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In the United States, acute low back pain, with or without radiculopathy, is the leading cause of years lived with disability and the third ranking cause of disability-adjusted life-years. Uncomplicated acute low back pain and/or radiculopathy is a benign, self-limited condition that does not warrant any imaging studies. Imaging is considered in those patients who have had up to 6 weeks of medical management and physical therapy that resulted in little or no improvement in their back pain. It is also considered for those patients presenting with red flags, raising suspicion for a serious underlying condition, such as cauda equina syndrome, malignancy, fracture, or infection. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Cerebrovascular disease is a broad topic. This document focuses on the imaging recommendations for the varied clinical scenarios involving intracranial aneurysms, vascular malformations, and vasculitis, which all carry high risk of morbidity and mortality. Additional imaging recommendations regarding complications of these conditions, including subarachnoid hemorrhage and vasospasm, are also covered. While each variant presentation has unique imaging recommendations, the major focus of this document is neurovascular imaging techniques. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Syncope and presyncope lead to well over one million emergency room visits in the United States each year. Elucidating the cause of syncope or presyncope, which are grouped together given similar etiologies and outcomes, can be exceedingly difficult given the diverse etiologies. This becomes more challenging as some causes, such as vasovagal syncope, are relatively innocuous while others, such as cardiac-related syncope, carry a significant increased risk of death. While the mainstay of syncope and presyncope assessment is a detailed history and physical examination, imaging can play a role in certain situations. In patients where a cardiovascular etiology is suspected based on the appropriate history, physical examination, and ECG findings, resting transthoracic echocardiography is usually considered appropriate for the initial imaging. While no imaging studies are considered usually appropriate when there is a low probability of cardiac or neurologic pathology, chest radiography may be appropriate in certain clinical situations. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Movement disorders and neurodegenerative diseases are a variety of conditions that involve progressive neuronal degeneration, injury, or death. Establishing the correct diagnosis of a movement disorder or neurodegenerative process can be difficult due to the variable features of these conditions, unusual clinical presentations, and overlapping symptoms and characteristics. MRI has an important role in the initial assessment of these patients, although a combination of imaging and laboratory and genetic tests is often needed for complete evaluation and management. This document summarizes the imaging appropriateness data for rapidly progressive dementia, chorea, Parkinsonian syndromes, suspected neurodegeneration with brain iron accumulation, and suspected motor neuron disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Degenerative disease of the central nervous system is a growing public health concern. The primary role of neuroimaging in the workup of patients with probable or possible Alzheimer disease has typically been to exclude other significant intracranial abnormalities. In general, the imaging findings in structural studies, such as MRI, are nonspecific and have limited potential in differentiating different types of dementia. Advanced imaging methods are not routinely used in community or general practices for the diagnosis or differentiation of forms of dementia. Nonetheless, in patients who have been evaluated by a dementia expert, FDG-PET helps to distinguish Alzheimer disease from frontotemporal dementia. In patients with suspected dementia with Lewy bodies, functional imaging of the dopamine transporter (ioflupane) using SPECT may be helpful. In patients with suspected normal-pressure hydrocephalus, DTPA cisternography and HMPAO SPECT/CT brain may provide assessment. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Ataxia can result from an abnormality in the cerebellum, spinal cord, peripheral nerves, and/or vestibular system. Pathology involving the brain, such as infarct or hydrocephalus, can also present with ataxia as part of the symptom constitution, or result in symptoms that mimic ataxia. Clinical evaluation by history and careful neurological examination is important to help with lesion localization, and helps determine where imaging should be focused. In the setting of trauma with the area of suspicion in the brain, a head CT without intravenous contrast is the preferred initial imaging choice. If vascular injury is suspected, CTA of the neck can be helpful. When the area of suspicion is in the spine, CT or MRI of the spine can be considered to assess for bony or soft-tissue injury, respectively. In the setting of ataxia unrelated to recent trauma, MRI is the preferred imaging modality, tailored to assess the brain or spine depending on the area of suspected pathology. The use of intravenous contrast is generally helpful. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Neuroendocrine dysfunction includes suspected hyper- and hypofunction of the pituitary gland. Causative lesions may include primary masses of the pituitary such as pituitary microadenomas and macroadenomas, as well as extrinsic masses, typically centered in the suprasellar cistern. Clinical syndromes related to hormonal dysfunction can be caused by excessive hormonal secretion or by inhibited secretion due to mass effect upon elements of the hypothalamic-pituitary axis. Additionally, complications such as hemorrhage may be seen in the setting of an underlying mass and can result in hormonal dysfunction. MRI with high-resolution protocols is the best first-line test to evaluate the sella turcica and parasellar region. CT provides complementary information regarding bony anatomy, and may be appropriate as a first-line test in certain instances, but it provides less detail and lesion characterization when compared to MRI. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Visual loss can be the result of an abnormality anywhere along the visual pathway including the globe, optic nerve, optic chiasm, optic tract, thalamus, optic radiations or primary visual cortex. Appropriate imaging analysis of visual loss is facilitated by a compartmental approach that establishes a differential diagnosis on the basis of suspected lesion location and specific clinical features. CT and MRI are the primary imaging modalities used to evaluate patients with visual loss and are often complementary in evaluating these patients. One modality may be preferred over the other depending on the specific clinical scenario. Depending on the pattern of visual loss and differential diagnosis, imaging coverage may require targeted evaluation of the orbits and/or assessment of the brain. Contrast is preferred when masses and inflammatory processes are differential considerations. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Objective To determine the diagnostic value of acute infarcts in multiple cerebral circulations (AIMCC) on MRI diffusion-weighted imaging (DWI) for cardioembolism (CE) stroke subtype in adult patients hospitalized with acute ischemic stroke, we conducted a systematic literature review and meta-analysis. Methods MEDLINE was searched via PubMed for articles reporting patients hospitalized with acute ischemic stroke with MRI DWI categorized as AIMCC vs other and use of Trial of Org 10172 in Acute Stroke Treatment (TOAST) Criteria for cardioembolism subtype. Measures of diagnostic accuracy were calculated from the retrieved studies. Results Seven eligible articles comprised 5813 patients. Bivariate random effects models estimated sensitivity 0.19 (95% CI, 0.13 to 0.27), specificity 0.89 (0.86 to 0.91), positive predictive value 0.37 (0.30 to 0.45), negative predictive value 0.76 (0.7 to 0.82), positive likelihood ratio 1.70 (1.13 to 2.57) and negative likelihood ratio 0.91 (0.83 to 1). Interpretation The pattern of AIMCC on DWI is of limited diagnostic value. It is not sufficiently accurate to exclude cardiac pathology by a negative test nor does a positive test indicate a major increase in the probability of identifying a potential cardioembolic source.

