Extrapyramidal Movement Disorders Research Articles

Protective effect of remote ischemic preconditioning on blood pressure control in magnetic resonance-guided focused ultrasound operations

Backrgound. Magnetic resonance-guided focused ultrasound (MR-FUS) is a new non-invasive technology for the surgical treatment of extrapyramidal movement disorders for such pathologies as essential tremor, Parkinson’s disease, etc. In these cases, the brain is injured and a zone of ischemia is formed. Arterial hypertension (AH) is one of the most common pathologies, which is often accompanied by neurological diseases. Objective. To investigate the effect of the remote ischemic preconditioning (RIPC) on blood pressure (BP) during MR-FUS surgery. Design – blinded, randomized, controlled, 2-group study with sham preconditioning. Materials and Methods. Patients were randomized into the RIPC group (cuff systolic BP (SBP) >50 mmHg, n=42) and the group with sham RIPC (cuff diastolic BP (DBP), n=39) before surgery in regime 3 cycles each 5 min with 5 min rest between cycles. Results. While there was a decrease in SBP and DBP before and after the operation in the RIPC group, there was an increase (p<0.001) in the sham RIPC group. Using the Difference-in-Difference equation for SBP, SBP was 8.9 (5.9–11.9) mm Hg higher in the sham RIPC group than in the RIPC group (p<0.01). Conclusion. As a result, MR-FUS operations showed a significant decrease in BP during RIPC compared to the imitation, which confirms the angioprotective effect of preconditioning.

Effect of Bacille-Calmette-Guerin vaccine against rotenone-induced Parkinson's disease: Role of neuroinflammation and neurotransmitters.

Parkinson's disease (PD) is an extrapyramidal movement disorder associated with a hypokinetic condition generated by impairment in dopaminergic neuronal viability in the nigrostriatal region of the brain. Current medications can only provide symptomatic management; to date, no permanent cure is available. To compensate for this lacuna, researchers are gaining interest in antigen-based therapy, and Bacille-Calmette-Guerin (BCG) is one of the vaccineswith a high safety margin that acts by stimulating immunoreactive T-cells in the CNS and reducing expression of pro-inflammatory cytokines including interleukin (IL)-1β and tumor necrotic factor (TNF-α) to produce neuroprotection. A previous study reported that BCG exerts a neuroprotective effect against several neurodegenerative disorders, such as Alzheimer's disease. The objective of this study is to explore the neuroprotective effect of the BCG vaccine against the rotenone model of PD. Rotenone (1.5 mg/kg, s.c) for 28 days, and BCG vaccine (2 × 107 cfu, i.p) single dose was injected to rats, and behavioral assessments were performed on the 21st and 28th day. On the 29th day, rats were sacrificed, and brains were isolated for biochemical and neurochemical estimation. BCG vaccine significantly restored rotenone-induced motor deficits (open field test, narrow beam walk, and rotarod), biochemical levels (GSH, SOD, catalase, MDA, and nitrite), neurotransmitters (dopamine, 5-hydroxy tryptamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, hemovanillic acid, and 5-hydroxy indoleacetic acid), and levels of inflammatory cytokines (IL-1β and TNF-α) in the striatum. It also prevents histopathological changes by reducing eosinophilic lesions in the striatum. From the results, we conclude that BCG vaccine showed neuroprotection through antioxidant and anti-inflammatory effect. Thus, in the future, it can be used as a neuroprotective agent for other neurological disorders, including PD.

