A 4-Year-Old Child with a Giant Cerebral Hydatid Cyst: A Case Report.

Echinococcosis is the most common cestode infection globally caused by the Echinococcus species. The most common organ involvement is the lungs and liver, but other organs can be rarely involved. Here, we present a case with a giant cerebral hydatid cyst. A 4-year-old boy presented with abnormal gait and walking at Marmara University School of Medicine Pendik Training and Research Hospital, Istanbul, Türkiye in September 2022. Cranial magnetic resonance imaging showed a cyst of 13 cm in diameter. The cyst was enucleated successfully with no rupture. Oral albendazole therapy was started. There was no eosinophilia, and the echinococcal indirect hemagglutination test was negative. Ultrasonography detected an anechoic cystic lesion in the liver. He was evaluated for deep-organ involvement; however, no cysts were detected in other organs. The histopathological examination was compatible with a hydatid cyst. Although intracranial hydatid disease in children is rare, it should be considered among the differential diagnoses in patients with neurological symptoms, especially in endemic regions.

Clinical factors, management, and outcomes of children under 3 years old with central nervous system tumors: single-center experience.

PURPOSE: Children under 3 years old represent a notable portion, about 25 to 30%, of all central nervous system tumor (CNS) cases. Their clinical course, prognosis, and treatment significantly differ from older children. This single-center retrospective study aims to comprehensively analyze survival factors in children under three diagnosed with CNS tumors. METHODS: Between April 2012 and December 2023, cases under 3 years of age with CNS tumors diagnosed at our center were retrospectively evaluated. RESULTS: Among 279 CNS tumor cases, 42 (15%) were evaluated. The 5-year overall and event-free survival rates were 67.4% (95% CI 47.5-81.1) and 39.8% (95% CI 24.2-55.0), respectively. Gender, symptom onset to diagnosis time, pathological neurological findings at diagnosis, and tumor location did not significantly impact survival (p > 0.05). However, cases with neurological symptoms showed significantly higher event-free survival rates (p < 0.05). Patients with embryonal tumors, metastases, inability for total surgical excision, relapsed/progressive diseases, and who under 1 year old had significantly lower survival rates (p < 0.05). Radiotherapy timing did not affect survival (p > 0.05). Event-free survival rates remained unchanged after the third year. CONCLUSION: The current treatments have been observed to have a positive impact on survival rates. Nonetheless, there is a need for novel treatments for patients with embryonal tumors, metastases, aged under 1 year, and those where total surgical excision is not feasible or in cases with progressive/relapse disease. This study underscores the importance of the first 3 years regarding relapse, progression, or mortality risk.

Deep Learning-Assisted Segmentation and Classification of Brain Tumor Types on Magnetic Resonance and Surgical Microscope Images.

OBJECTIVE: The primary aim of this research was to harness the capabilities of deep learning to enhance neurosurgical procedures, focusing on accurate tumor boundary delineation and classification. Through advanced diagnostic tools, we aimed to offer surgeons a more insightful perspective during surgeries, improving surgical outcomes and patient care. METHODS: The study deployed the Mask R-convolutional neural network (CNN) architecture, leveraging its sophisticated features to process and analyze data from surgical microscope videos and preoperative magnetic resonance images. Resnet101 and Resnet50 backbone networks are used in the Mask R-CNN method, and experimental results are given. We subsequently tested its performance across various metrics, such as accuracy, precision, recall, dice coefficient (DICE), and Jaccard index. Deep learning models were trained from magnetic resonance imaging and surgical microscope images, and the classification result obtained for each patient was combined with the weighted average. RESULTS: The algorithm exhibited remarkable capabilities in distinguishing among meningiomas, metastases, and high-grade glial tumors. Specifically, for the Mask R-CNN Resnet 101 architecture, precision, recall, DICE, and Jaccard index values were recorded as 96%, 93%, 91%, and 84%, respectively. Conversely, for the Mask R-CNN Resnet 50 architecture, these values stood at 94%, 89%, 89%, and 82%. Additionally, the model achieved an impressive DICE score range of 94%-95% and an accuracy of 98% in pathology estimation. CONCLUSIONS: As illustrated in our study, the confluence of deep learning with neurosurgical procedures marks a transformative phase in medical science. The results are promising but underscore diverse data sets' significance for training and refining these deep learning models.

