The Genetic Drivers of Juvenile, Young, and Early-Onset Parkinson's Disease in India.

BACKGROUND: Recent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome-wide association study (GWAS) identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused. OBJECTIVE: The aim was to identify genetic risk factors for PD in a South Asian population. METHODS: A total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early-onset PD) were recruited from 10 specialty movement disorder centers across India over a 2-year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case-only and case-control genetic analyses for PD diagnosis and AoO. RESULTS: A genome-wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease. CONCLUSIONS: This study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association of Catechol-O-Methyltransferase Gene Polymorphisms and Haplotypes in the Levodopa-Induced Adverse Events in Subjects with Parkinson's Disease.

The presence of dyskinesia is the most common side effect of chronic administration of levodopa in Parkinson's disease (PD) subjects. Genetic polymorphisms in levodopa metabolizing gene, catechol-O-methyl transferase (COMT), is shown to influence the inter-individual variability in drug response and adverse events. In the present study, the association of COMT rs6269, rs4633, rs4818, and rs4680 polymorphisms and haplotypes on pharmacokinetics and adverse events with levodopa was investigated in 150 PD patients. The age of onset of PD was 58.00 ± 10 yrs. The most common side effect faced by 78% of the subjects was dyskinesia. The AUC of levodopa was found to be significantly higher in subjects with dyskinesia (1695 ± 113 ng/ml/hr, p < 0.0001) than those without dyskinesia (1550 ± 122 ng/ml/hr). We found that the frequency of subjects presenting dyskinesia was significantly higher in subjects carrying variant genotype of COMT rs6269, rs4633, and rs4680 than that with wild genotype and these subjects presented higher AUC of levodopa. In addition, in subjects with dyskinesia, the AUC of levodopa was found to be significantly higher with low COMT (ACCG) haplotype. The association of COMT rs6269, COMT rs4633, COMT rs4818, and COMT rs4680 variant genotypes with the risk of dyskinesia due to levodopa therapy showed an ROC AUC of 0.67 indicating the moderate prediction of dyskinesia (p = 0.0021) with these COMT variants. In conclusion, PD subjects carrying the variant genotypes of COMT strongly influence high levodopa-induced dyskinesia. Hence the genotyping of COMT before the levodopa therapy will be useful to reduce the adverse events associated with the chronic levodopa treatment.

Patterns of peripheral neuropathy in Sjogren's syndrome in a tertiary care hospital from South India.

INTRODUCTION: Sjogren's syndrome (SS) is a systemic autoimmune disease that apart from involving the exocrine glands can affect any organ. Involvement of the peripheral nervous system results in a wide spectrum of neuropathic manifestations. OBJECTIVE: To evaluate the clinico-electrophysiological patterns as well as pathological characteristics of neuropathy in SS patients presenting to a neuromuscular clinic in a tertiary hospital from South India. MATERIALS AND METHODS: This is a retrospective study from the Departments of Neurology, Rheumatology, and Pathology from Nizam's Institute of Medical Sciences. Twenty-one patients with the diagnosis of SS and peripheral neuropathy, seen between 2010 and 2016 were analyzed. Clinical records, conventional nerve conduction studies, and lip and nerve biopsy reports were collected. RESULTS: Twenty one patients with SS had associated neuropathy. Female-to-male ratio was 2:1. In 14 (66.7%) patients, neuropathy was the initial manifestation, while in 4 (20%), exocrinopathy preceded neuropathy. The patterns of neuropathy included mononeuropathy multiplex (MNM) in 7 patients (30%), ganglionopathy in 4 (20%), length-dependant trigeminal autonomic neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in 2 (10%), and cranial neuropathy in 1 (10%). Eighteen (86%) were seropositive with either anti Ro/SS-A or anti La/SS-B antibodies. Schirmer's test was positive in 13 (61.9%) patients. Nerve biopsy showed vasculitis in 5 patients and demyelinating and axonopathy in 2 patients each. CONCLUSIONS: We conclude that neuropathy is frequently the initial presentation of SS. MNM is the most common pattern followed by ganglionopathy. The pattern of neuropathy helps in arriving at the diagnosis of SS. Serology is a useful initial laboratory test. However,confirmation of SS is not by mere serology. Schirmer's test and lip biopsy are equally essential for the diagnosis, especially in seronegative patients when the clinical index of suspicion is high.