The Clinical And Molecular Spectrum Of ZFYVE26-Associated Hereditary Spastic Paraplegia (SPG15) (P13-11.005)

<h3>Objective:</h3> To describe the clinical and molecular features of <i>ZFYVE26</i>-related hereditary spastic paraplegia (HSP) in order to raise awareness to this rare disease, facilitate an early diagnosis and promote clinical trial readiness. <h3>Background:</h3> <i>ZFYVE26</i>-associated hereditary spastic paraplegia (HSP-<i>ZFYVE26</i>, SPG15) is a rare early-onset form of progressive HSP, characterized by progressive spasticity and a variety of other neurological symptoms. <h3>Design/Methods:</h3> 44 individuals with bi-allelic variants in <i>ZFYVE26</i> were recruited from our Registry for Early-onset Hereditary Spastic Paraplegia (NCT04712812). A cross-sectional analysis of demographic, clinical and molecular data was conducted using a standardized questionnaire. Results were compared to 65 previously published cases. Disease severity was quantified using the Spastic Paraplegia Rating Scale (SPRS), the SPRS Spasticity Subscore and the SPATAX Disability Score. Plasma neurofilament light chain (NfL) concentrations were measured using the SiMoA HD-X Analyzer. <h3>Results:</h3> While symptom onset was in early childhood, a molecular diagnosis was reached at a median age of 14.4 years (IQR=6), indicating a significant diagnostic delay. 45 distinct variants in <i>ZFYVE26</i> were identified. Most patients presented with developmental delay or learning disabilities. This preceded the onset of motor symptoms by several years. Spasticity in the lower extremities involved the ankles first, with subsequent progression to proximal areas. Extrapyramidal movement disorders and neurogenic bladder dysfunction were common. Brain MR imaging showed a thin corpus callosum and signal changes of the anterior forceps as well as non-specific cortical and cerebellar atrophy in a subset. Clinical rating scales showed moderate correlation with disease duration (SPRS score: 25.2±13.3 (SD), <i>R</i>_m²=0.51;, SPRS Spasticity Subscore: 7.3±4.3 (SD), <i>R</i>_m²=0.47; SPATAX disability score: 3.2±4.3 (SD), <i>R</i><i>_m</i>²=0.63). NfL levels were significantly increased in HSP-<i>ZFYVE26</i> patients and showed an inverse correlation with age. <h3>Conclusions:</h3> We delineate the clinical, neuroimaging and molecular spectrum of <i>ZFYVE26</i>-related HSP, demonstrate the progressive evolution of the disease and validate clinical rating scales as quantitative disease monitoring tools. <b>Disclosure:</b> Dr. Saffari has nothing to disclose. Miss Jordan has nothing to disclose. Dr. Mo has nothing to disclose. Bo Zhang has nothing to disclose. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regenxbio . Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Centene. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for PTEN Research. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Sahin has received research support from NIH. The institution of Dr. Sahin has received research support from Tuberous Sclerosis Alliance. The institution of Dr. Sahin has received research support from Charities Aid Foundation. The institution of Dr. Sahin has received research support from Simons Foundation Autism Research Initiative. The institution of Dr. Sahin has received research support from Aucta Pharmaceuticals . The institution of Dr. Sahin has received research support from Loulou Foundation. Dr. Blackstone has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. Dr. Blackstone has received personal compensation in the range of $500-$4,999 for serving as a Consultant for FIrstThought. Dr. Blackstone has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Asha Therapeutics. Dr. Blackstone has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Ficksman &amp; Conley, LLP. The institution of Dr. Yang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Syngeos. Dr. Ebrahimi-Fakhari has received personal compensation in the range of $0-$499 for serving as a Consultant for Alcimed Inc.. The institution of Dr. Ebrahimi-Fakhari has received research support from CureAP4 Foundation, CureSPG50 Foundation, Spastic Paraplegia Foundation, Manton Center for Orphan Disease Research, BPAN Warriors Foundation, NIH/NINDS. Dr. Ebrahimi-Fakhari has received publishing royalties from a publication relating to health care.

