Repeat MRI Scan Research Articles

REVERSIBLE LEUKOENCEPHALOPATHY AS A PRESENTATION OF CEREBRAL AMYLOID ANGIOPATHY

A 73 year old man with a past medical history of hypertension, osteoathritis and asthma presented to the local district general hospital with recurrent episodes of spontaneously resolving encephalopathy.The initial...

CEREBRAL WHITE MATTER DISEASE IN PATIENTS WITH MALIGNANCY: PML VERSUS TOXIC LEUCOENCEPHALOPATHY DUE TO CHEMOTHERAPY

BackgroundSystemic malignancy and its treatment can produce a variety of cerebral abnormalities. Malignancy itself can lead to metastatic disease and paraneoplastic encephalomyelitis Patients on chemotherapy can develop the Posterior Reversible...

30 Year-Old Male with Headaches

30 Year-Old Male with Headaches

MRI signal changes in the skull base bone after endoscopic nasopharyngectomy for recurrent nasopharyngeal carcinoma

Objective To evaluate the signal changes of the skull base after salvage surgury via endoscopic transnasal approach for local recurrent nasopharyngeal carcinoma. Methods Twenty patients with nasopharyngeal carcinoma after radiation failure underwent nasophargeryngectomy via an endoscopic transnasal approach were selected from April 2006 to December 2011,including 16 males and 4 females with 31 to 67 years old.Each patient had previously received irradiation and experienced recurrence after 8 to 83 months of completed irradiation.All patients underwent MRI no more than 2 weeks before the salvage surgery and were subjected to repeat MRI scans 2 weeks,3 months,6 months later and semi-annually thereafter,with the follow-up time of 6 to 45 months (median 18 months).A two-sided Chi-square test was used to compare the signal changes and the tendency of changes on all presurgical and postsurgical MR images. Results The MRI signal changes were detected at 92 sites of skull-base between 2 weeks and 3 months after the surgery,which was hypointense on T1WI with moderate to marked contrast enhancement.In the follow-up period,the signal abnormalities at 36 sites of skull base had resolved or restored to the normal,and 34 sites remained stable,while in 22 sites,the MR signal changes became more obvious.The skull base bones adjacent to the region of the resection were more likely to show signal changes than nonadjacent areas (72 vs.20,χ2=33.128,P<0.01).The signal changes were more common on the ipsilateral skull base to the recurrent tumor in contrast to the contralateral skull base (68 vs 24,χ2=21.182,P<0.01). Conclusions The skull base signal changes after salvage surgury via endoscopic transnasal approach for local recurrent nasopharyngeal carcinoma,and it occurs in specific location.Most of sites tend to resolve or be stable at the follow up. Key words: Nasopharyngeal carcinoma; Neoplasm recurrence,local; Skull base; Magnetic resonance imaging

Hypophysitis due to IgG4-related disease responding to treatment with azathioprine: an alternative to corticosteroid therapy

Fifteen cases of lymphocytic hypophysitis due to IgG4-related disease have been reported demonstrating marked improvement with corticosteroid therapy. This is the first case of IgG4-related hypophysitis demonstrating improvement with azathioprine, where corticosteroids were initially tried but ceased due to concern regarding enlargement of the pituitary infiltrate. Case description and review of 15 cases reported in the literature. A 40 year old male was diagnosed with IgG-4 related disease based on pituitary and lacrimal gland biopsies associated with raised serum concentration of IgG4. The patient was commenced on prednisolone 30 mg/day, as rapid response to prednisolone treatment has been described in the literature for other cases of IgG4-related hypophysitis. Over the next 3 months, prednisolone treatment resulted in a reduction of serum IgG4 levels, but repeat MRI scan showed an enlarging pituitary mass with new optic nerve compression. Azathioprine 75 mg twice daily was commenced and in the subsequent 3 months, IgG4 levels normalised (0.58 g/L) and MRI scan showed 50% shrinkage of the pituitary mass. After 10 months of azathioprine treatment the MRI showed a normal sized pituitary but persistence of the infraorbital nerve thickening. Hypophysitis due to IgG4-related disease usually demonstrates prompt response to corticosteroids. This case highlights the need to image promptly after starting treatment to exclude an enlarging pituitary mass despite corticosteroid treatment. Alternative therapy with azathioprine can result in marked improvement. It should be remembered that IgG-4 related hypophysitis is part of a multi-organ disease.