Primary angiitis of the central nervous system (PACNS) is a vasculitis of small arteries and veins of unknown cause restricted to the central nervous system (CNS), and controversy and disagreement exist over the means to establish the diagnosis. Cerebral arteriography, cerebrospinal fluid examination, and MRI singly or in combination do not have sufficiently demonstrated positive predictive value to establish the diagnosis. An alternative diagnosis is established at biopsy in 35% of cases. Histologic confirmation is required for the diagnosis of PACNS. Patients without histologic confirmation should not be included in case reports, case series, or reviews.

We report two patients with midbrain infarction with pupil-sparing third nerve palsies and hemiataxia: one with contralateral ataxia (Claude's syndrome) and one with ipsilateral ataxia (which we refer to as reverse Claude's syndrome). We highlight the importance of a thorough neurologic evaluation with partial oculomotor palsies and describe, to our knowledge, the fourth account in the literature of a pupil-sparing third nerve palsy with ipsilateral cerebellar ataxia.

We evaluated safety and feasibility of the transvenous limb perfusion gene delivery method in muscular dystrophy. A dose escalation study of single limb perfusion with 0.9% saline starting with 5% of limb volume was carried out in adults with muscular dystrophies under intravenous analgesia/anesthesia. Cardiac, vascular, renal, muscle, and nerve functions were monitored. A tourniquet was placed above the knee with inflated pressure of 310 mm Hg. Infusion was carried out with a clinically approved infuser via an intravenous catheter inserted in the saphenous vein with a goal infusion rate of 80 ml/minute. Infusion volume was escalated stepwise to 20% limb volume in seven subjects. No subject complained of any post procedure pain other than due to needle punctures. Safety warning boundaries were exceeded only for transient depression of limb tissue oximetry and transient elevation of muscle compartment pressures; these were not associated with nerve, muscle, or vascular damage. Muscle magnetic resonant imaging (MRI) demonstrated fluid accumulation in muscles of the perfused lower extremity. High-pressure retrograde transvenous limb perfusion with saline up to 20% of limb volume at above infusion parameters is safe and feasible in adult human muscular dystrophy. This study will serve as a basis for future gene transfer clinical trials.

