Tremor measurements in a 22-year cohort study of workers exposed to hand-held vibrating tools.

OBJECTIVES: The objectives of this cohort study were to evaluate possible long-term effects of occupational exposure to hand-arm vibration (HAV) in terms of increased tremor. The aims were to evaluate whether exposure during follow-up, baseline hand-arm vibration syndrome (HAVS), baseline manual dexterity or current medical conditions or life-style habits might be associated with increased tremor. A further aim was to compare two different activation conditions: postural vs rest tremor. METHODS: Forty men (current age: 60.4 years) who had previously worked as manual workers in a specialized engineering and construction company enrolled in the study. Their hand functions had been examined in 1994. At the baseline examination, 27 had been diagnosed with HAVS, while 13 were not exposed. The follow-up examination in 2016-2017 comprised the CATSYS Tremor Pen® for measuring postural and rest tremor and the Grooved Pegboard Test for assessing manual dexterity. Blood samples were taken for assessing biomarkers that might have impact on tremor. RESULTS: Neither cumulative exposure to HAV during follow-up nor HAVS at baseline were associated with increased tremor. A test for manual dexterity at baseline was significantly associated with increased tremor (Tremor Intensity) at follow-up. Blood markers of current medical conditions and tobacco consumption were associated with increased tremor. Rest tremor frequency was higher than postural tremor frequency (p < 0.001). CONCLUSIONS: The main findings of this 22-year cohort study were no indications of long-term effects on tremor related to HAV exposure and previous HAVS status. However, baseline manual dexterity was significantly associated with increased tremor at follow-up. Activation conditions (e.g., hand position) are important when testing tremor.

Lamotrigine Induces Tremor among Epilepsy Patients Probably via Cerebellar Pathways.

Lamotrigine, a frequently used antiepileptic drug, inhibits voltage-gated sodium-channels. By suppressing the release of glutamate and aspartate, lamotrigine acts as a membrane stabilizer, and it is also effective in bipolar disorder and migraine. However, lamotrigine is known to induce tremor among 4-10% of patients. We examined the lamotrigine-induced tremor in 28 epilepsy patients (age: 38.06 ± 13.56 years; 24 females and 4 males) receiving lamotrigine monotherapy and compared the data to 30 age- and sex-matched controls (age: 33.06 ± 10.71 years; 25 females and 5 males). Tremor was visually assessed by clinical tremor rating scales. Quantitative characteristics (intensity, center frequency and frequency dispersion) which are regularly used to differentiate various tremor syndromes were measured by validated, sensitive biaxial accelerometry in resting, postural and intentional positions. Regularity of repetitive finger and hand movements and reaction time were also determined. Data were statistically analyzed. Clinical tremor rating scales detected pathological tremor in three patients (10%), while accelerometry revealed tremor in seven patients (25%). Center frequency of patients with pathological tremor was similar to controls, but the frequency dispersion was significantly lower and tremor intensity was significantly higher in both postural and intentional positions. Rhythmic movements and reaction time were normal. Our results show that objective measurements detect pathological intention tremor in 25% of epilepsy patients receiving lamotrigine monotherapy. Quantitative characteristics suggest the involvement of the cerebellum in the pathomechanism of lamotrigine-induced tremor. Determining the parameters of drug-induced tremor syndromes might help to understand the complex action of tremor generator networks.

You're The Flight Surgeon.

Beauvais A, Tate J, Kluesner JK. You're the flight surgeon: hypoglycemia. Aerosp Med Hum Perform. 2019; 90(9):826-829.

Tongue tremor in neurofascin-155 IgG4 seropositive chronic inflammatory polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with anti-neurofascin-155 antibodies is a subgroup of CIDP with tremor and poor response to intravenous immunoglobulins. A 23-year-old male presented with a 6-month history ataxic-stepping gait, stocking tactile hypoesthesia, areflexia, tremor at limbs and tongue. Neurophysiology and cerebrospinal fluid analysis supported the diagnosis of CIDP. Tongue EMG was negative. Serum was positive for neurofascin-155 IgG4. His symptoms improved with intravenous methylprednisolone and then immunoglobulins, but not the tremor. Neurofascin-155 antibodies binding to cerebellar neurons suggests its central origin. This is the first neurofascin-155 antibody-seropositive patient with also tongue tremor, who is candidate to rituximab.

