Acute amnestic syndrome is an uncommon acute clinical presentation of neurological disease (1). Differential diagnosis encompasses many disorders such as transient global amnesia (TGA) and Wernicke-Korsakoff syndrome; moreover, the involvement of different anatomical structures can be responsible of this neurological syndrome (1).

The fornix is both a commissure, a projection, and an association tract, mainly composed of fibers that represent the major hippocampal output. It has a key role within the Papez circuit (Figure 1), which is central in memory storage and is a part of the cholinergic, GABAergic and glutamatergic neurotransmission systems (4). The neural and neurochemical connections of the fornix with the nearby structures are reported in Figure 2. The fornices, as a part of this extended hippocampal-diencephalic system, are thought to contribute to the efficient encoding and normal recall of new episodic information (5). Specifically, considering amnesia as a symptom, the hippocampal formation, amygdala, paralimbic cortices, medial and anterior nuclei of the thalamus, mammillary bodies, basal forebrain and ventral striatum are all critical structures. Bilateral lesions to any of these components can cause significant episodic memory deficits, predominantly anterograde amnesia (6, 7); the severity of the memory deficit is related to the volume of damage of the affected structure (8).

Fornix vascularization (Table 1) is mainly provided by the subcallosal artery (ScA), which vascularizes also the genu of the corpus callosum, the septal nuclei and anterior cingulum in some subjects (9). The medial or lateral posterior choroidal arteries arising from the posterior circulation can also be involved (10).

The consequences of forniceal injury in humans can be seen from post-operative cases involving forniceal transection or injury. The typical syndrome includes anterograde amnesia (11–26), that can be associated with a temporally graded retrograde amnesia (particularly in cases of fornix bilateral columns damage) (27). A lateralized fornix function has also been suggested by clinical reports, with the right fornix involved in visuospatial memory and the left fornix in verbal memory (20).

Overall, structural lesions in the fornix account for a minority of cases of anterograde amnesia, and several etiologies have been reported, including ischemic, inflammatory, neoplastic, and iatrogenic lesions (21, 28–30). Due to its rarity, acute amnestic syndrome due to fornix lesions has been mainly described in case reports and short case series.

The aim of this study is to systematically review the existing literature regarding cases of acute amnestic syndrome associated with fornix lesions, with a focus on clinical features, etiology, and differential diagnosis, to provide useful information to improve the diagnosis and treatment of these patients on clinical grounds.

This review is reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (31).

A total of 2,330 records were initially retrieved. After duplicates removal, 1,501 records were assessed for eligibility through abstract screening. 116 were included for full text review and 52 of them, reporting 55 cases, were finally included in the review. Study selection process is described in detail in Figure 3 (31, 34), and quality assessment in Supplementary Table S2. Details on included cases are provided in Supplementary Table S3.

A total of 55 cases were included in the analysis. Twenty-seven patients (49%) were female with a mean (±SD) age of 58 (±14). As expected, focusing on acute/subacute onset, vascular etiology was highly prevalent, being responsible of 43/55 (78%) of cases, 40 (74%) of which were due to acute ischemic stroke (29, 35–71) and 3 (5%) to hemorrhagic stroke (72–75).

Neoplastic etiology was the second most common, being identified in 15% of patients. The associated amnestic syndrome was caused either by fornix infiltration [B cell lymphoma (28, 76), pineal germinoma (77), spongioblastoma (78)] or following an acute intratumoral hemorrhage with secondary forniceal damage (79, 80), facilitated by antithrombotic therapy (81). Less frequently inflammatory (30, 82), traumatic (83), or toxic (84) etiologies were described (Table 2).

Neuroimaging revealed bilateral forniceal involvement in most patients (48/55, 87%). Corpus callosum (23/55, 42%) and more rarely caudate nuclei (5/55, 9%) and thalamus (2/55, 4%) were also injured.

The amnestic syndrome was characterized by an anterograde amnesia in all patients, which was associated with retrograde amnesia in 15/55 (27%) of cases. The retrograde memory impairment was often limited to the recent past and had a significant temporal gradient, coherently with what previously discussed on the role of the fornix in memory function (85, 86).

Amnesia was often an isolated presentation. Other cognitive deficits were present in 37% of cases, predominantly an executive dysfunction.