Partially reversible bilateral Lenticular fork sign and acute Parkinsonism in diabetic uremic syndrome (P5-11.005)

<h3>Objective:</h3> Not applicable <h3>Background:</h3> Diabetic uremic syndrome is a concept that has been increasingly recognized since it was proposed in 2003. It differs from uremic encephalopathy. Hereby, we describe the first case of North African Arab descent with end-stage renal disease and diabetes who developed acute Parkinsonism with bilateral lenticular fork sign and uremia that partially resolved after extensive dialysis therapy. <h3>Design/Methods:</h3> Not applicable <h3>Results:</h3> <h3>Case Description:</h3> 65 years old man with end-stage renal disease on peritoneal dialysis and newly diagnosed diabetes millets presented with a 3-day history of unsteady gait, generalized weakness, mild dysarthria, mild dysphagia, drowsiness, and changes in concentration. Examination revealed a mask face, dysphagia, absent gag reflex, dysphonia, generalized motor weakness more prominent in lower limbs, bradykinesia, absent knee reflexes, and myoclonic jerks. Laboratory studies showed urea 25 mmol/L, Creatinin 922 umol/L, arterial pH 7.25, and normal lactate. The lumbar puncture study was unremarkable. CT head showed swollen hypodense bilateral lentiform nuclei with a hypodense rim delineating the basal ganglia and giving the appearance of a lentiform fork sign. MRI showed bilateral T2 and FLAIR putamen and globus pallidus hyperintensity and significant lactate peak in the bilateral basal ganglia on MR spectroscopy. EMG study was evident of axonal polyneuropathy. IVIG course was commenced, and motor weakness improved. The peritoneal dialysis was intensified, and later treatment was switched to hemodialysis. Acidemia resolved, and uremia significantly improved. Two weeks post-admission, the fork sign on MRI significantly regressed, and the patient’s Parkinsonian symptoms partially improved. <h3>Conclusions:</h3> Development of acute or subacute extrapyramidal movement disorder in end-stage renal disease associated with diabetes should promote the possibility of diabetic uremic syndrome with bilateral basal ganglia lesions forming fork sign appearance that occurs early on brain imaging. Usually, extensive dialysis, preferable hemodialysis, leads to a total resolution of brain imaging and partial resolution of clinical findings. <b>Disclosure:</b> Dr. Nofal has nothing to disclose. Dr. Noorain has nothing to disclose. Dr. Safan has nothing to disclose. Dr. Adeli has nothing to disclose. Dr. Sokrab has nothing to disclose.

Novel SERAC1 Variant Presenting With Adult-Onset Extrapyramidal Dystonia-Parkinsonism Phenotype: A Case Report.

To report a novel likely pathogenic variant in the SERAC1 gene associated with early adult-onset parkinsonism and progressive dystonia. Clinical, biochemical, and imaging assessments were performed on 2 affected adult brothers with a genetically unsolved progressive neurologic disorder followed by whole-genome sequencing. A homozygous likely pathogenic variant in the SERAC1 gene (c.[129-2A > C], p.[(?)];[(?)]) was discovered. We describe a novel homozygous variant in the serine active site-containing protein 1 gene (SERAC1) in 2 brothers with a progressive extrapyramidal movement disorder of early onset parkinsonism and dystonia. Previous variants have been associated with a severe 3-methylglutaconic aciduria with dystonia, deafness, hepatopathy, encephalopathy and Leigh-like syndrome, or juvenile onset complicated spastic paraparesis. Our cases expand the phenotype of SERAC1 variants, with an adult-onset presentation of dystonia-parkinsonism.

Expansion of the phenotypic and molecular spectrum of CWF19L1-related disorder.

Pathogenic variants in CWF19L1 lead to a rare autosomal recessive form of hereditary ataxia with only seven cases reported to date. Here, we describe four additional unrelated patients with biallelic variants in CWF19L1 (age range: 6-22 years) and provide a comprehensive review of the literature. The clinical spectrum was broad, including mild to profound global developmental delay; global or motor regression in infancy or adolescence; childhood-onset ataxia and cerebellar atrophy; and early-onset epilepsy. Since only two previously reported patients were adults, our cohort expands our understanding of the evolution of symptoms from childhood into early adulthood. Taken together, we describe that CWF19L1-related disorder presents with developmental and epileptic encephalopathy with treatment-resistant seizures and intellectual disability in childhood followed by progressive ataxia and other extrapyramidal movement disorders in adolescence.