Prevalence of neuropathy in patients with impaired glucose tolerance using various electrophysiological tests.

BACKGROUND: Neuropathy is often an associated feature woth long-standing type II diabetes mellitus. Neuropathy may occur even in subjects with impaired glucose tolerance. OBJECTIVE: To study the prevalence of neuropathy using different electrophysiological techniques in subjects with impaired glucose tolerance (IGT) and no other identifiable cause of neuropathy. MATERIALS AND METHODS: The study was conducted on 30 age-matched controls and 58 subjects with impaired oral glucose tolerance test (OGTT) attending diabetic awareness. Prediabetes was defined using World Health Organization (WHO) criteria. All subjects had normal glycosylated hemoglobin HbA (1c), vitamin B12 levels, and thyroid function. Neuropathy was evaluated by nerve conduction studies (NCS) performed on one upper and both lower limbs, dorsal sural nerve, medial and lateral planter nerve conductions using conventional techniques. Neuropathy was also evaluated by autononic function tests, and quantitative sensory testing (QST). The subjects were followed up for 4 years. RESULTS: Out of 58 subjects, 19 (32.8%) had neuropathy. Nerve conduction studies showed evidence of neuropathy in 14 (24.13%) subjects, autonomic neuropathy was detected in 8 (13.8%), and QST was found to be abnormal in 16 (27.6%) subjects. Twenty subjects (34.5%) developed diabetes mellitus in the follow-up period. CONCLUSIONS: Neuropathy was detected in 32.8% subjects with IGT. Small fiber neuropathy was most common. Of all the three parameters studied, QST was found to be most sensitive technique for the detection of neuropathy. Assessment of medial plantar and dorsal sural NCS increases the sensitivity in the detection of neuropathy.

Levodopa Equivalent Daily Dosage: Geographical Variations and Real-Life Modules in Parkinson's Disease.

BACKGROUND: The Levodopa Equivalent Daily Dosage (LEDD) calculation algorithms help in capturing and harmonization of Parkinson's Disease (PD) therapies. Analyzing these updates is essential for validating their effectiveness. OBJECTIVE: To assess updated LEDD conversion factors in capturing the newer therapies in PD and therapy modules in different geographical cohorts. METHODS: Data were sourced from 10 Centers from 6 countries representing 2 different continents. The study compared the LEDD conversion factors proposed by Tomlinson et al and Jost et al, alongside investigating demographic disparities. RESULTS: The analysis involved 2943 subjects; 87% (n = 2577) met the UK Brain Bank criteria for PD. The LEDD differed significantly across methodologies (Tomlinson vs. Jost, 598 mg vs 610 mg, P < 0.0001). Geographical disparities highlighted variations in PD onset age (P < 0.0001). Jost and Tomlinson's calculations demonstrated consistency within but significant differences across countries (P < 0.0001).Age at onset revealed statistically significant differences in LEDD requirements (P < 0.0001), which were particularly higher in 21-50 years (718 mg vs 566 mg). This subgroup also demonstrated increased usage of non-Levodopa therapies (P < 0.0001). Men exhibited higher total LEDD (P = 0.001). 34% reported dyskinesia, associated with higher LEDD (756 mg, P < 0.0001). Surgically treated patients also had higher LEDD (P < 0.0001) and a significant difference between Jost and Tomlinson dosages (761 mg vs716mg) reflecting the incorporation of newer therapeutic molecules. CONCLUSION: This analysis delineates the importance of updated LEDD algorithms and intricacies in the landscape of PD treatment, underscored by geographical, age-related, and gender-specific variations, in real-life management scenarios.

Dystonia Deafness Syndrome: A Rare Deep Brain Stimulation Responsive Dystonia.

Dystonia deafness syndrome (DDS) is a rare syndrome characterized by childhood onset sensorineural deafness followed by adult-onset dystonia. We here report the first case of DDS from India caused by ACTB gene mutation presented with deafness, generalized dystonia and scoliosis who showed improvement after Deep brain stimulation.

Effect of Medication and Deep Brain Stimulation on Gait in Parkinson's Disease and its Quantitative Analysis Using Mobishoe - A Comparative Study.

