Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT): A Preventable Cerebellar Disorder.

We report a case study of a 60-year-old man with bipolar disorder on stable lithium treatment who developed severe toxicity while admitted to ICU with sepsis and multiorgan failure. Despite unchanged lithium administration, his serum levels escalated due to renal dysfunction, resulting in lithium toxicity. After regaining consciousness, he exhibited a cerebellar syndrome marked by ataxia, tremor, and scanning speech. MRI revealed cerebellar atrophy. Following discontinuation of lithium and hemodialysis, the patient's symptoms remained static. The patient was diagnosed with syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), a chronic cerebellar disorder characterized by persistent ataxia, nystagmus, and gait abnormalities extending beyond two months post-lithium exposure. The disorder has a predilection for cerebellar and basal ganglia dysfunction. MRI findings include cerebellar gliosis and atrophy and leptomeningeal enhancement. This case report highlights that SILENT is both preventable and permanent, urging heightened awareness among clinicians to facilitate early detection and intervention. Patients on lithium with compromised renal function or fever necessitate vigilant lithium level monitoring, dose adjustment, or cessation, to forestall enduring morbidity. This case emphasizes the significance of recognizing and managing SILENT, particularly in critical care settings, to mitigate long-term cerebellar impairment and optimize patient outcomes.

A De Novo HECW2 Variant in a Patient with Acetazolamide-Responsive Episodic Ataxia.

To the best of our knowledge, this is the first case to address episodic ataxia (EA) as a possible phenotypic feature of HECW2-related disorder. This single case study describes a 26-year-old female born at term with mild intellectual disability, neonatal hypotonia, and a history of febrile seizures who presented with paroxysmal events since the age of 2. These episodes include frequent falls due to imbalance, dilated pupils, vertigo, diaphoresis, nausea, vomiting, and nystagmus. Brain imaging was normal. A prolonged electroencephalogram (EEG) revealed interictal epileptiform discharges but failed to capture her clinical events. For several years, she was treated for presumed focal seizures with preserved awareness and trialed on adequate dosing of several antiepileptic medications without improvement. After 25 years, given the more prolonged nature of her episodes and the mild interictal cerebellar signs, empiric treatment with acetazolamide was initiated for a presumed diagnosis of EA. Acetazolamide treatment led to a dramatic reduction in event frequency and severity. The initial EA genetic panel was negative. Clinical exome sequence analysis revealed a novel pathogenic de novo missense variant in the HECW2 gene [c.3829 T > C;(p.Tyr1277His)], located in the HECT domain. HECW2 variants are associated with neurodevelopmental delay, hypotonia, and epilepsy. This study expands the genetic and clinical spectrum of HECW2-related disorder and adds EA to the phenotypic spectrum in affected individuals.

Opicapone for the treatment of Parkinson's disease: a review.

Purpose: Levodopa formulations are the workhorses of the labor against motor symptoms management in Parkinson's disease (PD). Progression of PD on levodopa inevitably leads to motor fluctuations. It is important to understand the safety and efficacy of opicapone, the most recent addition to the clinician's armamentarium against these fluctuations.Materials and methods: We review the development of COMT inhibitors in the treatment of PD as well as the efficacy and safety data reported in the currently published literature of opicapone in PD. The "currently published literature" is defined as all published, PubMed indexed trials including the word "opicapone." Finally, we compare opicapone to the competitor pharmaceuticals on the market to treat symptom fluctuations in PD and share our opinion of opicapone's place in clinical practice.Results: From the reported results of phase 3 and 4 trials of opicapone in PD, it is a safe and efficacious option to combat motor fluctuations for our PD patients taking levodopa. A reduction of "off" time by up to 1 h per day can be expected, increasing "on" time with fewer dyskinesias. Opicapone is not generally hepatotoxic, and the most reported side-effects-dyskinesia, dry mouth, dizziness, diarrhea, and constipation-were seen in only 1.4% of the OPTIPARK (a large phase 4 clinical trial) study population.Conclusions: One should consider utilizing opicapone, perhaps in combination with other augmenting medications with different mechanisms of action, to help treat motor and non-motor fluctuations in PD.

Sublingual apomorphine in treatment of Parkinson's disease: a review.

