A Case Series of Isolated Smiling Tremor: What Is the Phenomenology?

BACKGROUND: Five cases of tremor only upon smiling have been reported where no facial tremor is present at rest, when talking, or with full smile. CASES: This report highlights four cases of tremor upon partial smiling, discusses the phenomenology of smiling tremor, and reviews the current literature. Four subjects with lower facial tremor present only upon smiling underwent movement disorders evaluation with video. Tremor frequencies were determined by parsing the video clips into 1-second intervals and averaging the number of oscillations per interval and were determined to be high-frequency 8 to 10 Hz irregular facial tremors with harmonic variations upon moderate effort in all cases. Slight or full-effort smiling did not elicit facial muscle oscillations. Subjects had no other signs of tremor, dystonia, or parkinsonism on examination or in family history. CONCLUSIONS: Tremor upon smiling only, or isolated smiling tremor, is a unique task- and position-specific tremor of the facial musculature.

Biallelic Loss-of-Function Variants in BICD1 Are Associated with Peripheral Neuropathy and Hearing Loss.

Hearing loss and peripheral neuropathy are two clinical entities that are genetically and phenotypically heterogeneous and sometimes co-occurring. Using exome sequencing and targeted segregation analysis, we investigated the genetic etiology of peripheral neuropathy and hearing loss in a large Ashkenazi Jewish family. Moreover, we assessed the production of the candidate protein via western blotting of lysates from fibroblasts from an affected individual and an unaffected control. Pathogenic variants in known disease genes associated with hearing loss and peripheral neuropathy were excluded. A homozygous frameshift variant in the BICD1 gene, c.1683dup (p.(Arg562Thrfs*18)), was identified in the proband and segregated with hearing loss and peripheral neuropathy in the family. The BIDC1 RNA analysis from patient fibroblasts showed a modest reduction in gene transcripts compared to the controls. In contrast, protein could not be detected in fibroblasts from a homozygous c.1683dup individual, whereas BICD1 was detected in an unaffected individual. Our findings indicate that bi-allelic loss-of-function variants in BICD1 are associated with hearing loss and peripheral neuropathy. Definitive evidence that bi-allelic loss-of-function variants in BICD1 cause peripheral neuropathy and hearing loss will require the identification of other families and individuals with similar variants with the same phenotype.

Neuromuscular disorders in pregnancy.

Many neuromuscular disorders preexist or occur during pregnancy. In some cases, pregnancy unmasks a latent hereditary disorder. Most available information is based on case reports or series or retrospective clinical experience or patient surveys. Of special interest are pregnancy-induced changes in disease course or severity and likelihood for baseline recovery of function postpartum. Labor and delivery present special challenges in many conditions that affect skeletal but not smooth (uterine) muscle; so labor complications must be anticipated. Anesthesia for cesarean section surgery requires special precautions in many disorders. The types of conditions reviewed are broad and include examples of autoimmune, hereditary, and compressive/mechanical processes. Disorders include carpal tunnel syndrome and other focal neuropathies, Bell palsy, myasthenia gravis, and other neuromuscular junction disorders, acute and chronic inflammatory neuropathy, hereditary and acquired muscle diseases, spinal muscular atrophy, amyotrophic lateral sclerosis, channelopathies, autonomic neuropathy, and dysautonomia. Many commonly used therapies have fetal animal but no proven human toxicity concerns, complicating treatment and risk decisions. Weaning off effective therapeutic agents or preemptive aggressive treatment or surgery prior to planned pregnancy is an option in some conditions.

Lack of effect on ambulation of dalfampridine-ER (4-AP) treatment in adult SMA patients.

SMA is a genetically determined motor system disorder that results in muscle weakness, selective motor neuron death, muscle atrophy, and impaired functional mobility. In SMA model systems, long-term treatment with 4-aminopyridine (4-AP) has been shown to improve motor function. To assess tolerability and preliminary efficacy of 4-AP on walking ability, endurance and EMG in adult ambulatory SMA patients, we conducted a double blind, placebo control, crossover pilot study with dalfampridine (4-AP, 10 mg BID). The study is comprised of a short-term (2 weeks) treatment arm with 1-week washout and a long-term (6 weeks) treatment arm with a 2-week washout. The primary outcome measure, for which the study was powered, was the 6 min walk test (6MWT, distance and percent fatigue); secondary outcome measures were the Hammersmith Functional Motor Scale Expanded (HFMSE), Manual Muscle Testing (MMT), Myometry with Hand held Dynamometry, HHD) and Quantitative Gait Analyses. We performed electrophysiology, including CMAP and H-reflex, during the short-term treatment trial. The mean age of the 11 participants enrolled was 37.7 ±â€¯11.9 years; 54.5% were male. Dalfampridine was safe and well tolerated and no patient suffered a serious adverse event related to treatment. We observed no statistically significant positive effects of dalfampridine treatment on our primary functional motor outcome (6MWT distance, fatigue). Dalfampridine had a positive effects on H-reflex and H/M ratio but not on CMAP amplitude. The effect on the H-reflex is of interest, as it suggests dalfampridine may enhance neuronal activity, an effect observed in SMA Drosophila and mouse models at doses (mg/kg) not recommended for clinical use. Larger studies with dalfampridine in SMA patients are needed to confirm our findings, especially in light of studies in other populations showing drug effects in only a subset of patients.