AB1100 A case of frozen hip – a diagnosis we should consider more often?

BackgroundAdhesive Capsulitis of the hip or “frozen hip” is not a diagnosis well documented in rheumatological textbooks or literature. There are only a few isolated case reports of adhesive capsulitis...

CPC-091 Natalizumab in Cypriot Patients with Relapsing Remitting Multiple Sclerosis: Three Year Data on Safety, Efficacy and Frequency of Anti-JC Virus Antibodies

BackgroundNatalizumab (NAT) is a recombinant humanised anti-α4-integrin antibody used in treating Relapsing Remitting (RR) Multiple Sclerosis (MS).Purpose To evaluate the long-term safety and efficacy of NAT in Cypriot patients, to...

Abstract WP120: Granuloctye-Colony Stimulating Factor in Ischemic Stroke Trial (GIST): A Pilot Study

Introduction: Granulocyte-colony stimulating factor (G-CSF) is upregulated in models of cerebral ischemia. This may promote hematopoietic stem cell (HSC) mediated central nervous system repair. We hypothesize that exogenous G-CSF may promote recovery after acute ischemic stroke. We examined the safety and feasibility of this therapy with a double-blind, randomized pilot study of G-CSF in patients with acute stroke. Methods: Patients with ischemic stroke and motor deficits greater than 2 on the National Institutes of Health Stroke Scale (NIHSS) were randomized to receive a four-day course of G-CSF (10 μg/kg sc) or matching placebo within ten days of stroke occurrence, followed by a second cycle after six weeks. Primary outcomes were safety measures including recurrent stroke, mortality, toxicity as measured by the NCI Common Toxicity Scale, and worsening of disability as measured by modified Rankin Scale (mRS), Barthel index, NIHSS and Glasgow Outcome Scale (GOS). Testing occurred at 1.5, 3, 6 and 12 months after treatment. MRI, CT perfusion and functional MRI were obtained at 3 months with repeat MRI scan at 12 months, and neuropsychological testing was conducted at 6 and 12 months. Results: Nine patients were randomized; mean pre-treatment NIH Stroke Scale was 8.8. Elevation of circulating leukocytes and CD34+ cells were observed after G-CSF administration compared to placebo. Adverse events including diarrhea, dehydration, bone pain, and asymptomatic leukocytosis were seen more frequently in the G-CSF treated cohort, but there were no recurrent strokes or deaths in either group. Disability did not worsen in any patients, with no significant change in median mRS, NIHSS, GOS or Barthel index between groups at 1.5, 3, 6 or 12 months after treatment. No significant changes in neuropsychological testing or imaging parameters were observed. Conclusions: G-CSF administration in ischemic stroke patients appears to be safe and feasible, with no increase in mortality or worsening of disability observed in this pilot study. Larger randomized trials would be needed to determine efficacy of this potential novel therapy for stroke recovery.

