup in a mouse model of myotonia congenita.
Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warmup. These data suggested that enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are approved by the US Food and Drug Administration for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested that both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested that side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine's hypoexcitability side effects.
We conclude that ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita.

PMID: 25515836 [PubMed - as supplied by publisher]

Movement disorders : official journal of the Movement Disorder Society 2015 Feb

Authors: Sharp ME, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Orbe Reilly M, Ruiz D, Louis ED, Comella C, Nance M, Bressman S, Scott WK, Tanner C, Waters C, Fahn S, Cote L, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Payami H, Molho E, Factor SA, Nutt J, Serrano C, Arroyo M, Pauciulo MW, Nichols WC, Clark LN, Alcalay RN, Marder KS

Abstract
Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS).
The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers.
Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13).
First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.

PMID: 25393808 [PubMed - as supplied by publisher]

JAMA neurology 2014 Jan

Authors: Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Orbe Reilly M, Ruiz D, Louis ED, Comella CL, Nance MA, Bressman SB, Scott WK, Tanner CM, Mickel SF, Waters CH, Fahn S, Cote LJ, Frucht SJ, Ford B, Rezak M, Novak KE, Friedman JH, Pfeiffer RF, Marsh L, Hiner B, Payami H, Molho E, Factor SA, Nutt JG, Serrano C, Arroyo M, Ottman R, Pauciulo MW, Nichols WC, Clark LN, Marder KS

Abstract
Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients.
Among patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers.
Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers.
Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose.
Carriers had an earlier age at onset of PD (P < .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains.
In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.

PMID: 24190026 [PubMed - as supplied by publisher]

Skeletal muscle 2012 Aug 30

Authors: Kraner SD, Novak KR, Wang Q, Peng J, Rich MM

Abstract
During the acute phase of critical illness myopathy (CIM) there is inexcitability of skeletal muscle. In a rat model of CIM, muscle inexcitability is due to inactivation of sodium channels. A major contributor to this sodium channel inactivation is a hyperpolarized shift in the voltage dependence of sodium channel inactivation. The goal of the current study was to find a biochemical correlate of the hyperpolarized shift in sodium channel inactivation.
The rat model of CIM was generated by cutting the sciatic nerve and subsequent injections of dexamethasone for 7 days. Skeletal muscle membranes were prepared from gastrocnemius muscles, and purification and biochemical analyses carried out. Immunoprecipitations were performed with a pan-sodium channel antibody, and the resulting complexes probed in Western blots with various antibodies.
We carried out analyses of sodium channel glycosylation, phosphorylation, and association with other proteins. Although there was some loss of channel glycosylation in the disease, as assessed by size analysis of glycosylated and de-glycosylated protein in control and CIM samples, previous work by other investigators suggest that such loss would most likely shift channel inactivation gating in a depolarizing direction; thus such loss was viewed as compensatory rather than causative of the disease. A phosphorylation site at serine 487 was identified on the NaV 1.4 sodium channel α subunit, but there was no clear evidence of altered phosphorylation in the disease. Co-immunoprecipitation experiments carried out with a pan-sodium channel antibody confirmed that the sodium channel was associated with proteins of the dystrophin associated protein complex (DAPC). This complex differed between control and CIM samples. Syntrophin, dystrophin, and plectin associated strongly with sodium channels in both control and disease conditions, while β-dystroglycan and neuronal nitric oxide synthase (nNOS) associated strongly with the sodium channel only in CIM. Recording of action potentials revealed that denervated muscle in mice lacking nNOS was more excitable than control denervated muscle.
Taken together, these data suggest that the conformation/protein association of the sodium channel complex differs in control and critical illness myopathy muscle membranes; and suggest that nitric oxide signaling plays a role in development of muscle inexcitability.

