Multiple Cranial Nerve Palsies Research Articles

A Rare Event at Birth: A Case Report of Multiple Cranial Nerve Palsy

A Rare Event at Birth: A Case Report of Multiple Cranial Nerve Palsy

Long-term outcome in neuroZika: When biological diagnosis matters.

To characterize the full spectrum, relative frequency, and prognosis of the neurologic manifestations in Zika virus (ZIKV) postnatal infection. We conducted an observational study in consecutive ZIKV-infected patients presenting with neurologic manifestations during the French West Indies 2016 outbreak. Eighty-seven patients, including 6 children, were enrolled. Ninety-five percent of all cases required hospitalization. Guillain-Barré syndrome was the most frequent manifestation (46.0%) followed by encephalitis or encephalomyelitis (20.7%), isolated single or multiple cranial nerve palsies (9.2%), other peripheral manifestations (6.9%), and stroke (1.1%). Fourteen patients (16.1%), including one child, developed a mixed disorder involving both the central and peripheral nervous system. Mechanical ventilation was required in 21 cases, all of whom had ZIKV RNA in at least one biological fluid. Two adult patients died due to neuroZika. Clinical follow-up (median 14 months; interquartile range, 13-17 months) was available for 76 patients. Residual disability (modified Rankin Scale score ≥2) was identified in 19 (25.0%) patients; in 6 cases (7.9%), disability was severe (modified Rankin Scale score ≥4). Among patients with ZIKV RNA detected in one biological fluid, the risk of residual disability or death was higher (odds ratio 9.19; confidence interval 1.12-75.22; p = 0.039). NeuroZika spectrum represents a heterogeneous group of clinical neurologic manifestations. During an outbreak, clinicians should consider neuroZika in patients presenting with cranial nerve palsies and a mixed neurologic disorder. Long-term sequelae are frequent in NeuroZika. ZIKV reverse-transcription PCR status at admission can inform prognosis and should therefore be taken into consideration in the management of hospitalized patients.

Hypereosinophilic syndrome presenting with inflammation in the retroparotid space and showing Villaret's syndrome

AbstractBackgroundHypereosinophilia syndrome (HES) is a rare disease characterized by the association between hypereosinophilia and eosinophil‐mediated organ infiltration and damage or dysfunction. The cause of hypereosinophilia is classified as neoplastic, reactive and idiopathic. However, hypereosinophilia causes tissue and organ damage, regardless of the underlying etiology. The common manifestations are pulmonary, skin and gastrointestinal. Rarely, neurological lesions are manifested. As neurological lesions of HES, mononeuritis multiplex, radiculopathy, optic neuritis, meningitis and cerebral infarction have been reported.Case presentationA 43‐year‐old woman suffered from dysphagia and hoarseness, after symptoms of fever and sore throat 1 month earlier. On admission, her physical examination was unremarkable, except for neck pain on the right side. The neurological examination showed “Villaret's syndrome”: Horner's sign on the right side, and paralysis of the right glossopharyngeal nerve, vagus nerve, accessory nerve and hypoglossal nerve. Laboratory tests showed marked eosinophilia and it gradually worsened. The maximum eosinophil count increased to 3474/mm3. Magnetic resonance imaging showed a high‐intensity area with contrast effect spreading in the retroparotid space in the short T1 inversion recovery image, and a high‐intensity area spreading in the deep gray matter of the cerebrum in the fluid‐attenuated inversion recovery image. Treatment started with steroid pulse therapy. After therapy, eosinophils normalized on the next day, and multiple cranial nerve palsy improved gradually and normalized. Six months later, the abnormal signal of the retroparotid space had disappeared on magnetic resonance imaging.ConclusionsHES is a multisystem dysfunction secondary to eosinophilic infiltration. In rare cases, HES causes inflammation in the retroparotid space and causes Villaret's syndrome.

Multiple Cranial Nerve Palsies in Mantle Cell Lymphoma: A Case Report and Literature Review

Involvement of cranial nerves is unspecific and can occur in inflammation, different types of nerve tumours and in malignancies. Central Nervous System (CNS) dissemination during the Mantle Cell Lymphoma (MCL) is unusual. We report a rare case of a patient followed for mantle cell lymphoma, which brutally instituted multiple cranial nerve palsies, brain imaging showed a bilateral sphenoid sinusitis. Cytology later showed the presence of mantle cells in cerebrospinal fluid analysis. We review literature for the Central Nervous System involvement in Mantle cell lymphoma and we discuss possible change of therapeutic strategies. Although the cranial nerves involvement is extremely rare in Mantle cell Lymphoma, physicians should be aware of such patterns of Central Nervous System (CNS) involvement for the early diagnosis and adequate selection of treatment modality.