Background Three randomized trials of intra-arterial thrombolysis (IAT) for acute ischemic stroke ≤6 hours were conducted without intravenous tissue plasminogen activator (IV-tPA) treatment of patients in the control groups now known to benefit. Methods The effect of IV-tPA treatment on 130 control subjects in the Prolyse in Acute Cerebral Thromboembolism (PROACT), PROACT II, and Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) studies was modeled using linearly weighted time-dependent odds ratios (ORs) from pooled IV-tPA trials. In the PROACT trials, the model assumed that 50% (36/73) were treated at 4.5 hours, the median time to arteriography. For MELT, the model assumed treatment at arrival plus 90 minutes based on hospital arrival times obtained from the principal investigator. The OR of 1.31 for all 130 controls (91 presumed treated ≤4.5 hours; OR 1.44) was applied to the original control data to derive the adjusted control outcome, and this was compared to the IAT group. Sensitivity analyses were performed. Results Meta-analysis of the original data revealed a statistically significant benefit for IAT ( P = .03). After adjustment for the effect of IV-tPA in controls, there was no longer a significant treatment benefit for IAT ( P = .26). Loss of significant IAT treatment benefit persisted if either the OR for benefit of IV-tPA or the number of treated controls was more than halved. These 3 randomized trials of IAT for acute ischemic stroke ≤6 hours would not likely have shown a benefit if eligible controls had been treated with IV-tPA. Conclusions Whether IAT is superior to IV-tPA in IV-tPA–eligible patients or better than placebo in IV-tPA–ineligible patients remains to be determined.

In 1985, the International Study of Extracranial-to-Intracranial Arterial Anastomosis demonstrated no benefit from extracranial-to-intracranial arterial bypass operations in treatment of patients with extensive cerebrovascular disease including those with occlusions of the internal carotid artery. Interest in the potential use of extracranial-to-intracranial arterial bypass operations, however, has been rekindled by evidence that some patients with occlusion of the internal carotid artery have a poor collateral circulation and a high risk for recurrent ischemic events. Other patients with adequate perfusion after occlusion have a low likelihood for recurrent stroke. Restricting surgical treatment to only those patients judged to have a high risk for recurrent stroke might improve the usefulness of the bypass operation. A new clinical trial is proposed, testing the potential usefulness of extracranial-to-intracranial arterial bypass operations for treatment of carefully selected patients with occlusion of the internal carotid artery. Several issues that are being addressed in this new trial are described in this article.

Preventing further stroke in patients with complete carotid artery occlusion remains a difficult challenge because there is no therapy proven effective for this prevention. These patients comprise approximately 15% of patients with carotid artery territory transient ischemic attacks or infarction. Patients with symptomatic carotid artery occlusion have an overall risk of subsequent stroke of 7% per year and a risk of stroke ipsilateral to the occluded carotid artery of 5.9% per year. The presence of severe hemodynamic failure demonstrated by increased oxygen extraction fraction (OEF) of the brain, in a cerebral hemisphere distal to a symptomatic occluded carotid artery, is an independent predictor of subsequent ischemic stroke with a risk comparable to that seen in medically treated patients with symptomatic severe carotid artery stenosis.

Two small case series of platelet mitochondrial complex I activity assays in Huntington’s Disease (HD) report discrepant results. We measured platelet complex I and complex I/III activity in 21 subjects with early gene-positive HD and 14 age-matched controls. The 21 participants with HD that we studied are greater than the total of 16 in the two previously published of platelet ETS activity in HD. Reductions ?>>10% were excluded with 80% confidence. A systemic defect in complex I activity is not present in early HD when striatal neuronal degeneration is already present.