PMID: 22935229 [PubMed - as supplied by publisher]

American journal of physiology. Regulatory, integrative and comparative physiology 2011 Jun

Authors: Kraner SD, Wang Q, Novak KR, Cheng D, Cool DR, Peng J, Rich MM

Abstract
The processes that trigger severe muscle atrophy and loss of myosin in critical illness myopathy (CIM) are poorly understood. It has been reported that muscle disuse alters Ca(2+) handling by the sarcoplasmic reticulum. Since inactivity is an important contributor to CIM, this finding raises the possibility that elevated levels of the proteins involved in Ca(2+) handling might contribute to development of CIM. CIM was induced in 3- to 5-mo-old rats by sciatic nerve lesion and infusion of dexamethasone for 1 wk. Western blot analysis revealed increased levels of ryanodine receptor (RYR) isoforms-1 and -2 as well as the dihydropyridine receptor/voltage-gated calcium channel type 1.1 (DHPR/Ca(V) 1.1). Immunostaining revealed a subset of fibers with elevation of RYR1 and Ca(V) 1.1 that had severe atrophy and disorganization of sarcomeres. These findings suggest increased Ca(2+) release from the sarcoplasmic reticulum may be an important contributor to development of CIM. To assess the endogenous functional effects of increased intracellular Ca(2+) in CIM, proteolysis of α-fodrin, a well-known target substrate of Ca(2+)-activated proteases, was measured and found to be 50% greater in CIM. There was also selective degradation of myosin heavy chain relative to actin in CIM muscle. Taken together, our findings suggest that increased Ca(2+) release from the sarcoplasmic reticulum may contribute to pathology in CIM.

PMID: 21474431 [PubMed - as supplied by publisher]

Disease-a-month : DM 2011 Mar

Authors: Caccappolo E, Alcalay RN, Mejia-Santana H, Tang MX, Rakitin B, Rosado L, Louis ED, Comella CL, Colcher A, Jennings D, Nance MA, Bressman S, Scott WK, Tanner CM, Mickel SF, Andrews HF, Waters C, Fahn S, Cote LJ, Frucht S, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer RF, Marsh L, Hiner B, Siderowf AD, Ross BM, Verbitsky M, Kisselev S, Ottman R, Clark LN, Marder KS

Abstract
The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

PMID: 21447423 [PubMed - as supplied by publisher]

Archives of neurology 2010 Sep

Authors: Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Ross BM, Verbitsky M, Kisselev S, Louis ED, Comella C, Colcher A, Jennings D, Nance MA, Bressman SB, Scott WK, Tanner C, Mickel S, Andrews H, Waters C, Fahn S, Cote L, Frucht S, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Siderowf A, Ottman R, Marder K, Clark LN

Abstract
To assess the frequency and clinical characteristics of carriers of previously identified mutations in 6 genes associated with early-onset Parkinson disease (PD) and provide empirical data that can be used to inform genetic counseling.
Cross-sectional observational study.
Thirteen movement disorders centers.
Nine hundred fifty-three individuals with early-onset PD defined as age at onset (AAO) younger than 51 years. Participants included 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Intervention Mutations in SNCA, PRKN, PINK1, DJ1, LRRK2, and GBA were assessed. A validated family history interview and the Unified Parkinson Disease Rating Scale were administered. Demographic and phenotypic characteristics were compared among groups defined by mutation status. Main Outcome Measure Mutation carrier frequency stratified by AAO and ethnic background.
One hundred fifty-eight (16.6%) participants had mutations, including 64 (6.7%) PRKN, 35 (3.6%) LRRK2 G2019S, 64 (6.7%) GBA, and 1 (0.2%) DJ1. Mutation carriers were more frequent in those with an AAO of 30 years or younger compared with those with AAO between 31 and 50 years (40.6% vs 14.6%, P < .001), in individuals who reported Jewish ancestry (32.4% vs 13.7%, P < .001), and in those reporting a first-degree family history of PD (23.9% vs 15.1%, P = .01). Hispanic individuals were more likely to be PRKN carriers than non-Hispanic individuals (15.6% vs 5.9%, P = .003). The GBA L444P mutation was associated with a higher mean Unified Parkinson Disease Rating Scale III score after adjustment for covariates.
Individuals of Jewish or Hispanic ancestry with early-onset PD, those with AAO of 30 years or younger, and those with a history of PD in a first-degree relative may benefit from genetic counseling.

PMID: 20837857 [PubMed - as supplied by publisher]