Gyriform restricted diffusion in adults: looking beyond thrombo-occlusions

Diffusion-weighted imaging (DWI) is one of the most robust imaging sequences used in MRI especially in clinical neuroradiology. Since its advent in the mid-1980s, DWI has been the mainstay in acute stroke imaging. In acute brain parenchymal ischaemia following vascular thrombo-occlusion, failure of sodium-potassium adenosine triphosphate (ATP)-dependent (Na⁺/K⁺-ATPase) pumps forms the premise of cytotoxic oedema or accumulation of water within neurons. The lack of transmembrane motion of water, in other words ‘restriction’ of their random Brownian motion, causes hyperintense signal on DWI and hypointense signal on apparent diffusion coefficient (ADC) images [1‐3]. These changes initially affect the grey matter due to its high metabolic activity and high astrocyte density [2].

Apart from a vascular thrombo-occlusive process causing restricted diffusion in the cortical grey matter, several other aetiologies may result in a similar pattern of GRD [4]. Prompt identification of these other pathologies is vital for appropriate patient management and ensuring a favourable outcome. To the best of our knowledge, there is limited literature comprehensively describing the clinico-radiological features of these conditions. This review focuses on identifying and describing non-stroke causes of GRD in adults with the aim to educate the trainee radiologist, especially as these cases are often read as urgent/on-call scans. We have provided multiple imaging examples and a table describing a pattern-based approach to these conditions, to facilitate learning.

Broad overview of non-stroke causes of GRD in adults:

Hypoxic-ischaemic encephalopathy (HIE) is a devastating neurological condition, often leading to death or severe neurological disability. It is caused by a myriad of aetiologies, including cardiac arrest, hypotension, trauma, drowning and asphyxiation. As the name suggests, the common pathophysiological events leading to HIE include global reduction of cerebral blood supply and low blood oxygen tension [5, 6].

In adults, HIE primarily affects grey matter structures (selective neuronal necrosis). This selective vulnerability of grey matter is due to its high metabolic activity and presence of abundant dendrites and capillaries. At the molecular level, prolonged anoxia converts oxidative phosphorylation to anaerobic metabolism. This leads to depletion of ATP, increased lactate, cytotoxic oedema and cell death. These changes limit the transmembrane motion of water, thus producing hyperintense signal in the grey matter on DWI [5‐7].

MRI is vital for diagnosing HIE and identifying the age of insult. DWI is the first imaging sequence to show the changes of HIE (within 1 h). Restricted diffusion is typically seen in the cerebral cortex (especially perirolandic and visual cortices), deep grey nuclei (basal ganglia and thalami), cerebellum and hippocampi (Fig. 1). DWI hyperintense signals generally fade by the end of the first week, a phenomenon known as pseudonormalisation (Fig. 2). During this early subacute phase (24 h–2 weeks), injured grey matter structures show T2 hyperintensity and swelling [5‐7]. Gyrifom enhancement of the injured cortex may be seen in this phase [8, 9]. In the chronic stage, T1 hyperintense changes of cortical necrosis are seen along with residual T2 hyperintensity and gliosis in the basal ganglia [5].

MRI following a single seizure or status epilepticus may often show GRD. Seizures induce changes in neuronal activity, vascular tone and blood oxygenation resulting in a mismatch between brain energy delivery and consumption. Hyperperfusion occurs due to increased glucose and oxygen metabolism. Eventually anaerobic metabolism ensues, resulting in lactic acidosis, depletion of energy substrates and failure of Na⁺/K⁺-ATPase pump leading to cytotoxic oedema. This resultant cytotoxic oedema and selective vulnerability of the grey matter explains the GRD. It is important to note that seizure-related restricted diffusion is often reversible, thereby indicating that cell death is not inevitable and that the causative pathophysiological pathways are possibly different from those of ischaemic infarction [3, 4, 10‐13].

