Fahr's disease in a patient with recurrent pneumonias, parkinsonism and dementia.

Fahr's disease is a rare condition characterised by the presence of idiopathic familial bilateral basal ganglia calcifications, transmitted in an autosomal-dominant fashion. Diagnosis is based on clinical features of neuropsychiatric and somatic symptoms in conjunction with radiological findings. Our patient, a man in his early 50s, presented with pneumonia. History was significant for five admissions in the last 2 years for pneumonia and falls, with gradual cognitive and motor decline since his late 30s. Hypophonia, bradykinesia and dementia were noted on examination. CT of the brain revealed bilateral thalamic calcinosis, consistent with Fahr's syndrome. Further investigations and retrospective history taking, and similar radiological findings within first-degree and second-degree relatives with early deaths, transitioned the diagnosis from Fahr's syndrome to Fahr's disease. We present this case of Fahr's disease to emphasise the value of collaboration among multidisciplinary professionals to improve quality of care for such patients.

Wilson Disease: A Case Report of Psychosis Preceding Parkinsonism.

BACKGROUND A first psychotic episode requires the exclusion of toxic-metabolic, inflammatory, infective, and neoplastic causes. Wilson disease is a rare, autosomal recessive disorder of copper metabolism and can present with neuropsychiatric symptoms secondary to copper accumulation in the brain. CASE REPORT We describe the case of a 48-year-old man with parkinsonism on a background of longstanding schizophrenia and psychotic depression in the setting of previously undiagnosed Wilson disease. The common history of neuropsychiatric disturbance and neuroleptic use complicated the assessment of parkinsonism. However, close attention to the temporal appearance of symptoms and signs differentiated his case from drug-induced parkinsonism, which commonly develops hours to weeks after commencement or uptitration of antipsychotic medication. The early features of sialorrhea and dysarthria were also atypical for idiopathic Parkinson disease. The diagnosis was confirmed by serum copper testing and supported by Kayser-Fleischer rings on bedside ophthalmological examination. Magnetic resonance imaging (MRI) of the brain demonstrated copper accumulation in the basal ganglia and pons, contributing to the characteristic neurological manifestations of an akinetic-rigid syndrome with dysarthria. CONCLUSIONS Serum copper testing is easily obtained and should be considered as part of the first-line investigations for new neuropsychiatric disturbances. Although rare, Wilson disease, if diagnosed early, is a potentially treatable and reversible cause of psychosis. With advanced disease, extrapyramidal findings on examination correlate with MRI brain changes, aiding the clinical assessment in differentiating the disease from drug-induced parkinsonism.

[Autoimmune encephalitis and paraneoplastic neurological syndromes presenting atypical parkinsonism: a scoping review].

Recent studies have demonstrated that atypical parkinsonism can be presented in autoimmune encephalitis and paraneoplastic neurological syndromes. However, it is unclear which anti-neural antibodies are involved and when these diseases should be suspected. To address these clinical questions, we conducted a scoping review and analyzed 38 articles. The literature shows that many anti-neural antibodies, including unknown ones, have been reported in progressive supranuclear palsy, corticobasal syndrome, and multiple system atrophy. Moreover, the following symptoms and signs suggest the possibility of autoimmune encephalitis and paraneoplastic neurological syndromes: early onset, acute or subacute progression, the presence of a neoplasm, significant weight loss, abnormal cerebrospinal fluid findings, the absence of typical brain magnetic resonance imaging findings, and the existence of atypical physical examination signs.

A Prospective Study on the Relationship between Iron Supplement Intake, Hemoglobin Concentration, and Risk of Parkinsonism.

The findings regarding whether the greater iron level or intake is a risk factor to Parkinson's disease (PD) or parkinsonism was not clear. The purpose of this study is to establish a consistent association between iron supplementation and parkinsonism risk, we conducted a large-scale prospective cohort study using comprehensive longitudinal data from the UK Biobank. The longitudinal cohort data of 385,898 participants (including 911 cases) who were middle to old aged British adults and joined the UK Biobank study from 2006 to 2010 and were followed up until 2018 was analyzed. The associations between iron supplement intake, hemoglobin levels and all cause subsequent parkinsonism risk after corrections of potential confounders (sex, age, household income, education length, employment status, deprivation level, body mass index, physical activity level, household numbers, smoking and drinking levels, health status, blood pressure) were investigated. Analyses revealed that (a) iron supplementation was significantly associated with higher parkinsonism risk, (b) greater hemoglobin was weakly and insignificantly associated with lower parkinsonism risk, and (c) multivitamin or vitamin C supplement intake was not significantly associated with parkinsonism risk. Regardless of whether the subjects were classified as anemic, normal, or polycythemic or in the hemoglobin level quintile, there was no nonlinear association between hemoglobin and parkinsonism risk. Parkinsonism risk did not differ between participants reporting supplementary iron intake with or without vitamin C or multivitamin supplement intake. Furthermore, polygenic risk score of PD negatively correlated with hemoglobin level, while it did not associate with intake of iron supplement or multivitamin or vitamin C supplement intake. The results suggest excessive iron intake may increase parkinsonism risk. Interventional studies are warranted to examine whether iron intake restriction is beneficial for individuals without clinical iron deficiency.