PURPOSE: A majority of advanced Parkinson's disease (PD) patients on oral levodopa experience motor fluctuations, including sudden OFF and delayed ON periods. Fast-acting rescue medications are a vital part of the clinician's armamentarium in the treatment of motor fluctuations. Sublingual apomorphine is the first sublingual rescue medication on the market for the treatment of OFF times in PD.Materials and Methods: Here, we review the development and pharmacology of apomorphine in the treatment of PD as well as the safety and efficacy of sublingual apomorphine established in clinical trials. Finally, we compare sublingual apomorphine to the other rescue medications available and provide our opinion on the use of sublingual apomorphine in clinical practice.Results: Clinical trials have demonstrated that sublingual apomorphine is a safe and effective option in the treatment of motor fluctuations in PD. In a Phase II trial, 100% of patients who achieved a full ON response did so within 30 min and 40% did so within 15 min. The mean duration of effect was 50 min. In a Phase III trial, 77.3% of patients achieved a full ON response. Side effects such as nausea, dizziness and somnolence were common but were generally mild. No patients experienced worsening dyskinesia.Conclusions: Sublingual apomorphine will provide patients with motor fluctuations due to advanced PD another safe and effective option for the treatment of OFF times.

Genotype-Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review.

This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet-derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet-derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis-regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one-third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants (<70%) was lower in comparison to the remaining three genes (>85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal-dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype-phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Influenza B-associated encephalitis with rapid improvement with oseltamivir.

A 25-year-old female veterinarian presented with 1-week of flu-like symptoms followed by progressive encephalopathy. She was originally from Nicaragua and had been in the USA for 4 months. In the emergency department, she was confused and non-verbal with meningismus and facial myoclonus, but with an otherwise non-focal neurological exam. MRI brain abnormalities were consistent with viral encephalitides. Influenza B was detected via nasopharyngeal swab PCR. Mental status improved rapidly with oseltamivir. In such presentations, especially during flu season, influenza encephalitis must be considered, to facilitate early recognition of this entity and allow for targeted treatment.

Features in essential tremor and the development of Parkinson's disease vs. parkinsonism.

BACKGROUND: Patients with essential tremor (ET) are at higher risk to develop Parkinson's disease (PD). Recent studies suggest that propranolol (common treatment for ET) can augment pathologic expression of alpha-synuclein. We studied features associated with the development of Parkinson's disease with antecedant essential tremor (ET-PD) compared with ET-plus with parkinsonism (PK). DESIGN: Retrospective case series from a tertiary movement disorders center including patients with ET and PD, found to have ET-PD or ET-plus (PK). RESULTS: We analyzed two groups: (1) ET-plus (PK) (n = 33) and (2) ET-PD (n = 35). Constipation and anosmia were more common in the ET-PD group (73% and 48%) than in the ET-plus (PK) group (33% and 19%). The ET-plus (PK) group was more likely to undergo dopamine transporter (DAT) scans compared with the ET-PD group (73% vs. 34%) and less likely to receive levodopa trials (21% vs. 91%). There were no significant differences in self-reported REM sleep behavior disorders or beta-blocker use. Similar rates of depression, anxiety, cognitive complaints, and family history of tremor or PD were reported in both groups. CONCLUSION: ET-PD and ET-plus (PK) can be clinically difficult to differentiate as they have overlapping motor and non-motor features. Beta-blocker use did not predict development of ET-PD or ET-plus (PK); however, anosmia and constipation may be helpful non-motor distinguishing features. DAT scans and levodopa trials may be valuable in clarifying the diagnoses.

Gender Disparities in Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVES: This study sought to determine whether there is a gender disparity in patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease (PD) at a single health system, and better understand the reasons for this discrepancy. MATERIALS AND METHODS: We analyzed data from the University of Miami DBS Database, which included 3251 PD patients, using chi-square, repeated measures ANOVA, and t tests to examine gender differences in the number of patients referred for surgery, reasons for referral, number receiving/not receiving surgery, reasons for not receiving surgery, and postsurgical outcomes. RESULTS: During the study period, 207 PD patients were referred for DBS (75.8% male), and 100 underwent surgery (77.0% male). Of those who did not receive surgery, the most common reasons were need for further medical optimization (26.2%), suboptimal performance on neuropsychological evaluation (22.4%), other reason (20.6%), lost to follow-up (18.7%), or patient preference (12.2%). However, in women one of the most common reasons was patient preference (28.0%), and this was significant compared to men (p < 0.001). Men were more likely to be lost to follow-up (p = 0.046). There was no statistically significant difference in postsurgical outcomes. CONCLUSIONS: Despite similar postsurgical improvements, women were less likely to undergo DBS surgery due to their own preference, while men were more likely to be lost to follow-up. These data underscore the need for increased education and awareness of DBS so that all patients with PD who qualify for surgery can benefit from this procedure.

How tandem gait stumbled into the neurological exam: a review.