Post-seizure MRI often shows restricted diffusion in the hippocampi and/or in any of the cerebral cortices (Fig. 3). Unilateral or bilateral involvement may be seen, not corresponding to any vascular territory or boundary. GRD is often associated with gyral/cortical swelling and T2/ FLAIR hyperintensity [3, 4, 10‐12]. Reversible/transient restricted diffusion has also been described in the basal ganglia and in the splenium of the corpus callosum [12, 13]. Contrast enhancement may occur due to a local increase in metabolism, vasodilation or a blood-brain barrier breach [12]. DWI signal abnormalities have been shown to correspond to areas of hypermetabolism on positron-emission tomography and maximum ictal electro-encephalographic (EEG) activity [4]. Serial post-ictal MRI studies may show either persistence or resolution of DWI signal abnormalities and sometimes cortical volume loss/gliosis [12].

Having discussed seizure-related GRD in detail, it is important to remember that the primary indication of brain MRI in post-ictal patients is to investigate the cause of seizures such as space-occupying lesions (e.g. neoplasms) or structural lesions (e.g. mesial temporal sclerosis). In this context, it is vital to not miss a focal parenchymal abnormality characterised by T2 hyperintensity (with/without focal restricted diffusion), mass effect, perilesional vasogenic oedema and/or enhancement which indicates the true causative pathology of the seizure [12].

The brain relies heavily on an uninterrupted supply of glucose for optimal functioning. Neurons have a rapid metabolic rate and can neither generate nor store significant amounts of glucose. Hence, sudden decline in blood glucose can jeopardise neuronal homeostasis within minutes. The neurological symptoms of hypoglycaemic encephalopathy typically occur at blood glucose levels less than 2.9 mmol/L. These include altered mentation, confusion, lethargy and seizures. If left untreated, these can progress to drowsiness, coma and even death. Common causative factors of severe hypoglycaemia are insulin/oral hypoglycaemic drug overdose, insulinomas, sepsis and alcohol abuse [14‐17].

At the molecular level, hypoglycaemia arrests protein synthesis, leading to intracellular calcium influx and release of aspartate. Aspartate is a neurotoxin which is known to cause preferential neuronal necrosis in the cerebral cortex, neostriatum and hippocampus. Additionally, hypoglycaemia also causes an increase in the concentration of extracellular glutamate, which promotes the influx of calcium and sodium into cells inducing apoptosis [14‐17].

MRI is the imaging modality of choice for the diagnosis of hypoglycaemic encephalopathy and to determine prognosis. The earliest changes are seen on DWI with the involved areas showing restricted diffusion. On the basis of topographic distribution of signal abnormalities, common imaging patterns include (1) predominant grey matter involvement (cortex, neostriatum and hippocampus), (2) predominant white matter involvement (internal capsules, splenium of corpus callosum) and (3) mixed grey and white matter involvement [16] (Figs. 4 and 5).

DWI signal abnormalities may be unilateral or bilateral and may also show corresponding T2/FLAIR hyperintensity. Haemorrhages have not been reported in hypoglycaemia although contrast enhancement may occur [16, 17]. Patients with extensive cortical and white matter involvement may present as a diagnostic dilemma, with HIE, hyperammonemia, seizures and encephalitis being close imaging differentials. The thalami, cerebellum and brainstem have slightly lower energy requirements and may be spared from the effects of hypoglycaemia, a feature which may help differentiate from HIE. In all situations, the clinical context and biochemical findings must be reviewed carefully to arrive at the correct diagnosis [16, 17]. Follow-up imaging plays a crucial role in prognostication. Patients with focal involvement of the splenium or internal capsules show good prognosis, whereas, insults to the neostriatum and diffuse cortical involvement often result in poor outcomes [16].