Sequential peripheral neuropathy and myelopathy in a neurosarcoidosis patient

A 66-year-old male was referred to our department for evaluation of severe quadriparesis along with marked sensory and autonomic dysfunction. His past medical history was remarkable only for a remote gastrectomy due to gastric ulcer. He was in his usual state of health until 18 months ago, when he noted numbness of the left hand and foot along with numbness and weakness of the right hand. These symptoms were gradually worsening, with numbness in all four limbs, gait imbalance and clumsiness of the right arm. Initial clinical and electrophysiological evaluation at another hospital suggested multiple root or plexus damage but MRI of the cervical spine and brachial plexus were unrevealing. Subsequent electrodiagnostic studies indicated a demyelinating polyneuropathy. The patient was treated with periodic infusions of intravenous immunoglobulin (IVIg), with little or no improvement. During the last 4 months the patient had been bedridden, with severe quadriparesis, numbness of the limbs and trunk, loss of sphincter control, dry mouth, dry eyes and episodic hyperidrosis. Neurologic examination on admission at our department revealed asymmetrical flaccid arm and leg weakness, a bilateral Babinski sign, a ‘gloves-stockings’ pattern of hypoesthesia with a sensory trunk level at Th9, severe proprioceptive loss especially in the legs and signs of autonomic dysfunction. Repeat nerve conduction velocity studies were consistent with the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) (Table 1), CSF contained 24 lymphocytes/mm with normal protein and glucose; CT scans of the chest, abdomen and pelvis were negative for tumor as was detailed autoimmune workup. Based on the signs implying a spinal cord lesion, the inflammatory CSF and lack of improvement with IVIg, a repeat MRI scan of the cervical spine revealed an intraspinal enhancing lesion extending from C2 to C6, as well as scattered enhancing lesions in the thoracic cord (Fig. 1a, b). The patient was treated with prednisolone 75 mg/day, with remarkable and immediate improvement of the weakness. Repeat MRI of the cervical and thoracic spine revealed diffuse areas of myelopathy mainly in the cervical level, with milder enhancement, no edema or mass effect (MRI of the brain was unremarkable). Repeat spinal tap confirmed mild inflammatory CSF with eight lymphocytes, normal protein and glucose, no oligoclonal bands, negative for infectious agents, mycobacteria, antitreponema antibodies or malignant cells. Nerve conduction studies were unchanged. A thorough review of the imaging studies identified small mediastinal lymphadenopathy as well as axillar lymphadenopathy, markedly on the right. A biopsy from the right axilla yielded several enlarged lymph nodes with histopathological features of chronic granulomatous inflammation, with few sites of necrosis. P. Maiovis (&) S. Michelaki P. Ioannidis D. Karacostas 2nd Department of Neurology, AHEPA University Hospital, St Kyriakidi 1, 54636 Thessaloniki, Greece e-mail: panmaio@hotmail.com

A rapid, novel method of volumetric assessment of MRI-detected subchondral bone marrow lesions in knee osteoarthritis is comparable to worms: preliminary validation

A rapid, novel method of volumetric assessment of MRI-detected subchondral bone marrow lesions in knee osteoarthritis is comparable to worms: preliminary validation

Meniscal scaffolds: Early experience and review of the literature

IntroductionMeniscal scaffold implants support the in-growth of new "meniscus like" tissue with the aim of alleviating post-meniscectomy knee pain and preventing further articular cartilage degeneration. Patients and methodsTwenty-three patients underwent meniscal scaffold implantation (14 medial, 9 lateral) with either the Menaflex (ReGen Biologics) (n=12) or Actifit (Orteq) (n=11) scaffolds. Minimum follow-up was 1year with a mean of 24.1months (18–27) for the Menaflex and 14.7months (12–18) for the Actifit groups. Mean age at surgery was 35years (17–47) with a mean Outerbridge grade of 1.9 in the affected compartment. Eight (36%) underwent concurrent osteotomy, ligament reconstruction or microfracture of the tibial plateau. KOOS, Lysholm, Tegner activity and IKDC scores were collected pre-operatively and at six-month interval post-surgery. Assessment of the reconstruction was obtained with MRI scanning and arthroscopy. One scaffold tore and was revised at 19months post-operatively. ResultsTwenty-one out of 23 (91.3%) had a significant improvement in knee scores when compared to pre-surgery levels at latest follow-up. Second-look arthroscopy in 14 at 1-year post-implantation showed variable amounts of regenerative tissue. There was no progression in chondral wear noted on repeat MRI scanning. ConclusionTreatment with meniscal scaffold implants can provide good pain relief for the post-meniscectomy knee following partial meniscectomy. Longer follow-up is required to ascertain whether they also prevent the progressive chondral wear associated with a post-meniscectomy knee.

155 A case series; a Miller Fisher Syndrome epidemic

Miller Fisher Syndrome (MFS) classically consists of a triad of ataxia, areflexia and ophthalmoplegia. Facial nerve involvement has also been reported in up to 45.7% of patients and antiganglioside antibodies...