Pentoxifylline and Vitamin E Can Restrict Radiation Necrosis via Vascular Pathways, Experimental Study in an Animal Model.

OBJECTIVE: Radiation necrosis (RN) is a long-term side effect of Gamma Knife stereotactic radiosurgery that may require surgical intervention. Pentoxifylline and vitamin E have previously been shown to be effective in the treatment of RN in the published literature, but there are no data on the prophylactic use of these molecules or, more importantly, whether prophylaxis is required. METHODS: The iatrogenic RN model included 50 Sprague-Dawley rats of both sexes. There were 7 treatment subgroups established. Gamma-Plan 8.32 was used to plan after magnetic resonance scans were performed in a specially designed frame. The injection doses used in the treatment groups were vitamin E (30 mg/kg/day in a single dose) and pentoxifylline (50 mg/kg/day in 2 doses). Control magnetic resonance scans were performed at the end of a 16-week treatment, and the subjects were decapitated for pathological evaluations. RESULTS: The intensity of hypoxia - inducible factor 1α immunoreactivity is statistically significantly lower in the therapeutic vitamin E, prophylactic pentoxifylline and vitamin E, and therapeutic pentoxifylline and vitamin E groups than in the other groups. Similarly, the intensity of vascular endothelial growth factor immunoreactivity was reduced in the therapeutic vitamin E and prophylactic pentoxifylline and vitamin E treatment modality groups. When compared with other groups, the therapeutic pentoxifylline group had significantly fewer vascular endothelial growth factor-immunoreactive cells in the perinecrotic area, with an accompanying decreased contrast enhancement pattern. CONCLUSIONS: Both vitamin E and pentoxifylline are effective for the treatment and/or restriction of RN, either alone or in combination. The use of these molecules as a preventive measure did not outperform the therapeutic treatment.

Langerhans cell histiocytosis located in the spheno-orbital bone and the pons: illustrative case.

BACKGROUND: This is a case of aggressive Langerhans cell histiocytosis (LCH) with an atypical intracranial location. OBSERVATIONS: In this report, the authors present the diagnosis and treatment of a 12-year-old male patient diagnosed with LCH. The patient was admitted to the emergency department with left-sided facial palsy, and a solid lesion with mass effect in the pons was found. A biopsy was performed via suboccipital craniotomy, and the diagnosis was LCH. A chemotherapy regimen was started since the LCH sample was the resistant type. The patient showed improvement in his neurological deficit following treatment. LESSONS: This rare localized and aggressive case's diagnosis process and treatment choices may apply to future cases.

Challenges in the Management of a 7-Year-Old Child with Thyrotropin-Secreting Pituitary Adenoma and the Review of the Literature.

INTRODUCTION: Thyrotropin-producing pituitary adenoma (TSHoma) is a very rare disease, representing less than 1% of the pituitary tumours and presenting with elevated thyroid hormones and normal/high TSH concentrations. CASE PRESENTATION: A 7-year-old boy with nervousness was referred by his psychiatrist for elevated free T4, T3, and TSH levels. Initial evaluation revealed an elevated α-subunit. Pituitary magnetic resonance imaging (MRI) demonstrated a macroadenoma. The patient underwent a trans-sphenoidal tumour resection (TSS) which showed positive immunohistochemical staining for TSH, growth hormone, and prolactin in tumoral tissue. Euthyroidism was achieved for 1 year after TSS, then recurrence of tumour with elevated TSH and thyroid hormone levels necessitated a re-operation with TSS followed by gamma-knife radiosurgery. The euthyroid state was achieved and lasted for 2.5 years this time, but due to the recurrence, medical treatment had been commenced with cabergoline and octreotide. Euthyroidism was maintained for the last 4 years on monthly octreotide treatment. A repeat MRI demonstrated no pituitary mass, but a mass in the sphenoidal sinus had been detected. Removal of this mass by surgery did not achieve euthyroidism. 68Ga-DOTA-TATE positron emission tomography/computed tomography showed residual tissue extending from the pituitary region to the sphenoid sinus. The patient's bone age was advanced by 2 years at diagnosis which became 4 years in 1 year after the diagnosis and remained so throughout follow-up, leading to a final height of -3.3 SDS below his target height at the age of 16 years. CONCLUSION: The diagnosis, treatment, and follow-up of TSHomas are challenging, and short stature due to accelerated bone maturation is a complication of paediatric TSHomas.

