Waxing and waning consciousness in a patient with a midbrain cavernous malformation: illustrative case

Abstract

BACKGROUND

Understanding the intricate relationship between consciousness and the midbrain’s structures remains a significant challenge in neuroscience. Transient lesions are perfect examples of the physiological functioning mechanism of these structures.

OBSERVATIONS

The authors present the case of a 49-year-old female who experienced a transient disorder of consciousness due to a midbrain hematoma following surgical interventions to remove a cavernous malformation in the midbrain. This case explores the interplay between the ascending reticular activating system (ARAS) and the thalamic centers, highlighting the role of structural disruptions in influencing consciousness levels. Notably, the patient’s recovery correlated with the resolution of midbrain edema, reinstating normal ARAS function and consciousness.

LESSONS

In patients affected by midbrain lesions, edema can lead to a fluctuating neurological status, which can be difficult to diagnose. This case highlights the midbrain’s crucial role in the consciousness network and the need to comprehend the intricate connections between subcortical and cortical structures for a comprehensive understanding of human consciousness.

https://thejns.org/doi/10.3171/CASE2411

The key role of the anterior-most segment of the brainstem in supporting arousal, alertness, and wakefulness is well-known from the cornerstone work of Moruzzi and Magoun,¹ who demonstrated the crucial role of structures such as the locus coeruleus, raphe nuclei, posterior tuberomammillary hypothalamus, and pedunculopontine tegmentum, generally known as the “ascending reticular activating system” (ARAS), for cortical activation through excitatory reticulothalamocortical projections. Subsequent studies enriched the knowledge of the ARAS by highlighting the role of nonthalamic pathways^{2, 3} and the different neurotransmitters, such as serotonin, dopamine, noradrenaline, acetylcholine, and glutamate, involved in the “extended” ARAS network.^{2, 4}

In the last few decades, a multitude of theories concerning consciousness have arisen,^{5, 6} and one of the most advanced among them speculates about the presence of the so-called neural correlates of consciousness (NCCs),⁷ that is, the minimum set of neural mechanisms allowing one person to be conscious rather than unconscious. NCCs pave the way for rethinking the role of the midbrain nuclei and the ARAS as the enabling condition for consciousness. According to this interpretation, the ARAS is thought of as a modulatory system determining wakefulness periods and boosting alertness and attention, thus allowing the convergence of self (internal, homeostatic, and regulatory) and nonself (environmental) signals.^{4, 8, 9}

However, the debate about what consciousness is has gradually shifted from precisely identifying the specific role of ARAS structures to understanding the functioning of cortical areas such as the prefrontal, frontoparietal,^{10, 11} and occipitotemporoparietal^{7, 12} regions, alongside the midbrain and other subcortical structures, which have gradually lost their centrality from a theoretical point of view. Nevertheless, evidence supporting the pivotal role of the midbrain and the ARAS in determining arousal and wakefulness, as well as their functional integrity as a necessary condition (although not sufficient) for consciousness, needs to be described to enlarge the current debate on NCCs. To this end, we present the peculiar case of a patient with a temporary disorder of consciousness (DOC) related to the transient effect of a mesencephalic hematoma.

Illustrative Case

A 49-year-old female was admitted to the local emergency department reporting an episode of space-time disorientation. Her previous clinical history was irrelevant, and she reported neither significant comorbidities nor health risk factors. A brain computed tomography (CT) scan showed a right midbrain hematoma, and contrast magnetic resonance imaging (MRI) documented an underlying 23-mm-maximum-diameter midbrain cavernous malformation with inhomogeneous high signal on T2 fluid-attenuated inversion recovery (FLAIR) and T1 turbo spin echo contrast sequences and a T2-hypointense hemosiderin ring (Fig. 1). The lesion had a typical “popcorn” appearance. Neither a developmental venous anomaly nor other vascular abnormalities were associated with the cavernous malformation; thus, it was classified as a type II lesion according to the Zabramski classification, which groups cavernous malformations into 4 different classes depending on their radiological appearance.¹³ Since the mass effect with partial obliteration of the cerebral aqueduct was apparent, an urgent endoscopic third ventriculostomy was performed, and the patient was discharged without any neurological deficit. Genetic evaluation excluded any mutations compatible with cavernomatosis. After 6 months, as the hematoma was reabsorbed, the cavernomatous lesion was subjected to CyberKnife (24 Gy) stereotactic radiosurgery, without evidence of significant volume reduction. The patient started a period of clinical and radiological follow-up. Approximately 10 years later, after a second bleeding occurred, causing left hemiparesis, surgical removal of the cavernoma was planned.