Anti-IgLON5 Disease with Isolated Hemichorea: A Case Report and Review of the Literature.

Anti-IgLON5 disease is an autoimmune encephalopathy with sleep disturbances as a hallmark in the majority of reported cases. Additional clinical symptoms are heterogenous and include movement disorders, bulbar dysfunction, autonomic disorders, and neurocognitive impairment. Here, we report the case of an 87-year-old woman presenting with isolated progressive hemichorea. An extensive diagnostic work-up revealed antibodies against IgLON5 in the serum. Neither history nor polysomnography (PSG) unveiled signs and features of sleep dysfunction typically reported in anti-IgLON5 disease. In an extensive literature review we identified twelve other studies reporting about patients with confirmed anti-IgLON5 disease and chorea as extrapyramidal movement disorder in their clinical phenotype. Subsequently, clinical characteristics of these patients were carefully evaluated. Our results support the diversity of clinical phenotypes in anti-IgLON5 disease, adding isolated hemichorea to the spectrum of presenting symptoms. As sleep-related disorders are often not the leading reason for consultation and only revealed by PSG examination, we suggest that screening for antibodies against IgLON5 should be considered in patients presenting with unexplained movement disorders, including isolated hemichorea.

The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15.

In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

First use of MRI-guided focused ultrasound to treat patients with essential tremor in Russia

Introduction. Treatment with MRI-guided focused ultrasound (MRgFUS) is a new, non-invasive surgical technique for treating extrapyramidal movement disorders. This article presents the first use of MRgFUS in Russia for treating patients with essential tremor (ET).&#x0D; Materials and methods. Patients (n = 26; 17 men and 9 women) aged 2182 years (median age 46.0 years) and with severe and refractory ET, underwent MRgFUS thalamotomy (ExAblate 4000, Insightec). One side was treated in 22 patients (left thalamus in 18 and right thalamus in 6), both sides were treated concurrently in two patients, and both sides were treated consecutively in two patients. Tremor was assessed using the Clinical Rating Scale for Tremor (CRST). Because international clinical specialists could not visit Russia due to the COVID-19 pandemic, MRgFUS was performed via telehealth on May 5, 2020, in a world first.&#x0D; Results. A satisfactory result was achieved in 25 (96%) out of 26 patients. CRST scores improved by 64.7% on the side of the operation, by 10.2% on the control side, and by 37.5% overall. Intraoperative side effects included headache during sonication (42.3%), vertigo (15.4%), nausea (11.5%), vomiting (7.7%), numbness (3.8%), ataxia (3.8%), and pathological response to cold exposure (3.8%). The symptoms resolved immediately after surgery. Unstable gait was noted in five patients, which completely resolved two weeks after surgery. Median postoperative follow-up duration was 109 days [53; 231], with a maximum of 625 days. No relapses (if the hyperkinesia had completely disappeared) or increased tremor (if reduced after surgery) were observed.&#x0D; Conclusion. The efficacy of MRgFUS for ET was 96%, with no long-term complications. Both bilateral concurrent and bilateral consecutive MRgFUS thalamotomy is possible, but its efficacy and safety should be assessed in a randomized study. In a world first, MRgFUS was successfully implemented using telehealth.

Akinetic rigid syndrome as a presenting feature of subacute sclerosing pan encephalitis

Atypical presentations of subacute sclerosing panencephalitis include hemiparesis, acute disseminated encephalomyelitis, cerebellar ataxia, visual disturbances, symptoms suggestive of the intracranial space- occupying lesion, and extrapyramidal movement disorders. Parkinsonism as the presenting feature of subacute sclerosing panencephalitis is a rare occurrence. Here we report a child who presented with bradykinesia and rigidity, underwent extensive investigations, finally turned out to be subacute sclerosis panencephalitis.