Association of Serum Indirect Bilirubin Concentrations with Motor Subtypes of Parkinson's Disease.

INTRODUCTION: We aimed to investigate the change of serum indirect bilirubin (IBIL) concentrations in patients with Parkinson's disease (PD) and whether IBIL concentrations were associated with the motor subtypes of PD. METHODS: A case-control study was performed to evaluate differences in bilirubin concentrations between 78 PD subjects and 78 controls. Venous blood samples were collected, and total bilirubin (TBIL), direct bilirubin (DBIL), and IBIL concentrations were analyzed between PD subjects and controls. PD patients were classified into three motor subtypes: tremor-dominant (TD), intermediate (I), and postural instability and gait disorder (PIGD). It was evaluated whether there were differences in IBIL concentrations between the different motor subtypes and between motor subtypes and controls. RESULTS: PD patients had lower IBIL concentrations compared to controls (6.51 ± 4.03 vs. 10.82 ± 4.61, p< 0.001). There was no significant difference in IBIL concentrations between PD males and PD females (6.66 ± 3.64 vs. 6.22 ± 4.79, p =0.655). IBIL concentrations had negative relationships with levodopa-equivalent daily dose (LEDD) (R = -0.452, p < 0.001) and positive relationships with tremor score (R = 0.360, p = 0.001). IBIL concentrations were significantly lower for PIGD than for TD subtype (4.88 ± 4.03 vs. 9.00 ± 4.15, p< 0.001). The lower IBIL concentrations in PD compared to controls were mainly driven by the PIGD patients. CONCLUSIONS: PD subjects showed lower levels of IBIL compared to controls. Higher IBIL levels were associated with TD motor subtype in PD, which could be related to the antioxidative properties of IBIL.

Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor/Ataxia Syndrome: a Pilot Study.

Currently, there is no effective treatment for the fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. In this pilot study, we evaluated whether allopregnanolone, a natural neurosteroid that exerts beneficial effects in neurodegenerative diseases, nervous system injury, and peripheral neuropathies, could improve lymphocytic bioenergetics and plasma pharmacometabolomics in six males with FXTAS (68 ± 3 years old; FMR1 CGG repeats 94 ± 4; FXTAS stages ranging from 3 to 5) enrolled in a 12-week open-label intervention study conducted at the University of California Davis from December 2015 through July 2016. Plasma pharmacometabolomics and lymphocytic mitochondria function were assessed at baseline (on the day of the first infusion) and at follow-up (within 48 h from the last infusion). In parallel, quantitative measurements of tremor and ataxia and neuropsychological evaluations of mental state, executive function, learning, memory, and psychological symptoms were assessed at the same time points. Allopregnanolone treatment impacted significantly GABA metabolism, oxidative stress, and some of the mitochondria-related outcomes. Notably, the magnitude of the individual metabolic response, as well as the correlation with some of the behavioral tests, was overwhelmingly carrier-specific. Based on this pilot study, allopregnanolone treatment has the potential for improving cognitive and GABA metabolism in FXTAS aligned with the concept of precision medicine.

Circulating catecholamines are associated with biobehavioral factors and anxiety symptoms in head and neck cancer patients.