FIG. 1.

Preoperative axial CT (A) showing a hyperdense lesion in the midbrain. Preoperative axial T2-weighted FLAIR image (B) and T1-weighted turbo spin echo image (C) after contrast administration confirming the presence of an inhomogeneous hyperintense lesion in the right paramedian midbrain with typical “popcorn” imaging characteristics, compatible with a cavernous malformation. Mass effect on the cerebral aqueduct is present. Preoperative sagittal T2-weighted FLAIR image (D) showing an additional cavernous malformation in the right thalamus; supratentorial ventricles are normal.

While the patient was under general total intravenous anesthesia with propofol and remifentanil, surgery was performed with intraoperative monitoring (IOM) including continuous electroencephalography (EEG), free-running electromyography, brainstem auditory evoked responses, somatosensory evoked potentials (SSEPs) for stimulation of the 4 limbs, transcranial motor evoked potentials from left and right abductor brevis pollicis (ABP) and abductor hallucis (AH) muscles, and corticobasal motor evoked potentials (Cb-MEPs) from left and right levator palpebrae superioris (LPS), lateral rectus, masseter, and orbicularis oris muscles. The patient was placed in a semisitting position, and under neuronavigational assistance (StealthS8, Medtronic Inc.), a lateral suboccipital craniotomy was performed to allow a supracerebellar infratentorial surgical route. Through the ambient and quadrigeminal cisterns, a pathological intramesencephalic blackberry-shaped nodule was excised. A slight decrease in the amplitude (i.e., about 50% with respect to the baseline) of Cb-MEPs of the right and left LPS muscle and in the amplitude of the left ABP and AH muscles was detected via IOM. Surgery was uneventful from an anesthesiological point of view.

Immediate postoperative brain CT did not document any complication. Therefore, the patient was transferred to the intensive care unit (ICU), where sedation was progressively reduced. After recovery from the anesthesia, ideomotor slowness appeared together with moderate left hemisome hyposthenia and bilateral third cranial nerve deficit, with palpebral ptosis and mydriasis.

After 24 hours (postoperative day [POD] 1) of ICU monitoring, the patient underwent serial CT studies (Fig. 2), which showed the postsurgical cavity in the anterior right midbrain, with a small hyperdense hematoma just caudal and posterior to the cavity. On POD1, the Glasgow Coma Scale (GCS) score was 12 (E1, V5, M6), and the only postoperative neurological deficit was bilateral palpebral ptosis.

FIG. 2.

POD1 axial CT demonstrates a small hyperdense hematoma in the midbrain just posterior to the surgical cavity. Mass effect on the cerebral aqueduct is stable with respect to preoperative imaging. No hypodensity compatible with ischemia is present.

Forty-eight hours after surgery (POD2), the patient required new orotracheal intubation because of a progressive decrease in the level of consciousness (GCS score 6: E1, V1, M4). Urgent MRI confirmed complete removal of the cavernous malformation and showed a small hematoma with slight postsurgical edema around the cavity (Fig. 3), with no evidence of ischemic lesions. During her ICU stay, the patient showed repeated periods of wakefulness with a GCS score of 10 (E3, V1, M6), Coma Recovery Scale–Revised (CRS-R) score of 22/23, and bispectral index (BIS) value of 95, alternating with periods of impaired consciousness lasting 3–4 hours with a GCS score of 3 (E1, V1, M1), CRS-R score of 0/23, and BIS of 35–45. On POD3 and POD4, 2 CT studies and a second MRI study documented only minimal contusive areas from manipulation of the surgical path and a small pneumocephalus. The patient started anti-edema therapy with 18% mannitol and continued receiving a high dosage of corticosteroids.

FIG. 3.

POD4 MRI was performed because of a fluctuating neurological status. A: Axial T1-weighted imaging confirms the small subacute hyperintense hematoma posterior to the cavity. No signs of new hemorrhage were present. B: Sagittal T2-weighted FLAIR image shows the midbrain hematoma.