Peripheral neuropathy symptoms in wild type transthyretin amyloidosis.

To propose a correlation between polyneuropathy and ATTRwt based on retrospective analysis of patients with ATTRwt. We reviewed 151 ATTRwt patients followed by the amyloid cardiac clinic (group A) for symptoms of neuropathy and 12 patients with ATTRwt evaluated in the Neurology Department (group B) with objective measures of neuropathy. Medical history, electrodiagnosis, laboratory and skin biopsies were assessed; 30.5% of group A had neuropathy symptoms. Alternative explanations for neuropathy symptoms were explored, including, age, gender, BMI, diabetes mellitus, B12 deficiency. No difference was observed for BMI, age, gender and spine disease for those with and without neuropathic symptoms (P > .05). All of group B (n = 12) were diagnosed with neuropathy, confirmed by electrodiagnostic testing or skin biopsy, while two patients had not yet developed cardiac symptoms. We observe a higher prevalence of neuropathic symptoms in ATTRwt patients than previously believed. Neuropathic symptoms may precede cardiac symptoms. Our findings suggest a possible causative relationship that requires further investigation.

Update on Chemotherapy-Induced Peripheral Neuropathy.

PURPOSE OF REVIEW: The purpose of this study was to briefly discuss chemotherapy-induced peripheral neuropathy (CIPN) and detail the most important and most recent chemotherapeutic agents implicated. This review will examine neuropathy mechanisms, risk factors, and clinical patterns; novel and prospective drugs with similar effects that are less well known to neurologists are discussed. RECENT FINDINGS: CIPN is increasingly recognized for its clinical importance and effect on patient quality of life. Identification of risk factors is ongoing and may enable future risk stratification. Newer classes of agents and new members of existing classes are continually recognized, notably immune check point inhibitors, other monoclonal antibody treatments, novel immunomodulatory agents, and proteasome inhibitors. Advances regarding established classes including taxanes, platins, and vinca alkaloids are also reviewed. CIPN is an important often dose-limiting toxicity. Multiple agents cause neuropathy; various clinical patterns are described. Future studies should aim at improved understanding of toxicity mechanisms and development of preventive and therapeutic strategies.

Syncope: Case Studies.

Syncope, or the sudden loss of consciousness, is a common presenting symptom for evaluation by neurologists. It is not a unique diagnosis but rather a common manifestation of disorders with diverse mechanisms. Loss of consciousness is typically preceded by a prodrome of symptoms and sometimes there is a clear trigger. This article discusses several cases that illustrate the various causes of syncope. Reflex syncope is the most common type and includes neurally mediated, vasovagal, situational, carotid sinus hypersensitivity, and atypical forms. Acute and chronic autonomic neuropathies and neurodegenerative disorders can also present with syncope.

Bortezomib-associated demyelinating neuropathy--clinical and pathologic features.

OBJECTIVES: Bortezomib is a proteasome inhibitor that is frequently used for multiple myeloma and lymphoma. A sensory predominant axonal neuropathy is associated with bortezomib treatment but a demyelinating neuropathy is also described primarily based on electrodiagnostic findings. We report a series of patients treated with bortezomib who developed peripheral neuropathy and were found to have demyelinating features on electrodiagnostic testing. METHODS: Four patients who developed a bortezomib-induced peripheral neuropathy underwent electrophysiological testing, and 1 patient had a nerve biopsy. RESULTS: The four patients with bortezomib-induced peripheral neuropathy had demyelinating features on their electrophysiological testing. The nerve biopsy performed in 1 patient demonstrated a demyelinating component in a background of axonal degeneration. CONCLUSIONS: Although most toxic neuropathies are symmetrical axonal neuropathies, bortezomib is part of a small list of agents that may cause a demyelinating polyneuropathy and axonal degeneration. These findings have been confirmed by nerve biopsy.