Ammonia is predominantly produced in the gastrointestinal tract as a by-product of amino acid metabolism, purine-pyrimidine cycle and the action of gut flora [18]. The normal blood ammonia concentration is < 35 μmol/L [19]. It is normally metabolised by the liver (urea cycle). This role is taken over by the kidneys, brain and skeletal muscles in hepatic failure [18, 20]. This alternate metabolism is inefficient, increasing the brain-blood ammonia ratio (normally in the order of 2) up to fourfold in liver failure [21]. Within the brain, astrocytes rapidly metabolise ammonia and glutamate to glutamine; however, this is physiologically costly, leading to increased cellular osmolarity and astrocyte damage. This further provokes inflammatory cascades and disrupts autoregulation, all contributing to cerebral oedema [20, 22].Other important causes of non-hepatic hyperammonaemic encephalopathy include drugs (valproate, barbiturates), adult-onset citrullinemia, surgery (e.g. ureterosigmoidostomy), parenteral nutrition and Reye syndrome [20, 22]. Patients with acute hyperammonaemic encephalopathy usually present with progressive drowsiness, seizures and coma. Prolonged hyperammonaemia can lead to severe brain injury, death or long-term sequelae such as intellectual impairment [20, 22].

There are very few studies describing early imaging findings of acute hyperammonaemic encephalopathy in adults [21‐23]. Rosario et al. and Takanashi et al. in independent studies have described cortical restricted diffusion in hyperammonaemia. In their studies, symmetric involvement of the insular cortex and cingulate gyrus was a common feature [22, 23] (Fig. 6). Restricted diffusion was also associated with T2/FLAIR hyperintensity. Occipital and perirolandic cortical involvement was also described [20, 21]. Bi-thalamic involvement may be seen [20, 22].

If treatment is administered in the acute phase, the signal changes may be potentially reversible. Parenchymal enhancement has been poorly studied; the limited studies that described contrast administration during imaging did not detect enhancement. Over time, pseudonormalisation of ADC signal has been described with increasing FLAIR hyperintensity. These changes occur approximately over 8 days after peak plasma levels of ammonia [20, 22].

Cerebritis is the primary manifestation of brain parenchymal infection [24, 25]. Infection can result from haematogenous dissemination or contiguous spread from infected paranasal sinuses, mastoid air cells or meninges [25, 26]. Neuroparenchymal infection passes through four pathological stages: (1) early cerebritis, (2) late cerebritis, (3) early capsular and (4) late capsular. The stage of cerebritis lasts for 10 to 14 days, characterised by ill-defined parenchymal softening with necrosis, oedema, vascular congestion and foci of haemorrhage. There is no liquefaction in this stage. If untreated, these changes eventually progress to frank abscess formation [27]. Patients with cerebritis may clinically present with headache, fever or altered mental status with or without associated sinusitis/discharging ear, etc. [25, 26].

At MRI, cerebritis appears as a poorly demarcated focal parenchymal/cortical lesion showing T1 hypointensity and T2/FLAIR hyperintensity. GRD encountered in this phase is due to high cellularity/infiltration of neutrophils, ischaemia and cytotoxic oedema (Fig. 7). Faint/subtle gyriform contrast enhancement and haemorrhages may occur at this stage [24, 25, 28]. Proximity of this cortical lesion to a known diseased site like an infected sinus or mastoid can aid in the diagnosis. If untreated, the stage of cerebritis progresses to abscess formation characterised by a central necrotic core with T2W hyperintensity, central restricted diffusion and peripheral rim enhancement [24].

The herpes family consists of double-stranded DNA viruses. Of the eight known Herpesviridae, Herpes simplex-1 virus encephalitis (HSVE) remains a significant cause of worldwide sporadic encephalitis in adults. Primary HSV1 infection affects the oral/nasopharyngeal mucosa and reaches the brain along the branches of the trigeminal nerve. The viral gene remains dormant in the trigeminal ganglion to reactivate in the event of immunosuppression. Viral tropism due to reactivation primarily affects the orbitofrontal and mesiotemporal lobes (limbic system). Cytotoxic injury of the cortex and grey matter structures are key features of viral encephalitides [29, 30].