A new method for quantification of frontal retrusion and complex skull shape in metopic craniosynostosis: a pilot study of a new outcome measure for endoscopic strip craniectomy.

OBJECTIVE: The objective of this study was to propose a new skull outline-based method to objectively quantify complex 3D skull shapes and frontal and supraorbital retrusion in metopic craniosynostosis using 3D photogrammetry. METHODS: A standard section from 3D photogrammetry, which represents the trigonocephalic shape, was used in this study. From the midpoint of the area of this section, half diagonals were calculated to the skull outline at 5° increments in the anterior half of the head. These half diagonals were used to create a sinusoidal curve, and the area under the sinusoidal curve (AUC) was used to represent the mathematical expression of the trigonocephalic head shape. The AUC from 0° to 180° (90° from the midline to each side) was calculated and is referred to as AUC0→180. The AUC from 60° to 120° (30° from the midline to each side) was also calculated and is referred to as AUC60→120. A total of 24 patients who underwent endoscopic strip craniectomy and 13 age- and sex-matched controls were included in the study. The AUC values obtained in patients at different time points and controls were analyzed. RESULTS: The mean preoperative AUC60→120 and AUC0→180 in the patients were significantly lower than those in control individuals. The increase in both AUC60→120 and AUC0→180 values is statistically significant at the discontinuation of helmet therapy and at final follow-up. Receiver operating characteristic curve analysis indicated that AUC60→120 is a more accurate classifier than AUC0→180. CONCLUSIONS: The proposed method objectively quantifies complex head shape and frontal retrusion in patients with metopic craniosynostosis and provides a quantitative measure for follow-up after surgical treatment. It avoids ionizing radiation exposure.

Modified endoscopic strip craniectomy technique for sagittal craniosynostosis: provides comparable results and avoids bony defects.

PURPOSE: This study describes a modified technique addressing bony defects and incomplete ossification after endoscopic strip craniectomy (ESC) for SC followed by postoperative helmet therapy (PHT). The study aims to delineate quantitative and qualitative outcomes of this modified ESC technique followed by PHT and discern the optimal duration of PHT following ESC. A secondary aim is to address the effects of the technique on bony defects. METHODS: Patients undergoing ESC followed by PHT between 2017 and 2021 were included. Patient sex, age at surgery, duration of surgery, red blood cell transfusion, length of hospital stay, PHT duration, cephalic index (CI) at multiple time points, and bony defect information were collected. Descriptive and correlative analysis was done. RESULTS: Thirty-one patients (25 male, 6 female) were operated in study period. Mean age at surgery was 12.81 weeks, mean duration of surgery was 57.50 min, average transfused RBC volume was 32 cc, mean length of hospital stay was 1.84 days, mean PHT duration was 33.16 weeks, and mean follow-up time was 63.42 weeks. Mean preoperative CI was 70.6, and mean CI at the end of PHT was significantly higher, being 77.1. Maximum improvement in CI (CImax) took place at week 22.97. PHT duration did not have a correlation with CI at last follow up. There were no bony defects. CONCLUSION: Modified ESC technique is effective in successful correction of sagittal craniosynostosis. CImax already takes place, while PHT is continuing, but there is no certain time point for dishelmeting. The technique avoided bony defects and incomplete ossification.

Atypical Teratoid Rhabdoid Tumor in a Newborn: Can IVF Be a Risk Factor?

BackgroundIn recent years, with the widespread use of assisted reproductive technologies, questions have arisen regarding the possible relationship between these infertile parents with assisted conception procedures and childhood cancers. Case report: We present a 23-day-old newborn conceived by in vitro fertilization (IVF) with a 53 × 46 × 38 mm intracranial mass detected by magnetic resonance imaging on the 15th postnatal day. The mass, removed on 23rd postnatal day, was an Atypical Teratoid Rhabdoid Tumor (ATRT), WHO grade 4. Conclusions: As far as we know, this is the only neonatally detected ATRT. Further studies are needed to investigate whether there is a causal relationship between IVF and childhood cancers.

Intermediate-Grade Meningeal Melanocytoma in a 19-Month- Old Child with Difficulties in Differential Diagnosis and Management.