Discordant phenotype in monozygotic female twins with Lys35Thr TTR familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy is the hereditary form of transthyretin amyloidosis that is rapidly progressive. Discordant expression of Val30Met transthyretin amyloid in monozygotic twins has been reported in the past, in Europe and Asia. We report the first case of discordant expression of Lys35Thr transthyretin amyloid in female monozygotic twins in North America with eye involvement and peripheral neuropathy.

Neurologic complications of alcoholism.

PURPOSE OF REVIEW: This review serves as an overview of neurologic conditions associated with alcohol abuse or withdrawal, including epidemiology, clinical symptoms, diagnostic approach, and treatment. RECENT FINDINGS: Frequent alcohol abuse and frank alcoholism are very common among adults in the United States. Although rates decline with each decade, as many as 10% of the elderly drink excessively. Given the ubiquitous nature of alcoholism in society, its complications have been clinically recognized for generations, with recent advances focusing on improved understanding of ethanol's biochemical targets and the pathophysiology of its complications. SUMMARY: The chronic effects of alcohol abuse are myriad and include neurologic complications through both direct and indirect effects on the central and peripheral nervous systems. These disorders include several encephalopathic states related to alcohol intoxication, withdrawal, and related nutritional deficiencies; acute and chronic toxic and nutritional peripheral neuropathies; and myopathy. Although prevention of alcoholism and its neurologic complications is the optimal strategy, this article reviews the specific treatment algorithms for alcohol withdrawal and its related nutritional deficiency states.

Clinical evolution of pure upper motor neuron disease/dysfunction (PUMMD).

INTRODUCTION: PLS is defined as pure upper motor neuron disease/dysfunction (PUMND) beyond 48 months after symptom onset. We know little about its early stages, but such knowledge would help to identify the mechanisms underlying PLS and ALS and determine why PLS patients seem to be protected against lower MND (LMND). METHODS: We reviewed 622 MND cases during a 4-year period and identified 34 patients with PUMND (5.4%). RESULTS: Among 23 cases with follow-up data/electromyograms (EMGs; 2 had only 1 EMG), 13 (57%) remained classified as PUMND, and 8 (35%) developed LMND (mean, 51.4 months after onset). Of these 8, LMND developed in 3 after 48 months from symptom onset. Patients with PUMND and LMND were more functionally impaired (P = 0.02). Separately, we identified 5 patients with PUMND who developed LMND long after 48 months (range, 50-127 months). CONCLUSIONS: PLS belongs to the ALS spectrum, and perhaps all cases eventually develop LMND.

Association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors treated with adjuvant paclitaxel chemotherapy.

Neurotoxicity is a common side-effect during taxane therapy. The prevalence and severity of long-term neurotoxicity following therapy is unknown. The authors conducted a cross-sectional study of 50 consecutive patients with stage I-III BC, who were within 6 months and 2 years of completing adjuvant taxane therapy and a prospective study of 50 women initiating taxane therapy. Patients in the cross-sectional study underwent a one-time evaluation while patients in the prospective study underwent evaluation at baseline, following therapy, and 3, 6, 9, and 12 months after completing therapy. Assessments included quantitative sensory testing (QST) for touch perception and vibration threshold and the FACT-GOG Neurotaxane (FACT/GOG-Ntx). For the cross-sectional study, 81% of the women reported symptoms of numbness and/or discomfort in the hands and/or feet in the past week. Severe symptoms were reported in 27% of patients for the hands and 25% for the feet. In the cross-sectional analysis, hand numbness/discomfort correlated with hand vibration QST. In the prospective study, the mean scores on the FACT/GOG-Ntx decreased from 37.5 to 28.7 post-treatment (P = 0.0002), and remained low 12 months after treatment. The changes in hand/foot numbness/discomfort were significantly associated with change in vibration threshold. No significant change was seen in touch perception. Numbness and discomfort in the hands and feet are common for up to 2 years following taxane therapy, and are associated with vibration threshold. The FACT/GOG-Ntx is an appropriate outcome measure for clinical trials evaluating ways to prevent long-term neurotoxicity in BC survivors.

Experience with the Awaji Island modifications to the ALS diagnostic criteria.

Amyotrophic lateral sclerosis (ALS) remains a clinical diagnosis without validated biomarkers. To increase diagnostic sensitivity, an expert group modified the Airlie House diagnostic criteria and formulated new recommendations at a meeting on Awaji Island. Our retrospective analysis of patients referred over a 6-month period to the electromyography (EMG) laboratory for suspected motor neuron disease (MND) showed a higher agreement of the Awaji modifications than the Airlie House criteria with the clinical diagnosis of ALS.

Development of recurrent facial palsy during plasmapheresis in Guillain-Barré syndrome: a case report.