Background: Embryofetal developmental toxicity associated with oral administration of vitamin A analogs has led to concern about risks from topical application. Objective: This study was conducted to evaluate the potential developmental toxicity of tretinoin emollient cream when applied to the skin of pregnant New Zealand white rabbits during organogenesis (gestational days 7 through 19). Methods: Twenty rabbits each were randomly assigned to a control group (group I) or to receive vehicle (group II) or tretinoin emollient cream topically at dosages of 10 (0.05 mg/kg* NO LABEL*The milligrams per kilogram dosage refers to the amount of active ingredient (tretinoin). The 0.05 mg/kg and 0.5 mg/kg groups were treated with 0.005% and 0.05% wt/wt tretinoin emollient cream formulation. The 0.05% tretinoin emollient cream is the Renova clinical formulation. The 10 and 100 times clinical multiples refer to Renova clinical multiples and are based on a 50 kg adult patient's applying 500 mg of 0.05% tretinoin emollient cream formulation daily to yield a clinical dosage of 0.005 mg/kg., group III) or 100 (0.5 mg/kg*, group IV) times that used clinically in humans. Does and fetuses were examined for tretinoin-induced toxic effects, and maternal plasma tretinoin and metabolite levels were measured. Results: The rate of abortion was increased significantly in does in group IV ( p ≤ 0.01) compared with the control group. Dosage-dependent increases in incidence and severity of skin reactions occurred in groups administered the vehicle and the two dosages of tretinoin. Does in groups III and IV had clinical and necropsy observations that were considered direct or indirect effects of tretinoin administration, persistent weight loss, and reduced feed consumption. Maternal endogenous plasma tretinoin levels were below the lower limit of quantitation of 5 ng/ml and were not significantly altered with treatment. Group IV had significantly reduced mean fetal body weight ( p ≤ 0.01) and a greater frequency of resorptions compared with group I. Although external, visceral, or skeletal alterations occurred at significantly greater levels in group III, they were unrelated to tretinoin administration because the fetal incidences were not dosage dependent, and the litter incidence did not significantly differ from the control group values. Conclusion: Maternally toxic dosages of tretinoin were associated with an increased incidence of abortions and resorptions and reduced fetal body weight, two end points of developmental toxicity. Consistent with the absence of detectable tretinoin plasma levels, however, no changes in fetal morphology were attributable to tretinoin administration. (J Am Acad Dermatol 1997;36:S67-S76.)

Spontaneous intracerebral hemorrhage (ICH) is a common and devastating disease. It comprises about 10% of all cerebrovascular disease and affects 37,000 Americans each year.33, 56, lZ1 The annual incidence in the United States of 15 per 100,000 is twice that of subarachnoid hemorrhage (SAH).24 Mortality rates are among the highest for any cerebrovascular disease. Up to half of all patients with ICH die within 30 days of their 58, lo3, 167 and for patients followed 1 year or more, the fraction rises to two thirds.53, 58, 63, 83, 94, 167 Hypertension is common in the early period after ICH.16, 17, 34, 35, 76, la0 In patients admitted in the first few hours after ICH, systolic blood pressure and diastolic blood pressure average approximately 190 mm Hg and 100 mm Hg, re~pectively.~~, 103,180 Although definitions for hypertension vary among studies, hypertension is present in most patients in the acute period after ICH.35, 48, I4l, 166 The presence of higher blood pressure is most strongly associated with prior history of hyperten~ion~~, 76, la0 and proximity to hem~rrhage.'~, 79, la0 Other factors that are associated with higher blood pressure include younger age and larger lesions with worse initial clinical state.16 The cause of this acute hypertensive

This issue of Neurologic Clinics is devoted to cerebrovascular disease. Over the past four decades, the field of cerebrovascular diseases has progressed from recommendations based on experience and opinion to guidelines based on data frommultiple, wellexecuted, randomized clinical trials. Nevertheless, there remain areas of uncertainty and controversy for which current data available from clinical trials have failed to produce consensus within the community of stroke practitioners. For this issue, thirteen of these areas were selected, and experts in each area were asked to provide up-todate articles defining theproblem, reviewingpertinent data, describing the areas of controversy, and providing conclusions regarding efficacy based on the available evidence. The thirteen topics include treatments for acute ischemic stroke and intracerebral hemorrhage, prevention of subsequent stroke (in patientswith symptomatic and asymptomatic carotid stenosis, cervical artery dissection, patent foramen ovale, unruptured arteriovenous malformations, and “aspirin failure”), and the appropriate use of diagnostic testing for intracerebral hemorrhage, hypercoagulability, and suspected primary angiitis of the central nervous system. I amdeeply grateful to all the authorswhodevoted their time to writing such high-quality articles that I had very little to do and learned a lot. I would also like to express my gratitude to Elsevier for providing me the opportunity to organize and edit this issue and to the editorial staff at Neurologic Clinics for their assistance in making it an easy task. William J. Powers, MD H. Houston Merritt Distinguished Professor and Chair Department of Neurology University of North Carolina at Chapel Hill Room 2131, CB #7025, 170 Manning Drive Chapel Hill, NC 27514, USA