Background: Movement abnormalities pertaining to balance, posture, and gait are observed in Parkinson's disease patients. Gait characteristics vary widely and their analysis has been performed traditionally in gait labs. Freezing and festination usually occur at an advanced stage of the disease and are associated with reduced quality of life. Therapeutic strategies and surgical interventions are often modulated by the physician depending upon the clinical manifestations. Introduction of accelerometers and wireless data transmission systems made quantitative gait analysis possible and cost-effective. Objective: To assess spatiotemporal gait parameters (step height, length (spatial), and swing support time of each foot and double support time (temporal)) in subjects who underwent deep brain stimulation surgery using a purpose-built instrument-Mobishoe. Methods: A simple footwear-based gait sensing device-Mobishoe was built in-house. Thirty-six participants were included in the study after obtaining consent. Participants were made to wear Mobishoe and walk an empty corridor of 30m before Deep Brain Stimulation (DBS) in the drug on and off stated and post DBS in DBS stimulation on and medication off state (B1M0), DBS stimulation off-medication off state (B0M0), DBS stimulation off-medication on (B0M1), and DBS stimulation on and on medication (B1M1). Data was electronically captured and analyzed offline in MATrix LABoratory (MATLAB). Various gait parameters were extracted and analyzed. Results: Improvement in gait parameters was observed when the subject was on medication, on stimulation, or on both when compared to baseline. Improvement was similar with both medication and stimulation and was synergistic when both were used. Significant improvement was noted in spatial characteristics when the subjects were on both the treatments, which is the ideal treatment modality. Conclusion: Mobishoe is an affordable device which can measure spatiotemporal characteristics of gait. The best improvement was seen when the subjects were on both the treatment groups and the improvement can be justified as a synergistic effect of stimulation and medication.

Chaudhuri's Dashboard of Vitals in Parkinson's syndrome: an unmet need underpinned by real life clinical tests.

We have recently published the notion of the "vitals" of Parkinson's, a conglomeration of signs and symptoms, largely nonmotor, that must not be missed and yet often not considered in neurological consultations, with considerable societal and personal detrimental consequences. This "dashboard," termed the Chaudhuri's vitals of Parkinson's, are summarized as 5 key vital symptoms or signs and comprise of (a) motor, (b) nonmotor, (c) visual, gut, and oral health, (d) bone health and falls, and finally (e) comorbidities, comedication, and dopamine agonist side effects, such as impulse control disorders. Additionally, not addressing the vitals also may reflect inadequate management strategies, leading to worsening quality of life and diminished wellness, a new concept for people with Parkinson's. In this paper, we discuss possible, simple to use, and clinically relevant tests that can be used to monitor the status of these vitals, so that these can be incorporated into clinical practice. We also use the term Parkinson's syndrome to describe Parkinson's disease, as the term "disease" is now abandoned in many countries, such as the U.K., reflecting the heterogeneity of Parkinson's, which is now considered by many as a syndrome.

18F-FDG PET/CT Findings in a Rare Case of Paraneoplastic Vestibulocerebellar Syndrome Associated With Isolated Antiamphiphysin Antibodies.

ABSTRACT: Paraneoplastic cerebellar degeneration (PCD) is an immune-mediated neurological disease characterized by adaptive immune response against onconeural antigens physiologically expressed in the cerebellum. It is characterized by presence of highly specific onconeural autoantibodies such as anti-Yo, anti-Hu, anti-Ri, and anti-Ma2 in the serum and cerebrospinal fluid as diagnostic biomarkers. Antiamphiphysin autoantibody-related paraneoplastic encephalitis is a less commonly seen autoimmune neurological disorder usually presenting as stiff person syndrome. We present an unusual case of isolated antiamphiphysin antibody-related PCD presenting as vestibulocerebellar syndrome with associated sensorineural hearing loss and sensory neuropathy. FDG PET helped in topographical localization of brain lesion along with early detection of extragonadal germ cell tumor in the retroperitoneum.

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 1: Genetic Disorders.

We selected several "imaging pearls" presented during the Movement Disorder Society (MDS) Video Challenge for this review. While the event, as implicated by its name, was video-centered, we would like to emphasize the important role of imaging in making the correct diagnosis. We divided this anthology into two parts: genetic and acquired disorders. Genetic cases described herein were organized by the inheritance pattern and the focus was put on the imaging findings and differential diagnoses. Despite the overlapping phenotypes, certain described disorders have pathognomonic MRI brain findings that would provide either the "spot" diagnosis or result in further investigations leading to the diagnosis. Despite this, the diagnosis is often challenging with a broad differential diagnosis, and hallmark findings may be present for only a limited time.

Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India.

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD-relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment.

Dementia with Lewy bodies research consortia: A global perspective from the ISTAART Lewy Body Dementias Professional Interest Area working group.

Dementia with Lewy bodies (DLB) research has seen a significant growth in international collaboration over the last three decades. However, researchers face a challenge in identifying large and diverse samples capable of powering longitudinal studies and clinical trials. The DLB research community has begun to focus efforts on supporting the development and harmonization of consortia, while also continuing to forge networks within which data and findings can be shared. This article describes the current state of DLB research collaborations on each continent. We discuss several established DLB cohorts, many of whom have adopted a common framework, and identify emerging collaborative initiatives that hold the potential to expand DLB networks and diversify research cohorts. Our findings identify geographical areas into which the global DLB networks should seek to expand, and we propose strategies, such as the creation of data-sharing platforms and the harmonization of protocols, which may further potentiate international collaboration.

Impact of home confinement during COVID-19 pandemic on sleep parameters in Parkinson's disease.

BACKGROUND: Literature shows that home confinement during coronavirus disease 2019 (COVID-19) pandemic has significantly affected sleep. However, such information regarding subjects having Parkinson's disease (PD) is unavailable. METHODS: This cross-sectional study was conducted using a questionnaire, developed and validated by experts. PD subjects from nine centers across India were included. Questionnaire assessed presence as well as change in sleep-related parameters and PD symptoms during home confinement. Restless legs syndrome (RLS) and REM sleep behavior disorder (REMBD) was diagnosed using validated questionnaire. Additionally, changes in physical activity, adoption of new hobbies during home confinement and perceived quality of life were assessed. RESULTS: Of 832 subjects, 35.4% reported sleep disturbances. New-onset/worsening of sleep disturbances (NOWS) was reported by 23.9% subjects. Among those with sleep disturbances (n = 295), insomnia symptoms worsened in half (51.5%) and nearly one-fourth reported worsening of RLS (24.7%) and REMBD (22.7%) each. NOWS was common in subjects lacking adequate family support during home confinement (P = 0.03); home confinement > 60 days (P = 0.05) and duration of PD > 7 years (P = 0.008). Contrarily, physical activity >1 h/day and engagement in new hobbies during home confinement were associated with better sleep. NOWS was associated with worsening of motor as well as non-motor symptoms of PD (P < 0.001) and poorer life quality (P < 0.001). CONCLUSION: Home confinement during COVID-19 pandemic was significantly associated with NOWS among PD subjects. NOWS was associated with global worsening of PD symptoms and poorer life quality. Physical activity >1 h/day and adoption of new hobbies during home confinement were associated with better sleep.

Functional Outcome of Bilateral Subthalamic Nucleus-Deep Brain Stimulation in Advanced Parkinson's Disease Patients: A Prospective Study.

BACKGROUND: Deep brain stimulation (DBS) is an accepted modality of treatment in patients with Parkinson's disease (PD). Although DBS was approved in advanced PD, it is being done in early PD as well. It was mainly developed to help the patients of PD to overcome the adverse motor effects associated with treatment and treatment failure. OBJECTIVE: The objective is to study the efficacy of subthalamic nucleus (STN)-DBS procedure in patients with PD. MATERIALS AND METHODS: This was a prospective, single-center, follow-up observational study using a direct, structured interview of 40 selected PD patients. Preoperative assessment using Unified PD Rating Scale-III (UPDRS-III), Montreal Cognitive Assessment (MOCA), and Parkinson's Disease Questionnaire-39 were done. All the patients underwent DBS. Postoperatively, similar assessment was done during follow-up period of 6 months. The results were analyzed using Student's t-test. RESULTS: The total score of UPDRS-III was reduced by 35% after STN-DBS intervention which was statistically significant (P < 0.05). STN-DBS intervention was successful in significantly reducing all UPDRS-III subscores but failed to reduce the scores in case of postural stability. MOCA scores of the patients were not found to be affected by STN-DBS intervention (P = 0.1466). Similar findings were also observed for MOCA subscores, but there was significant improvement of verbal fluency in all patients. Quality of life(QoL) improved significantly in all patients after STN-DBS intervention in all areas. Lower baseline UPDRS-III scores were found to enhance the QoL both in "off" and "on" state. However, prolonged disease duration and older age at PD onset were found to be hampering factors in the improvement of QoL. CONCLUSIONS: STN-DBS is a safe procedure and can be performed in all patients of PD who develop disabling motor fluctuations to improve their QoL irrespective early or advanced disease.

Genetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research.

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.

Validation of the 2015 diagnostic criteria for neuromyelitis optica spectrum disorders in a cohort of South Indian patients.

BACKGROUND: Neuromyelitis Optica spectrum disorders (NMOSD) are one of the most common CNS demyelinating disorders as they will present with disabling recurrent demyelinating attacks. Hence, it is of paramount importance to diagnose early, and early diagnoses and intervention will prevent further relapses associated with NMOSD. New international consensus criteria have been proposed and studies validating its application towards diagnoses of NMOSD in south Asian population are meagre. Hence we validated the proposed International Panel for NMO Diagnosis (IPND), 2015 criteria to study the clinical, demographic profile and sero-status of patients who are presenting with core clinical symptoms of NMOSD in South India and compare it with 2006 criteria. METHODS: A retrospective study was conducted in a tertiary hospital for a period of one year. Patients who had at least one core clinical feature of NMOSD were included. Demographics and clinical data were recorded and analysed. Cases were evaluated using 2015 IPND and 2006 criteria for all patients, data was analysed using SPSS. RESULTS: A total of 110 patients were included and 91(82.72%) patients fulfilled IPND 2015 criteria. Out of 91 patients, 70 patients were AQP4 antibody positive and 21 were negative. Out of 110, only 30 (27.2%) satisfied 2006 criteria (24 or 80% were seropositive). 2015 criteria were more sensitive in identifying 61 new NMOSD cases juxtaposed to 2006 criteria, this difference was statistically significant (P<0.05). CONCLUSION: The 2015 IPND criteria were more sensitive and specific than previous 2006 criteria as it covered diverse clinical manifestations of NMOSD. Applying this criteria, NMOSD could be diagnosed among patients with monophasic illness, isolated recurrent optic neuritis, isolated recurrent myelitis, cerebral syndrome, diencephalic syndrome, brainstem syndrome and area postrema syndrome, thus improving the diagnostic yield.

Predictors of Intracerebral Hemorrhage in Acute Stroke Patients Receiving Intravenous Recombinant Tissue Plasminogen Activator.

BACKGROUND: Symptomatic Intracerebral hemorrhage (sICH) is a serious complication of recombinant tissue-plasminogen activator (rt-PA) therapy for acute ischemic stroke (AIS). OBJECTIVE: To estimate the prevalence and predictors of sICH in patients after receiving IV rt-PA for AIS. MATERIAL AND METHODS: Consecutive patients of AIS thrombolysed between January 2010 and June 2016 in a University hospital in Hyderabad (India) were studied prospectively for sICH and it's various variables compared with the control group without sICH to determine any sigificantant difference. RESULTS: Out of 113 patients , sICH was detected in 12 (10.61%) whose mean age(58±12.0 years) and gender ratio ( 2:1 ) was not statistically significant from controls. In s ICH group mean NIHSS score was 16.53± 5.81 vs 10.19± 5.06 in controls (p<0.001), gap between stroke onset and thrombolysis was 227.50±46.15 min vs 178.50± 69.20 min in controls(p=0.018). At presentation mean blood sugar was 208.75±90.97 mg/dl in sICH group vs 146.83±70.21 mg/dl in controls (p=0.002). Prior diabetes was in 7(53.30%) vs 23 (22.8%) in controls (p= 0.014)and hypertension in 11 (91.7%) vs (56(55.4%) in controls (p= 0.026) The mortality in sICH was 7 (58.30%)vs 4 (4.94%) in controls (p<.0.001). At 3 months mean mRS ofsICH patients was 5.57± 0.54 vs 2.17± 1.69 in controls (p<.05). CONCLUSION: High NIHSS score, increased stroke onset to thrombolysis time , high blood sugar at presentation ,prior diabetes and hypertension increase the chances of sICH. None of these contraindicate thrombolysing strokes but should caution the physician.