Diffusion-weighted MR imaging (DWI) is a technique used to assess the random Brownian motion of water molecules within a certain voxel of tissue. In other words, DWI is used to determine the ease of molecular diffusivity of water within a tissue. Many pathologies cause restricted extracellular diffusion of water protons including infarction, cytotoxic edema, high cellularity within tissue, viscous fluid, demyelination, and metabolic disturbances. Restricted diffusion is seen as high-signal intensity on DWI with corresponding reduced apparent diffusion coefficient (ADC) values. ADC is a measurement of the diffusion of water molecules in a given tissue. ADC values are measured in units of 10-6mm2/s with ranges of reference values known for specific tissues within the brain. DWI is expressed with a b-value that is dependent on the characteristics of a sequence. The b-value will rise with increased diffusion weighting of the sequence, with a b-value of 1000 s/mm2 being sufficient enough to provide diagnostic value.1 Not all hyperintense regions on DWI images are due to restricted diffusion. Areas of hyperintensity on T2-weighted imaging (T2WI) may also be seen on diffusion imaging because DWI is intrinsically T2-weighted. This process is referred to as “T2 shine-through,” and can be mitigated with higher b values.2 The most common use of DWI is in the setting of acute ischemia by determining the presence of restricted diffusion from cytotoxic edema secondary to cell death. We will discuss other central nervous system (CNS) abnormalities where restricted diffusion plays an important diagnostic role in determining the underlying etiology of a CNS abnormality.
Stroke is a major cause of morbidity and mortality throughout the world with more than 795 000 cases occurring in the US each year. Approximately 80% of these events occur secondary to an acute ischemic event, often due to arterial thrombosis.3 Neurons lack the ability to store energy; therefore, brain tissue is hypersensitive to ischemia. In the absence of oxygen, a neuron can only maintain viability for 2 to 3 minutes.3 Acute ischemia often presents with an irreversible central core infarct and surrounding hypoperfused tissue described as the penumbra. Increased intracellular water accumulation and decreased rate of molecular water diffusion occur within the injured tissue. Therefore, the earliest findings of ischemic stroke are restricted diffusion on DWI, and corresponding low ADC values typically seen in the vascular distribution of the occluded vessel. Corresponding reduced signal on ADC maps separates stroke from T2 shine-through (Figure 1).4 These findings have been found to occur as early as 30 minutes after onset of ischemia with a sensitivity of 88% to 100% and specificity of 86% to 100%.3 In contrast, CT and conventional MRI have < 50% sensitivities within the first 6 hours after the event.3
Hypoxic ischemic brain injury commonly occurs in the setting of profound hypotension, reduced blood oxygenation, and cerebral hypoperfusion. Common causes in adults include postcardiac arrest, shock and drug overdose. Additionally, this can be seen in neonates due to perinatal asphyxia.5 Imaging patterns are variable and depend on duration and severity of the hypoxic events. Mild to moderate global injury leads to watershed infarcts, which manifest on MRI as cerebral cortical and subcortical white matter T2 hyperintensity with restricted diffusion between major arterial territories (Figure 2).6 In severe injuries, grey matter structures such as the basal ganglia, thalami, and hippocampi are affected first due to their high metabolic demand. DWI is the first sequence to show pathology, and can demonstrate hyperintensity in the affected areas within hours of the inciting event. Increased T2-signal can typically be seen after approximately 24 hours in the early subacute phase.7 This is due to increased edema in the injured gray matter structures.
Acute hypertensive encephalopathy, also known as posterior reversible encephalopathy syndrome (PRES), is a neurotoxic state that is most likely due to an inability of the posterior circulation to autoregulate in response to acute changes in blood pressure. It is most commonly associated with eclampsia and severe hypertension. PRES has also been associated with severe systemic infection, autoimmune disease, post-transplant patients on cyclophosphamide, and in patients undergoing high-dose chemotherapy.8 Some of the many associated clinical symptoms include altered mentation, seizures, visual disturbances, and nausea. MR characteristics include T2-hyperintensity in the cortex and subcortical white matter of the occipital and parietal regions. Focal areas of restricted diffusion on DWI can be seen in up to 26% of cases (Figure 3).8 Although PRES is predominantly composed of vasogenic edema that resolves over time, these focal areas of restricted diffusion are likely secondary to cytotoxic edema from cell death in more severe cases.