Metachronous nasopharyngeal carcinoma masquerading as a base of skull metastasis in a case of primary extraskeletal vulvar Ewing's sarcoma

Ewing’s sarcoma (ES) and primitive neuroectodermal tumor (PNET) resemble each other and commonly affect the skeletal system. Extraskeletal ES/PNET is a rare neoplasm. Here, we report a case of primary vulvar ES in an 18-year-old adolescent girl confirmed by histopathology and immunohistochemistry, who underwent surgery followed by adjuvant chemotherapy. Following 1 year of chemotherapy, she presented with multiple cranial nerve palsies (VI, IX, X, and XII). Contrast tomography of the base of the skull and nasopharynx showed a heterogeneous mass lesion involving the base of skull, sphenoid sinus, and left nasopharynx. Biopsy from the left nasopharyngeal mass revealed it to be well-differentiated squamous cell carcinoma, which was initially thought of metastasis to the base of the skull. In spite of its aggressive nature, a patient of primary sarcoma presenting with a second lesion should be adequately investigated before considering it as a metastatic lesion.

Invasive aspergillosis of tympanomastoid cavity

Invasive aspergillosis of the tympanomastoid cavity is an extremely rare clinical incidence in comparison to the invasive fungal infections of the paranasal sinus and other parts of the body. Delay in the diagnosis and treatment of this rare clinical entity often leads to fatal complications such as skull base osteomyelitis and progressive multiple cranial nerve palsies. The invasive aspergillosis of the tympanomastoid region should be considered as a differential diagnosis for atypical mastoiditis in immunocompromised patients. Here, we report a case of invasive aspergillosis of the tympanomastoid region in a 60-year-old diabetic patient with facial nerve palsy. The diagnosis was done by the demonstration of fungi in the tissue with Gomori methenamine silver staining and confirmed with molecular diagnosis. Surgical debridement of the tympanomastoid region was done along with long-term voriconazole therapy.

Eye-associated multiple cranial nerve palsies

Eye-associated multiple cranial nerve palsies

CNTNAP1-Related Congenital Hypomyelinating Neuropathy

BackgroundCongenital hypomyelinating neuropathy is a rare form of hereditary peripheral neuropathy characterized by nonprogressive weakness, areflexia, hypotonia, severely reduced nerve conduction velocities, and hypomyelination. Mutations in contactin-associated protein 1 (CNTNAP1) were recently described as a cause of congenital hypomyelinating neuropathy. CNTNAP1-associated congenital hypomyelinating neuropathy is characterized by severe hypotonia, multiple distal joint contractures, and high mortality in the first few months of life. MethodsWhole-exome sequencing was performed in two siblings with congenital hypotonia. Detailed phenotyping data were compared with previously reported cases. ResultsA novel, heterozygous compound mutation of CNTNAP1 was identified in both siblings. We also reviewed 17 patients harboring 10 distinct mutations from previously published studies. All patients presented with severe hypotonia, respiratory distress, and multiple cranial nerve palsies at birth. Six of 19 patients survived beyond infancy and required chronic mechanical ventilation. Seizures were common in the surviving patients. ConclusionsThese findings suggest that CNTNAP1-related congenital hypomyelinating neuropathy is a distinct form of hereditary neuropathy that affects both the central and peripheral nervous systems with no clear phenotype-genotype correlation. Our findings also indicate that arthrogryposis multiplex congenita and early lethality are not universal outcomes for patients with congenital hypomyelinating neuropathy.