Extraocular Muscle Enlargement as a Paraneoplastic Effect of Breast Carcinoma in a Male Patient

The authors report a rare case of a male patient who was diagnosed with breast cancer following investigations for proptosis secondary to extraocular muscle enlargement. A 65-year-old man presented with complaints of double vision and proptosis. CT scan of the orbits showed bilateral superior rectus muscle enlargement. On further investigation, the patient was detected to have a right breast mass. Biopsy of the mass showed an intermediate-grade carcinoma in situ. The patient underwent a right radical mastectomy following which his proptosis and symptoms of double vision resolved. Repeat MRI scans showed reduction in the size of the superior rectus muscle after mastectomy. Extraocular muscle enlargement has not been previously identified as a paraneoplastic effect of breast carcinoma in a male patient. Extraocular muscle enlargement can be a presenting feature of malignancies, and an appropriate systemic workup for the occult primary when all other preliminary tests are negative should be considered.

Treatment with olaparib in a patient with PTEN-deficient endometrioid endometrial cancer

A 58-year-old woman presented with metastatic endometrioid endometrial adenocarcinoma after being previously treated with surgery and adjuvant radiotherapy for early-stage endometrial cancer. She had received several lines of chemotherapy for multiple relapses over 9 years and displayed a profound sensitivity to platinum-containing regimens. CT scans demonstrated progressing liver, lung and peritoneal metastases and MRI detected multiple intracerebral metastases. New brain metastases secondary to progressive endometrioid endometrial carcinoma. On the basis of her sensitivity to repeated platinum treatment she was treated with the oral poly(ADP)-ribose polymerase (PARP) 1 inhibitor olaparib as part of a phase I trial. Repeat MRI scan at week 10 of treatment showed a significant reduction in the size of the brain metastases without steroid treatment or radiotherapy and the patient reported subjective improvement in tumor-related symptoms. After 8 months of olaparib treatment the patient developed objective disease progression. The tumor biopsy was negative for somatic BRCA1 and BRCA2 mutations, but displayed loss of PTEN, which has been suggested to be another predictive marker for sensitivity to PARP inhibitors. The patient remained alive for 10 months after completing olaparib, having gone on to derive further clinical benefit from repeat exposure to platinum-based therapy.

Natural History of Hearing Deterioration in Intracanalicular Vestibular Schwannoma

Intracanalicular vestibular schwannomas have a range of treatment options that can preserve hearing: microsurgery, stereotactic radiotherapy, and conservative observation. To evaluate the natural course of hearing deterioration during a period of conservative observation. A retrospective case review was performed on 47 patients with a unilateral intracanalicular vestibular schwannoma. Evaluation of growth was monitored by repeat MRI scanning. Repeated pure-tone and speech audiometry results were evaluated for subgroups of patients showing growth or no growth and by subsite location of tumor in the internal auditory canal. Patients had a mean follow-up of 3.6 years. Over the entire population, the pure-tone average thresholds at 0.5, 1, 2, and 3 kHz and the word recognition scores both significantly deteriorated from 38 to 51 dB HL, and from 66% to 55%, respectively. Overall, 74% of subjects with good hearing, according to the 50/50 rule, maintained hearing above this rule. There were no significant differences in hearing loss by subsite in the internal auditory canal (porus, fundus, central) or by growth status (stable, growing, shrinking). Only 6 patients showed a large hearing change. This happened early during follow-up, with relatively stable hearing after this. Hearing will deteriorate in some intracanalicular vestibular schwannomas, regardless of tumor growth. Hearing deterioration, if on a large scale, most likely occurs early in follow-up. The present results using conservative management in these tumors appear similar to those reported for stereotactic radiotherapy or microsurgery.