Gut-Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders.

Human lifestyle and dietary behaviors contribute to disease onset and progression. Neurodegenerative diseases (NDDs), considered multifactorial disorders, have been associated with changes in the gut microbiome. NDDs display pathologies that alter brain functions with a tendency to worsen over time. NDDs are a worldwide health problem; in the US alone, 12 million Americans will suffer from NDDs by 2030. While etiology may vary, the gut microbiome serves as a key element underlying NDD development and prognosis. In particular, an inflammation-associated microbiome plagues NDDs. Conversely, sequestration of this inflammatory microbiome by a correction in the dysbiotic state of the gut may render therapeutic effects on NDDs. To this end, treatment with short-chain fatty acid-producing bacteria, the main metabolites responsible for maintaining gut homeostasis, ameliorates the inflammatory microbiome. This intimate pathological link between the gut and NDDs suggests that the gut-brain axis (GBA) acts as an underexplored area for developing therapies for NDDs. Traditionally, the classification of NDDs depends on their clinical presentation, mostly manifesting as extrapyramidal and pyramidal movement disorders, with neuropathological evaluation at autopsy as the gold standard for diagnosis. In this review, we highlight the evolving notion that GBA stands as an equally sensitive pathological marker of NDDs, particularly in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and chronic stroke. Additionally, GBA represents a potent therapeutic target for treating NDDs.

A Patient with Glucose Transporter Type 1 Deficiency Syndrome

Glucose transporter type 1 deficiency syndrome (GLUT-1 DS) is an inborn error of metabolism that results in defective glucose transport and consequently a reduced supply of glucose to the brain. Here, we describe a patient with a molecularly proven GLUT-1 mutation who presented with severe paroxysmal choreoathetosis. Different regional changes involving bilateral mesial temporal lobes were revealed using positron-emission tomography (PET). Several cases of GLUT-1 DS have been studied from the point of view of hyperkinetic movement disorders rather than epilepsy and ataxia. It is usual for these patients to first present with dystonia, choreoathetosis, parkinsonism, and paroxysmal exercise-induced dyskinesia, including dystonic, choreoathetotic, and ballistic movements. F18-fluorodeoxyglucose PET revealed hypometabolism in bilateral mesial temporal lobes along with the cerebellar cortex, confirming an impaired glucose metabolism effect on the area responsible for the extrapyramidal movement disorders.

Assessing Children with Poor Coordination Can Be Tricky - A Review on Ataxia and Ataxia Mimickers and a Study of Three Children with Severe Epilepsy.

While ataxia is a relatively common presenting feature in pediatric patients, it represents only one possible cause of uncoordinated movements. Other possible causes of uncoordinated movements include ingestion of toxic substances, musculoskeletal diseases, psychogenic disorders, extrapyramidal movement disorders, peripheral neuropathies, spasticity from any cause, and epilepsy. Therefore, primary health care providers must recognize and exclude other etiologies of uncoordinated movements before attaching the label “ataxia” to any patient presenting with poor coordination. Once the presence of ataxia is confirmed, the cause should be investigated. As ataxia may be vestibular, sensory, or cerebellar in origin, medical practitioners must evaluate the diverse symptoms and signs to effectively differentiate the various types of ataxia. Three case studies are presented to illustrate the complexity associated with the assessment of ataxia. Each case will discuss a pediatric patient who displays cerebellar ataxia as a concurrent feature of a gene-specific developmental and epileptic encephalopathy. These cases will provide an example of how ataxia may be differentiated from other causes of uncoordinated movements related to epilepsy and anti-seizure medications, namely: nonconvulsive seizures, postictal state, and medication side effects or toxicity. The assessment of poor balance can be challenging at times; however, with knowledge of the differential diagnosis of poor balance, medical practitioners will be able to confidently determine the presence of true ataxia from various ataxia mimickers, thereby allowing for timely and accurate diagnosis, and appropriate management.