Cyclohexanone oxime (CHO) was given po to male and female Fischer 344 rats at dose levels of 10, 25, 75, 150, and 300 mg/kg, five times a week for a period of 2 weeks. Control animals received distilled water. All animals given intermediate dose levels (10, 25, 75, and 150 mg/kg) and one half of the animals which were dosed at the high dose (300 mg/kg) as well as one half of the controls were terminated 14 days after administration of the first dose. The remaining rats received no treatment for an additional 14 days and were sacrificed on Day 28 of the study (recovery phase). Dose-related decreases in erythrocyte number, hemoglobin, and hematocrit, with an accompanying increase in reticulocytes and circulating nucleated erythrocytes, were observed in both sexes at Day 14. Methemoglobin levels, determined only at the high dose, were elevated in both sexes at this time. Splenomegaly and hepatomegaly were observed in both sexes at 14 and 28 days. Histopathological examination of the spleen and bone marrow revealed dose-related erythroid hyperplasia at 14 days which subsided by Day 28. The above effects were more pronounced in males. Erythrocyte numbers were only slightly depressed and reticulocytes mildly elevated in males at Day 28. Hematological values were not statistically different from controls in females at this time. These results suggest that CHO induces oxidative damage to the erythrocyte, resulting in a hemolytic anemia accompanied by increased erythropoiesis. The toxic effects appear reversible upon cessation of exposure.

Cerebrospinal fluid lymphocytosis (more than 50 percent lymphocytes or mononuclear cells) occurred in 14 of 103 cases of bacteriologically proved acute bacterial meningitis. Patients with cerebrospinal fluid lymphocytosis accounted for 32 percent (13 of 41) of all patients with bacterial meningitis with a cerebrospinal fluid white blood cell concentration of 1,000/mm 3 or less. Cerebrospinal fluid lymphocytosis was significantly more common in neonates and in those without meningismus, but occurred in all ages and without any clear identifying clinical characteristics. The most common etiologic organisms were Streptococcus pneumoniae (five), Neisseria meningitidis (two), and Hemophilus influenzae (two). Cerebrospinal fluid lymphocytosis is common in acute bacterial meningitis when the cerebrospinal fluid white blood cell concentration is below 1,000/mm 3 . It is therefore of little value in differentiating bacterial meningitis from viral, fungal, and tuberculous meningitis.

Dermal exposure of rabbits to cyclohexanone oxime (CHO) for 24 hr at 0, 0.8, 2, and 5 g/kg caused dose-related reticulocytosis on the day after dosing as well as a decrease in hemoglobin in the 5-g/kg females 7 days postdosing. Gavage of rats 5 days a week for 13 weeks at levels of 0, 0.25, 2.5, and 25 mg/kg resulted in a dose-related decrease in erythrocyte number, hemoglobin, and hematocrit, with an accompanying increase in circulating reticulocytes and nucleated erythrocytes, in both sexes. Also seen were corneal opacities and an increased incidence of Howell-Jolly bodies. Results suggested an increased erythropoiesis in the spleen and bone marrow. The data from satellite groups terminated at 30 and 60 days revealed no effect at the lower test level, but results from the end of the study showed a clear cumulative dose response down to the 0.25-mg/kg level. Males were affected earlier and at lower doses than females. These results, along with those of a subacute study with a recovery period, suggest that CHO induces an oxidative attack on erythrocytes which appears reversible upon cessation of exposure.

Frequency-spread on F -region ionograms is to be explained primarily with the aid of large-scale irregularities of ionization density in the F -region of the ionosphere. Large-scale irregularities are ones whose sizes extend from the Fresnel scale up to the outer scale. This means scales ranging from about two kilometres up to some tens of kilometres, or wavelengths ranging from about ten kilometres up to several hundred kilometres. Irregularities of scale in excess of the Fresnel scale cause refractive scattering of a vertically incident wave on its upward journey through the F -region and on its return journey. Irregularities also cause the critical surface separating underdense ionization from overdense ionization to be rough. Irregularity scales from the Fresnel scale up to the outer scale cause reflection from this surface to take the form of glints. However, this mechanism by itself does not produce enough frequency-spread to explain satisfactorily the more extensive forms of spread- F . In these circumstances refractive scattering of a wave on its upward journey into the F -region ceases to be small-angle scattering before the reflecting stratum is reached. Return of energy to the ionosonde becomes possible by multiple refractive scattering alone. This is diffuse scattering by irregularities ofionization density with scales ranging from the Fresnel scale up to the outer scale. The mathematical theory of scintillation needs to be extended so as to cover development of large-angle multiple refractive scattering.