Studies have shown that stress-related catecholamines may affect cancer progression. However, little is known about catecholamine secretion profiles in head and neck cancer patients. The present study investigated plasma norepinephrine and epinephrine levels in head and neck squamous cell carcinoma (HNSCC) patients and patients with oral leukoplakia, as well as their association with clinicopathological and biobehavioral variables and anxiety symptoms. A total of 93 patients with HNSCC and 32 patients with oral leukoplakia were included. Plasma norepinephrine and epinephrine levels were measured by high performance liquid chromatography with electrochemical detection (HPLC-ED), and psychological anxiety levels were measured by the Beck Anxiety Inventory (BAI). Plasma norepinephrine and epinephrine concentrations were significantly higher in patients with oral and oropharyngeal squamous cell carcinoma (SCC) compared to non-cancer patients. Oral SCC patients displayed plasma norepinephrine levels about six times higher than oropharyngeal SCC patients, and nine times higher than oral leukoplakia patients (p < .001). Plasma epinephrine levels in oral SCC patients were higher compared to the oropharyngeal SCC (p = .0097) and leukoplakia (p < .0001) patients. Oropharyngeal SCC patients had higher plasma norepinephrine (p = .0382) and epinephrine levels (p = .045) than patients with oral leukoplakia. Multiple regression analyses showed that a history of high alcohol consumption was predictive for reduced plasma norepinephrine levels in the oral SCC group (p < .001). Anxiety symptom of "hand tremor" measured by the BAI was an independent predictor for higher plasma norepinephrine levels in HNSCC patients (ß = 157.5, p = .0377), while the "heart pounding/racing" symptom was independently associated with higher plasma epinephrine levels in the oropharyngeal SCC group (ß = 15.8, p = .0441). In oral leukoplakia patients, sleep deprivation and worse sleep quality were independent predictors for higher plasma norepinephrine levels, while severe tobacco consumption and higher anxiety levels were factors for higher plasma epinephrine levels. These findings suggest that head and neck cancer patients display sympathetic nervous system hyperactivity, and that changes in circulating catecholamines may be associated with alcohol consumption, as well as withdrawal-related anxiety symptoms.

Plasma transferrin level correlates with the tremor-dominant phenotype of Parkinson's disease.

Accumulating evidence suggests that iron metabolism may be involved in the pathophysiology of Parkinson's disease (PD), and particularly in motor phenotype. This investigation aimed to examine plasma iron metabolism related indicators in patients with tremor-dominant phenotype of PD and determine less invasive, potential markers from plasma, which could partially reflect pathophysiological mechanisms of the brain. Seventy-six PD patients were recruited and thirty-three of them were classified into the tremor-dominant PD (TD-PD) group and forty-three into the non-tremor dominant PD (NT-PD) group, as determined by clinical characteristics. Plasma iron, ceruloplasmin, transferrin and ferritin levels were measured using Beckman Coulter AU biochemical assays, immune transmission turbidimetry method, scatter turbidimetry method and chemiluminescence method, respectively. Spearman's correlation analysis and multiple linear regression analysis were used for further study. Compared to healthy controls, TD-PD patients exhibited lower plasma iron level (p = 0.006) and higher transferrin level (p < 0.001). Plasma transferrin level was much higher in the TD-PD as compared to NT-PD (p = 0.003). Furthermore, plasma transferrin level was positively correlated with the severity of tremor in TD-PD (r = 0.358, p = 0.041). Multiple linear regression further demonstrated significant associations of plasma transferrin level with severity of tremor in TD-PD (regression coefficient = 0.253, P = 0.016), independently from other confounding factors. The elevated plasma transferrin level, combining with decreased plasma iron level might be given considerable weight in the recognition of parkinsonian tremor.

Tremor Associated with Chronic Inflammatory Demyelinating Polyneuropathy and Anti-Neurofascin-155 Antibodies.

Background: Tremor is an underrecognized feature in certain neuropathy subtypes. Phenomenology shown: We show a patient with a disabling neuropathic tremor and mild cerebellar syndrome associated with chronic inflammatory demyelinating polyneuropathy (CIDP) and anti-neurofascin-155 (NF155) antibodies. Educational value: Anti-NF155 testing should be considered in patients with CIDP and disabling tremor because of therapeutic implications.

Benign Neonatal Shudders, Shivers, Jitteriness, or Tremors: Early Signs of Vitamin D Deficiency.

Jitteriness and tremors in the newborn period typically precipitate an extensive, invasive, and expensive search for the etiology. Vitamin D deficiency has not been historically included in the differential of tremors. We report a shivering, jittery newborn who was subjected to a battery of testing, with the only biochemical abnormality being vitamin D deficiency. A second case had chin tremors and vitamin D deficiency. Review of our patients suggests that shudders, shivers, jitteriness, or tremors may be the earliest sign of vitamin D deficiency in the newborn. Neonates who present with these signs should be investigated for vitamin D deficiency.

Relationship between the plasma levels of neurodegenerative proteins and motor subtypes of Parkinson's disease.