Intermediate-grade meningeal melanocytoma (IGM) is a rare tumor that has not been reported in children so far. It is speculated to have more aggressive clinical behavior with undefined best management options. In this study, we present a 19-month-old girl as the first case with IGM in English literature. Preoperative diagnosis was ambiguous, given the unclear patient history and radiological features resembling a growing skull fracture or a congenital parietal bone agenesis subtype. During surgery, a dark gray-black dural area (5 × 7 cm in size) was found and then excised. However, the surgery was complicated due to brain edema and swelling, warranting a second surgery for reconstruction and dural repair. Of the 16 reported adult patients, 14 showed a high recurrence rate without adjuvant radiotherapy; 2 showed no recurrence with adjuvant radiotherapy. No adjuvant radiotherapy was given to our patient since she was 19 months old at the time of diagnosis and showed no recurrence at 48-month follow-up until now. Close monitoring with radiological imaging is of paramount importance for such cases.

How do presentation age and CSF opening pressure level affect long-term prognosis of pseudotumor cerebri syndrome in children? Experience of a single tertiary clinic.

BACKGROUND: Diagnosis and treatment of pseudotumor cerebri syndrome in children is still a challenge for clinicians. The aim of this study is to reveal the influence of presentation age and CSF opening pressure on long-term prognosis of pseudotumor cerebri and share our clinical data of the very young age (≤ 5-year) group. METHOD: This retrospective study includes the patients followed by the Marmara University Pediatric Neurology Clinic between years 2012 and 2020 diagnosed with definite, probable, or suggestive pseudotumor cerebri syndrome according to modified Friedman criteria. Patients were classified into three groups according to presentation age: group 1: ≤ 5 years old; group 2: 6-10 years; and group 3 > 10 years old. CSF opening pressure was also categorized into three groups as CSF < 20 cmH20; CSF 20-30 cmH20; and CSF > 30 cmH20. RESULTS: One hundred three patients, 62.1% female (n = 64), were enrolled in the study. Group 1 consisted of 16 patients (60% male), group 2 consisted of 30 patients (63.3% female), and group 3 consisted of 57 patients (66.7% female). The mean CSF opening pressure did not differ between the three age groups in our study (p > 0.05). Treatment response was not correlated with CSF opening pressure. Papilledema presence and level of CSF opening pressure were independent of age (p > 0.05). CONCLUSIONS: Age at presentation and CSF opening pressure at diagnosis are not any predictive factors that influence long-term prognosis of pseudotumor cerebri syndrome in children. Evaluation and follow-up of children should be done in personalized approach.

Cranial MRI Abnormalities and Long-term Follow-up of the Lesions in 770 Girls With Central Precocious Puberty.

CONTEXT: Central precocious puberty (CPP) may arise from central nervous system (CNS) lesions in a few affected girls. Recently, the incidence of girls with CPP has increased mostly in 6-8 year olds, in whom the necessity of magnetic resonance imaging (MRI) is debated. OBJECTIVE: To investigate the frequency, long-term outcome and potential predictors of CNS lesions in a large cohort of girls with CPP. METHODS: A multicenter cohort of 770 Turkish girls with CPP who had systematic cranial MRI between 2005 and 2017. Age at puberty onset was <6 years in 116 and 6-8 years in 654. CNS lesions were followed until final decision(6.2 ± 3.1 years). Potential predictors of CNS lesions were evaluated by univariate analyses. RESULTS: A total of 104/770 (13.5%) girls had abnormal brain MRI. Of these, 2.8% were previously known CNS lesions, 3.8% had newly detected and causally related CNS lesions, 3.1 % were possibly, related and 3.8% were incidental. Only 2 (0.25%) neoplastic lesions (1 low grade glioma and 1 meningioma) were identified; neither required intervention over follow-up of 6 and 3.5 years respectively. Age at breast development <6 years (odds ratio [OR] 2.38; 95% CI 1.08-5.21) and the peak luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio >0.6 (OR 3.13; 95% CI 1.02-9.68) were significantly associated with CNS lesions. However, both patients with neoplastic lesions were >6 years old. CONCLUSION: Although age and LH/FSH ratio are significant predictors of CNS lesions, their predictive power is weak. Thus, systematic MRI seems to be the most efficient current approach to avoid missing an occult CNS lesion in girls with CPP, despite the low likelihood of finding a lesion requiring intervention.