Other neurological deficits were quite rare and affected only 14% of patients. Confusion and confabulation were reported, respectively, in 14 (25%) and 8 (14%) of patients. Confabulation was more frequent (60%) in patients with caudate nucleus involvement than in those without caudate nucleus lesions (8%). Confusion was also associated with corpus callosum (CC) involvement and was present in 43% of patients with CC lesions versus 9% of patients without CC damage.

Follow-up data were reported in 41/55 (75%) of patients. No standardized outcome reporting prevented a detailed analysis of the recovery trajectory of memory deficit after the acute phase. However, from available information, the outcome at last follow-up (median follow-up of 3 months) was: no improvement in 14/41 (34%), partial improvement in 17/41 (41%) and complete recovery in 10/41 (23%) patients. The characteristics of reported cases are summarized in Table 2.

Acute amnestic syndrome with anterograde memory deficit is an uncommon clinical presentation and poses a significant diagnostic challenge. To our knowledge, we are reporting the largest and most comprehensive systematic review of case reports of acute amnestic syndrome due to non-iatrogenic lesions of the fornix.

Our review highlights that, apart from surgical cases where the diagnosis is straightforward, several different etiologies should be considered. However, when the symptom onset is acute, as for other neurological syndromes, the most relevant etiology is cerebrovascular disease: this rare stroke syndrome should be considered in these cases. In particular, our study confirm that the ScA is the main culprit vessel, and, in the majority of cases, the etiology of stroke is small vessel disease.

A first significant finding is that the clinical characteristics of the amnestic syndrome associated with fornix lesions seem to be non-specific, and often memory deficit occurs in isolation. As a consequence, the clinical picture widely overlaps with that of more frequent etiologies like Wernicke-Korsakoff syndrome and, especially, TGA. While additional neurological deficits are a strong element against a diagnosis of TGA, they are unfortunately quite rare, especially if fornix alone is involved. These results are in line with previous findings on ischemic amnesia (87).

Several neurological diseases should be considered in the differential diagnosis. TGA is the most common and typically presents with isolated anterograde amnesia with a limited retrograde component. Focal neurological deficits are absent, and the transient nature of the memory deficit is a key element for diagnosis, but of limited utility during the acute evaluation. MRI can demonstrate hippocampal punctate diffusion lesions (HPDL) (Figures 5A,B) or rarely extra-hippocampal punctate diffusion lesions (E-HPDL), but it can also be normal (88, 89).

Wernicke-Korsakoff syndrome is another mimic, but the medical history often reveals the cause of the thiamine deficit aiding in the diagnostic process; MRI can show hyperintensity in T2/FLAIR in mammillary bodies, medial thalami, hypothalamus, tectal plate, periaqueductal area; rarer in cerebellum, brainstem, basal ganglia (Figures 5C,D) (90, 91).

Transient epileptic amnesia (TEA) is a form of late-onset temporal lobe epilepsy that can present with the same syndrome (92). However, memory deficit is prevalently retrograde and of short duration (<1 h), episodes are often recurrent, and electroencephalography can show epileptiform abnormalities in the hippocampal-mesial temporal lobe regions (93).

Limbic encephalitis (Figures 5E,F), dissociative amnesia and neoplasms as lymphoma (Figures 5G,H) are other potential differential diagnosis but are usually more easily distinguishable from the clinical characteristics, and amnesia is rarely the only neurological symptom. The principal characteristics of the main pathologies included in the differential diagnosis are summarized in Table 4.

Our analysis has also shown that extraforniceal involvement (e.g., corpus callosum, caudate nuclei) seems to be associated with higher prevalence of additional clinical features, like confabulation and confusion. In cases of ischemic stroke, the involvement of RAH territory is often responsible of this clinical presentation. Confabulation in the context of caudate nuclei stroke has previously been reported and may explain these findings (122). Moreover, the concomitant ScA and RAH involvement has already been proposed as a variable that can aggravate the clinical picture in patients with fornix infarction following AcoA aneurysms treatment (123) and our study supports this finding. Other focal neurological deficits are rare and point to the involvement of other structures outside the limbic system, often in the context of embolism (38).

