Stunting and wasting in neurological Wilson disease: Role of copper, zinc, and insulin-like growth factor-I.

OBJECTIVES: Copper (Cu) and zinc (Zn) are important trace elements for the growth and development of children. In Wilson disease (WD), impaired Cu metabolism may affect growth. This study was conducted to evaluate the height and weight of children with neurological WD and correlate these with serum Cu, Zn, and insulin-like growth factor-I (IGF-I). METHODS: This prospective cohort study was conducted in a tertiary care teaching institute. Children with neurologic WD were included. The height, weight, and body-mass index of each child were measured and categorized according to the revised national growth chart. Serum Cu, Zn, calcium, alkaline phosphatase, albumin, thyroid-stimulating hormone, and urinary-Cu were measured. Serum IGF-1 was measured by enzyme-linked immunosorbent assay. The relationship between height and weight with trace elements and IGF was analyzed using parametric or non-parametric tests. RESULTS: There were 52 children (5-18 years) with neurologic WD. Thirty-six (69.2%) children had normal height, 12 (23.1%) were tall, and 4 (7.7%) were stunted. Forty-six (88.5%) children had normal weight and six (11.5%) children were underweight. IGF-1 correlated with height, weight, duration of treatment, and serum Zn level. About 15.4% of children had stunting and/or wasting, which was associated with low levels of serum IGF-I, Zn, and calcium. CONCLUSIONS: Stunting and/or wasting occurs in 15.4% of children with neurologic WD and is associated with reduced serum IGF-I, Zn, and calcium concentration. Adjunctive Zn and calcium treatment may help in achieving normal growth.

NMR based CSF metabolomics in tuberculous meningitis: correlation with clinical and MRI findings.

We report the potential role of 1H Nuclear Magnetic Resonance (NMR) based metabolomics in tuberculous meningitis (TBM). We also correlate the significant metabolites with clinical-radiological parameters. Forty-three patients with TBM were included, and their severity of meningitis was graded as stages I to III, and patients with positive Mycobacterium tuberculosis or its nucleic acid was considered as definite TBM. 1H NMR-based metabolomic study was performed on (CSF) samples, and the significant metabolites compared to healthy controls were identified. Outcome at three months was defined as death, poor and good based on the modified Rankin Scale. These metabolites were compared between definite and probable groups of TBM, and also correlated with MRI findings. About 11 metabolites were found to be significant for distinguishing TBM from the controls. In TBM, lactate, glutamate, alanine, arginine, 2-hydroxyisobutyrate, formate, and cis-aconitate were upregulated, and glucose, fructose, glutamine, and myo-inositol were downregulated compared to the controls. For differentiating TBM from the controls, the AUC of the ROC curve generated using these significant metabolites was 0.99, with a 95% confidence interval from 0.96 to 1, demonstrating that these metabolites were able to classify cases with good sensitivity and specificity. Lactate concentration in CSF correlated with hemoglobin, CSF glucose, and infarction. The outcome did not correlate with metabolomics parameters. NMR-based CSF metabolomics have a potential role in differentiating TBM from the controls.

Recurrent Spontaneous Cerebrospinal Fluid Leaks at Multiple Levels.

Intracranial hypotension due to multiple spinal epidural cerebrospinal fluid (CSF) leak is rare and has multiple etiologies. These patients require epidural blood patches (EBP). We report a patient with recurrent paraplegia due to intracranial hypotension following recurrent epidural CSF leak. Cerebrospinal fluid leak was noted at D1, D10, D11, and L2 levels. Autologous epidural blood patch (EBP) at lower thoracic (3 ml) and lumbar region (4 ml) was performed. The patient developed paraplegia with sensory level at D2 for which 3 ml of EBP was done at D1 level after two months. Following EBP, the patient developed quadriplegia and root pain, which recovered in one month. The patient was free of symptoms for 18 months. Spinal epidural CSF leak should be suspected in patients with features of low pressure headache and recurrent paraplegia at multiple levels. Nuclear scintigraphy and CT myelography help in localizing the site of leak.

Standard versus sequential anti-tubercular treatment in patients with tuberculous meningitis: a randomized controlled trial.

