Reversible hypoxic brain injury: the penumbra conundrum of Grinker

Abstract

A female patient, aged 61 years, presented to us with a 3-day history of fever and altered sensorium. She was discharged from another hospital 1 week back where she was admitted for community-acquired pneumonia. She was put on mechanical ventilation for threatened airway and her magnetic resonance brain imaging showed evidence of delayed posthypoxic leucoencephalopathy, also known as Grinker’s myelinopathy. She was discharged 1 month later, on room air with a tracheostomy tube in situ. On follow-up after 5 months, she was ambulating with support and carried out activities of daily living independently.

Background

Delayed posthypoxic leucoencephalopathy (DPHL) is a rare condition wherein it is a close mimic of acute hypoxic encephalopathy in adults but with a better prognosis. Hence, recognition of this condition is important. There occurs a delayed neurological deterioration after an initial hypoxic insult to the brain. The radiological picture is almost quite pathognomonic. Management of this condition is conservative, but in many cases, amantadine and magnesium sulfate have been tried.

Case presentation

A 61-year-old woman presented to us with a 3-day history of fever, irrelevant talking and inability to recognise her family members. She also had hypertension and hypothyroidism, which were controlled on medication. She was apparently well till 1 month back when she developed acute onset fever, shortness of breath and altered sensorium. For these complaints, she was admitted and evaluated at an outside hospital where she was diagnosed as a case of community-acquired pneumonia. She was managed in intensive care unit with ventilator support. MRI of the brain at that time showed multiple small areas of diffusion restriction involving centrum semiovale on both sides, suggestive of internal border zone infarcts (figure 1). She was discharged in a stable condition.

Figure 1.

Baseline MRI. (A) T2-weighted axial images of the brain showing punctate areas of hyperintensities involving bilateral centrum semiovale and right posterior limb of the internal capsule. (B) Diffusion-weighted images showing diffusion restriction (hyperintense signal) involving bilateral centrum semiovale suggestive of internal border zone infarcts, likely to be secondary to haemodynamic compromise and acute infarcts involving bilateral occipital deep white matter and right posterior limb of the internal capsule.

A week after discharge, her relatives noticed that she was less responsive and her ability to recognise family members had decreased. These symptoms progressed gradually over the next 2 weeks to complete unresponsiveness, after which she was brought to our hospital. On examination, her Glasgow coma scale (GCS) score was E3V1M4; however, her vitals were stable (GCS varies from 3 to 15; with a lower score meaning worse condition). She had increased tone in all four limbs with an extensor plantar response with increased reflexes. Her higher mental functions and gait could not be assessed. She was intubated for airway protection and investigated for altered sensorium.

Investigations

Her laboratory parameters at the time of admission are given in table 1. As her blood glucose levels, electrolytes, metabolites and cerebrospinal fluid study were normal, she underwent MRI of the brain with gadolinium enhancement. It showed diffuse bilateral symmetrical, deep and periventricular white matter changes with sparing of U-fibres in T2-weighted images with the corresponding areas showing diffusion restriction in diffusion-weighted images, suggestive of DPHL, also known as Grinker’s myelinopathy (figures 2 and 3). We again reviewed her history and previous hospital records which suggested that there was a delay in intubation during the last admission which may have caused haemodynamic compromise resulting in a hypoxic insult. This event was corroborated by the initial MRI findings of internal border zone infarcts, which were commonly seen associated with haemodynamic compromise. The lucid interval between the hospital discharge and current presenting symptoms, synced with the natural course of Grinker’s myelinopathy as well.

Table 1.

Laboratory values of the patient at the time of hospital admission

	Reference range *	At admission
Haemoglobin (g/dL_	12–15	10.9
Total leucocyte count (cells/µL)	4000–11 000	13 100
Platelet count (cells/µL)	250 000–400 000	417 000
Urea (mg/dL)	10–50	21
Creatinine (mg/dL)	0.5–1.8	0.6
Sodium (mEq/L)	130–149	135
Potassium (mEq/)	3.5–5	4.4
Total calcium (mg/dL)	8.5–10.5	8.7
Phosphate (mg/dL)	2.5–4.5	3.7
Uric acid (mg/dL)	2–7.4	3.5
Total bilirubin (mg/dL)	0.20–1.20	0.4
Total protein (g/dL)	6–8	6.6
Albumin (g/dL)	3.5–5	2.9
Globulin (g/dL)	2–3.5	3.7
AST (U/L)	0–50	104
ALT (U/L)	0–50	180
ALP (IU/L)	80–240	184
TSH (U/mL)	0.3–5	2.3
CSF
Total cells (cells/µL)	0–15	Nil
Protein (mg/dL)	15–45	32
Glucose (mg/dL)	45–80	126
GeneXpert	Negative	Negative

*Reference value at the All India Institute of Medical Sciences, New Delhi; may vary from different laboratories.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; TSH, thyroid-stimulating hormone.