On POD5, bilateral cortical responses to SSEPs and brainstem responses to brainstem auditory evoked potentials were present. A 24-hour EEG examination showed a lack of physiological alpha background activity, associated with slow-wave abnormalities. Neither clear EEG patterns related to sleep nor the presence of seizures was detected.

Mechanical ventilation was set as pressure support for the presence of a valid respiratory drive and to avoid hypercapnia. Sedation was maintained with intravenous remifentanil, and a neurological evaluation with complete suspension of sedation was performed 3 times per day. The patient’s periods of unconsciousness gradually reduced in parallel with the resolution of the contusion profile of the pontine reticular formation. Anti-edema therapy and mechanical ventilation were necessary until the resolution of the contusion occurred after POD6. On POD7, the patient was successfully extubated after standard respiratory weaning, and the GCS score was 14 (E3, V5, M6), noting only bilateral palpebral ptosis with diplopia at eye opening. There were no other organ failures, and all vital signs were normal. On POD8, the patient was transferred from the ICU to the neurosurgery ward, where she remained without further complications until POD20, when she was discharged to the rehabilitation ward with only bilateral ptosis, oculomotor deficit, and slight left hemisome hemiparesis (modified Rankin Scale score 3), without any deficit of consciousness.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

The neural basis of consciousness is one of the major unsolved challenges in neuroscience, given the complexity of the topic and the difficulty in obtaining uniform data from patients with different etiologies, clinical pictures, and clinical and healthcare needs. Furthermore, there is no univocal acceptance of the numerous theories that have been formulated on the nature of consciousness.^{14, 15}

The presented case highlights the complex relationship between the midbrain and consciousness. Brainstem cavernomas and subsequent surgical interventions resulted in fluctuations in consciousness ranging from wakefulness to deep coma. In this challenging and uncertain scenario, single cases in which isolated lesions determine abnormalities of arousal, awareness, and consciousness can add useful information that is not possible to collect from the majority of patients with DOCs who have widespread brain damage usually deriving from traumatic, anoxic, and/or vascular events. In the present work, we describe a patient showing a transitory and intermittent DOC following a small hematoma and edema in the paramedian midbrain.

The ARAS is located in the anterior-most segment of the brainstem and is primarily composed of four main components, each containing groups of nuclei. They are the locus coeruleus, raphe nuclei, posterior tuberomammillary hypothalamus, and pedunculopontine tegmentum, and each functions with its own specific neuropeptide. Generally, these nuclei are activated by the lateral hypothalamus (LH), which releases the neuropeptide orexin in response to light hitting the eyes, stimulating arousal and the transition from sleep to wakefulness.¹⁶

The locus coeruleus is located within the upper dorsolateral pons of the brainstem. When it is activated by orexin from the LH, it releases norepinephrine. Norepinephrine has an excitatory function widely distributed within the brain, acting on both the alpha and beta receptors of neurons and glial cells distributed throughout the brain. It functions primarily on wakefulness and arousal.¹⁷ The raphe nuclei are in the midline throughout the brainstem within the pons, midbrain, and medulla. Most neurons located in the raphe nuclei are serotonergic. The more rostral raphe nuclei appear to be important for pain sensation and mood regulation. In the ARAS, these nuclei communicate with the suprachiasmatic nucleus, playing a role in circadian rhythms and contributing to arousal and attention.¹⁸

The tuberomammillary nucleus is located within the posterior aspect of the hypothalamus. The neurons in these nuclei are primarily histaminergic. They are important in wakefulness and cognition and play an important role in arousal.^{19, 20} The lateral and dorsal pedunculopontine tegmentum contains mainly cholinergic neurons. Cholinergic neurons project to the thalamus and cortex, promoting desynchronization of the brain, facilitating the transition from slow sleep rhythms to high-frequency, low-amplitude wake rhythms.²¹ Current neuroanatomy models of the human ARAS are based largely on animal studies, so they may not fully reflect human anatomy. Indeed, it is still unknown which pathways in the human ARAS changed throughout evolution and which new connections have formed during the phylogenetic development of the human arousal system.²² What is now widely accepted is the need to focus not on single anatomical structures but on their connections.