BACKGROUND: To compare the safety and efficacy of sequential anti-tubercular treatment (ATT) regimen with the standard regimen in tuberculous meningitis (TBM). METHODS: This single-centre, open-label, parallel group randomized controlled trial was conducted from May 2017 to June 2019 in India. Treatment-naïve patients with TBM fulfilling the inclusion criteria were randomized to four drug ATT regimens (rifampicin, isoniazid, ethambutol and pyrazinamide) administered either simultaneously (standard arm) or one after another (sequential arm) in a 1 : 1 ratio. The primary endpoint was drug-induced hepatitis (DIH) and the secondary endpoints were in-hospital death and disability at 3 and 6 months using a modified Rankin Scale. RESULTS: A total of 97 patients with TBM were recruited; 15 did not meet the inclusion criteria and 2 refused to participate. The median age of the patients was 26 y (range 15-75) and 37 (46.2%) were males. The patients in the sequential arm had fewer cases of DIH (20% vs 42.5%; p=0.03). The patients in the sequential arm had lower in-hospital mortality (2.5% vs 17.5%; p=0.025) and better 6-month outcomes (25.0% vs 50.0%; p=0.02) compared with the standard arm. CONCLUSIONS: Sequential ATT was associated with a lower frequency of DIH, lower in-hospital mortality and better 6-month outcome. TRIAL REGISTRATION: Clinical Trials Registry of India (ctri.nic.in) identifier: REF/2016/09/012214/CTRI/2017/10/010072.

MRI findings in Pott's spine and correlating clinical progress with radiological findings.

PURPOSE: To document magnetic resonance imaging (MRI) changes in Pott's spine and to correlate these with clinical findings and outcome. METHODS: Patients with Pott's spine having more than one set of MRI were included in the study. Patients were grouped according to timing of their second MRI. The MRI findings included changes in bone, disc, spinal cord, and soft tissue. The MRI changes were categorized into improvement, no change, or worsening. "Paradoxical worsening" was defined as radiological worsening in setting of clinical improvement, as described by improvement of Nurick's grade. Outcome was defined by mRS scale at three, six, and 12 months. The MRI findings and outcome were correlated. RESULTS: The results are based on 36 patients. The MRI changes included vertebral changes in form of spondylodiscitis in 33 (92%), epidural abscess in 29 (81%), spinal cord changes including edema and granuloma in 17 (47%), paravertebral abscess in 29 (81%), and vertebral body collapse in 12 (33.3%) patients. At three months, clinical improvement occurred in eight out of 12 patients, deterioration in two, and no change in two. Spinal MRI revealed improvement in one patient only; whereas eight had deterioration and three had no change. At six months, all nine patients improved clinically, but MRI showed improvement in only four, while another four showed deterioration and one had no change. In the nine and 12 months group, while all patients clinically improved, MRI showed minimal worsening. CONCLUSION: In Pott's spine, the clinical improvement precedes the radiological improvement.

Astrocyte activation following nitrous oxide exposure is related to oxidative stress and glutamate excitotoxicity.

BACKGROUND AND AIMS: Nitrous oxide is commonly used as an anesthetic agent and its exposure produces prolonged inactivation of vitamin B12. Nitrous oxide toxicity is associated with central nervous system changes which are similar to sub-acute combined degeneration (SACD). Astrocytes have important role in neurotoxic injuries, but have not been evaluated in N2O toxicity. In the present study, we have evaluated the changes in astrocytes in N2O exposed rats and correlated with neurobehavioral changes, oxidative stress and glutamate level. MATERIAL AND METHODS: Adult wistar male rats were exposed to N2O oxygen mixture in 1:1 ratio at a rate of 2 L/min for 120 min for 60 days. Control rats underwent similar exposure to oxygen. At the end of exposure, spontaneous locomotor activities (total distance travelled, time resting, time moving, number of rearing, stereotypic count) and grip strength were evaluated. Plasma glutathione (GSH), total antioxidant capacity (TAC), serum malonodialdehyde (MDA) and serum homocysteine (Hcy) were measured by spectrophotometer. Glutamate in the cerebral cortex and cerebellum were measured by colorimetry. Immunohistochemistry for astrocyte (GFAP) phenotypic analysis and its activation in brain and spinal cord were measured using image J software in N2O exposed and control rats. RESULTS: The N2O exposed rats had significant reduction in total distance travelled, time moving and number of rearing whereas time resting increased compared to the control rats. Hcy, glutamate and MDA levels were significantly increased, however GSH and TAC level decreased in N2O exposed group compared to the controls. Astrocyte phenotype and its activation was significantly altered more so in spinal cord compared to cerebral cortex and was associated with neurobehavioral changes, oxidative stress and glutamate level. CONCLUSIONS: N2O related clinical dysfunction may be related to changes in astrocyte activation which is related to oxidative stress and glutamate neurotoxicity.