Radiation-induced Brain Calcification Leads to L-dopa-resistant Parkinsonism and Cerebellar Ataxia.

We experienced a young patient who presented with progressive parkinsonism and cerebellar ataxia. Brain magnetic resonance imaging revealed progressive brain calcification, expanding from the bilateral basal ganglia to the central pons, caused by a delayed reaction to the radiation therapy that she had received to treat craniopharyngioma 14 years earlier. Heterogeneous clinical symptoms due to radiation-induced brain calcification have been described, but parkinsonism has never been reported. While dopamine transporter-single photon emission computed tomography revealed only slight damage to the dopaminergic striatal pathway, the extension of calcification to the periventricular white matter was likely responsible for her parkinsonism.

Parkinsonism and prolonged cognitive decline as a manifestation of cryptococcal meningitis in a renal transplant patient.

We report a case of a 67-year-old male recipient of a second renal allograft, presenting with a 9-month history of progressive cognitive and physical decline with features of Parkinsonism. He was HIV-negative. Serum and cerebrospinal fluid (CSF) cryptococcal antigen was positive though CSF culture was sterile. He had progressive deterioration despite induction and consolidation antifungal treatment. Postmortem brain examination confirmed a large burden of yeast forms in the substantia nigra with widespread chronic meningitis. The significant delay in presentation and diagnosis owing to the atypical, subacute neurocognitive features serves as a timely reminder of the variety of neurological presentations that may be associated with cryptococcal infection in solid organ transplant recipients.

Parkinsonism in viral, paraneoplastic, and autoimmune diseases.

Secondary parkinsonism, namely parkinsonism due to causes other than idiopathic neurodegeneration, may have multiple etiologies. Common secondary etiologies of parkinsonism such as drug-induced or vascular etiologies are well documented. Other secondary causes of parkinsonism such as infectious (mainly viral and prion-like diseases), autoimmune (systemic/drug-induced) and paraneoplastic etiologies are rare but are a topic of increasing interest. Older examples from the existing literature demonstrate the intricacies of viral infection from the last pandemic of the 20th century on the development of hypokinetic symptoms experienced in post-encephalitic patients. Viral and prion-like infections are only part of a complex interplay between the body's immune response and aberrant cell cycle perturbations leading to malignancy. In addition to the classic systemic autoimmune diseases (mainly systemic lupus erythematosus - SLE, and Sjögren syndrome), there have been new developments in the context of the current COVID-19 pandemic as well as more prominent use of immunotherapies such as immune checkpoint inhibitors in the treatment of solid tumors. Both of these developments have deepened our understanding of the underlying pathophysiologic process. Increased awareness and understanding of these rarer etiologies of parkinsonism is crucial to the modern diagnostic evaluation of a patient with parkinsonian symptoms as the potential treatment options may differ from the conventional levodopa-based therapeutic regimen of idiopathic Parkinson's disease. This review article aims to give an up-to-date review of the current literature on parkinsonian symptoms, their pathogenesis, diagnostic methods, and available treatment options. Many potential future directions in the field of parkinsonian conditions remain to be explored. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

Chronic subdural hematoma-induced parkinsonism: A systematic review.