Chorea precipitated by phototherapy as initial presentation of systemic lupus erythematosus

Dear Editor, Chorea is a well-recognised albeit rare neuropsychiatric manifestation of systemic lupus erythematosus (SLE). We describe here a case of a 67-year-old woman presenting with chorea, which affected her left lower limb and both upper limbs after phototherapy. Chorea is an extrapyramidal movement disorder characterised by non-repetitive, abrupt, involuntary jerky movements that may be

Analysing the reasons for rejection of neurosurgery intervention in patients with Parkinson’s disease referred to an extrapyramidal movement disorders clinic

We present findings of a 10-year retrospective study, analysing the reasons for rejection of neurosurgical intervention (deep brain stimulation or DBS) in patients with Parkinsons disease, who were referred to an extrapyramidal movement disorders clinic and then to a neurosurgery centre. It was found that after screening, 78.6% of patients referred as candidates for neurosurgical treatment to an extrapyramidal movement disorders clinic were rejected, while 21.4% of patients were referred to a neurosurgery centre, where 12% underwent surgery. The main reasons for rejecting potential DBS candidates were: early referral, inadequate pharmacotherapy, levodopa-resistant symptoms, atypical/secondary Parkinsonism, cognitive reasons, psychological reasons, comorbidity, abnormal MRI, poor response to levodopa medication and declined surgery. Furthermore, the number of self-referrals decreased, the number of patients referred by neurologists increased, the number of rejections of unsuitable DBS candidates decreased, and the number of suitable candidates referred to the extrapyramidal centre increased during the time period of 10 years. In addition, the number of patients who were referred to the neurosurgery centre and underwent surgery there increased, which suggests greater awareness of the selection criteria among doctors, as well increased knowledge and experience among neurologists in both primary healthcare and specialized centres.

The extrapyramidal syndromes of chronic kidney disease and dialysis (EPS-CKDD): diagnostic criteria, risk factors and prognosis.

Acute extrapyramidal movement disorders in dialysis patients are rare, inconsistently defined and have uncertain aetiology and prognosis. Define diagnostic criteria, prognosis and risk factors. Retrospective case series review of 20 patients (14 female, mean age 62 years) receiving dialysis for a median of 15 (interquartile range 4-35) months who presented with acute parkinsonism (AP = 11) or chorea/athetosis (CA = 9). All patients had type 2 diabetes (HbA1c 6.8 ± 1.0) and had received metformin. Lactic acidosis was present in 2 patients at presentation and serum lactate was elevated in 7/15 patients tested. No patient had abnormal copper or thyroid metabolism and 5/8 patients tested returned marginal abnormalities in heavy metal screening. Magnetic resonance imaging (MRI) revealed characteristic bilateral symmetric T2 hyperintensity of the basal ganglia (BG), predominantly putamen and globus pallidus (the lentiform nucleus) and more extensive involvement of the external and internal capsules in patients with AP presentation. Post-mortem demonstrated cytotoxic necrosis of the BG. Therapy included thiamine, intensive dialysis and cessation of metformin. Two patients died acutely, nine recovered and nine had residual symptoms. Median survival did not differ by presentation: AP 24 [95% confidence interval (CI) 21-27] and CA 33 (95% CI 32-35) months, P = 0.21. There are two distinct clinical extrapyramidal movement disorders associated with specific diagnostic MRI imaging that support the diagnosis of the extrapyramidal syndromes of chronic kidney disease and dialysis. The associations with diabetes, metformin and metabolic acidosis suggest a common pathogenic mechanism but require additional study. Early recognition and treatment may improve outcomes.