Tandem gait testing is an integral part of the neurological exam. It is informative in a wide variety of disorders ranging from cerebellar disease to vestibular and peripheral neuropathies, parkinsonism, and other neurodegenerative conditions. We discuss the history and development of tandem gait testing as well as its technique, utility, and limitations in the assessment of neurological conditions. Tandem gait has emerged as a tool in the assessment of cerebellar disease, Huntington disease, idiopathic Parkinson's disease, atypical parkinsonism, peripheral neuropathies, and vestibulopathies. Its origin can be deduced from experimental observation and clinical experience as far back as the early nineteenth century. Despite the long history and ubiquitous performance of tandem gait testing, there is no standardized, guideline-based protocol to model for more homogenous research and clinical practices. Such a protocol should be developed using historical texts and manuscripts as well as the consensus of the medical research community. With standard protocols, further studies could define the sensitivity of abnormal tandem gait testing in cerebellar disorders, more diffuse neurodegeneration, and peripheral pathologies. Tandem gait can be a useful marker of dysfunction in neurologic conditions whose pathologies extend beyond the vermis or vestibulocerebellar module to include interconnected networks throughout the nervous system.

Treating the Neurologic Manifestations of Wilson's Disease With Liver Transplantation.

Wilson's Disease (WD) manifests with systemic and neuropsychiatric symptoms, caused by an ATP7B genetic mutation, leading to an accumulation of copper. Presentations are diverse and the diagnosis should be considered in anyone under 50 with a new onset movement disorder. Early recognition and treatment can limit morbidity. While liver transplantation (LT) is recommended in WD patients with hepatic failure, its use for pure neurologic indication remains controversial. We present a patient who failed medical management and underwent LT for pure neurologic indications. Subsequent neurologic symptom improvement supports the use of LT for patients with pure neurologic manifestations of WD.

Blepharoclonus in Parkinsonism.

Background and Objectives: In clinical practice, we have observed that patients with Parkinson disease (PD) often have blepharoclonus, but its prevalence is not well described in the literature. Understanding the relative frequencies of blepharoclonus in PD and atypical parkinsonian syndromes may shed light on the diagnostic utility of this clinical sign. We aimed to assess (1) the frequency of blepharoclonus in patients with PD in a single-center cohort; (2) the association of blepharoclonus with disease stage, tremor severity, and non-motor symptoms; and (3) the frequency of blepharoclonus in synucleinopathy vs non-synucleinopathy-associated parkinsonism. Methods: We prospectively enrolled 85 patients, 75 with PD and 10 with atypical parkinsonism. Blepharoclonus was considered present if eyelid fluttering was sustained for >5 seconds after gentle eye closure. For each patient, demographics were collected, and we completed selected questions from the MDS-UPDRS (Unified Parkinson's Disease Rating Scale) part 2, REM Sleep Behavior Disorder Questionnaire, and MDS-UPDRS part 3 tremor assessments and recorded the presence/absence of dyskinesia. Results: 63 of 75 patients with PD (84%) had blepharoclonus. Among the 10 patients with atypical parkinsonism, 5 had synucleinopathy syndromes. Blepharoclonus was present in 3 of 5 patients with synucleinopathy and 0 of 5 patients with non-synucleinopathy-associated parkinsonian syndromes. Discussion: Blepharoclonus is prevalent in our PD cohort, suggesting possible utility as a clinical marker for PD. The absence of blepharoclonus in a patient with parkinsonism may suggest a non-synucleinopathy (e.g., tauopathy). Analysis of a larger cohort of both PD and atypical parkinsonism would be needed to establish whether blepharoclonus distinguishes PD from atypical parkinsonism, or synucleinopathy from non-synucleinopathy.

Pulmonary embolism versus pulmonary vasculitis in Hughes-Stovin syndrome: Characteristic computed tomography pulmonary angiographic findings and diagnostic and therapeutic implications. HSS International Study Group.

BACKGROUND AND AIM: Hughes-Stovin syndrome (HSS) is a rare systemic vasculitis with widespread venous/arterial thrombosis and pulmonary vasculitis. Distinguishing between pulmonary embolism (PE) and in-situ thrombosis in the early stages of HSS is challenging. The aim of the study is to compare clinical, laboratory, and computed tomography pulmonary angiography (CTPA) characteristics in patients diagnosed with PE versus those with HSS. METHODS: This retrospective study included 40 HSS patients with complete CTPA studies available, previously published by the HSS study group, and 50 patients diagnosed with PE from a single center. Demographics, clinical and laboratory findings, vascular thrombotic events, were compared between both groups. The CTPA findings were reviewed, with emphasis on the distribution, adherence to the mural wall, pulmonary infarction, ground glass opacification, and intra-alveolar hemorrhage. Pulmonary artery aneurysms (PAAs) in HSS were assessed and classified. RESULTS: The mean age of HSS patients was 35 ± 12.3 years, in PE 58.4 ± 17 (p < 0.0001). Among PE 39(78 %) had co-morbidities, among HSS none. In contrast to PE, in HSS both major venous and arterial thrombotic events are seen.. Various patterns of PAAs were observed in the HSS group, which were entirely absent in PE. Parenchymal hemorrhage was also more frequent in HSS compared to PE (P < 0.001). CONCLUSION: Major vascular thrombosis with arterial aneurysms formation are characteristic of HSS. PE typically appear loosely-adherent and mobile whereas "in-situ thrombosis" seen in HSS is tightly-adherent to the mural wall. Mural wall enhancement and PAAs are distinctive pulmonary findings in HSS. The latter findings have significant therapeutic ramifications.