A study of hyperhomocysteinemia in cerebral venous sinus thrombosis.

BACKGROUND & OBJECTIVES: Vegetarianism may result in low vitamin B12 and acquired hyperhomocysteinemia leading to thrombotic conditions such as cerebral venous sinus thrombosis (CVST). The clinico-radiological presentation and outcome of patients with hyperhomocysteinemia may be different from those without, but there is a paucity of information. This study was undertaken to find out the relationship of homocysteine (Hcy) with vitamin B12, folic acid and methyltetrahydrofolate reductase (MTHFR) mutation in the patients with CVST, and compare clinico-radiological severity and outcome of patients with and without hyperhomocysteinemia. METHODS: Ninety-six CVST patients in whom Hcy level was measured, were included, and their risk factors and neurological, magnetic resonance (MR) imaging and MR venography findings were noted. They were evaluated for prothrombotic conditions including Hcy, vitamin B12, folic acid and MTHFR 677C→T mutation. Three month outcome was categorized as death, poor and good. RESULTS: Seventy three per cent patients had risk factors; hyperhomocysteinemia in 52.1 per cent, protein S deficiency in 47.8 per cent, protein C deficiency in 19.4 per cent, MTHFR 677C→T mutation in 30.7 per cent, antinuclear antibody 11 per cent, and Factor V Leiden mutation in two per cent each. Thirty two per cent patients with hyperhomocysteinemia had no other thrombotic cause, and 22 per cent of them had either vitamin B12 and or folic acid deficiency only. The patients with hyperhomocysteinemia more frequently had vitamin B12 deficiency (70 vs. 13%), MTHFR 677C→T mutation (47.5 vs. 9.1%) and superior sagittal sinus thrombosis (78 vs. 56.5%) than normal Hcy group. The clinico-radiological severity and outcome were similar. INTERPRETATION & CONCLUSIONS: Hyperhomocysteinemia was an important correctable risk factor of CVST in patients from northern India, and majority of them had either low vitamin B12 level or MTHFR mutation.

A Study of Hyponatremia in Acute Encephalitis Syndrome: A Prospective Study From a Tertiary Care Center in India.

PURPOSE:: To evaluate the frequency and causes of hyponatremia in acute encephalitis syndrome (AES) and its effect on outcome. PATIENTS AND METHODS:: Consecutive patients with AES were subjected to neurological evaluation including Glasgow Coma Scale, focal weakness, movement disorder, and reflex changes. The etiology of AES was based on blood and cerebrospinal fluid enzyme-linked immunosorbent assay and polymerase chain reaction. We have categorized patients into neurological or systemic AES. Hyponatremia was diagnosed if 2 consecutive serum sodium levels were below 135 mEq/L, 24 hours apart. Serum and urinary osmolality and electrolytes were measured on alternate days. Fluid intake, output, and body weight were measured daily. The hyponatremia was categorized into syndrome of inappropriate secretion of antidiuretic hormone (SIADH), cerebral salt wasting (CSW), or miscellaneous group. Outcome at 1 month was assessed by modified Rankin scale. RESULTS:: Of 79 patients, 34 had neurologic AES and 45 had systemic AES; 22 (27.8%) patients had hyponatremia. The neurologic AES as compared to systemic AES was more commonly associated with hyponatremia (38.2% vs 20%, P = .07), need longer hospitalization (25.0 vs 12.5 days, P = .003), and longer time for sodium correction (13.3 vs 8.2 days, P = .05). The hyponatremia was due to CSW in 12 patients, SIADH in 2 patients, and indeterminate in 8 patients. Thirty-six patients had poor outcome (15 died) and 43 had good outcome which was not related to hyponatremia. CONCLUSION:: Hyponatremia occurs in one-third of patients with AES, being commoner in neurologic AES, and CSW is the commonest cause.