BACKGROUND: Chronic subdural hematoma (CSDH) is one of the most common neurosurgical cases, especially in elderly individuals. Secondary parkinsonism due to CSDH is a rare entity. The mechanism of parkinsonism symptoms in chronic subdural hematoma has been suggested to include direct mechanical compression of the basal ganglia due to hematoma or indirectly through brain structure changes due to space lesions and vascular disorders. Surgery on the subdural hematoma provides a favorable outcome for parkinsonism symptoms. OBJECTIVES: To systematically review the literature on CSDH-induced parkinsonism. SEARCH METHODS: This is a systematic review on case reports. Literature search was performed using the predefined keywords on PubMed, ProQuest, and Google Scholar. We also provided our own case report and compared it with published studies. RESULT: Sixteen cases from 13 case reports/series were identified, predominantly consisting of male patients with the mean age of 66.5 ± 9.73 years. The most common symptoms were rigidity, gait disturbance, and bradykinesia, observed in 12 (75%) cases each. The second and third most common symptoms were tremor (11; 68.75%) and facial masking (8; 50%), respectively. Other reported symptoms were dysphasia (3; 18.75%), dysarthria (3; 18.75%), and urinary incontinence (2; 12. 5%). Time gap between the symptom onset and CSDH diagnosis and unilateral location seemed to influence the outcome. CONCLUSION: Only 16 CSDH-induced parkinsonism were identified since the 1960s. This condition is thought to occur due to basal ganglia compression. Surgery on the subdural hematoma provides a favorable outcome for parkinsonism symptoms. Timely CSDH diagnosis might yield better outcome. However, further research on CSDH-induced parkinsonism is needed, especially in the mechanisms and treatment outcomes.

Clinical Outcome and Striatal Dopaminergic Function After Shunt Surgery in Patients With Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Participants with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [123I]-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years. RESULTS: We enrolled 115 patients with iNPH. Of 102 patients without significant levodopa response and no signs of atypical parkinsonism, 92 underwent FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery (p < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 (p < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in patients who declined surgery (p < 0.01). CONCLUSIONS: This prospective interventional study highlights the pathophysiologic relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and postsurgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with iNPH.

Fahr's syndrome due to hypoparathyroidism revisited: A case of parkinsonism and a review of all published cases.

INTRODUCTION: Fahr's syndrome due to hypoparathyroidism refers to bilateral basal ganglia (BG) calcifications and manifests with movement disorders, seizures, cognitive and behavioral symptoms. CASE PRESENTATION: We report a case of a 74-year-old woman, who presented with parkinsonism due to post-surgical hypoparathyroidism and normal DaT scan, despite extensive calcifications of the BG, periventricular white matter, and cerebellum. METHODS: A comprehensive literature review of all reported cases of Fahr's syndrome due to hypoparathyroidism was conducted in the electronic databases PubMed and Web of science. Moreover, demographic and clinical characteristics of the patients overall were calculated and associated with radiological findings. RESULTS: We reviewed a total of 223 cases with Fahr's syndrome due to hypoparathyroidism (124 female, 99 male). Mean age on presentation was 44.6 ± 17.7 years. Thirty nine percent of patients had idiopathic hypoparathyroidism, 35.4 % acquired and 25.6 % pseudohypoparathyroidism. Almost half of the patients had tetany, seizures or a movement disorder and approximately 40 % neuropsychiatric symptoms. The patients with a movement disorder had a 2.23 likelihood of having neuropsychiatric symptoms as well (OR 2.23, 95 % CI 1.29-3.87). Moreover, there was a statistically significant association between the phenotype severity (i.e. the presence of more than one symptom) and the extent of brain calcifications (χ2 = 32.383, p = 0.009). CONCLUSION: Fahr's syndrome is a rare disorder, which nonetheless manifests with several neurological symptoms. A head CT should be considered for patients with hypoparathyroidism and neurological symptoms. More studies using DaT scan are needed to elucidate the effects of calcifications on the dopaminergic function of the BG.

Psychiatric Disturbance or Parkinsonism as a Presentation of CNS Lymphoma: Observational Retrospective Study and Review of Literature.

OBJECTIVE: To evaluate the incidence of and characterize the presentation of neuropsychiatric symptoms and/or Parkinsonism as a presentation of central nervous system lymphoma (CNSL) in either its primary CNSL form or when it spreads to the brain in systemic diffuse large B-cell lymphoma (secondary CNSL). PATIENTS AND METHODS: With Institutional Review Board approval we identified patients who had been treated at Mayo Clinic from 1998 to 2018 and were recorded to have a combination of ICD 9/10 codes for CNSL and various psychiatric diagnoses. RESULTS: A total of 20 of the 232 patients (9%) were noted to have neuropsychiatric symptoms preceding diagnosis. The average age at diagnosis was 62, with even split for sex. The majority (85%) of patients had primary CNSL. The average duration of symptoms before the diagnosis was 4.8 months. Confusion (80%), depression (40%), apathy (30%), anxiety (30%), and agitation (30%) were the most common symptoms identified. The majority (65%) of patients had subcortical lesions followed by the frontal lobe (50%). Parkinsonism was identified in 5 of the 20 patients with 4 demonstrating resolution of symptoms with treatment of the lymphoma. CONCLUSIONS: Neuropsychiatric symptoms are a rare but notable symptom before the presentation of CNSL. There is an increasing awareness of neurological illness presenting as pure psychiatric disturbance, prompting the need to exclude organic and treatable diseases, particularly in elderly patients. Acknowledgment and diagnosis are important for an appropriate management as there is a significant impact on patient and caregiver quality of life.