Unfortunately, the study of connectivity remains difficult because of the limited feasibility of histological tract tracing using postmortem dye injections.² While functional neuroimaging studies in humans have revealed activation in the brainstem and thalamus during arousal,²³ these studies did not provide information about neuroanatomical connectivity between different network nodes. Even tractography reconstructions of diffusion tensor imaging data lack the necessary precision to identify the crossing nerve fibers,²⁴ which are a prominent structural feature of the ARAS.⁴ This technological gap was overdriven by a more sophisticated magnetic resonance technique, high angular resolution diffusion imaging (HARDI) tractography. HARDI tractography is based on the principle that the neuroanatomical trajectory of axon bundles can be delineated by measuring the directionality of water diffusion along these axons.²⁵ Using these methods, Edlow et al., in their elegant research, were able to identify all the key ARAS source nuclei implicated in arousal: cuneiform/subcuneiform nucleus, pontis oralis, median and dorsal raphe nuclei, locus coeruleus, pedunculopontine nucleus, parabrachial complex (combined medial and lateral parabrachial nuclei), and ventral tegmental area.² They demonstrated that the ARAS brainstem source nuclei connect primarily with the intralaminar, paraventricular, and reticular nuclei of the thalamus, justifying their close relationship with arousal. Our case can be considered a clinical demonstration of the close functional relationship that exists between the ARAS and the structures responsible for consciousness (Fig. 4).

FIG. 4.

Schematic representation of the ARAS and their connections. The cavernous malformation is located at the crossroads of the ARAS. ACh or ACH = acetylcholine; BF = basal forebrain; DA = dopaminergic neurons; Glu = glutamate; Hist = histamine; 5HT = serotonin; LC = locus coeruleus; LDT = laterodorsal tegmental nucleus; NA = noradrenaline; ORX = orexin; PB = parabrachial nucleus; PPT = pedunculopontine tegmental nucleus; SUM = supramammillary neurons; TMN = tuberomammillary nucleus; vPAG = ventral periaqueductal gray matter.

In our patient, the fluctuations of ARAS functioning, determined by the presence of mass effect due to the hematoma and edema in the midbrain, may have been sufficient to cause a transitory disruption of the ignition by preventing the crossing of the critical threshold to maintain a normal level of consciousness. Probably, in our patient, this alteration was incomplete given that the DOC was fluctuating and reversible over time, with a progressive decrease in edema following anti-edema therapy. Indeed, once the edema was resolved, the patient had a complete recovery of ARAS functioning with a complete restoration of the consciousness level.

Lessons

The midbrain occupies a pivotal position in the intricate network of structures involved in consciousness. While the precise mechanisms by which the ARAS sustains consciousness remain to be fully elucidated, integrating findings from neuroscience, clinical neurology, and neuroimaging holds promise for unraveling the complex nature of consciousness. In our case, the oscillation of the patient’s consciousness can be traced back to the direct contusion and the dysfunction due to edema of the connection structures between the ARAS and the thalamic centers. Once the contusion was resolved, the patient had a complete recovery of the midbrain integrative function structures with the restoration of consciousness.

Future research should continue to explore the role of the midbrain in consciousness, considering the interplay between subcortical and cortical structures to achieve a comprehensive understanding of this fundamental aspect of human cognition.

Acknowledgments

This work was supported by the Italian Ministry of Health (RRC2024).

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Mazzaglia, Falco, Ferroli, Gemma. Acquisition of data: Mazzaglia, Falco, Magnani. Analysis and interpretation of data: Falco, Rossi Sebastiano, Gemma. Drafting the article: Mazzaglia, Falco, Savoldi, Magnani, Castelli. Critically revising the article: Mazzaglia, Falco, Savoldi, Magnani, Castelli, Ferroli, Gemma. Reviewed submitted version of manuscript: Mazzaglia, Falco, Rossi Sebastiano, Castelli. Approved the final version of the manuscript on behalf of all authors: Mazzaglia. Study supervision: Castelli.

Correspondence

Guido Mazzaglia: Fondazione IRCCS Istituto Neurologico C. Besta, University of Milan, Italy. guido.mazzaglia@istituto-besta.it.