Does adjunctive corticosteroid and aspirin therapy improve the outcome of tuberculous meningitis?

BACKGROUND: Stroke is common in tuberculous meningitis (TBM), and aspirin has been shown to reduce mortality. A combination of aspirin and corticosteroid may be more useful in this condition. AIM: To evaluate the effect of aspirin and corticosteroid adjunctive therapy alone or in combination in determining the outcome of TBM. MATERIALS AND METHODS: One hundred and fifty-three patients with TBM were evaluated from a prospectively maintained registry. The diagnosis of TBM was based on the clinical, magnetic resonance imaging (MRI)/computed tomography (CT), and cerebrospinal fluid criteria. The baseline clinical, laboratory, and radiological findings were noted. All patients received the standard 4-drug antituberculous (rifampicin, isoniazid, pyrazinamide, and ethambutol) treatment. Group I patients received in addition, aspirin, in the dose of 150 mg daily; group II patients received aspirin 150 mg plus prednisolone 40 mg daily; and, group III patients received none of these adjunctive therapies. The outcome at 3 months was defined in terms of death or functional disability. RESULTS: Group I had 44, group II had 50, and group III had 41 patients. The baseline characteristics of all these patients were similar, except in group II, where patients had more severe meningitis and focal deficits compared to the patients in group I and III. At 3 months, 32 (23%) patients died; 8 (18.2%) in group I, 9 (18%) in group II, and 14 (34.1%) in group III. There was insignificant survival benefit in group II (hazard ratio [HR], 1.55; 95% confidence interval (CI), 0.96-26.49; P = 0.07). The three-month functional outcome and side effects were not significantly different in the three groups. CONCLUSION: Aspirin with corticosteroid adjunctive treatment seems to be beneficial in reducing mortality in TBM.

Evaluation of optic nerve functions in subacute combined degeneration using visual evoked potential and diffusion tensor imaging-a pilot study.

OBJECTIVE:: To evaluate optic nerve involvement in subacute combined degeneration (SACD) using diffusion tensor imaging (DTI) and visual evoked potential (VEP) studies, and their changes following cobalamine treatment. METHODS:: Six patients with SACD and six healthy matched controls were included. Visual acuity, field of vision, and color vision were tested. Pattern shift VEP was done, and P100 latency and amplitude were measured. Optic nerve MRI, and DTI of optic nerve to muscle ratio were measured, and fractional anisotropy ratio (FAR), axial diffusivity ratio (ADR), radial diffusivity ratio (RDR), and mean diffusivity ratio (MDR) were calculated. The patients received hydroxyl cobalamine 1000 µg intramuscularly and their clinical examination, VEP and DTI studies were repeated at 3 months. RESULTS:: The age of the patients ranged between 16 and 60 years and two were females. Their visual acuity, field of vision, and color vision were normal. P100 latency was prolonged in five patients (10 eyes) and amplitude was reduced in one (1 eye). The SACD patients had reduced FAR (1.94 ± 0.55 vs 2.81 ± 0.42; p = 0.01) and increased MDR (1.00 ± 0.04 vs 0.95 ± 0.01; p = 0.01) and RDR (0.96 ± 0.03 vs 0.89 ± 0.01; p = 0.002) compared to the controls. The FAR value correlated with P100 latency (r = -0.88). At 3 months, FAR value increased which was associated with improvement in P100 latency. CONCLUSION:: In SACD patients, optic nerve FAR is reduced and correlates with P100 latency. Both these parameters improve on cobalamine treatment. ADVANCES IN KNOWLEDGE:: Subclinical VEP abnormalities are common in SACD but conventional MRI sequence of optic nerve is normal. DTI of optic nerve reveals reduced fractional anisotropy (FA) values which improve after cobalamine treatment. FA values correlate with prolongation of P100 latency. DTI and VEP abnormalities suggest subclinical optic nerve myelin dysfunction.

Does Metabolic Syndrome Determine Severity and Disability of Chronic Low Backache?