The aim of our study is to examine the plasma levels of the four kinds of neurodegenerative proteins in plasma: α-syn, T-tau, P-tau181, and Aß-42 in Parkinson's disease (PD) and to evaluate the relationship between their plasma levels and PD motor subtypes. 84 patients with PD were enrolled in our study, and finally, 73 of them were classified into the tremor-dominant subtype (TD) and the postural instability gait difficulty subtype (PIGD). Their motor performance was evaluated by a series of clinical assessments: Freezing of Gait Questionnaire (FOGQ), Timed Up and Go (TUGs), Tinetti balance, and Tinetti gait. Plasma levels of these proteins were measured by enzyme-linked immunosorbent assay (ELISA). The plasma level of α-syn was significantly higher in PD patients when compared to controls (p = 0.004), and significantly higher in the PIGD group when compared to the TD group (p = 0.03). While the plasma level of Aß-42 was significantly lower in PD patients than in controls (p = 0.002), and significantly lower in the PIGD group than in the TD group (p = 0.05). In PD patients, the plasma level of α-syn (r = -0.355, p < 0.001) was significantly related to the severity of Tenitti Gait score, even after performing multiple linear regression (p = 0.002). While the plasma level of Aß-42 (r = -0.261, p < 0.05) was significantly associated with the severity of PIGD score and remained correlate when performed multiple linear regression (p = 0.005). The patients with PIGD subtype are characterized with a lower level of plasma Aß-42 and a higher plasma level of α-syn, which may be used as biomarkers for diagnosis and progression of the subtypes of PD.

Novel Blood Biomarkers Are Associated with White Matter Lesions in Fragile X- Associated Tremor/Ataxia Syndrome.

BACKGROUND: The need for accessible cellular biomarkers of neurodegeneration in carriers of the fragile X mental retardation 1 (FMR1) premutation (PM) alleles. OBJECTIVE: To assess the mitochondrial status and respiration in blood lymphoblasts from PM carriers manifesting the fragile X-associated tremor/ataxia syndrome (FXTAS) and non-FXTAS carriers, and their relationship with the brain white matter lesions. METHODS: Oxygen consumption rates (OCR) and ATP synthesis using a Seahorse XFe24 Extracellular Flux Analyser, and steady-state parameters of mitochondrial function were assessed in cultured lymphoblasts from 16 PM males (including 11 FXTAS patients) and 9 matched controls. The regional white matter hyperintensity (WMH) scores were obtained from MRI. RESULTS: Mitochondrial respiratory activity was significantly elevated in lymphoblasts from PM carriers compared with controls, with a 2- to 3-fold increase in basal and maximum OCR attributable to complex I activity, and ATP synthesis, accompanied by unaltered mitochondrial mass and membrane potential. The changes, which were more advanced in FXTAS patients, were significantly associated with the WMH scores in the supratentorial regions. CONCLUSION: The dramatic increase in mitochondrial activity in lymphoblasts from PM carriers may represent either the early stages of disease (specific alterations in short-lived blood cells) or an activation of the lymphocytes under pathological situations. These changes may provide early, convenient blood biomarkers of clinical involvements.

ß-glucuronidase mRNA levels are correlated with gait and working memory in premutation females: understanding the role of FMR1 premutation alleles.

Fragile X tremor ataxia syndrome (FXTAS) is a late-onset disorder manifesting in a proportion of FMR1 premutation individuals (PM: 55-199 CGG triplet expansions). FXTAS is associated with elevated levels of FMR1 mRNA which are toxic. In this study, relationships between neurocognitive and intra-step gait variability measures with mRNA levels, measured in blood samples, were examined in 35 PM and 35 matched control females. The real-time PCR assays measured FMR1 mRNA, and previously used internal control genes: ß-Glucuronidase (GUS), Succinate Dehydrogenase 1 (SDHA) and Eukaryotic Translation Initiation Factor 4A (EI4A2). Although there was significant correlation of gait variability with FMR1 mRNA levels (p = 0.004) when normalized to GUS (FMR1/GUS), this was lost when FMR1 was normalized to SDHA and EI4A2 (2IC). In contrast, GUS mRNA level normalized to 2IC showed a strong correlation with gait variability measures (p < 0.007), working memory (p = 0.001) and verbal intelligence scores (p = 0.008). PM specific changes in GUS mRNA were not mediated by FMR1 mRNA. These results raise interest in the role of GUS in PM related disorders and emphasise the importance of using appropriate internal control genes, which have no significant association with PM phenotype, to normalize FMR1 mRNA levels.

Skewed X Inactivation in Women Carrying the FMR1 Premutation and Its Relation with Fragile-X-Associated Tremor/Ataxia Syndrome.

BACKGROUND: Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a late-onset multisystem neurological disorder characterized by intention tremor and cerebellar ataxia. OBJECTIVE: We hypothesized that in FMR1 premutation females with FXTAS, a normal X chromosome might more frequently be inactivated; therefore, the aim of this study was to determine the relationship between skewed X chromosome inactivation (XCI) and FXTAS. METHODS: We studied the XCI patterns of cases of FMR1 premutation in 10 women with FXTAS and 21 without FXTAS. RESULTS: The distribution of XCI patterns in the FXTAS and no-FXTAS groups showed differences regarding the allele presenting severe skewed XCI. In the FXTAS group, all cases preferentially inactivated the non-expanded X chromosome, whereas in the no-FXTAS group, all inactivated the expanded X chromosome. Nevertheless, no significant differences were found on comparing XCI frequencies among FMR1 premutation carriers with and without FXTAS. As expected, we found statistically significant differences in the skewed XCI on comparing FMR1 premutation women and controls. CONCLUSION: Although the reduced sample size and blood XCI patterns are two limitations of this study, our results suggest that the skewed XCI of the normal FMR1 allele may be a risk factor for the development of FXTAS. Furthermore, our findings also support the protective effect of the expression of a normal FMR1 allele.

Association between serum uric acid and motor subtypes of Parkinson's disease.

The aim of this study was to evaluate serum uric acid (UA) levels and serum uric acid/creatinine ratios (UA/Cr) in patients with non-tremor dominant (NTD) Parkinson's disease (PD) compared to tremor dominant (TD) PD and healthy controls (HC). UA is believed to have a protective effect on the central nervous system against oxidative damage and neuronal cell death which could impact on progression and motor subtypes of PD. Serum UA levels and UA/Cr were determined in 100 PD patients and 100 age and sex matched HC. Subtypes of PD were classified into TD and NTD. Patients with PD showed statistically significantly lower serum UA (p=0.007) and serum UA/Cr ratios (p<0.001) than HC. Patients with NTD PD had statistically significantly lower serum UA (p<0.001) and serum UA/Cr (p=0.001) than in patients with TD PD. Patients with mild PD severity also had significantly higher serum UA (p=0.015) and serum UA/Cr (p=0.004) than patients with moderate to severe disease. Our study suggests that UA has a pathogenic role in the clinical subtype of PD. Serum UA levels together with serum UA/Cr are potentially useful biomarkers to indicate risk, severity and motor subtype of PD.

Lead exposure and tremor among older men: the VA normative aging study.

BACKGROUND: Tremor is one of the most common neurological signs, yet its etiology is poorly understood. Case-control studies suggest an association between blood lead and essential tremor, and that this association is modified by polymorphisms in the δ-aminolevulinic acid dehydrogenase (ALAD) gene. OBJECTIVE: We aimed to examine the relationship between lead and tremor, including modification by ALAD, in a prospective cohort study, using both blood lead and bone lead-a biomarker of cumulative lead exposure. METHODS: We measured tibia (n = 670) and patella (n = 672) bone lead and blood lead (n = 807) among older men (age range, 50-98 years) in the VA Normative Aging Study cohort. A tremor score was created based on an approach using hand-drawing samples. ALAD genotype was dichotomized as ALAD-2 carriers or not. We used linear regression adjusted for age, education, smoking, and alcohol intake to estimate the associations between lead biomarkers and tremor score. RESULTS: In unadjusted analyses, there was a marginal association between quintiles of all lead biomarkers and tremor scores (p-values < 0.13), which did not persist in adjusted models. Age was the strongest predictor of tremor. Among those younger than the median age (68.9 years), tremor increased significantly with blood lead (p = 0.03), but this pattern was not apparent for bone lead. We did not see modification by ALAD or an association between bone lead and change in tremor score over time. CONCLUSION: Our results do not strongly support an association between lead exposure and tremor, and suggest no association with cumulative lead biomarkers, although there is some suggestion that blood lead may be associated with tremor among the younger men in our cohort.