Figure 2.

MRI brain 5 weeks after the acute hypoxic event. (A) T2-weighted axial images of the brain showing confluent hyperintensities in the periventricular and deep white matter of the bilateral supratentorial brain. (B) Diffusion-weighted imaging showing bilateral symmetric restricted diffusion in the same regions of brain parenchyma, as in T2-weighted images.

Figure 3.

MRI brain T2-weighted axial image showing characteristic sparing of U-fibres.

Outcome and follow-up

She underwent a tracheostomy and was discharged on room air to her home, as no hospice facility was available. She was followed up monthly on an out-patient basis and at the last follow-up (5 months after onset), she was ambulating with support, had her tracheostomy tube removed and she had full cognitive ability. A repeat MRI (figure 4) of the brain, however, showed an incomplete resolution of white matter changes.

Figure 4.

MRI brain at 5-month follow-up. (A) FLAIR axial image showing patchy hyperintensities in the periventricular regions (reduced comparatively with the last imaging). (B) Diffusion-weighted image showing bilateral symmetric restricted diffusion in the same regions of the brain parenchyma as the FLAIR images. FLAIR, fluid-attenuated inversion recovery.

Discussion

DPHL, also known as Grinker’s myelinopathy, is a rare condition that occurs following a period of prolonged hypoxia to the brain. The condition was first described by Roy Richard Grinker who was an American neurologist and psychiatrist.¹ The literature regarding the incidence of this condition is sparse and is confounded because of the lack of a gold standard for diagnosis and a long list of differential diagnoses. Plum and Posner² defined three aetiologies for DPHL anoxic, anaemic and ischaemic.³ Our case had anoxic anoxia, possibly due to the delay in intubation during her previous hospital visit.

There is an initial hypoxic event followed by neurological deterioration in DPHL. The patient improves after initial deterioration for about 3 weeks subsequently deteriorate again. Lee and Marsden⁴ described two forms of clinical presentation of this condition: parkinsonism or akinetic mutism. The first type is characterised by tremor and rigidity with festinant gait while the second type is characterised by abnormal behaviour, psychomotor retardation followed by mutism. The MRI findings of DPHL are pathognomonic: diffuse hyperintensity of cerebral white matter are present on T2-weighted sequences, particularly in the dorsal frontal and parietal lobes in centrum semiovale. This pattern is distinct from that seen in acute hypoxic‐ischaemic injury, which involves predominantly the grey matter structures.⁵

The cause for the delayed posthypoxic white matter deterioration remains obscure. One possible explanation relates to the half-life for myelin-related proteins, which is in the same time frame (mean 19 days) as the onset of symptoms seen in DPHL.⁶ Another explanation is that hypo-oxygenation restricted to hemispheric white matter results in delayed apoptosis of the oligodendrocytes responsible for myelin production. Additionally, there have been reports of patients with decreased arylsulfatase-A levels in the serum, suggesting that this could represent a predisposing factor. In other reported cases, it has been in the normal range too. We did not measure arylsulfatase A in our patient due to the non-availability of the same.

There is no definite treatment for this condition. There are case reports of instituting amantadine in cases of DPHL with parkinsonism with a certain amount of success.⁷ In most of the cases, the condition is self-limited to a resolution of the symptoms happening within 2 to 4 weeks.⁸

Our case brings into attention the neglected entity of DPHL, also known as Grinker’s myelinopathy, which presents with neurological deterioration after a lucid interval from the index injury causing hypoxic brain damage.

Learning points.

• Delayed post-hypoxic leucoencephalopathy (DPHL) is a diagnosis of exclusion which occurs a few weeks after an initial hypoxic insult to the brain.

• MRI findings of diffuse hyperintensity and diffusion restriction of the deep and periventricular white matter of central semiovale with typical sparing of the cerebral cortex and subcortical U-fibres suggest DPHL.

• DPHL has a better outcome than any other cause of anoxic encephalopathy.