Sarcoid uveitis in a patient with multiple neurological lesions: a case report and review of the literature

BackgroundNeurosarcoidosis is a rare complication, and cranial neuropathy is the most frequent manifestation of this disease. However, few cohesive reports have discussed multiple cranial neuropathies in Japanese patients with sarcoidosis. The present report discusses the case of a patient with sarcoid uveitis and multiple neurological findings. We further review relevant literature regarding Japanese patients with multiple cranial nerve palsies published within the past 34 years (from January 1982 to December 2016).Case presentationWe report findings associated with the case of a 56-year-old Japanese woman with granulomatous pan-uveitis who was later diagnosed as having sarcoidosis by skin and transbronchial lung biopsies. She presented right-sided Bell’s palsy and was treated with orally administered prednisolone. However, while prednisolone was tapered, she developed facial (VII) and vagus (X) nerve palsies, followed by brain parenchyma lesions, which were not associated with any additional neurological symptoms. Furthermore, she exhibited increased intraocular pressure in her right eye, and she underwent trabeculectomy. Our review of the literature revealed that 64 Japanese patients with sarcoidosis experienced multiple cranial nerve palsies between 1982 and 2016. The most commonly affected cranial nerves were the facial (VII) (73.4%) and glossopharyngeal/vagus (IX/X) nerves (48.4%). Palsies of two distinct cranial nerves were found in 40.6% of the patients, followed by palsies of three (23.4%) and four (18.8%) nerves. Almost all patients (98.3%) received systemic steroid therapy, and total or partial remission was achieved in almost all patients (96.5%).ConclusionsAccording to the literature, patients with multiple cranial nerve palsies associated with sarcoidosis respond well to orally administered steroid therapy. However, our findings suggest that careful follow-up is necessary for patients with neurosarcoidosis due to potential aggravation of neuropathy.

Lower cranial nerve palsy during radiotherapy for glottic cancer in a patient with Wegener's granulomatosis: An interesting case report.

The aim of the present study was to report an unusual case of multiple lower cranial nerve palsies in a patient with Wegener's granulomatosis (WG) during radiotherapy for glottic cancer. WG is an autoimmune disease characterized by necrotizing granulomas mainly in the upper and lower respiratory tract or kidneys; however, the involvement of cranial nerves is not uncommon. Prior to the use of cyclophosphamide (CYC) the 1-year mortality rate was ~82%; the introduction of rituximab (RTX) has revolutionized the course of the WG, with remission rates comparable to those of CYC and superior effectiveness in relapsing patients. Hypogammaglobulinemia and B-cell depletion are the best known monitored side effects affecting survival due to secondary infections. Immunodepression and relapse with lower cranial nerve palsy have a negative impact on prognosis. We herein present the case of a heavily pre-treated GPA patient with secondary immunosuppression, who underwent radiotherapy for glottic cancer and developed multiple low cranial nerve palsies during treatment, which was interrupted at 60 Gy. The possible related causes and the association between previous immunosuppressive treatments and radiotherapy were also analyzed to elucidate the cause of this complication.

Primary Central Nervous System Lymphoma Presenting with Peripheral Neuropathy; A Rare Case of Coincident PCNSL and Mononeuritis Multiplex

A 43-year-old male presented with diplopia and right sixth-nerve palsy. Brain magnetic resonance imaging (MRI) demonstrated a lesion in the right periventricular area. High-dose corticosteroid pulse therapy did not resolve the symptom. After one month, his diplopia progressed and he developed weakness of the left lower limb. Detailed examination revealed left sixth-nerve palsy, dropped foot, waddling gait, atrophy of the gluteal muscles and mild atrophy and weakness of the right upper limb. Neurological examination supported evidence of multiple cranial nerve palsies along with asymmetrical peripheral neuropathy. Electrodiagnostic studies were compatible with a mononeuritis multiplex. Rheumatologic evaluations were normal. Malignancy work-up were normal, except for some insignificant lymph nodes. Bone marrow aspiration and biopsy were normal. The second brain MRI detected multiple homogenous enhancing lesions in the right periventricular area.The result of stereotactic biopsy and immunohistochemistry staining demonstrated primary B-cell CNS lymphoma (PCNSL). Mononeuritis multiplex has not been reported as a paraneoplastic manifestation of PCNSL yet. In other words, it is not clear whether involvement of the peripheral nervous system in our patient is a paraneoplastic manifestation of PCNSL or a coincidence of PCNSL and hematologic lymphoma presenting with peripheral vasculitic neuropathy. It is recommendedthat future studies focus more on symptoms associated with PCNSL to recognize the exact relationship between PCNSL and peripheral neuropathy.

