Partial recovery of vegetative state after a massive ischaemic stroke in a child with sickle cell anaemia

Abstract

A 15-year-old patient with sickle cell disease with recessive homozygous haemoglobin S/HbSS suffered several crises developmentally after the last of which the patient fell into coma. CT scan then revealed a large infarct of the right cerebral hemisphere. Three weeks after the event, the patient began to demonstrate spontaneous eye opening and spastic quadriparesis with no evidence of command-following, gestural or verbal communication, visual pursuit or purposeful motor behaviour. Our case was in an ‘unresponsive wakefulness syndrome’ with atrophy of lateral and frontal regions of both hemispheres, demonstrated by MRI and preservation of circulation in the posterior arterial system, documented by MR angiography. Currently observed are spontaneous eye opening, preserved visual and auditory startle reflexes, normal brainstem reflexes, and grasp, palmomental and sucking reflexes. Our case demonstrates partial recovery of awareness with significant brain lesions, reflecting preserved brain activity as an indication of the modular nature of functional networks.

Background

Coma can result from metabolic or structural diffuse bihemispheric cortical or white matter damage after neuronal or axonal injury or from focal brainstem lesions that affect the ponto-mesencephalic tegmentum or paramedian thalami bilaterally. Nonetheless, coma is a time-limited condition (it usually does not last longer than a few weeks), leading to brain death, but some patients show favourable outcome, recovering arousal signs, that is, open their eyes spontaneously or on stimulation, but remain unaware of self or environment (show only reflex motor response), fulfilling the diagnosis of unresponsive wakefulness syndrome (UWS).¹

The term ‘persistent vegetative state’ (PVS) was coined by Jennett and Plum in 1972 to describe the condition of patients with severe brain damage in whom coma has progressed to a state of wakefulness without detectable awareness.² These cases mean a tragedy for medical care, patients’ families and society. More recently, UWS, which can be erroneously considered as ‘vegetative’-like, has been recognised using a more descriptive and unbiased term: ‘unresponsive wakefulness syndrome’.^{3 4}

The management of patients with UWS in childhood is an even more difficult task to accomplish. A fundamental problem arises as to the relevance and applicability of adult criteria to children. Because of limitations of the examination of cerebral function as well as the observation that nervous system function in infants and children is in the process of maturation, there is substantial concern about the validity and reliability of currently used criteria.⁵

We report a case that was a UWS patient with partially recovered awareness, in spite of significant brain lesions, which spared the posterior regions. Schiff et al⁶ have reported the apparent existence of isolated vestiges of functional brain networks in UWS cases associated with complex behavioural fragments, emphasising that such preserved brain activity is a novel indication for the modular nature of functional networks, underlining brain function. Laureys et al,⁷ based on MRI, positron emission tomography (PET) and other neuroimaging studies, have supported the notion that the medial, parietal (precuneus) and adjacent posterior cingulate cortices appear to be the brain areas that differentiate minimally conscious states (MCSs) from UWS. These richly connected multimodal posterior associative areas seem to be important regions for subserving human awareness.^{8 9}

This case demonstrates partial recovery of awareness with significant brain lesions that reflects preserved brain activity and serves as an indication of the modular nature of functional networks in the brain.¹⁰

Case presentation

We report a case with significant atrophy of lateral and frontal regions of both hemispheres, demonstrated by MRI, and preservation of circulation in the posterior arterial system, documented by MR angiography (MRA). At the age of 6 months, the child was diagnosed with sickle cell disease (SCD), in the form of hereditary recessive homozygous haemoglobin S/HbSS. During the first 7 years of life, the child reportedly suffered several SCD-related crises (aplastic anaemia, pain and so on).

On 18 December 2006, the patient felt a strong headache, and 4 days later began to speak incoherently, falling into coma a few hours later. CT scan revealed a significantly large infarct of the right cerebral hemisphere. The patient was not treated with intravenous thrombolysis. Antiplatelet medication was begun using clopidogrel. The following day the child partially recovered consciousness, but 2 days later, the child again became comatose. Three weeks later, our patient began to demonstrate spontaneous eye opening and spastic quadriparesis, with no evidence of command-following, gestural or verbal communication, visual pursuit or purposeful motor behaviour. The patient was diagnosed as UWS at that time.

The patient was 15 years old at the time of admission to our facility, in June 2016, with the diagnosis of UWS in a chronic condition. We did not care for the patient during her previous acute or subacute clinical evolution. That is the reason why we did not present the initial neuroimaging studies of the patient.

A detailed history obtained from the patient’s father gave us the possibility to learn that since the child was approximately 1 year old, several events of loss of consciousness were evidenced resulting in left and/or right hemiparesis, with partial recovery. These focal neurological deficits incremented during patient’s lifetime. With this information we concluded that the patient had suffered many silent ischaemic strokes affecting several arterial territories (anterior and middle cerebral arteries in both hemispheres, sparing posterior cerebral arteries territories).

When admitted to our Institute of Neurology and Neurosurgery, the child demonstrated spontaneous eye opening and preserved visual and auditory startle reflexes. Brainstem reflexes were normal, and grasp, palmomental and sucking reflexes were obtained. The patient demonstrated a spastic quadriparesis. Nonetheless, the patient fixated and tracked family members and a moving mirror and oriented toward new sounds. When the patient’s father spoke, the patient responded by smiling, related to the emotional content of stimuli. The child repeated vocalisations or gestures that occurred in direct response to the father’s conversation. The patient, at times, demonstrated gestural yes/no responses. The parents indicated that these responses had developed since 2006. According to the presence of inconsistent but clearly discernible behavioural evidence of consciousness awareness, we changed the diagnosis from UWS to MCS.^{1 3}

Investigations

EEG showed diffuse theta and delta activity, brainstem auditory evoked potentials demonstrated preserved conduction through the auditory pathway within the brainstem, bilaterally and somatosensory evoked potentials showed delayed but preserved bilateral cortical components.