Clinical Reasoning: A 62-Year-Old Woman With Transient Vision Loss.

Transient visual loss (TVL) is a common complaint in the emergency department, with numerous possible etiologies. Prompt evaluation and management of TVL can potentially prevent progression to permanent visual loss. In this case, a 62-year-old woman presented with acute, painless, unilateral TVL. Two weeks before presentation, the patient reported bitemporal headaches and paresthesia of the distal extremities. A review of systems revealed chronic fatigue, cough, diffuse arthralgias, and decreased appetite for the previous 6 months. This case highlights the diagnostic approach to patients with TVL. Some common and rare causes associated with this clinical manifestation are briefly reviewed.

Hypermobile Ehlers-Danlos Syndrome: A Prodromal Subtype of Functional Movement Disorders?

Background: The phenotypic diversity of functional movement disorders (FMD) is considered a reflection of its many etiological subtypes. Ehlers-Danlos syndrome (EDS), a joint hypermobility syndrome, also has variable phenotypes, which may include functional symptoms. Objectives: To determine the prevalence of combined diagnoses of FMD and EDS. Methods: We searched our Electronic Medical Records for patients carrying diagnostic codes for EDS and FMD. Further data extraction was done through chart review. Results: Of 11,621 patients evaluated from January 1, 2016 to May 1, 2022, 16 carried a diagnosis of EDS, of which 9 (56.3%) were also diagnosed with FMD. Conversely, a diagnosis of FMD was documented in 190 (1.6%), of whom 16 (8.4%) were diagnosed with EDS. In all EDS-FMD cases, the diagnosis of EDS preceded the onset and diagnosis of FMD. Conclusions: The co-occurrence of FMD and EDS is beyond chance, suggesting association. EDS may represent a prodromal subtype of, and share common pathophysiologic features with, FMD.

Updated Perspectives on the Management of Drug-Induced Parkinsonism (DIP): Insights from the Clinic.

Parkinsonism refers to the clinical combination of bradykinesia, rigidity, tremor, and postural instability. Parkinsonism is often neurodegenerative, but it can be secondary or iatrogenic, as in drug-induced parkinsonism (DIP), which is the topic of this review. We review the pathophysiology of DIP, differentiate DIP and idiopathic Parkinson's disease (PD), list culprit medications in the development of DIP, discuss the diagnosis of DIP as well as the motor and nonmotor signs and symptoms that can help with differentiation of DIP and PD, and detail the management of DIP.

Amantadine Revisited: A Contender for Initial Treatment in Parkinson's Disease?

The best practice for the initiation of symptomatic motor treatment for Parkinson's disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson's disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson's disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.

Takotsubo Cardiomyopathy as a Manifestation of Dysautonomia in Guillain-Barré Syndrome: A Case Series and Review of the Literature.

Guillain-Barré syndrome (GBS) is an inflammatory polyneuropathy that classically presents with low back pain, sensory paresthesias, and rapidly progressive weakness. Patients with GBS can develop dysautonomia, and Takotsubo cardiomyopathy (TCM) is a rare potential manifestation of this dysautonomia. This association has been reported only 12 times in the literature so far, which we review here. We present two cases of GBS associated with TCM, to increase awareness with regard to this comorbid relationship, which would encourage prompt initiation of proper supportive care to avoid morbidity and mortality. We report the case of two patients - a 58-year-old man and a 79-year-old woman - who developed TCM in the setting of axonal variants of GBS. Electrodiagnostic results, cerebrospinal fluid profiles, and echocardiogram findings were consistent with these diagnoses. Both patients were treated with intravenous immunoglobulin (IVIG) in an intensive care unit (ICU) setting. Echocardiogram findings were reversible. TCM should be recognized as a potential complication of GBS in patients with dysautonomia. This case series adds to the sparse body of literature describing the association between these two conditions. It is not clear if patients with axonal variants of GBS are more predisposed to developing TCM; further, larger case series in the future may help identify the risk factors associated with it. We hope to shed more light on this possible association to expedite the diagnosis and management of this condition.