"Ears of the Lynx" MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia.

BACKGROUND AND PURPOSE: The "ears of the lynx" MR imaging sign has been described in case reports of hereditary spastic paraplegia with a thin corpus callosum, mostly associated with mutations in the spatacsin vesicle trafficking associated gene, causing Spastic Paraplegia type 11 (SPG11). This sign corresponds to long T1 and T2 values in the forceps minor of the corpus callosum, which appears hyperintense on FLAIR and hypointense on T1-weighted images. Our purpose was to determine the sensitivity and specificity of the ears of the lynx MR imaging sign for genetic cases compared with common potential mimics. MATERIALS AND METHODS: Four independent raters, blinded to the diagnosis, determined whether the ears of the lynx sign was present in each of a set of 204 single anonymized FLAIR and T1-weighted MR images from 34 patients with causal mutations associated with SPG11 or Spastic Paraplegia type 15 (SPG15). 34 healthy controls, and 34 patients with multiple sclerosis. RESULTS: The interrater reliability for FLAIR images was substantial (Cohen κ, 0.66-0.77). For these images, the sensitivity of the ears of the lynx sign across raters ranged from 78.8 to 97.0 and the specificity ranged from 90.9 to 100. The accuracy of the sign, measured by area under the receiver operating characteristic curve, ranged from very good (87.1) to excellent (93.9). CONCLUSIONS: The ears of the lynx sign on FLAIR MR imaging is highly specific for the most common genetic subtypes of hereditary spastic paraplegia with a thin corpus callosum. When this sign is present, there is a high likelihood of a genetic mutation, particularly associated with SPG11 or SPG15, even in the absence of a family history.

Aggressive leptomeningeal hemangioblastomatosis of the central nervous system in a patient with von Hippel-Lindau disease.

Hemangioblastomas of the central nervous system are the most common tumors seen in patients with von Hippel-Lindau (VHL) disease. A very rare case of diffuse leptomeningeal hemangioblastomatosis obliterating large areas of the subarachnoid space, both intracranial and within the spinal canal, which developed during a relatively short period, in a patient with VHL disease is presented.

Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship.

Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least eight overlapping phenotypes. The clinical features of these patients have some similarities but also have marked differences. NER is involved in protection against sunlight-induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes.

The neurogenetics of mucolipidosis type IV.

BACKGROUND: Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family. OBJECTIVE: To comprehensively characterize the clinical and genetic abnormalities of MLIV. METHODS: Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every 1 to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used. RESULTS: All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found. CONCLUSIONS: MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.

Meningiomas in lymphangioleiomyomatosis.

CONTEXT: Lymphangioleiomyomatosis (LAM), a cystic lung disease associated with progressive respiratory failure, is found predominantly in women of childbearing age and therefore has been treated with progesterone and other hormonal agents. However, meningiomas have progesterone receptors, and progesterone is believed to be a mitogen for meningioma cells in culture. Since 30% to 40% of patients with tuberous sclerosis complex (TSC) have LAM, we routinely screen patients with LAM for brain lesions found in TSC. OBJECTIVE: To determine the prevalence of meningiomas in women with LAM. DESIGN AND SETTING: Analysis of results from ongoing routine screening protocols initiated in December 1995 at the National Heart, Lung, and Blood Institute. PATIENTS: Two hundred fifty women with sporadic LAM who were referred for screening by magnetic resonance imaging (MRI) and/or computed tomography (CT) of the brain. MAIN OUTCOME MEASURES: Presence of meningiomas on MRI and/or CT scans. RESULTS: Eight women with LAM (3 with and 5 without a diagnosis of TSC) had lesions on MRI scans compatible with meningiomas. Five of the patients had been treated with progesterone. Multiple meningiomas were observed in 2 patients. CONCLUSIONS: Women with LAM appear to have a high prevalence of meningiomas. We recommend that patients with LAM be screened for meningiomas regardless of diagnosis of TSC. In view of the lack of a documented effect of progesterone on progression of lung disease in LAM and the reported mitogenic response of meningiomas to progesterone, we recommend that the drug not be given to LAM patients with an MRI result consistent with diagnosis of meningioma.