Penetrating Craniocerebral Injury by the Hook of a School Desk.

INTRODUCTION: Although penetrating cranial injuries are rare in pediatric patients, these injuries can lead to morbidity and mortality. Removal of a gigantic foreign body from the cranium requires proper management as it has high risk of further brain damage and seizures. CASE PRESENTATION: We report the case of a patient with cranial injury caused by hitting the head to the hook of a school desk. Due to the extreme nature of the injury, the following additional steps were necessary: taking help from a local firefighter team to cut the desk, surgical removal of the foreign body, and cranioplasty after 6 months. Following this, he was discharged without neurological deficits. DISCUSSION/CONCLUSION: Neurotrauma is one of the major causes of death in children. The damage and effect of the injuring foreign body depends on its size, shape, velocity, trajectory, and entry point. It should be kept in mind that any high-frequency processes applied on the extracranial parts of conductive objects, such as metal bars, may trigger seizures. Preoperative extracranial intervention for huge penetrating foreign bodies should be performed under anticonvulsant administration and intubation to decrease the risk of epileptic seizures and its complications.

Deep brain stimulation as treatment for dystonic storm in pantothenate kinase-associated neurodegeneration syndrome: case report of a patient with homozygous C.628 2 T > G mutation of the PANK2 gene.

Pantothenate kinase-associated neurodegeneration (PKAN) syndrome is an autosomal-recessive neurodegenerative disease that causes progressive generalized dystonia. Currently, the disorder remains pharmacologically intractable. Herein we report the first case in which deep brain stimulation helped to relieve dystonic storm in a patient with PKAN syndrome who had homozygous c.628 2 T > G mutation of the PANK2 gene. A 10-year-old boy with PKAN disease presented with dystonic storm and was admitted to the emergency department. Examination revealed generalized dystonia and impaired breathing due to involvement of the respiratory muscles. The patient underwent surgery for bilateral globus pallidus internus deep brain stimulation. The patient showed marked response to treatment.

Neural tube defect family with recessive trait linked to chromosome 9q21.12-21.31.

PURPOSE: Meningomyelocele is one of the most common and socioeconomically, psychologically, and physically debilitating neurodevelopmental diseases. A few chromosomal locus and genes have been identified as responsible for the disease; however, clear evidence still needs to be produced. This study aimed to show evidence of a strong genetic linkage in a novel chromosomal locus in a family with this neural tube defect. METHODS: We identified a neural tube defect family in eastern Turkey, where two of six offspring had operations due to thoracolumbar meningomyelocele. The parents were of a consanguineous marriage. We collected venous blood from six offspring of the family. Whole genome linkage analysis was performed in all offspring. RESULTS: A theoretical maximum logarithm of an odds score of 3.16 was identified on chromosome 9q21.12-21.31. This result shows a strong genetic linkage to this locus. CONCLUSIONS: Our results identified a novel chromosomal locus related to meningomyelocele and provide a base for further investigations toward the discovery of a new causative gene.

Brain abscess due to Streptococcus intermedius secondary to mastoiditis in a child.

BACKGROUND: Brain abscess is a rare but serious, life-threatening infection in children. It may arise from parameningeal infections such as otitis media, sinusitis and mastoiditis. CASE DESCRIPTION: A ten-year-old boy with the diagnosis of glycogen-storage disease and obesity was admitted to the emergency room with complaints of vomiting, decreased level of consciousness, imbalance on walking. On neurological examination, the patient was ataxic. His cranial magnetic resonance imaging (MRI) examination showed mastoiditis on the right side and 39 × 34 mm abscess formation with surrounding edema on the right cerebellar hemisphere. The patient underwent surgery to drain the abscess, microbiological samples were obtained and empirical antibiotic treatment with vancomycin and piperacillin-tazobactam were started. Postoperative cranial MRI examination showed that the lesion regressed 10 × 10 mm with a reduction in the edema. On the second week of the treatment, the antibiotics were switched to vancomycin and meropenem because of the relapsing fever. The therapy was continued for 6 weeks. A final MRI (after completing antibiotherapy) showed resolution of the cerebellar abscess. The child's clinical condition improved and he was discharged without any sequelae. DISCUSSION AND EVALUATION: Children with congenital heart disease and an immonocompromised state are particularly at risk. Streptococcus intermedius is usually a commensal microorganism in the normal flora of the mouth which can cause brain abscess rarely in children. Brain abscess induced mortality rates are still relatively high, even with the advancement of imaging technologies, the combination of surgical drainage and antimicrobial therapy. CONCLUSION: This case is one of the few reported cases of cerebellar abscess caused by S. intermedius in an immunocompetent child, due to its low virulence, a rare occurence and timely management resulting in fully healed.