Emergency presentations of movement disorders.

Movement disorders are typically perceived as being gradually progressive conditions that are managed in outpatient settings. However, they may manifest de novo with an acute severe phenotype or an acute decompensation. A movement disorder becomes an emergency when it evolves acutely or subacutely over hours to days; delays in its diagnosis and treatment may cause significant morbidity and mortality. Here we address the clinical presentation, diagnosis and management of those movement disorder emergencies that are principally encountered in emergency departments, in acute receiving units or in intensive care units. We provide practical guidance for management in the acute setting where there are several treatable causes not to be missed. The suggested medication doses are predominantly based on expert opinion due to limited higher-level evidence. In spite of the rarity of movement disorder emergencies, neurologists need to be familiar with the phenomenology, potential causes and treatments of these conditions. Movement disorder emergencies divide broadly into two groups: hypokinetic and hyperkinetic, categorised according to their phenomenology. Most acute presentations are hyperkinetic and some are mixed.

Levodopa-responsive parkinsonism in a patient with corticobasal degeneration and bilateral choroid plexus xanthogranulomas.

Corticobasal degeneration (CBD) has substantial overlap of clinical features with other neurodegenerative diseases including Parkinson's disease (PD). Its clinical diagnostic accuracy is the lowest among the common neurodegenerative diseases, and its antemortem diagnosis is more challenging when CBD is comorbid with another brain disease. We report an elderly male patient with multiple medical conditions and a family history of essential tremor. He presented with progressive tremor that was initially thought to be essential tremor and later diagnosed as PD despite head computerized tomography showing bilateral intraventricular masses and other minor changes. The clinical diagnosis of PD was supported by his responsiveness to low-dose levodopa. However, postmortem neuropathological examination revealed CBD and bilateral choroid plexus xanthogranulomas with mild ventricular enlargement and multifocal ependymal lining injury presumably due to mild hydrocephalus. CBD is typically levodopa-unresponsive, but hydrocephalus-associated parkinsonism is commonly levodopa-responsive. We raise awareness of the present comorbidity and atypical parkinsonism due to the choroid plexus xanthogranuloma-induced hydrocephalus for the clinical diagnosis and management of parkinsonism.

Parkinsonism in autoimmune diseases.

Parkinsonism can be manifested and complicate either systemic or organ-specific autoimmune diseases. Even though it is a rare co-morbidity, it merits attention from clinicians as it affects the quality of life of patients. In systemic autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome reported cases of parkinsonism are attributed to the underlying disease and its mechanisms, whether this is brain vasculitis or immune complexes. Regarding antibody-mediated autoimmune neurological disorders, parkinsonism is, in most cases, a manifestation within the spectrum of each disorder and is attributed to the action of humoral and cellular immunity in brain regions such as the basal ganglia. Depending on the pathophysiology, immunotherapy can be effective, while Parkinson's specific therapies are usually less effective.

Farrerol protects dopaminergic neurons in a rat model of lipopolysaccharide-induced Parkinson's disease by suppressing the activation of the AKT and NF-κB signaling pathways.

Neuroinflammation, characterized by the activation of microglia, is one of the major pathologic processes of Parkinson's disease (PD). Overactivated microglia can release many pro-inflammatory cytokines, which cause an excessive inflammatory response and eventually damage dopaminergic neurons. Therefore, the inhibition of neuroinflammation that results from the overactivation of microglia may be an method for the treatment of PD. Farrerol is a 2,3-dihydro-flavonoid obtained from Rhododendron, and it possesses various biological functions, including anti-inflammatory, antibacterial and antioxidant activities. However, the effect of farrerol on neuroinflammation has not been investigated. The present study uncovered a neuroprotective role for farrerol. In vitro, farrerol markedly decreased the production of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), cyclooxygenase 2 (COX-2) and induced nitric oxide synthase (iNOS), induced by lipopolysaccharide (LPS) in BV-2 cells. This anti-inflammatory effect was regulated via inhibiting NF-κB p65 and AKT phosphorylation. Furthermore, we found that farrerol alleviated microglial activation and dopaminergic neuronal death in rats with LPS-induced PD. Pretreatment with farrerol markedly improved motor deficits in rats with LPS-induced PD. Taken together, our results indicate that the neuroprotective effect of the farrerol, which prevents microglial overactivation in rats with LPS-induced PD, may provide a potential therapy for patients suffering from PD.