Cord compression resulting from Fibrous Dysplasia (FD) of the spine : a case report

Event Abstract Back to Event Cord compression resulting from Fibrous Dysplasia (FD) of the spine : a case report I Scott1*, J Lucas2, G Gnanasegaran3, C Silve4, I Fogelman5 and G Hampson1 1 Guy's Hospital, Osteoporosis clinic, United Kingdom 2 Guy's Hospital, Orthopaedics, United Kingdom 3 Guy's Hospital, Nuclear Medicine, United Kingdom 4 Hospital Bichat, Molecular Genetics Laboratory, France 5 Guy's Hospital, Osteoporosis clinic, France The patient was a 59 year old man who was diagnosed with fibrous dysplasia (FD) 20 years previously. CT scan at the time showed involvement of the 3rd, 5th and 8th rib only. He remained asymptomatic until recently when he started getting pain in his chest and upper back. Neurological examination was normal. Repeat CT and MRI scan confirmed progression of the bone lesions with grossly expanded sclerotic bone and lytic lesions involving particularly T2, T4 and T5. There was complete destruction of the vertebral body of T3 with bulging of the FD lesions into his spinal canal at T3. There was also involvement of his ribs consistent with polyostotic FD. 99TC-MDP bone scan showed intense uptake involving the r-sided ribs and upper thoracic spine. An 18 F FDG PET scan showed increased FDG uptake in the expansile and lytic lesions of the spine (cervical and thoracic spine) and right ribs. The appearances were in keeping with metabolically active disease. He was referred to the metabolic bone clinic for treatment with i.v bisphosphonate. Laboratory findings confirmed increased bone turnover (alkaline phosphatase : 209 (35-129 IU/L), P1NP : 172 (28-80 ug/L) and hypophosphataemia (0.6 mmol/L). However, bisphosphonate treatment was delayed due to a planned knee operation. He developed progressive myelopathy with difficulty in walking and sensory loss at T5 sensory level and required emergency admission. MRI confirmed encroachment upon the spinal canal causing cord compression. He underwent urgent T4/T5 thoracic laminectomy and cord decompression. Histology showed bone fragments containing irregular trabeculae of woven bone and an aneurysmal bone cyst containing osteoclast giant cells. There was no evidence of malignancy. Post-operatively he made an uneventful recovery and was treated medically with i.v Zoledronate and Calcium/vitamin D supplements with improvement in his bone pain. Mutation analysis of his peripheral blood cells did not show any mutation in the GNAS gene at position R201H. {BR}FD is a skeletal disorder characterised by abnormal fibro-osseous tissue. Skeletal involvement leads to pain, deformity and fractures. Treatment with bisphosphonate reduces pain and bone turnover. The molecular cause is due to post-zygotic activating mutations in the GNAS gene. Keywords: Bones, Bone Research Conference: 2011 joint meeting of the Bone Research Society & the British Orthopaedic Research Society, Cambridge, United Kingdom, 27 Jun - 29 Jun, 2011. Presentation Type: Clinical Case Topic: Abstracts Citation: Scott I, Lucas J, Gnanasegaran G, Silve C, Fogelman I and Hampson G (2011). Cord compression resulting from Fibrous Dysplasia (FD) of the spine : a case report. Front. Endocrinol. Conference Abstract: 2011 joint meeting of the Bone Research Society & the British Orthopaedic Research Society. doi: 10.3389/conf.fendo.2011.02.00060 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Sep 2011; Published Online: 30 Sep 2011. * Correspondence: Dr. I Scott, Guy's Hospital, Osteoporosis clinic, London, United Kingdom, ian.scott@gstt.nhs.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers I Scott J Lucas G Gnanasegaran C Silve I Fogelman G Hampson Google I Scott J Lucas G Gnanasegaran C Silve I Fogelman G Hampson Google Scholar I Scott J Lucas G Gnanasegaran C Silve I Fogelman G Hampson PubMed I Scott J Lucas G Gnanasegaran C Silve I Fogelman G Hampson Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Occipital interhemispheric transtentorial approach to the superior cerebellum

The occipital interhemispheric transtentorial approach is commonly used for pineal region tumors. However, there are few reports of this approach for lesions in the superior cerebellum. We present a 47-year-old male patient with an incidental cystic lesion in the superior cerebellum, detected on MRI consistent with cerebellar hemangioblastoma. The patient initially underwent stereotactic radiosurgery. After 5 months he presented with dizziness. A repeat MRI scan revealed an interval increase in lesion size. We performed surgery using the occipital interhemispheric transtentorial approach to remove the lesion. There were no intraoperative complications and the patient tolerated the procedure well. We describe our approach, supplemented by a short video, and review operative approaches to the superior cerebellum.