Another point that emerges is that, while this syndrome has been previously named “amnestic syndrome of the subcallosal artery” (29), it can also occur as a consequence of a posterior circulation stroke in exceedingly rare cases (38, 56). The presence of neurological deficits typical of posterior circulation involvement as ataxia or visual field deficits point to this uncommon circumstance (38).

A striking finding is that in the reported ischemic stroke cases, reperfusion therapy was never administered in the acute phase. This is probably due to a combination of delayed presentation to ED and delayed diagnosis. This is in line with previous literature on ischemic stroke presenting with amnesia, where Michel et al. reported that an ischemic etiology was considered in only 39% of cases (87). The main differential diagnosis was TGA, and many patients had an indistinguishable neurological presentation. Minor focal neurological signs, higher age, and more vascular risk factors were identified as potential clues to reach the correct diagnosis, but the discrimination based on the clinical syndrome was poor (87). Also in this cohort, ischemic patients had a high prevalence of vascular risk factors, but they were often quite young with a mean age of less than 60 years, further complicating the diagnosis. Considering that in most cases the etiology is small vessel disease, endovenous thrombolysis would be the only valid reperfusion therapy and the therapeutic window is narrow; therefore, waiting for the resolution of symptoms to confirm a TGA diagnosis is not possible.

Our study and previous ones on ischemic amnesia demonstrate that the use of MRI in the acute phase of the disease could be useful to assist clinician and would be especially valuable in this rare stroke presentation, where the decision based on the clinical data could be difficult.

As the need for a timely diagnosis clearly emerges from the literature, two useful radiological signs should be kept in mind to rapidly identify the peculiar appearance of acute ScA stroke in DWI sequence. The “goblet” sign (64) and the “watch out” sign (60) can be identified on axial images and are due to the fornix columns and the genu of the corpus callosum involvement, that are the main areas involved in ScA stroke (Figure 6). Beside these highly recognizable patterns, the use of 3D MRI sequences has been suggested to detect smaller infarcts (94).

In our study, only 26% of patients had a complete recovery at last follow-up, with three quarter of them having persistent memory deficit. Moreover, a rapid resolution of symptoms was extremely uncommon, as only one patient with a vascular etiology in our cohort had transient symptoms and was a case of hemorrhage and not of fornix infarction (70). The persistence of the amnestic syndrome in our cases confirms the crucial role of the fornix in the Papez circuit. The quality follow-up data is limited, so no definitive conclusions can be drawn.

Overall, the reported cases and especially data pointing to a non-specific clinical presentation, potential worse outcome, and absent reperfusion therapies utilization, strongly suggest the need to maintain a high index of suspicion to rapidly identify and timely treat patients with this rare stroke syndrome. Patients with different etiologies from ischemic stroke can also benefit from treatment and at least a partially restored memory function has been reported (75, 95).

The strengths of our review include a comprehensive systematic literature search, with specific criteria for inclusion and quality appraisal. However, this study has several limitations. Our findings are limited by the quality of reported data; this is especially relevant for the description of unspecific symptoms as confabulation and confusion. Not uniform follow-up and outcome reporting is another significant limitation. Most importantly, case series and reports are uncontrolled, and while they can suggest hypotheses, they cannot establish definitive associations and they are not robust enough for statistical inference.

Acute amnestic syndrome can be rarely caused by fornix lesions. In most cases of acute/subacute presentation the etiology is vascular, mainly caused by acute ischemic stroke involving the ScA territory. The differential diagnosis is challenging and the distinction from common mimics as TGA is often impossible only on a clinical basis. A high index of suspicion should be maintained to avoid misdiagnosis of time-dependent diseases and to provide adequate acute treatment. A significant percentage of patients with amnestic syndrome due to fornix lesions seems to have persistent memory deficits at follow-up. However, due to the limited quality of available data, more studies are needed to better understand their outcome and identify prognostic factors in patients with amnestic syndrome due to fornix lesions.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

FM: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing, Funding acquisition. FF: Conceptualization, Data curation, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing. AM: Visualization, Writing – review & editing, Conceptualization, Methodology. YM: Writing – review & editing, Data curation. MG: Visualization, Writing – review & editing, Conceptualization, Supervision. ACo: Supervision, Writing – review & editing. AP: Supervision, Validation, Writing – review & editing, Conceptualization, Data curation. ACa: Funding acquisition, Supervision, Validation, Writing – review & editing, Conceptualization.