Zoster Laryngitis with Multiple Cranial Nerve Palsy Progressed as Ascending Involvement

Background Herpes zoster of the head and neck commonly presents with Ramsay Hunt syndrome. However, vesicular eruptions may occur on the pharyngeal or laryngeal area with multiple lower cranial-nerve (CN) palsy. Case Report We report on the case of a 54-year-old man with herpes zoster of the pharynx and larynx with multiple CN palsy and persistent hiccups. He initially developed progressive dysphagia, hoarseness, and persistent hiccups (CN IX and X). After admission, Dizziness, hearing impairment, and peripheral facial palsy (CN VII and VIII) were complicated. The results of a polymerase chain reaction test of saliva and vesicular fluid from the ear and throat were strongly positive for varicella zoster virus. The progression of CN palsy was in an ascending sequence. Conclusion We suggest that the sequence of CN palsy may be either ascending or descending, depending on the initial site of involvement. Key Words: Herpes zoster; Cranial nerve diseases; Laryngitis; Hiccup

The Role of Surgical Debridement in Cases of Refractory Malignant Otitis Externa.

Malignant Otitis externa is a necrotizing condition of external ear involving causing the osteomyelitis of the bone and surrounding soft tissue leading to multiple cranial nerve palsies. Though most patients respond to oral ciprofloxacin but due to emerging resistance cases of refractory malignant otitis externa which are unresponsive to antibiotic therapy for at least 6weeks are being encountered lately. A study of 20 patients of refractory malignant otitis Externa was conducted at a tertiary care centre in north India; 10 patients were randomly allotted in group A and group B each. Group A was subjected to i/v ceftazidine 1 gm bd with oral ciprofloxacin 750mg bd and Group B was subjected to surgical debridement with oral ciprofloxacin 750mg bd. The improvement in symptoms was tabulated and statistical analysis was done using Mann-Whitney U test. There was better resolution of nocturnal pain in patients of group B who underwent surgical debridement although existing facial palsy didn't improve in both the groups. The improvement of symptoms in group B was statistically significant with P ≤ 0.05. We strongly recommend the role of surgical debridement in cases of refractory malignant otitis externa to relieve the patient of nocturnal pain. As the sample size of the study is small we are looking forward to the compilation of a multi institutional data so that a consensus on definitive protocol in cases unresponsive to oral multidrug therapy can be established.

P.032 Cavernous sinus masses: An unusual case and review of the literature

Background: We present a 67-year-old male with a two-week history of progressive double vision. Past medical history included oropharyngeal SCC, T4N2cM0, post-CCRT, and remote sarcoidosis. Clinically, the patient had multiple cranial nerve palsies affecting bilateral occular motor function. Neuroimaging showed an enhancing mass involving the sella and cavernous sinuses. Whole-body PET showed FDG-avid lesions in the sella and liver. Transsphenoidal biopsy of the sellar mass was obtained for tissue diagnosis. Methods: Details of the case were obtained from the patient’s EMR. Neuroimaging and neuropathology were reviewed with the appropriate subspecialists. A literature search was performed using multiple databases (PubMed, Web-of-Science) and relevant articles were included for review. Results: Sellar mass biopsy confirmed p16+ve SCC, identical to the patient’s known primary malignancy. On review of enhanced skull-base images, there was no evidence of direct tumor extension, favouring hematogenous spread. Conclusions: This case demonstrates the localizing potential of cavernous sinus masses. SCC metastases to the cavernous sinus are rare, and confer a poor prognosis.The presence of a p16 mutation has public health implications, as this mutation demonstrates more frequent and aggressive distant metastatic potential, and as a surrogate marker for high-risk HPV infection, represents a preventable risk-factor for a rapidly increasing cause of head and neck cancer in the Western world.

Primary Skull Base Lymphoma: Manifestations and Clinical Outcomes of a Great Imitator.

