All patients described in this series presented after acute exposure to opiates or other drugs of abuse and presented with decreased level of consciousness, with obstructive hydrocephalus secondary to cerebellar edema and with MRI findings of restricted diffusion in the cerebellar cortex, hippocampi, and basal nuclei. With aggressive medical and surgical management, most patients were able to live at home with variable degrees of assistance; this may be considered a favorable outcome given the life-threatening nature of the initial injury.

We propose that this constellation of findings represents a condition we term CHANTER syndrome. CHANTER is distinct from other recognized syndromes including acute ischemic stroke, anoxic brain injury, PRES, and described toxic and metabolic injuries. CHANTER shares some clinical and radiographic features with recently described cases of hippocampal restricted diffusion [9,10,11] and may represent a more severe spectrum of a similar condition.

It is important to distinguish CHANTER from other known clinical entities. Restricted diffusion in CHANTER syndrome may be mistaken for ischemic stroke, but the CHANTER syndrome pattern is not associated with a vascular distribution and does not correspond to vessel occlusions on angiographic imaging.

Heroin-associated spongiform leukoencephalopathy (HASL) is a toxidrome associated with inhaling heroin vapors in a manner termed “chasing the dragon.” It is characterized primarily by extensive, confluent white matter degeneration in the cerebrum and cerebellum [4, 12], in contrast to the gray matter involvement seen in CHANTER syndrome. It is typically described as a subacute process [12] and may not be associated with restricted diffusion [13]. We believe the acute onset of prominent cerebellar and hippocampal restricted diffusion, in the absence of significant white matter injury, distinguishes CHANTER from HASL.

Similar to HASL, PRES is an entity typically associated with predominantly white matter injury. While PRES can cause posterior fossa edema [2], and occasionally involves the basal nuclei [14], it primarily consists of white matter disease which is essentially absent in CHANTER syndrome.

Specific toxic or metabolic insults could produce gray matter injury, but all have significant imaging and clinical differences than CHANTER syndrome, as given in Table 2 [15,16,17,18,19,20]. One case report describes a patient exposed to carbon monoxide and benzodiazepines who developed injury in a pattern similar to CHANTER [21].

Table 2 Distinctive features of CHANTER syndrome, selected differential diagnoses, and similar cases Full size table

Anoxic brain injury following cardiac or respiratory arrest can cause restricted diffusion within gray matter of the hippocampus and cerebellum, specifically within Purkinje cells [22], but this is typically seen co-occurring with cortical gray matter diffusion restriction [23, 24]. Diffuse anoxic injury can be associated with diffuse cerebral edema, but is not typically associated with malignant cerebellar edema and obstructive hydrocephalus [8, 25]. If CHANTER could be considered a variant form of HIE, the disproportionate cerebellar edema with sparing of the cerebral cortex is notable.

CHANTER syndrome may represent a primary metabolic or mitochondrial failure of gray matter with some degree of anoxic injury precipitated by opiates or other drugs of abuse. Single case reports have described cerebellar edema after exposure to opiates, particularly in the pediatric population, either in isolation [26, 27] or with hippocampal [28] or other patterns of injury [29,30,31]. There are adult case reports of opiate exposure associated with cerebellar edema and hippocampal [32] or basal nuclei damage [33, 34] with some similarities to the cases presented here, although two of these adult cases involved heroin inhalation and were thought to represent HASL-like toxic leukoencephalopathies.

Individuals with active or historical opiate abuse who developed bilateral hippocampal diffusion restriction have been identified, including some with basal nuclei involvement [9]. Recognition of this pattern of injury prompted an alert by the Massachusetts Centers for Disease Control, leading to the identification of ten additional patients with similar findings [10]. The key difference from our case series is the absence of prominent cerebellar edema. A separate case series described sixteen patients with bilateral hippocampal restricted diffusion, including half occurring in the context of recreational drug exposures (most commonly narcotics), and half presumed related to cardiac arrest, seizure, or other etiologies [11]. A majority of patients in this series demonstrated extrahippocampal areas of restricted diffusion, frequently involving the basal nuclei and/or cerebellum. These cases, in conjunction with our own, may suggest the presence of a common pathway and a spectrum of disease severity, with the life-threatening cerebellar edema of CHANTER syndrome representing the most severe end, and isolated hippocampal injury a milder presentation of the same condition. In our series, imaging characteristics and the timing of edema progression are consistent with a pattern of cytotoxic edema, which can explain the development of obstructive hydrocephalus.

Similarities between CHANTER syndrome and these cases raise the possibility of CHANTER as an opiate-provoked toxidrome [35], perhaps exacerbated in the context of relative hypoxia [36]. This concept is indirectly supported by pathologic data. Postmortem analyses of heroin users have identified hippocampal Purkinje cell loss and evidence of reactive micro- or astroglial reactivity believed to be related to a combination of hypoxic and neurotoxic effects [37]. Fentanyl and related synthetic opiates have been linked to focal brain injury, including in the hippocampus [38], suggesting a potential pathophysiologic association. It is possible that interventions such as naloxone—received by patients described individually in the literature [26, 28,29,30,31,32, 34] as well as our cases—offer relative neuroprotection to the cerebral cortex and white matter [39], areas classically implicated in anoxic injury but relatively spared in CHANTER and similar cases. If indeed an opiate-associated phenomenon, the identification of CHANTER syndrome has important clinical implications in light of the ongoing opiate epidemic [40, 41].

While this case series reflects a consistent pattern of clinical and radiographic findings, it shares limitations inherent to all case series. Individuals came to our attention due to otherwise unexplained cerebellar edema resulting evaluation and management in a neurocritical care unit; it is likely that similar cases may not have been identified by virtue of triage to other intensive care units and/or early death due to herniation. While substance use, in particular with opiates, appears to be a commonality between a majority of our patients, and between our patients and those described in the literature, the documented acute exposure in our cases is heterogeneous. This may indicate a variety of provoking factors for a similar syndrome, or it may reflect an underdiagnosis of exposures, such as synthetic opiates that are not a part of standard toxicology assays [42]. An additional limitation is that we do not have histopathological confirmation of the mechanism and precise location of cellular injury. Nonetheless, the strikingly similar clinicoradiographic presentations in our case series suggest a common pathophysiologic process, and the potential need for urgent intervention highlights the importance of recognizing CHANTER syndrome as a potential novel clinicopathologic entity.