Venous infarction is a less common cause of stroke than its arterial counterpart. It is thought to occur most often in young women due to increased hypercoagulability when taking oral contraceptives and in pregnancy. However, more than 100 causes of venous thrombosis have been described, which occur secondary to direct involvement of the dural venous sinuses (trauma, infection), dehydration, endothelial damage, malignancy, or other underlying causes of hypercoagulability. Typical clinical presentation includes headache and focal neurologic deficits. Symptoms vary depending on thrombus location. The superior sagittal sinus is most commonly involved. Although less common, thrombosis will occur in the deep venous system approximately 16% of the time and the cortical veins approximately 17% of the time. On imaging, intracranial hemorrhage will occur approximately 30% to 40% of the time.9 Therefore, concern for venous infarct should be raised in patients with lobar intracranial hemorrhage of unknown origin as well as cerebral infarction that crosses typical arterial boundaries. MR findings of venous thrombus are variable depending on the age of blood product. However, DWI sequences remain extremely helpful in determining the presence of acute infarction within the territory of venous thrombosis.9
Cerebral pyogenic abscess is a serious condition usually occurring 10 to 14 days after the onset of underlying cerebral infection, referred to as cerebritis. Infection can be iatrogenic from sinonasal, skull base, or other intracranial procedures or spread hematogenously from lung and sinonasal infections, systemic disease, dental abscess, and in the setting of infective endocarditis. The most common bacteria involved is S. Pneumoniae. The typical appearance of brain abscess on MRI is a ring-enhancing lesion that is T2-hyperintense with low or intermediate signal intensity on T1-weighted imaging (T1WI) (Figure 4). Central restricted diffusion is often present on DWI with corresponding low ADC values. Research suggests that DWI may be more sensitive than conventional MR when trying to distinguish a cystic mass from a brain abscess. This is because the purulence within a brain abscess is very hyperintense on DWI with corresponding low ADC values. Necrotic and cystic tumors have intermediate signal intensity on DWI with elevated ADC values.10
Empyema is a life-threatening suppurative fluid collection in the epidural or subdural space, commonly due to bacterial meningitis, paranasal sinus disease, and otomastoiditis. Epidural empyemas often occur along the frontal convexities as a consequence of frontal sinusitis and erosion of the posterior wall of the frontal sinus, known as a “Pott’s puffy tumor.” Empyemas can also occur in the postsurgical or post-traumatic setting. Imaging features will demonstrate a rim-enhancing fluid collection within the subdural space. Lesions typically restrict diffusion. DWI sequences may be helpful in follow-up imaging of known infection with research showing that DWI sequences show changes earlier than contrast-enhanced T1WI (Figure 5).11 Chronic subdural hematoma may be difficult to differentiate from empyema, and T2*-weighted sequences such as gradient echo or susceptibility-weighted imaging can differentiate these entities.