The effect of untethering on urologic symptoms and urodynamic parameters in children with primary tethered cord syndrome.

OBJECTIVE: To evaluate urinary system symptoms (USSs) and urodynamic parameters (UPs) before and after untethering in children with primary tethered cord syndrome (pTCS). METHODS: USSs and UPs of patients undergoing untethering for pTCS during the period January 2008-July 2012 were evaluated preoperatively and at the postoperative third and 12th months. For analysis, patients were separated into 4 groups according to the presence of USSs: group 1, USSs preoperative positive and postoperative negative; group 2, USSs preoperative positive and postoperative positive; group 3, USSs preoperative negative and postoperative positive; group 4, USSs preoperative negative and postoperative negative. Preoperative and postoperative USSs and UPs were compared. RESULTS: Forty patients (average age, 7.2 years, follow-up of 2.8 years) were included. There were 13 patients in group 1, 11 in group 2, 3 in group 3, and 13 in group 4. All patients showed improvement when preoperative and postoperative USSs and UPs were compared. There was no correlation between USSs and UPs, both preoperatively and postoperatively. USSs and UPs at the postoperative third and 12th months were similar. Patients with no USS showed the most significant improvement in UP after untethering. CONCLUSION: Our study has demonstrated that untethering in patients with pTCS improves urologic symptoms and UPs. However, there is no correlation between improvement in symptoms and urodynamic findings. Urodynamic changes are similar at the postoperative third and 12th months. As the most significant improvement was seen in patients without USSs, it is important that these patients undergo urodynamic studies preoperatively and postoperatively.

Accessory lower limb associated with spina bifida: case report.

PURPOSE: Heterotopic redundancies, such as an accessory limb associated with spina bifida, are extremely rare anomalies. There are 12 cases of accessory limb associated with spinal bifida in literature. This report aims a detailed description of the additional case and an analysis of the findings in light. METHODS: A male baby was born at 40 weeks of gestation and was referred to the neurosurgery clinic with a diagnosis of accessory lower limb. On physical examination, the dorsal meningocele was located at the lumbosacral region and there was accessory lower limb on it. There was no open neural placode. RESULTS: The accessory limb was excised on postnatal day 3. CONCLUSIONS: Dysraphic appendages are rare and complicated anomalies. They should be investigated carefully, and all of the lesions must be repaired for babies' quality of life.

Experience of a tertiary care center on 100 newborns with neural tube defects.

The aim of this study was to analyze the sociodemographic features, postoperative complications, long-term problems, and cost of care of patients followed in the neonatal intensive care unit (NICU) with a diagnosis of neural tube defects (NTDs). Babies with NTD followed in the Neonatology Unit of Ondokuz Mayis University Faculty of Medicine between January 2003 and December 2011 were analyzed retrospectively. One hundred (1.2%) of 8408 babies admitted to the NICU were diagnosed as NTD during the study period. Of the cases with NTD, 74% of mothers were graduates of primary school/illiterate, and none had used folic acid (FA) preconceptionally. Prenatal diagnosis was made in 72%, but parents had chosen not to terminate the pregnancy. The most frequent type and site of NTD was meningomyelocele (82%) of the lumbosacral region (36%). In 80% of the babies, the NTD sac was closed with in the first 72 hours of life. The most frequently observed postoperative complications were wound infection and septicemia. The mortality rate of babies with NTD during the follow-up period was 7%, and all deaths occurred in the first year of life. Sixty-two percent of the patients had neurologic deficits on follow-up. Patients were rehospitalized during the follow-up for an average of 2.9 times. Neural tube defect (NTD) is a disabling problem, with operations, rehospitalizations and other costly treatments. Maternal education regarding preconceptional FA use/fortification of food with FA and appropriate guidance to the family with prenatal diagnosis will decrease the incidence and burden of the disease.