INTRODUCTION: Obesity may be associated with more severe and disabling low backache (LBA) due to alteration in biomechanics, but there are no such studies from developing countries. AIMS: We report the frequency of metabolic syndrome (MS) in chronic LBA (CLBA) and its association with severity and disability of CLBA. SUBJECTS AND METHODS: Consecutive patients with CLBA attending to the neurology service from October 2015 to February 2016 were included in the study. Clinical and demographic parameters were recorded. Routine biochemical test was done. The severity of pain was assessed by a 0-10 Numeric Rating Scale (NRS) and disability by Oswestry Disability Index (ODI) version 2. Comparison of variables was done by Chi-square or independent t-test and correlation by Karl Pearson or Spearman's rank correlation test. RESULTS: Seventy-none (39.3%) patients had MS as per the International Diabetic Federation (IDF) criteria and 68 (33.8%) as per the National Cholesterol Education Program Adult Treatment Panel III criteria. Abdominal obesity was the most common (171 [85.1%]) feature of MS. The patients with MS had longer duration of sitting work and did less frequently exercise. The NRS score (6.95 ± 1.06 vs. 6.65 ± 0.95; P = 0.04) and ODI score (54.91 ± 8.42 vs. 51.89 ± 8.54; P = 0.01) were higher in CLBA patients with MS compared to those without MS. CONCLUSION: About 40% patients with CLBA have metabolic syndrome, and they have more severe pain and disability.

The Role of Clinical Variables and VKORC1 Polymorphism in Efficacy and Stability of Acenocoumarol in Neurological Patients.

OBJECTIVE: To analyze the clinical importance of VKORC1 polymorphism and its correlation with stability of oral anticoagulation. PATIENTS AND METHODS: In a hospital-based study, the patients on oral anticoagulant (OAC) were included during 2013-2016. The patients received OAC for cardioembolic stroke, cerebral venous sinus thrombosis (CVST), and prevention of deep vein thrombosis (DVT). Demographic, clinical, and neurological findings were recorded. Stability of anticoagulation was determined by percentage of time international normalized ratio (INR) values were in therapeutic range. Time in therapeutic range (TTR) >65% was defined as stable and <65% was defined unstable. VKORC 1 polymorphism was studied by polymerase chain reaction and correlated with daily dose of OAC and stability of INR. RESULTS: A total of 157 patients with a median age of 40 years were included in the study. Ninety-two patients received OAC for secondary stroke prevention, 62 for CVST, and 3 for DVT. Out of 2976 INR reports, 1458 (49%) were in the therapeutic range, 997 (33.1%) were below the therapeutic range, and 521 (17.5%) were above the therapeutic level. Stable INR was obtained in 75 (47.77%) patients which was improved by drug modification in 3 and dietary adjustment in 12 patients. VKORC1 polymorphism revealed GG genotype in 127 (80.9%), GA genotype in 22 (14%), and AA genotype in 8 (5.1%) patients. Therapeutic range of INR was seen in 49%, below therapeutic range was seen in 31.5%, and above in 17.5%. CONCLUSION: VKORC1 polymorphism was related to mean daily dose of OAC but not to the stability of INR.

Reliability and validity of telephonic Barthel Index: an experience from multi-centric randomized control study.

Telephonic Barthel Index (BI) assessment is less time-consuming and more feasible than a face-to-face interview. The aim of this study was to test the validity as well as reliability of the BI administered by telephone in comparison with face-to-face assessment in a multi-centric study. The study was conducted during the course of a randomized controlled trial in which 120 patients with subacute strokes from five teaching hospitals from different parts of India were recruited. Central telephonic follow-up and face-to-face assessment of BI and modified Rankin Scale (mRS) at 3 and 6 months were done by trained and certified blinded researchers. Kappa or weighted kappa (wK) was estimated. Sensitivity and specificity at various cutoff levels of telephonic BI were calculated. Concurrent validity of the telephonic BI was assessed by correlating it with the mRS and National Institutes of Health Stroke Scales (NIHSS) at 3 and 6 months. We observed high sensitivity and specificity at various cutoff levels of BI. Moderate to substantial agreement was observed between the two methods at 6 months wK 0.72 (95% CI 0.70-0.77). Item-wise and center-wise kappa also reflected substantial agreement. The study shows that telephonic assessment of activities of daily living with the BI in moderate to severely disabled stroke patients is valid and reliable compared to face-to-face assessment. Our study shows that telephonic assessment requires smaller sample size compared to face-to-face assessment of BI.