Characteristics of Patients Experiencing Extrapyramidal Symptoms or Other Movement Disorders Related to Dopamine Receptor Blocking Agent Therapy.

PURPOSE/BACKGROUND: Dopamine receptor blocking agents (DRBAs), also known as antipsychotics, are medications widely used to treat a growing number of mental health diagnoses. However, their utility is limited by the potential to cause serious adverse movement reactions. Akathisia, dystonia, parkinsonism, and tardive dyskinesia (collectively known as extrapyramidal symptoms or EPSs) are associated with reduced social and occupational functioning, negative patient attitudes toward treatment, and nonadherence to pharmacotherapy. Neuroleptic malignant syndrome is a life-threatening reaction that can result from DRBA use and cause musculoskeletal dysfunction. The aim of this study is to profile patients who have developed DRBA-related movement adverse effects and identify risk factors significantly associated with each subtype of EPSs or other movement disorders (OMDs) such as neuroleptic malignant syndrome. METHODS/PROCEDURES: A report of all potential DRBA-related EPSs or OMDs occurrences within a large community hospital network was generated using International Classification of Diseases, Ninth Revision (ICD-9) and 10th Revision (ICD-10) billing codes. Each patient encounter was manually reviewed to confirm that a documented case of DRBA-related EPSs or OMDs had indeed occurred and subsequently determine the likely causative agent(s). FINDINGS/RESULTS: The resultant cohort of 148 patients experiencing unique DRBA-related EPS or OMD events was analyzed. The average patient was female, middle-aged, and overweight. The most common DRBAs precipitating EPSs or OMDs were haloperidol and quetiapine. In the population studied, age was significantly associated with the subtype of EPSs experienced such that those patients with akathisia and dystonia tended to be younger, whereas those with tardive dyskinesia tended to be older. Body mass index (BMI) category was also negatively correlated with the incidence of dystonia. In addition, it was observed that exposure to specific DRBAs, classes, and routes of administration significantly affected the risk of developing different subtypes of EPSs or OMDs in the study population. IMPLICATIONS/CONCLUSIONS: To our knowledge, this is the first study to describe an association between age and BMI with the risk of akathisia and dystonia, respectively, in patients taking DRBAs. Other trends observed with age and BMI in patients developing DRBA-related EPSs support previously reported findings. Expanding the knowledge base of individual characteristics associated with the risk of developing different subtypes of EPSs or OMDs can help providers and patients anticipate and attempt to mitigate these reactions, and may ultimately improve adherence to DRBA therapy.

Acute parkinsonism as an unexpected consequence of pituitary adenoma resection: A case report.

INTRODUCTION: Transsphenoidal resection of pituitary tumors is a surgery performed through the nose and sphenoid sinus to remove pituitary tumors. Disorders of sodium balance are common after transsphenoidal surgery involving the pituitary gland. Here, we report the clinical features of an original case of acute onset parkinsonism later confirmed to be secondary to transsphenoidal resection of pituitary adenoma. PATIENT CONCERNS: A 36-year-old female had received transsphenoidal pituitary resection for pituitary adenoma. Eight days after the surgery, she suffered from acute onset general weakness and nausea/vomiting. She was diagnosed with hyponatremia for which she was treated. Acute onset ataxia, bilateral hand tremor, and dysarthria were then noted on the 4th day of hyponatremia treatment. DIAGNOSIS: Based on history, clinical manifestation, and MRI brain images, a diagnosis of acute parkinsonism caused by isolated extrapontine myelinolysis (EPM) was made. INTERVENTIONS: Patient was treated with levodopa/carbidopa. OUTCOMES: Patient's symptoms and signs improved gradually and 2 month follow-up MRI brain showed significant resolution of the bilateral lentiform nuclei hyperintensities on the T2-weighted images. Her neurological deficits had subsided completely. LESSONS: This case highlights an unexpected association between transsphenoidal resection of pituitary tumors and acute parkinsonism which is a treatable manifestation of EPM. Correction of hyponatremia following transsphenoidal pituitary resections should be preceded cautiously because even gradual correction of hyponatremia can produce myelinolysis.