Objectives Primary skull base lymphoma (PSBL) represents a rare manifestation of extranodal lymphoma. Presenting with nonspecific symptomatology and imaging findings, PSBL often masquerades as more common cranial base pathology and thus can present a diagnostic challenge. The objectives of this study were to characterize the manifestations and clinical outcomes of PSBL. Study Design Case series and chart review. Setting Tertiary referral center. Subjects and Methods Review of 48 patients with PSBL treated between 1994 and 2016. Results The median age at diagnosis was 60 years. Diffuse large B-cell lymphoma comprised the most common subtype (56%). Presenting symptoms included diplopia (52%), trigeminal hypesthesia (38%), headache (29%), facial nerve weakness (25%), B-symptoms (fevers, night sweats, and/or weight loss) (25%), and hearing loss (21%). Discrete lesions commonly mimicked meningioma, schwannoma, and nasopharyngeal carcinoma. Diffuse lesions imitated neurosarcoidosis, granulomatosis with polyangiitis, and carcinomatosis meningitis. Only 26% of all initial clinical evaluations suspected lymphoma. The combination of restricted diffusion on diffusion-weighted imaging, an absence of flow voids or surrounding hyperostosis, bony erosion and/or marrow signal replacement, and heterogeneous contrast enhancement facilitated delineation between PSBL and common skull base pathology. Cerebrospinal fluid (CSF) analysis was diagnostic of lymphoma in 24% of cases. Lymphoma within CSF portended significantly worse overall survival (85% vs 18% at 3-years; P < .001). Conclusion A history significant for multiple cranial nerve palsies, B-symptoms, and imaging findings inconsistent with common skull base pathology should raise suspicion for PSBL. CSF analysis in the setting of PSBL can provide diagnostic and prognostic value for patients.

Syringobulbia in pediatric patients with Chiari malformation type I.

OBJECTIVE Syringobulbia (SB) is a rare entity, with few cases associated with Chiari malformation type I (CM-I) in the pediatric population. The authors reviewed all pediatric cases of CM-I-associated SB managed at their institution in order to better understand the presentation, treatment, and surgical outcomes of this condition. METHODS A prospectively maintained institutional database of craniovertebral junction abnormalities was analyzed to identify all cases of CM-I and SB from the MRI era (i.e., after 1984). The authors recorded presenting symptoms, physical examination findings, radiological findings, surgical treatment strategy, intraoperative findings, and outcomes. SB cases associated with tumors, infections, or type II Chiari malformations were excluded. RESULTS The authors identified 326 pediatric patients with CM-I who were surgically treated. SB was identified in 13 (4%) of these 326 patients. Headache and neck pain were noted in all 13 cases. Cranial nerve abnormalities were common: vagus and glossopharyngeal nerve dysfunction was the most frequent observation. Other cranial nerves affected included the trigeminal, abducens, and hypoglossal nerves. Several patients exhibited multiple cranial nerve palsies at presentation. Central sleep apnea was present in 6 patients. Syringomyelia (SM) was present in all 13 patients. SB involved the medulla in all cases, and extended rostrally into the pons and midbrain in 2 patients; in 1 of these 2 cases the cavity extended further rostrally to the cerebrum (syringocephaly). SB communicated with the fourth ventricle in 7 of the 13 cases. All 13 patients were treated with posterior fossa decompression with intradural exploration to ensure CSF egress out of the fourth ventricle and through the foramen magnum. The foramen of Magendie was found to be occluded by an arachnoid veil in 9 cases. Follow-up evaluation revealed that SB improved before SM. Cranial nerve palsies regressed in 11 of the 13 patients, and SB improved in all 13. CONCLUSIONS The incidence of SB in our surgical series of pediatric patients with CM-I was 4%, and all of these patients had accompanying SM. The SB cavity involved the medulla in all cases and was found to communicate with the fourth ventricle in 54% of cases. Posterior fossa decompression with intradural exploration and duraplasty is an effective treatment for these patients.

Botulinum toxin as an initial therapy for management of sixth nerve palsies caused by nasopharyngeal carcinomas.