MR virtual angioscopy of thoracic aortic atherosclerosis in homozygous familial hypercholesterolemia.

PURPOSE: The thoracic aorta is an important site of atherosclerotic disease in patients with homozygous familial hypercholesterolemia (HFH). Thoracic aortic atherosclerosis in patients with HFH was assessed with contrast-enhanced MR angiograms using exoscopic and endoscopic virtual angioscopy reconstructions and maximum intensity projections (MIPs). METHOD: Contrast-enhanced MR angiograms of the thoracic aorta of 15 patients with HFH and 8 normal volunteers were obtained. Perspective surface reconstructions of the MR angiograms including virtual angioscopy views were evaluated by three radiologists blinded to the diagnosis. RESULTS: Thoracic wall irregularity was depicted on 8 of 15 (53%) patient scans and only 1 of 8 (13%) normal subject scans using surface reconstructions. Wall irregularity scores of patients with HFH were significantly increased compared with controls (2.0 +/- 0.9 vs. 1.0 +/- 0.6; p = 0.008). There was excellent interobserver agreement (weighted kappa = 0.82 +/- 0.12). Virtual endoscopy views added diagnostic confidence compared with exoscopic surface renderings alone. MIP reconstructions were unable to depict wall irregularity. CONCLUSION: MR angiography with virtual angioscopy of the thoracic aorta depicts nonstenotic wall irregularity of thoracic aortic atherosclerosis in patients with HFH. This may be important for assessing disease progression and response to treatment and may be generalizable to routine (non-HFH) atherosclerosis.

Intramedullary and spinal canal tumors in patients with neurofibromatosis 2: MR imaging findings and correlation with genotype.

PURPOSE: To determine the appearance of spinal tumors on magnetic resonance (MR) images of patients with neurofibromatosis 2 (NF2), to assess the biologic behavior of these tumors, and to determine the correlation between NF2 germline mutations and these tumors. MATERIALS AND METHODS: Spinal MR images in 49 patients with NF2 were reviewed retrospectively. Intramedullary and intradural extramedullary tumors were counted, and imaging features and growth patterns of intramedullary tumors were determined. Medical records were reviewed for spinal tumor surgery. Data on spinal tumors and NF2 germline mutations in 37 patients from 19 families were analyzed for genotype-phenotype correlation. RESULTS: Thirty-one patients (63%) had spinal tumors: Twenty-six (53%) had intramedullary tumors, 27 (55%) had intradural extramedullary tumors, and 22 (45%) had at least one tumor of each type. Three (12%) patients with intramedullary tumors versus 16 (59%) with extramedullary tumors had undergone surgery for the respective types of tumors. Compared with patients with all other types of mutations, a higher percentage of patients with nonsense and frameshift mutations had intramedullary tumors (P <.025); these patients also had higher mean numbers of all tumors (P <.001), intramedullary tumors (P <.001), and nerve sheath tumors (NSTs) (P <.001). CONCLUSION: In patients with NF2 and spinal tumors, extramedullary tumors (predominantly NSTs) were present in higher numbers and were associated with more surgery than were intramedullary tumors. Our data suggest that the association between nonsense and frameshift mutations and severe NF2 may extend to specific categories of spinal tumors.

Do glucocorticoids cause spinal epidural lipomatosis? When endocrinology and spinal surgery meet.