Ventriculitis is a ventricular ependymal infection typically occurring in the setting of meningitis, ruptured cerebral pyogenic abscess, a complication of cranial surgery or trauma, or in the setting of indwelling ventricular catheters. Characteristic imaging findings on MR are ventriculomegaly with dependently layering intraventricular debris that restricts diffusion (Figure 6).12
Viral encephalitis can either be primary or secondary. In primary encephalitis, the virus directly involves the CNS. In secondary encephalitis, the virus spreads to the brain from another part of the body. Many viral pathogens can affect the CNS, although the most common cause of fatal sporadic necrotizing encephalitis is Herpes simplex encephalitis. HSV encephalitis classically presents as T2-hyperintensity with variable gyriform enhancement and restricted diffusion in bilateral mesial temporal lobes (Figure 7).13
Progressive multifocal leukoencephalopathy (PML) is a subacute opportunistic infection caused by reactivation of JC virus in the oligodendrocytes of immunocompromised patients, resulting in areas of demyelination. Imaging findings include asymmetric, predominantly subcortical, T2-hyperintensities that involve the u-fibers and lack mass effect or enhancement (Figure 8).13 PML lesions can demonstrate scattered areas of restricted diffusion at their periphery, which is thought to correlate with areas of lesion expansion.14
Creutzfeldt-Jakob disease (CJD) is a rapidly progressing CNS prion disease resulting in dementia and death usually occurring within the first year of symptom onset. CJD is transmitted by exposure to brain or nerve tissues via “prion” – a misfolded functional nucleic acid protein. Most cases happen sporadically. Patients undergoing transplantation or hormonal therapy are also at risk. Clinical symptoms of those exposed to CJD include rapidly progressing dementia, ataxia, or generalized myoclonus. Imaging findings demonstrate increased T2 signal and restricted diffusion in the supratentorial gray matter, cortex, and white matter. Increased signal in the dorsal thalamus (“pulvinar sign”) and posterior thalamus (“hockey stick sign”) are characteristic findings,13 and increased DWI signal may be the first abnormality seen on MR in early cases of CJD (Figure 9).15 There is no contrast enhancement or white matter involvement. Unfortunately, the prognosis is poor, with an 8.8-month survival rate.15
Toxoplasma gondii is a protozoan parasite that is known to infect the CNS in severely immunocompromised patients. Acute infection often occurs from reactivation of latent infections as 20% to 70% of all Americans are seropositive.16 On MRI, lesions have a predilection for deep gray matter structures, periventricular white matter, and the corticomedullary junction. Large lesions can demonstrate rim enhancement, occasionally with a central dot creating the “target sign” (Figure 10).13 On DWI sequences, these lesions may demonstrate mildly increased signal. However, ADC values are either the same or increased compared to surrounding white matter, which helps differentiate toxoplasmosis from cerebral abscess, which will demonstrate restricted diffusion with low ADC values.17
Meningioma is the most common extra-axial mass of the brain comprising 14% to 20% of all intracranial tumors.18 Approximately 7.2% of meningiomas are atypical (WHO grade II) and 2.4% are malignant (WHO grade III).18 Middle-aged women are most commonly affected, although meningioma is frequently seen in adults of all ages due to its high incidence. Ninety percent occur supratentorially with only 1 percent occurring outside the CNS. Meningiomas are iso- to hypointense on T1WI and iso- to hyperintense on T2WI. Avid homogenous enhancement is usually present after administrating gadolinium. DWI and ADC sequences demonstrate variable restricted diffusion (Figure 11). Views differ in the literature as to whether diagnostic ability can distinguish malignant and atypical subtypes from benign based on ADC values.18,19
Primary CNS lymphoma (PCNSL) is most often seen in immunocompromised patients, particularly those with AIDS. It is believed that decreased function of suppressor T-cells in immunosuppressed patients is the underlying cause of PCNSL. Just as in other areas of the body, PCNSL can have a wide variety of appearances on imaging and can be difficult to differentiate from other entities such as CNS toxoplasmosis. Signal is variable on T2WI with most cases demonstrating homogenous enhancement after the administration of contrast. Restricted diffusion will be noted due to lymphoma’s dense cellularity. It is important to note that corresponding ADC values will be lower than those in high-grade glial-based tumors such as GBM as well as metastasis (Figure 12).20 Further studies have shown that ADC values may have importance in the response of PCNSL to chemotherapy with values increasing in response to successful treatment.21
Glioblastoma (GBM) is a WHO grade IV intracranial neoplasm and the most common astrocytoma. Glioblastoma is the most lethal glioma with only about a 10% survival rate at 2 years. Glioblastoma can occur anywhere in the cerebrum but frequently spares the occipital lobes. MR findings are characterized by the presence of necrosis. Findings include T1 hypo- to isointensity, T2 hyperintensity, and enhancement of solid components. Restricted diffusion is common and will be seen in the solid components (Figure 13). Lower ADC values correlate with higher-grade tumors and, therefore, can help differentiate astrocytomas.22 The amount of T2-signal within the mass, degree of surrounding vasogenic edema, and postcontrast enhancement may have a direct relationship to long-term survival in patients with GBM.23 Patients with typically more favorable outcomes are younger than 45 years and have wild-type tumor genetics with MGMT methylation.