INTRODUCTION: Guillain-Barré syndrome is an immune-mediated polyneuropathy that is routinely initially treated with either intravenous immunoglobulin or plasmapheresis. To the best of our knowledge, no association between plasmapheresis treatment and acute onset of facial neuropathy has been reported. CASE PRESENTATION: A 35-year-old Caucasian man with no significant prior medical history developed ascending motor weakness and laboratory findings consistent with a diagnosis of Guillain-Barré syndrome. Plasmapheresis was initiated. Acute facial palsy developed during the plasma exchange that subsequently resolved and then acutely recurred during the subsequent plasma exchange. CONCLUSION: To the best of our knowledge, no prior cases of acute facial palsy developing during plasmapheresis treatment are known. Although facial nerve involvement is common in typical Guillain-Barré syndrome, the temporal association with treatment, near-complete resolution and later recurrence support the association. The possible mechanism of plasmapheresis-induced worsening of peripheral nerve function in Guillain-Barré syndrome is unknown.

Autonomic symptoms in carriers of the m.3243A>G mitochondrial DNA mutation.

BACKGROUND: The m.3243A>G mutation can cause multisystem medical problems and can affect the autonomic nervous system. OBJECTIVE: To study the frequency and spectrum of autonomic symptoms associated with the m.3243A>G mitochondrial DNA point mutation. Design, Setting, and Patients We studied a cohort of 88 matrilineal relatives from 40 families, including 35 fully symptomatic patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), 53 carrier relatives, and 16 controls using a questionnaire based on existing standard instruments for the evaluation of autonomic dysfunction. We compared the questionnaire with an expert evaluation. We compared data among the 3 groups using the Mantel-Haenszel chi(2) test to determine the statistical significance of differences between groups. RESULTS: Mutation carriers frequently had symptoms of autonomic dysfunction, specifically gastrointestinal and orthostatic intolerance. CONCLUSIONS: Carriers of the m.3243A>G mutation have frequent autonomic symptoms. The m.3243A>G mutation should be considered as an etiological factor in patients with autonomic dysfunction and a medical or family history suggestive of mitochondrial disease. Because some autonomic symptoms are treatable, early detection and proactive management may mitigate the burden of morbidity.

Autonomic testing: common techniques and clinical applications.

Laboratories able to test autonomic function are increasingly available and rely on batteries of well-accepted, noninvasive tests. Tests of parasympathetic cardiovagal, sympathetic vasoconstriction, and sudomotor (sweating) function are most commonly employed. Common examples include heart rate variability to various challenges, Valsalva maneuver, standing and tilt-table studies, and various sudomotor methods. New techniques and technical refinements continue to be described. Most studies rely on perturbations of complex systems and not direct assessment. Testing has helped to improve disease recognition and prompted advances in classification, pathophysiology, and treatment. Major areas impacted include hereditary and immune-mediated autonomic neuropathy, diabetic autonomic neuropathy, distal symmetric polyneuropathy, Parkinson disease and other autonomic failure syndromes, orthostatic intolerance, and unexplained syncope.

Neurological aspects of syncope and orthostatic intolerance.

Sudden falling with loss of consciousness from syncope and symptoms of orthostatic intolerance are common, dramatic clinical problems of diverse cause, but cerebral hypoperfusion is the ultimate mechanism in most. Cardiac, reflex, and orthostatic hypotension are important forms to consider. Syncope must be differentiated from seizures, psychiatric events, drop attacks, and other mimics. However, factors such as syncopal induced movements, ictal bradycardia, and insufficient clinical information can confound accurate diagnosis and hamper appropriate treatment. Progress in the diagnosis, treatment, and understanding of underlying mechanisms is continually advancing.

Update on medication-induced peripheral neuropathy.

Despite improvements in the identification of causes of peripheral neuropathy, idiopathic polyneuropathy remains common. Medication and toxic neuropathy account for a small but important percentage of potentially preventable or reversible causes of neuropathy. New drugs that can induce neuropathy have been approved over the past several years, including the anticancer agents bortezomib, ixabepilone, and oxaliplatin. We review the neurotoxic effects of tumor necrosis factor-alpha blockers infliximab and etanercept, the inflammatory arthritis agent leflunomide, and the antibiotic linezolid. The controversy of statin-induced neuropathy continues to unfold; the large Fremantle Diabetes Study has suggested that statins may have neuroprotective effects. Dichloroacetate is a promising agent for lactic acidosis-associated disorders, but toxic neuropathy is a treatment-limiting factor. We also describe a progressive inflammatory neuropathy in swine slaughterhouse workers that appears to be a toxin-induced immune response.