Here, we report pathogenetic aspects of spinal epidural lipomatosis (SEL) based on a literature review. SEL is a rare entity but can cause significant morbidity. Its symptoms can be identical to those of more common disorders such as vertebral and disc disease, and cord lesions (for example, transverse myelitis, multiple sclerosis and syringomyelia). Therefore, it often goes undiagnosed. In addition, SEL occurs in patients on glucocorticoid therapy, which can lead to myopathy, thereby mimicking the motor symptoms of SEL. Glucocorticoids seem to play a major role in the development of SEL, although idiopathic SEL has also been reported. The latter occurs almost exclusively in obese individuals who may have concurrent hypercortisolism. Once clinically suspected, SEL is best diagnosed by magnetic resonance imaging (MRI). Treatment of SEL is directed at reducing body weight in patients with idiopathic SEL, and at decreasing glucocorticoid excess in patients with endogenous or exogenous hypercortisolism. In severe cases, decompressive laminectomy might become necessary to alleviate the neurological symptoms caused by spinal cord compression.

Cushing's disease presenting with avascular necrosis of the hip: an orthopedic emergency.

Nontraumatic avascular necrosis (AVN) of the hip is commonly caused by exogenous glucocorticoid administration, whereas it has rarely been associated with endogenous hypercortisolism. We report a 30-yr-old woman with Cushing's disease whose presenting manifestation was early AVN of the hip. Although plain x-ray was negative, magnetic resonance imaging (MRI) of the hip showed stage 2 AVN. Her orthopedic disease was considered an emergency, and thus, it was treated with core decompression before the diagnosis of Cushing's syndrome (CS) was pursued further. The femur recovered fully, as demonstrated by her improved clinical picture and a subsequent MRI. AVN carries a poor prognosis, if not treated early. The diagnostic procedure of choice is MRI, because plain radiographs are falsely negative in early stages. This case illustrates that AVN can be the presenting manifestation of CS; to prevent irreversible effects on the femoral head, core decompression should not be delayed for the purpose of evaluation and treatment of CS.

Edema associated with calcified lesions in neurocysticercosis.

OBJECTIVE: To determine serial MRI and CT abnormalities around calcified cysts due to cysticercosis in previously treated patients during periods of seizure activity. BACKGROUND: Some patients with calcified lesions due to cysticercosis have seizures. How and why seizures occur in this setting are unknown. METHODS: Three patients with known, treated cysticercosis were studied prospectively by serial MRI and CT before, during, and after seizure activity. RESULTS: All three patients demonstrated edema surrounding calcified lesions. Two of three patients had repeated episodes involving the same calcified lesions, and their symptoms corresponded to the location of the lesion. Enhancement was present in the lesions demonstrating edema, but was also present surrounding other nonsymptomatic calcified lesions. CONCLUSIONS: Perilesional edema surrounding calcified lesions due to cysticercosis occurs in some patients at the time of seizure activity. Repeated seizure episodes tend to be associated with the same lesions. Although the mechanisms involved are unknown, long-term antiseizure medication is likely indicated in these patients. Current evidence does not support the use of specific antiparasitic treatment in these patients.

Incidental findings on brain magnetic resonance imaging from 1000 asymptomatic volunteers.

CONTEXT: Previous reports have discussed incidental disease found on brain magnetic resonance imaging (MRI) scans that had been requested for an unrelated clinical concern or symptom, resulting in a selection bias for disease. However, the prevalence of unexpected abnormalities has not been studied in a healthy population. OBJECTIVE: To evaluate the prevalence of incidental findings on brain MRI scans obtained for a healthy, asymptomatic population without selection bias. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of brain MRI scans obtained between May 17, 1996, and July 25, 1997, from 1000 volunteers who participated as control subjects for various research protocols at the National Institutes of Health. All participants (age range, 3-83 years; 54.6% male) were determined to be healthy and asymptomatic by physician examination and participant history. MAIN OUTCOME MEASURE: Prevalence of abnormalities on brain MRI by category of finding (no referral necessary, routine referral, urgent referral [within 1 week of study], and immediate referral [within 1 to several days of study]). RESULTS: Eighty-two percent of the MRI results were normal. Of the 18% demonstrating incidental abnormal findings, 15.1% required no referral; 1.8%, routine referral; 1.1%, urgent referral; and 0%, immediate referral. In subjects grouped for urgent referral, 2 confirmed primary brain tumors (and a possible but unconfirmed third) were found, demonstrating a prevalence of at least 0.2%. CONCLUSION: Asymptomatic subjects present with a variety of abnormalities, providing valuable information on disease prevalence in a presumed healthy population. A small percentage of these findings require urgent medical attention and/or additional studies.