Can increasing the dose of radiation by HDR brachytherapy boost following pre operative chemoradiotherapy for advanced rectal cancer improve surgical outcomes?

Preoperative radiotherapy has been shown to improve local control in advanced rectal carcinoma compared with surgery alone. Several large randomized trials have confirmed that chemoradiotherapy (CRT) is better than radiotherapy alone. This pilot study was designed to increase the radiation dose using high-dose rate (HDR) brachytherapy boost following preoperative CRT to evaluate whether this strategy improves the outcome of surgery without increase in toxicity. Since October 2004, we have used the new rectal HDR applicator for brachytherapy boost in 68 patients following CRT. The patients had CT and MRI Scans as part of staging. All had locally advanced disease either bulky low T2 or T3 with threatened circumferential resection margin and multiple suspicious lymph nodes. They were offered preoperative CRT either by 5-FU infusion 1 g/m(2) day 1-4 (week 1 + 5) or by oral capecitabine 825 mg/m(2) Monday-Friday for 5 weeks together with CT planned external beam RT 45Gy in 25 fractions over 5 weeks (CRT). Those downstage on repeat MRI scan were offered additional HDR Boost 10Gy directly to the tumour followed by surgery 6-8 weeks later [group A]. Four patients proceeded directly to surgery but because of involved resection margin had a HDR brachytherapy boost as postoperative treatment [group B]. Thirty patients were not planned for immediate surgery after CRT and brachytherapy boost, as they were either elderly or considered high risk for anaesthesia [group C]. There were 34 patients (median age 67 (range 39-81) years in group A, including 24 men). The PS was 0-1. The clinical stage at presentation was cT2 in five, cT3 in 23 and T4 in six patients and cN0 in 2, cN1 in 21 and N2 in 11. Thirty-three patients had CRT, and one had radiotherapy alone. All patients completed treatment without interruption. Twenty-nine patients had surgery following CRT and brachytherapy boost including anterior resection in 10 patients, Abdominoperineal excision (APR) in 18 and Hartmann's resection in one. Five patients did not have the intended surgery. Twenty-four (83%) patients had an RO resection compared with 63% having conventional preoperative CRT using bolus 5FU regimes. Pathological complete remission (pCR) was achieved in 9 (31%) compared with 12% patients having conventional CRT. There was no increase in G 3-4 toxicity from RT and no delay in wound healing or increase in anastomotic leakage. One of the four patients in group B developed local recurrence. The thirty patients in group C who had modified radical CRT followed by brachytherapy boost as a definitive treatment will be reported in a further communication. Increasing the dose of radiation by HDR brachytherapy boost appears to improve the RO resection and pCR rates compared with conventional CRT. The follow up is too short to judge its effect on disease-free survival. This study will be extended to compare this strategy in a randomized phase III trial with conventional CRT in patients who are not fit for more intensive CRT (HERCULES).

Spontaneous adrenal haemorrhage in a second trimester pregnancy

BackgroundSpontaneous adrenal haemorrhage (SAH) is an acute, spontaneous haemorrhage of the adrenal gland associated with acute abdominal pain in the absence of prior trauma or anticoagulant therapy. It is a...

Progressive multifocal leucoencephalopathy in an immunocompetent patient with favourable outcome. A case report

BackgroundTo report the clinical course of PML in an apparently immunocompetent patient treated with cidofovir.Case PresentationA 35-year-old immunocompetent man who developed progressive hemianopsia, aphasia, and limb weakness underwent repeated MRI scans of the brain, spinal fluid analyses, and brain biopsy. Before diagnosis was established based on brain biopsy, he was consecutively treated with methylprednisolone, acyclovir, ceftriaxone and plasmapheresis, but he deteriorated rapidly suggestive of the immune reconstitution inflammatory syndrome (IRIS). He started to recover two weeks after the initiation of treatment with cidofovir and has had no relapse at 3 1/2 years of follow-up. MRI has shown marked improvement.ConclusionsPML should be considered in immunocompetent patients with a typical clinical course and MRI findings compatible with PML. Treatment with cidofovir should be considered as early as possible in the disease course.