WDR45 Gene and Its Role in Pediatric Epilepsies

AbstractWD repeat domain 45 (WDR45) gene has been increasingly found in patients with developmental delay (DD) and epilepsy. Previously, WDR45 de novo mutations were reported in sporadic adult and pediatric patients presenting iron accumulation, while heterozygous mutations were associated with β-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation disorders, characterized by extrapyramidal movement disorders and abnormal accumulation of iron in the basal ganglia. Overall, people harboring WDR45 mutations have moderate to severe DD and different types of seizures. The phenotype of adult patients is characterized by extrapyramidal movement, dystonia, parkinsonism, language impairment, and involvement of the substantia nigra and in the globus pallidus at brain magnetic resonance imaging. Importantly, there are no findings of brain iron accumulation in brain in BPAN patients in the first decade of life, thus suggesting a progressive course of the disease. Comparatively, the main phenotype of pediatric patients is epilepsy with early onset, most of which present infantile spasms and arrest or regression of psychomotor development. The phenotype of patients with WDR45 mutations is variable, being different if caused by somatic mosaicism or germline mutations, and presenting with a different spectrum of manifestations in males and females. The treatment of affected individuals is symptomatic. Regarding the seizures, specific, gene-based approaches with specific antiepileptic drugs are not currently available. The early diagnosis of BPAN could be useful in some aspects, such as providing families a supportive treatment to their affected children.

Vishesha or Upa Grahonmadas: Various Psychiatric and Neuropsychiatric Conditions

Bhutavidya (Ayurvedic psychiatry) is one among the eight specialties of Ayurveda (an ancient Indian system of medicine). Bhutavidya deals with the diseases (psychiatric or neuropsychiatric) caused by “bhuta” or “graha” (idiopathic factors) and their management. Unmada (broad term which includes various psychiatric conditions) is a disease characterized by deranged mental functions. “Bhutonmada” (psychiatric conditions caused by idiopathic factors) is a type of unmada caused by affliction of “bhuta” or “graha.” Eighteen types of bhutonmada are explained in samhita's (ancient Ayurvedic texts). Previous works have explored these 18 grahonmadas and compared them with various psychiatric and neuropsychiatric conditions. Vishesha or Upa grahonmadas are the subtypes of these 18 grahonmadas, and their description is found only in “Ashtanga sangraha” (Ayurvedic textbook of medicine written by Vriddha Vagbhata). Description of 16 “Vishesha” or “Upa grahonmadas” is available in “Ashtanga sangraha.” Till date, no studies have been conducted on Vishesha grahonmadas, and the present study aims at exploring Vishesha grahonmadas with contemporary psychiatric conditions. Ayurvedic literature related to “Vishesha grahonmadas” has been collected from major classical Ayurvedic texts and from their commentaries. Electronic databases “Google” and “Google Scholar” have been searched to find out the relevant studies using appropriate keywords. Sixteen Vishesha grahonmadas explained in Ashtanga sangraha have shown resemblance with various psychiatric and neuropsychiatric conditions such as mood disorders, schizophrenia, frontotemporal dementia, Tourette's syndrome, extra pyramidal movement disorders, temporal lobe epilepsy, autism, personality disorders, Parkinson's disease, and attention-deficit/hyperactivity disorder. The contemporary perspective of ancient psychiatric concepts as demonstrated in the present article provides new insights and paves way further studies.

Fahr’s disease: familial idiopathic basal ganglia calcification with and without extrapyramidal disorders

Fahr’s disease (FD), also known as familial idiopathic basal ganglia calcification, is a neurodegenerative disease affecting cerebral micro vessels, mainly in the basal ganglia. It mostly presents with movement disorders, dementia and behavioral abnormalities. It is considered hereditary with an autosomal dominant transmission. Fahr’s disease is often underestimated and under diagnosed. We reported the clinical differences found in two patients with Fahr’s Disease. In particular, we described a case of Fahr’s disease with behavioral alteration with extrapyramidal movement disorders, and a rare case of Fahr’s disease with cognitive and behavioral alterations in absence of extrapyramidal movement disorders.

POLR3A variants with striatal involvement and extrapyramidal movement disorder

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant.