A Patient With Headache and Progressive Tremor

A 50-year-old man with no prior medical history sought care for new-onset daily headaches persisting for 3 months that did not improve after taking over-the-counter analgesics. He described asymmetric upper extremity action tremor and clumsiness affecting predominantly the right side. The patient’s wife also noted personality changes, anxiety, and depression. The review of systems was pertinent for a flulike syndrome in the weeks before his symptoms started. Neurologic examination showed reduced digit span, pyramidal signs with asymmetric hyperreflexia (right greater than left), and bilateral subtle lower extremity spasticity. He also had cerebellar ataxia and postural and action tremor of the upper extremities (right predominant). Ophthalmologic examination indicated mild bilateral optic disc edema with normal visual acuity. Brain magnetic resonance imaging showed linear radial perivascular enhancement in both cerebral hemispheres without associated T2 hyperintensities. Magnetic resonance imaging of the spine showed some hazy T2 hyperintensity in the thoracic cord with subtle gadolinium enhancement. Cerebrospinal fluid examination showed an opening pressure of 21 cm H2O, 63 white blood cells/µL with lymphocytic predominance, increased protein concentration of 130 mg/dL, and no oligoclonal bands. The patient’s cerebrospinal fluid was positive for immunoglobulin G antibodies specific for glial fibrillary acidic protein; no other neural autoantibodies were found in the serum or cerebrospinal fluid. The patient was diagnosed with autoimmune glial fibrillary acidic protein astrocytopathy. The patient was treated with high-dose intravenous corticosteroids followed by oral prednisone. The patient improved, the headaches disappeared, and he had only mild persistent tremor. After the corticosteroids were discontinued, he had an early relapse with increased headaches, confusion, and ataxia. Cerebrospinal fluid reevaluation showed reoccurrence of lymphocytic pleocytosis, and the patient was treated with oral prednisone. The corticosteroids were tapered over 6 months. Repeated imaging showed resolution of the abnormalities. At 3-year follow-up, the patient was relapse free. Autoimmune glial fibrillary acidic protein astrocytopathy is defined by the presence of glial fibrillary acidic protein-immunoglobulin G in the cerebrospinal fluid.

Positive modulation of cerebellar α6GABAA receptors for treating essential tremor: a proof-of-concept study in harmaline-treated mice

Background: The etiology of essential tremor (ET) remains unclear but may involve abnormal firing of Purkinje cells, which receive excitatory inputs from granule cells in the cerebellum. Since α6 subunit-containing GABAA receptors (α6GABAARs) are abundantly expressed in granule cells, we validated a hypothesis that α6GABAAR-selective positive allosteric modulators (PAMs) are promising pharmacological interventions for ET therapy. Methods: Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of four α6GABAAR-selective PAMs, the pyrazoloquinolinones Compound 6 and LAU-463 and their respective deuterated derivatives. Propranolol, a clinical anti-tremor agent, was employed as positive control. To investigate the involvement of cerebellar α6GABAARs in the anti-tremor effect of intraperitoneal (i.p.) Compound 6, furosemide, an α6GABAAR antagonist, was intra-cerebellarly (i.cb.) co-administered with Compound 6. The burrowing activity, an indicator of well-being in rodents, was measured concurrently. Results: Harmaline (10-30 mg/kg, s.c.) induced action tremor in ICR mice dose-dependently and markedly reduced their burrowing activity. Compound 6 (3 and 10 mg/kg, i.p.) significantly attenuated harmaline (20 mg/kg)-induced action tremor and burrowing activity impairment. Propranolol (20 mg/kg, i.p.) diminished tremor but failed to restore the burrowing activity in harmaline-treated mice. Importantly, both anti-tremor and burrowing activity restorative effects of Compound 6 (10 mg/kg, i.p.) was significantly reversed by co-administration of i.cb. furosemide at a dose (10 nmol/0.5 μl) having no effect per se. All four α6GABAAR PAMs exhibited a similar therapeutic efficacy. Conclusion: α6GABAAR-selective PAMs significantly attenuated action tremor and restored physical well-being in a mouse model mimicking ET by acting in the cerebellum. Thus, α6GABAAR-selective PAMs may be potential therapeutic agents for ET.

Thalamic Deep Brain Stimulation in Essential Tremor Plus Is as Effective as in Essential Tremor

The new essential tremor (ET) classification defined ET-plus (ET-p) as an ET subgroup with additional neurological signs besides action tremor. While deep brain stimulation (DBS) is effective in ET, there are no studies specifically addressing DBS effects in ET-p. 44 patients with medication-refractory ET and thalamic/subthalamic DBS implanted at our center were postoperatively classified into ET and ET-p according to preoperative documentation. Tremor suppression with DBS (stimulation ON vs. preoperative baseline and vs. stimulation OFF), measured via the Fahn–Tolosa–Marin tremor rating scale (TRS), stimulation parameters, and the location of active contacts were compared between patients classified as ET and ET-p. TRS scores at baseline were higher in ET-p. ET-p patients showed comparable tremor reduction as patients with ET, albeit higher stimulation parameters were needed in ET-p. Active electrode contacts were located more dorsally in ET-p of uncertain reason. Our data show that DBS is similarly effective in ET-p compared to ET. TRS scores were higher in ET-p preoperatively, and higher stimulation parameters were needed for tremor reduction compared to ET. The latter may be related to a more dorsal location of active electrode contacts in the ET-p group of this cohort. Prospective studies are warranted to investigate DBS in ET-p further.

Prevalence and Relationship of Rest Tremor and Action Tremor in Parkinson’s Disease

BackgroundDespite the significance of tremor in Parkinson’s disease (PD) diagnosis, classification, and patient’s quality of life, there is a relative lack of data on prevalence and relationship of different tremor types in PD.MethodsThe presence of rest tremor (RT) and action tremor (AT; defined as combination of both postural and kinetic tremor) was determined and RT severity was defined using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) at baseline in the Progression Marker Initiative (PPMI, n=423), the Fox Investigation for New Discovery of Biomarkers (BioFIND, n=118) and the Parkinson’s Disease Biomarkers Program (PDBP, n=873) cohorts.ResultsAcross baseline data of all three cohorts, RT prevalence (58.2%) was higher than AT prevalence (39.0%). Patients with RT had significantly higher (Chi-square test, p<0.05) prevalence of AT compared to patients without RT in the PPMI (40.0% versus 30.1%), BioFIND (48.0% versus 40.0%) and PDBP (49.9% versus 21.0%) cohorts. Furthermore, patients with AT had significantly (Student t-test, p<0.05) higher RT severity that those without AT in PPMI (5.7 ± 5.4 versus 3.9 ± 3.3), BioFIND, 6.4 ± 6.3 versus 3.8 ± 4.4) and PDBP (6.4 ± 6.6 versus 3.7 ± 4.4) cohorts.DiscussionThe RT is the most frequent tremor type and present in more than half of the PD patients. However, AT is also present in nearly one-third of the PD patients. Our results also indicate that RT and AT may have cross-interactions in PD.

The Rehapiano—Detecting, Measuring, and Analyzing Action Tremor Using Strain Gauges

We have developed a device, the Rehapiano, for the fast and quantitative assessment of action tremor. It uses strain gauges to measure force exerted by individual fingers. This article verifies the device’s capability to measure and monitor the development of upper limb tremor. The Rehapiano uses a precision, 24-bit, analog-to-digital converter and an Arduino microcomputer to transfer raw data via a USB interface to a computer for processing, database storage, and evaluation. First, our experiments validated the device by measuring simulated tremors with known frequencies. Second, we created a measurement protocol, which we used to measure and compare healthy patients and patients with Parkinson’s disease. Finally, we evaluated the repeatability of a quantitative assessment. We verified our hypothesis that the Rehapiano is able to detect force changes, and our experimental results confirmed that our system is capable of measuring action tremor. The Rehapiano is also sensitive enough to enable the quantification of Parkinsonian tremors.

Essential tremor: diagnosis and management

ABSTRACT Essential tremor is one of the most common movement disorders in adults and can affect both children and adults. An updated consensus statement in 2018 redefined essential tremor as an isolated action tremor present in bilateral upper extremities for at least three years. Tremor may also be present in other locations, commonly the neck or the vocal cords. Patients with additional neurologic symptoms are now categorized as “essential tremor plus.” Additional clinical features associated with the condition include but are not limited to cognitive impairment, psychiatric disorders, and hearing loss. When treatment is needed, propranolol and primidone are considered first line treatments. Patients who are severely affected are often offered deep brain stimulation. Although the ventral intermediate nucleus of the thalamus is the traditional surgical target, the caudal zona incerta is also being studied as a possible superior alternative. Magnetic resonance imaging guided high intensity focused ultrasound is a newer surgical alternative that may be ideal for patients with substantial medical comorbidities. Current research explores novel oral treatments, chemodenervation, and noninvasive neuromodulation for treatment of essential tremor.