Treatment of autoimmune premature ovarian failure.

There is no known immunosuppressive therapy for autoimmune premature ovarian failure that has been proven safe and effective by prospective randomized placebo-controlled study. Nevertheless, immunosuppression using corticosteroids has been used on an empirical basis for this condition. Here we present two cases of young women with premature ovarian failure who were treated with glucocorticoids in the hopes of restoring fertility. The first case illustrates the potential benefit of such therapy, and the second case illustrates a potential risk. The first patient with histologically proven autoimmune oophoritis was treated with alternate day glucocorticoid treatment. She had return of menstrual bleeding six times and ovulatory progesterone concentrations four times over a 16 week period. The second patient with presumed but unconfirmed autoimmune ovarian failure was referred to us after having been treated with a 9 month course of corticosteroids. During that treatment her menses did not resume. The corticosteroid treatment was complicated by iatrogenic Cushing syndrome and osteonecrosis of the knee. Identifying patients with autoimmune premature ovarian failure presents the opportunity to restore ovarian function by treating these patients with the proper immune modulation therapy. On the other hand, potent immune modulation therapy can have major complications. Corticosteroid therapy for autoimmune premature ovarian failure should be limited to use in placebo-controlled trials designed to evaluate the safety and efficacy of such treatment.

Bilateral condylar resorption in dermatomyositis: a case report.

Polymyositis is an inflammatory disease commonly affecting the striated muscle. When it is accompanied by characteristic skin lesions, the condition is called dermatomyositis. Bilateral condylar resorption has been reported with autoimmune conditions and chronic systemic steroids. We report the first documented case of bilateral condylar resorption in a patient with dermatomyositis. Possible etiologic factors and treatment outcomes are discussed.

Pituitary involvement by Wegener's granulomatosis: a report of two cases.

We describe two cases of pituitary involvement by Wegener's granulomatosis. At initial presentation, or during subsequent disease "flares," a pattern of pituitary abnormality was suggested. During periods of remission, we found the pituitary returned to a nearly normal appearance. Loss of the normal posterior pituitary T1 hyper-intensity matched a clinical persistence of diabetes insipidus, suggesting there is permanent damage to this structure by the initial disease process.

Juvenile idiopathic inflammatory myopathy: exercise-induced changes in muscle at short inversion time inversion-recovery MR imaging.

PURPOSE: To study the effect of exercise on short inversion time inversion-recovery (STIR) magnetic resonance (MR) images of thigh muscles in children with juvenile idiopathic inflammatory myopathy. MATERIALS AND METHODS: Thirty-two MR studies were performed in 19 patients with juvenile idiopathic inflammatory myopathy who performed stair-stepping exercise for up to 10 minutes (mean, 5.7 minutes). Baseline T1-weighted (n = 32) and STIR (n = 32) images and STIR images immediately (n = 32) and at 30 (n = 24) and 60 (n = 29) minutes after exercise were obtained at 0.5 T. Four radiologists graded STIR signal intensity changes, in observer performance experiments in which they were blinded to the order of image acquisition in relation to exercise. RESULTS: Changes in muscle signal intensity were observed on STIR images obtained immediately after exercise in 20 of 32 (63%) studies. The mean signal intensity score immediately after exercise (1.7 +/- 1.0 [SD]) increased compared with the mean baseline score (1.4 +/- 1.1) (P = .0005) and resolved by 30 minutes after exercise. The magnitude of exercise-induced changes correlated with the amount of work performed (r = 0.51, P = .003) but not with disease activity or baseline signal intensity when the changes were corrected for work (r < 0.17, P > .35). Radiologists demonstrated moderate to substantial agreement in the grading of signal intensity changes after exercise (kappa = 0.60-0.84). CONCLUSION: In patients with juvenile idiopathic inflammatory myopathy, stair-stepping exercise induces signal intensity changes on STIR MR studies of muscle for approximately 30 minutes after exercise, in a distribution that may mimic active muscle inflammation.