Multiple sclerosis (MS) is the most common demyelinating disease in the world and most commonly affects young females with peak age of 30 years. Demyelinating lesions in MS have a predilection for the supratentorial white matter, although infratentorial and spinal cord lesions are also common. Periventricular white matter lesions extending perpendicular to the lateral ventricles (“Dawson fingers”), callososeptal interface lesions, and juxtacortical white matter lesions are characteristic findings. Demyelinating lesions are best visualized on MRI with T2 and fluid-attenuated inversion recovery (FLAIR) sequences being the most sensitive. Radiologic diagnosis is possible when lesions are present in characteristic locations with dissemination in space and time (the modified McDonald criteria). There are multiple clinical subtypes and MS variants, and occasionally lesions can emerge in the form of large aggressive-appearing mass-like lesions. These lesions will have little surrounding edema and will not cause any significant mass effect when compared to aggressive tumors such as GBM.24 Additionally, these lesions will demonstrate incomplete ring enhancement after contrast administration with the incomplete portion of the ring lying on the gray matter side of the lesion (Figure 14).24 MS lesions are usually associated with increased diffusion. However, there are multiple reports of MS lesions with areas of restricted diffusion thought to be associated with active demyelination.25
Neuromyelitis optica (NMO) is a demyelinating disease caused by an autoantibody to the aquaporin 4 (AQP 4) water channel. Patients have variable clinical presentations, although this entity classically presents with bilateral optic neuritis and myelitis resulting in blindness and paraplegia. MR imaging of orbits may demonstrate edematous T2-hyperintense optic nerves, which enhance after administration of contrast. Traditionally, the brain is spared of demyelinating lesions. Lesions in the spine are characterized by longitudinal involvement of the cord for three or more contiguous vertebral segments. Lesions tend to involve the central gray matter along the central canal as this area corresponds to the most prominent expression of the AQP4 antigen.26 Information is limited regarding the diffusion imaging in NMO. However, it is believed that optic neuritis in NMO may restrict diffusion while optic neuritis from other causes does not.27
Acute disseminated encephalomyelitis (ADEM) is mediated by antigen-antibody complexes and usually occurs in children in the postviral setting, although it can also present after vaccinations, in exanthematous disease of childhood, or be idiopathic. ADEM has no gender predilection as with other demyelinating diseases. The underlying etiology is thought to be secondary to an allergic or cell-mediated immune cross-reaction with a viral protein. Symptoms present similar to acute MS. ADEM is usually a monophasic disease with most patients reaching full recovery. However, in the acute phase, mortality rate is approximately 10% to 20%.28 On MRI, multiple bilateral and usually asymmetric T2-hyperintense lesions will be present (Figure 15). In contrast to MS, ADEM favors subcortical and deep white matter regions without “Dawson’s fingers” or involvement of the callosal-septal interface. Lesions are typically larger than those in MS and can involve the brain and spine as well as white and gray matter. Involvement of the deep gray matter nuclei, thalamus, and brainstem is common with subcortical and u-fiber involvement occurring frequently. Lesions may demonstrate peripheral rim enhancement or restricted diffusion, likely secondary to the underlying active inflammatory process.28
Formerly known as central pontine myelinolysis (CPM), osmotic demyelination syndrome is a condition in which demyelination occurs secondary to rapid correction of electrolyte disturbances, most commonly hyponatremia. Oligodendroglial cells are particularly vulnerable to osmotic changes, and demyelination in this entity preferentially occurs in areas with higher concentrations of oligodendrocytes. Populations vulnerable to this condition include chronic alcoholics (60% to 70%), malnourished patients, chronically ill patients, patients with extensive burns, and transplant recipients.29 The imaging findings include isolated pontine lesions (most common) or combined types (central and extrapontine areas) that demonstrate symmetric, trident-shaped, hyperintense signal abnormality on T2WI or FLAIR images (Figure 16).30 Even before any signal abnormality is detected on T2WI or FLAIR images, restricted diffusion within the central pons may be identified within 24 hours of symptom onset.31 Extrapontine demyelination can occur in the basal ganglia, thalami, peripheral cortex, and hippocampi. Hyperintense lesions in the caudate and putamen can precede central pontine lesions. The important distinction from other entities is that the lesions do not demonstrate enhancement.30