In figure 1, MRI-T1 images reveal marked atrophy consistent with progressive cerebral cell loss in parietal, temporal and frontal lobes of both hemispheres, associated with dilated ventricles and wide cerebral sulci. Brain structures were mainly preserved in posterior areas of both hemispheres. Small tissue islands were preserved in both frontal lobes. MRA showed brain circulation confined to the posterior arterial system.

Figure 1.

MRI-T1 images in axial (A), coronal (B) and sagittal (C) views reveal marked atrophy consistent with progressive cerebral cell loss in parietal, temporal and frontal lobes of both hemispheres, associated with dilated ventricles and wide cerebral sulci. Brain structures are mainly preserved in posterior areas of both cerebral hemispheres. (D) Small tissue islands are preserved in frontal both lobes. MRA reveals brain circulation confined to the posterior arterial system.

In figure 2, MRI-T1 demonstrates significant brain injury, with some remaining tissue islands in the frontal and the occipital regions, and MRI fractional anisotropy (MRI-FA) shows connectivity between frontal and occipital tissue islands.

Figure 2.

In the first row, MRI-T1 demonstrates significant brain injury, with some remaining tissue islands in the frontal and the occipital regions. In the middle row, SPECT and MRI coregistered, show CBF tissue islands in the frontal and occipital regions. In the third row, MRI fractional anisotropy shows connectivity between frontal and occipital tissue islands.

In figure 3 (left), coregistered SPECT and MRI demonstrate cerebral blood flow in the frontal and occipital regions and MRI-FA connectivity between frontal and occipital regions.

Figure 3.

(Left) Single-Photon Emission Computed Tomography (SPECT) and MRI coregistered show cerebral blood flow in the frontal and occipital regions. This demonstrates MRI-FA connectivity between frontal and occipital regions. MRI-FA, MRI fractional anisotropy.

Differential diagnosis

A key issue in this case is the partial recovery of awareness with significant brain lesions of the frontal and temporal lobes of both hemispheres, mainly sparing the posterior regions of both hemispheres. Schiff et al⁶ have reported the apparent existence of isolated vestiges of functional brain networks in UWS cases, associated with complex behavioural fragments, emphasising that such preserved brain activity is an indication for the modular nature of functional networks, underlining brain function. Laureys et al,³ based on MRI, PET and other neuroimaging studies, have noted that richly connected multimodal posterior associative brain regions seem to be important regions subserving human awareness. According to the presence of inconsistent but clearly discernible behavioural evidence of awareness, we changed our diagnosis to from UWS to MCS.^{1 3}

Discussion

Stroke is an often-devastating complication that affects about 10% of children with SCD.¹¹ Some reports have shown that about 23% of children without focal neurological findings have abnormalities on MRI compatible with ischaemic injury. These ‘silent infarcts’ correlate with neuropsychological dysfunction and have been reported by numerous authors.^12–14 Stroke, including asymptomatic cerebrovascular events, is one of the most devastating complications of SCD.^{15 16} Strokes are due to large-artery vasculopathy involving the intracranial internal carotid arteries and proximal middle cerebral arteries, while silent strokes usually occur in the territory of penetrating arteries.¹¹

Stroke is a significant cause of morbidity and mortality in SCD.¹⁶ Stockman et al¹⁷ reported stenosis or occlusion of the large intracranial vessels in SCD by cerebral angiography. The supraclinoid internal carotid arteries were affected in all the studies, with less involvement of the middle and anterior cerebral arteries and relative sparing of the posterior circulation.¹⁷ Other authors have emphasised that non-invasive imaging by MRA correlates well with angiography.¹⁸

Hence, the above pathophysiological mechanisms might explain the MRI and MRA findings in our patient, showing marked atrophy in parietal, temporal and frontal lobes of both hemispheres, with preservation of blood circulation within the posterior arterial system.

The diagnosis of UWS is now more difficult by recognition of the MCS as a transitional phase in the partial recovery of awareness while emerging from the UWS.^{7 10} A key point in this case is the partial recovery of awareness with significant brain lesions, with sparing of the posterior regions of both hemispheres.¹⁹ Schiff et al⁶ have reported the apparent existence of isolated vestiges of functional brain networks in UWS cases associated with complex behavioural fragments, emphasising that such preserved brain activity is an indication for the modular nature of functional networks, underlining brain function. Laureys et al⁷, based on PET and other neuroimaging studies, have supported the notion that the medial parietal (precuneus) and adjacent posterior cingulate cortices appear to be the brain areas that differentiate MCS from UWS. These richly connected multimodal posterior associative areas seem to be important regions subserving human awareness.

Moreover, some tissue islands remained in the frontal lobes. A possible mechanism of rewiring among preserved cortex areas, and the thalamus, brainstem and other subcortical areas, which could be studied by diffusion tensor imaging, might explain the neuroplasticity processes involved in functional restoration of severely brain-injured patients.¹⁹

Outcome and follow-up

The patient remains alive and is currently in a MCS since her admission to the Institute for Neurology and Neurosurgery in July 2016.

Learning points.

• A patient with significant lesions due to brain infarcts (sickle cell anaemia), with only islands of tissue in the frontal and occipital lobes intact, emerged from unresponsive wakefulness syndrome to minimally conscious state.

• SPECT coregistered on MRI slices demonstrated cerebral blood remaining in frontal and occipital islands.

• Apparent Diffusion Coefficient (ADC)-MRI demonstrated network connections between those remaining areas of tissue, likely due to an axonal rewiring process, explaining clinical recovery.