Mucolipidosis type IV: characteristic MRI findings.

OBJECTIVE: The objective of this study is to characterize the brain abnormalities on head MRI of patients with mucolipidosis type IV. BACKGROUND: Mucolipidosis type IV is an autosomal recessive lysosomal storage disease of unknown etiology. Patients develop corneal clouding, retinal degeneration, spastic quadriparesis, and mental retardation. Patients with this disorder have not been studied systematically. METHODS: We studied prospectively 15 consecutive patients with mucolipidosis type IV using cranial MRI. RESULTS: Fourteen patients with these typical clinical findings had a hypoplastic corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities on T1-weighted head MRI images in the white matter, and increased ferritin deposition in the thalamus and basal ganglia. Atrophy of the cerebellum and cerebrum was observed in older patients, which may reflect disease progression. One patient with a mild clinical variant had a normal corpus callosum. CONCLUSION: Patients with mucolipidosis type IV have characteristic cranial MRI findings that suggest that this disorder causes both developmental and neurodegenerative abnormalities.

Proton magnetic resonance spectroscopic imaging in the clinical evaluation of patients with Niemann-Pick type C disease.

OBJECTIVES: 10 patients with Niemann-Pick disease type C (NP-C) were studied by proton magnetic resonance spectroscopic imaging (1H-MRSI) to assess the biochemical pathology of the brain and to determine whether this method can be useful to clinically evaluate these patients. METHODS: 1H-MRSI permits the simultaneous measurement of N-acetyl aspartate (NA), compounds containing choline (Cho), creatine plus phosphocreatine (Cre), and lactate (Lac) signal intensities from four 15 mm slices divided into 0.84 ml single volume elements. Spectroscopic voxels were identified from seven regions of interest. RESULTS: In patients with NP-C, NA/Cre was significantly decreased in the frontal and parietal cortices, centrum semiovale, and caudate nucleus; Cho/Cre was significantly increased in the frontal cortex and centrum semiovale. Significant correlations were found between clinical staging scale scores and 1H-MRSI abnormalities. CONCLUSION: 1H-MRSI showed diffuse brain involvement in patients with NP-C consistent with the pathological features of the disease. 1H-MRSI is an objective and sensitive tool to neurologically evaluate patients with NP-C.

Quantitative analysis of cerebral vasculopathy in patients with Fabry disease.

OBJECTIVE: This study's purpose was to obtain a quantitative natural history of the cerebrovascular involvement in Fabry disease. BACKGROUND: Fabry disease is an X-linked recessive disorder due to alpha-galactosidase A deficiency. Progressive accumulation of ceramidetrihexoside within the intima and media of cerebral blood vessels causes ischemic lesions in the majority of affected patients. Determination of the natural history of the cerebral vasculopathy in Fabry disease is important to assess the effects of therapeutic intervention in this disorder. METHODS: A longitudinal MRI study of 50 patients who had a total of 129 MRI scans was performed. The burden of cerebrovascular disease was determined using direct linear measurement. RESULTS: On T2-weighted MRI scans, 32% of the patients had no lesions (mean age, 33 years), 16% had gray matter lesions only (mean age, 36 years), 26% had lesions in white matter only (mean age, 43 years), and 26% had lesions in white and gray matter (mean age, 47 years). Disease burden increased with age, but no patient younger than 26 had lesions on MRI. All patients older than 54 had cerebrovascular involvement. The distribution of MRI-detectable lesions was typical of a small-vessel disease. Only 37.5% of patients with cerebral lesions had neurologic symptoms. CONCLUSION: These findings provide a predictable outcome measure to assess the effect of molecular interventions on the cerebrovascular circulation in Fabry disease.