Patients with HSVE typically present with fever, headache, altered mental status, seizures and focal neurological deficits. CSF typically shows pleocytosis, elevated protein and normal glucose. False-negative polymerase chain reaction test for HSV may occur early in the disease. Early clinical and imaging diagnosis and prompt treatment with acyclovir is crucial. MRI is the most sensitive imaging modality, especially in early stages of the disease. Classic imaging features include DWI hyperintensity and T2/FLAIR hyperintensity in the mesiotemporal and orbitofrontal lobes and insula (Fig. 8). Findings are typically bilateral and asymmetric but may be unilateral in the early stages. Extensive cortical swelling, vasogenic oedematous changes, haemorrhagic changes, mass effect, parenchymal and leptomeningeal enhancement are known features of HSVE [29‐31]. Isolated hippocampal involvement may be more common in immune-mediated limbic encephalitis or post-ictal conditions than in HSVE [29]. Untreated cases show fulminant parenchymal necrosis, haemorrhages and are often associated with high mortality rates ranging between 50 and 70%. Atrophy and encephalomalacia of affected regions are typical sequelae of HSVE [29‐31].

Creutzfeldt-Jakob disease (CJD) is a transmissible encephalopathy, grouped under prion (infectious proteins without nucleic acid) diseases, characterised by spongiform brain degeneration. Most cases are sporadic (sCJD), while 10% are hereditary. When infected, the healthy cellular prion proteins (PrP^C) are converted to scrapie isoforms (PrP^Sc), which cause neuronal death [32‐34].

Neurological symptoms include rapidly progressing dementia, myoclonus, pyramidal or extrapyramidal features, and akinetic mutism. Death occurs within a year of onset [32]. Periodic sharp-wave complexes and 14-3-3 proteins may be encountered on EEG and in the cerebrospinal fluid (CSF), respectively [35]. MR signal changes especially on DWI (sensitivity approximately 100%) precede clinical symptoms and EEG/CSF changes, making it the primary modality in early diagnosis [35, 36].

The typical MR imaging pattern seen in sCJD consists of DWI hyperintensity in the cerebral cortex and the basal ganglia. The insular cortex and the cingulate gyri (limbic system) as well as the superior frontal gyri are commonly involved. The perirolandic region is usually spared [36] (Fig. 9). Symmetric hyperintense DWI and T2W/FLAIR signals in the pulvinar nuclei of the thalami (“pulvinar” or “double hockey stick” sign) which are the hallmark of variant CJD (vCJD), are rare in sCJD (Fig. 10). Post-contrast enhancement does not occur [37]. With disease progression, the cortical signal abnormality may decrease or even disappear on DWI, owing to neuronal death and atrophy [36].

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) is a multi-system disorder grouped under mitochondrial metabolic diseases. It is caused by the inheritance of a mutated mitochondrial DNA in the maternal line. This abnormal DNA causes poor energy production, microvascular angiopathy and nitric oxide deficiency. Thus, high-energy requiring tissues, such as the brain and skeletal muscles, are affected [38].

Symptoms usually manifest by the age of 40. These include delayed and stunted growth, headache, recurrent stroke-like episodes, sensorineural hearing loss and cortical blindness [39, 40]. Genetic analysis or muscle biopsy to identify ragged red fibres using modified Gomori trichrome or succinate dehydrogenase stains are essential for a definitive diagnosis [38].

On MRI, MELAS shows a predilection for the parietal, temporal and occipital cortices, not conforming to vascular territories. Within 24 h of a stroke-like episode, affected areas demonstrate GRD with T2W prolongation (because of cytotoxic oedema from energy insufficiency) [38, 41] (Fig. 11). Angiograms are usually unremarkable. Lesions show a migratory, waxing and waning pattern with DWI changes paralleling the disease course. They resolve with clinical improvement only to recur in new locations with new symptom onset. Contrast enhancement may occur, and MR spectroscopy may show an elevated lactate peak at 1.33 ppm [38, 42]. Extensive petechial haemorrhages along the involved cortices have also been reported [42]. A compliation of the information from the references and the discussion from the various sections in the manuscript is summarised in Table 1.

Restricted diffusion involving the cerebral cortex is commonplace, especially in a high volume neurology/neuroimaging setting. Of the differentials, vascular thrombo-occlusion is the most common aetiology. However, occasionally, GRD may be caused by non-stroke conditions like metabolic encephalopathies, hypoxia, seizures and infections. These non-stroke conditions may be challenging to diagnose. Awareness of the various differentials and thorough knowledge of imaging features in conjunction with accurate clinical findings helps to clinch the accurate diagnosis and guide appropriate management.