Hypoglycemic encephalopathy develops in insulin-dependent diabetic patients who present with blood glucose levels < 50 mg/dL. Clinical manifestation includes altered mental status, loss of consciousness or seizures. The earliest imaging finding is hyperintense signal on DWI and corresponding low ADC value (in the range of 448.82 ± 92.34 × 10−6mm2/s).32 The most affected areas of the brain include the centrum semiovale, corona radiata, internal capsule, and splenium of the corpus callosum.33 Relative sparing of the cerebellum and thalami are important distinctions from hypoxic ischemic injury. According to a study performed by Dr. Kang et al, patients with frontal and parietal cortical involvement had a worse clinical outcome compared to patients with only white matter involvement.32
Wernicke encephalopathy is a devastating neurological disorder caused by vitamin B1 deficiency. This condition is often seen in the chronic alcoholic population, but also found in nonalcoholic populations with restricted diets.34 Clinical manifestations include altered mental status (most common), oculomotor abnormalities, and ataxia. The earliest imaging finding of Wernicke encephalopathy is slightly increased signal on DWI of the bilateral periventricular thalami and periaqueductal regions. As this entity progresses, imaging findings include symmetric T2 and FLAIR hyperintense lesions affecting medial thalami (85%), the periaqueductal gray matter, mammillary bodies, tectal plate, and the periventricular gray matter anterior to the fourth ventricle (Figure 17). A 2009 study by Zuccoli et al states that contrast enhancement of the mamillary bodies and thalamus was the most specific finding among the alcoholic population.35
Carbon monoxide (CO) is a colorless and odorless gas produced when fossil fuel is used for heating; thus, accidental CO poisoning is more prevalent in winter months. Carbon monoxide displaces oxygen from hemoglobin with higher affinity and causes hypoxia that can result in anoxic-ischemic encephalopathy. As previously discussed, the most vulnerable areas to hypoxic ischemic injury are the cerebral cortex with a predilection for the temporal lobes and hippocampi. Symmetric restricted diffusion of the globus pallidi is the most characteristic imaging finding of CO poisoning.36 However, the first imaging finding during the acute phase of exposure to carbon monoxide is hyperintense signal on DWI affecting cerebral hemispheric white matter with associated signal loss on ADC. Relative ADC values are typically in the range of 180 x 10−6mm2/s.37
Ethylene glycol is used in polyester manufacturing and as the primary compound in antifreeze, which can also contain methanol. Accidental or intentional ingestion of ethylene glycol can cause neurotoxicity presenting with confusion and ataxia. Imaging findings include restricted diffusion involving the bilateral basal ganglia, thalami, amygdala, hippocampus, and cerebral cortices. DWI will demonstrate hyperintense signal involving the cerebral cortex.38 Methanol toxicity presents with pallidal necrosis and optic nerve demyelination.39
When traumatic brain injury occurs, it can result in diffuse axonal injury (DAI) from rotational acceleration forces causing deformation of brain tissue and development of hemorrhagic or nonhemorrhagic traumatic lesions. Due to cellular swelling, or cytotoxic edema, FLAIR hyperintensity and restricted diffusion can be present in affected areas with low ADC values up to 18 days after the initial traumatic event.40 The most commonly involved areas of the brain include the splenium of the corpus callosum, gray/white matter interface (especially involving the frontal and temporal lobes), and dorsolateral midbrain. Hemorrhagic lesions in DAI will present as hypointense foci on susceptibility-weighted images. The DWI signal abnormality will return to normal after 30 days.41 In addition, in the setting of a high-velocity trauma, extremity long-bone fracture can occur and lead to propagation of bone marrow fat into the pulmonary vasculature. If a right-to-left cardiac shunt such as an atrial septal defect is present, fat emboli can travel to the CNS arterial vasculature and cause ischemic infarct, which can mimic the imaging pattern of diffuse axonal injury.42