PurposeThe purpose of this study is to evaluate the efficacy and safety of botulinum toxin injection as a primary treatment for strabismus in a cohort of patients with nasopharyngeal carcinoma (NPC)-related chronic sixth nerve palsy.Patients and methodsWe retrospectively reviewed all cases of NPC-related sixth nerve palsy receiving botulinum toxin injection in the Hong Kong Eye Hospital between January 2009 and January 2016. Only cases with diplopia for at least 6 months; and failed a trial of Fresnel prism therapy were recruited. We excluded cases with prior strabismus surgery and multiple cranial nerve palsies. Patients were offered botulinum toxin injection as primary treatment for their strabismus and were given further injections or offered surgery if diplopia persisted. Success with botulinum toxin was defined as a final distant orthophoria of <15 PD in primary gaze, no diplopia in primary position, and no head turn, as measured 6 months after the last injection, without requiring a second treatment.ResultsA total of 25 patients were included in the study. All patients received concurrent chemo-radiotherapy for NPC. There was a statistically significant reduction in the mean deviation at distant after the last injection compared to that at presentation (P<0.001, Wilcoxin signed rank test). Overall, 7 patients (28%) achieved clinical success and 15 patients (64%) remained diplopia-free by repeated botulinum toxin injections alone. Nine patients went on to receive definitive surgery and all achieved good ocular alignment after surgery. Transient ptosis or vertical deviation was seen in 7 patients, which resolved within 3 months and no serious complications arose from the treatment in our series.ConclusionsBotulinum toxin injection is a relatively less-invasive alternative to surgery that can be done under a topical anesthesia setting, which improves patient's quality of life via reduction in diplopia. It is a recommendable initial option in patients with chronic nerve palsies who may have higher risks associated with strabismus surgery.

Neurocutaneous Melanosis with Bilateral Temporal Lobe Lesions without Leptomeningeal Enhancement: A Distinct Entity or Subtype.

Neurocutaneous melanosis (NCM) is a rare congenital disorder. Most of the cases described in literature for this entity have involvement of the leptomeninges and other structures of brain such as brain stem, temporal lobes, and spinal meninges and no involvement of leptomeninges and presence of lesions in bilateral temporal lobes. NCM without the involvement of leptomeninges should be considered a distinct entity as the prognosis is favorable as compared to cases with leptomeningeal involvement who develop early hydrocephalus and multiple cranial nerve palsies.

Clinicoradiological aspects of pontine tegmental cap dysplasia: Case report of a rare hindbrain malformation.

Malformations involving the brainstem are very rare and present with a varied spectrum of clinical symptoms due to multiple cranial nerve palsies and pyramidal tract involvement. Of these, pontine tegmental cap dysplasia is a very unusual malformation, characterized by ventral pons hypoplasia and an ectopic dorsal band of tissue, projecting into the fourth ventricle, from dorsal pontine tegmentum. A 4-year-old male child, presenting with left facial nerve palsy, revealed hypoplastic ventral pons and an ectopic structure on magnetic resonance imaging (MRI). The ectopic structure was isointense to pons, arose from the left side of dorsal pontine tegmentum, at pontomedullary junction and protruded into the fourth ventricle, impinging upon the left seventh and eighth cranial nerves. Diffusion tensor imaging (DTI) depicted abnormal white matter tracts in ectopic tissue with absent transverse pontine fibres and abnormal middle and superior cerebellar peduncles. The typical MRI appearance, coupled with DTI, helped us reach an accurate diagnosis of pontine tegmental cap dysplasia, in a setting of neurological dysfunction.

Oculomotor palsy in diabetics

Oculomotor palsy is one of the most frequent neuro-ophthalmologic complications of diabetic patients. It generates less interest in the literature than the other ocular manifestations. Our goal was to study the clinical, epidemiological, therapeutic and prognostic characteristics of oculomotor palsy in the diabetic. This is a retrospective study of 24 diabetic patients with oculomotor palsy. The ophthalmological examination emphasized ocular motility. We performed an orthoptic assessment and a Hess-Lancaster test. Neuro-imaging was ordered in case of IIIrd and IVth nerve involvement, bilateral involvement, multiple ocular cranial nerve palsy or associated optic neuropathy. Treatment consisted of glucose management and alternating monocular occlusion or prisms for the diplopia. Data were entered and analyzed on SPSS 11.5 software. The mean age of the patients was 58.5±11.9 years. Binocular diplopia was the main symptom. The oculomotor palsy involved the VIth nerve in 50% of cases and was bilateral in two cases. Three patients also had an optic neuropathy. The mean duration of diabetes was 11.7±11 years; poorly controlled diabetes was found in 75% of cases and an association with diabetic retinopathy was noted in 56% of cases. Long-standing uncontrolled type 2 diabetes, hypertension, coronary artery disease, left ventricular hypertrophy, and elevated hematocrit are the most common risk factors. The VIth nerve is commonly involved. Certain characteristics of the pupillary light reflex can help to differentiate an ischemic insult from an aneurysmal injury to the IIIrd nerve.