Epidermoid cysts are benign intracranial congenital inclusion cysts that originate from ectodermal epithelial tissue from the pharyngeal pouch of Rathke during neural tube closure. The epidermoid cyst is lined by simple stratified cuboidal squamous epithelium and are isointense/hyperintense to cerebrospinal fluid (CSF) on T1WIs and T2WIs without internal contrast enhancement (Figure 18). The most useful distinction between epidermoid and arachnoid cyst is the restricted diffusion seen with epidermoid cysts.43 The average ADC value of epidermoid cysts measures 1197 × 10−6mm2/s, which is approximately isointense to brain parenchyma.44 The most common intracranial locations include the cerebellopontine angles (40% to 60%), suprasellar cistern, and fourth ventricle.45 Epidermoid cysts are often treated with surgical excision if symptomatic.44
Choroid plexus cysts, also known as xanthogranulomas, are common findings in utero between weeks 26 to 28 of gestation. Most choroid plexus cysts are 2 to 8 mm and often disappear on follow-up ultrasound screening.46 Choroid plexus cysts are fluid-filled structures and follow CSF signal on T2WIs with iso- to hyperintense signal on T1WI due to proteinaceous content (Figure 19). If choroid plexus cysts persist and are > 1 cm, they are often associated with trisomy 18, trisomy 21, Klinefelter syndrome, and Aicardi syndrome.46 On DWI, choroid plexus cysts demonstrate restricted diffusion with low ADC values.47
Status epilepticus can locally increase cerebral metabolic activity and result in vascular hyperperfusion, which ultimately may lead to cerebral edema and decreased cerebral diffusion. The most common imaging findings include focal restricted diffusion with a cortical or subcortical distribution and corresponding T2/FLAIR hyperintensity with mild enhancement on postcontrast images.48 According to Hubers et al, restricted diffusion is present at the seizure focus, the center of ictal activity with no clear location or laterality predilection.49 However, earlier studies have discussed that the temporal lobe or hippocampal structures were believed to be the most prevalent sites of restricted diffusion.
Wallerian degeneration refers to an anterograde degeneration of axons secondary to central neuronal injury and occurs in four distinct stages. In the first stage (within 4 weeks from the initial injury), myelin and axonal breakdown begins without visible signal abnormality on MRI. Later, there is myelin protein breakdown altering protein-lipid ratio in stage 2 (4 to 14 weeks) causing T2-hyperintense signal abnormality. Progression of gliosis and corresponding T2-signal abnormality occurs in stage 3 (14 weeks to months after the initial injury). Finally, stage 4 (years after the initial injury) shows atrophy of the involved corticospinal tract (Figure 20). Throughout the course of Wallerian degeneration, cytotoxic edema can be present leading to restricted diffusion of the involved white matter tract that can be seen as early as stage 1.50 A study by DeVetten et al stated that early ADC signal decrease after acute stroke can predict early Wallerian degeneration and may increase a patient’s clinical outcome by selecting patients for rehabilitation and neuroprotection trials.51
As we have seen, restricted diffusion patterns play an important role in the diagnosis of many CNS abnormalities. The ability to evaluate tissues on a cellular level gives us valuable knowledge of the underlying pathophysiologic processes within the CNS. Clinical medicine will benefit greatly as MRI continues to advance tissue characterization and more specific diagnoses. As such, the knowledge of typical restricted diffusion patterns of each CNS abnormality will assist radiologists in developing a succinct differential diagnosis guiding referring physicians to the correct diagnosis.
Daniel J, Cho Y, von Borstel D, Summers K. Decoding the Diffusion: Overview of Restricted Diffusion on Brain MRI. J Am Osteopath Coll Radiol. 2020;9(3):20-31.
