There are no widely accepted formal criteria for diagnosis of DPHL, however it can be made with appropriate clinical history and supplemental testing provided alternative diagnoses have been ruled out. Depending upon individual circumstances, the differential diagnosis can be quite broad, particularly if circumstances surrounding the initial hypoxic event are unclear. Therefore, all potential causes of delirium relevant to the individual case need to be explored. In the setting of psychosis, fluctuating level of consciousness, or odd repetitive behaviors, EEG should be obtained to consider non-convulsive status epilepticus. Generalized delta range slowing, indicative of diffuse encephalopathy, can be seen in more than half of cases [18
Serum analysis should be employed to rule out medical causes of both dementia and delirium. For example, uremic encephalopathy, parkinsonism related to liver failure and/or manganese neurotoxicity, or bismuth toxicity from overdose of over-the-counter sub-salicylate (“Peptobismal”) can all cause profound mental status changes [20
]. Empiric testing should include complete blood counts and chemistries, B12, TSH, and toxicology studies. Among patients at high risk for B12 deficiency (potential abusers of inhaled nitric oxide, post-bariatric surgery patients, vegans), methymalonic acid level should also be measured. If any evidence of infection is noted blood cultures, chest x-ray and urinalysis should be performed.
In most cases, lumbar puncture to rule out encephalitis will be indicated. In keeping with established clinical guidelines, encephalitis is viewed as a potential symptom of increased intracranial pressure. Hence, neuroimaging (discussed below) should be obtained before proceeding, findings from which are typically very informative with respect to the likelihood of DPHL. Protein, glucose, cell count, bacterial cultures and herpes simplex virus polymerase chain reaction are routine for ruling out encephalitis. Myelin basic protein, a marker of acute widespread demyelination, can be a valuable test in considering suspected DPHL. In all three of our cases, we reported levels of greater than 40ng/ml (normal range in our lab was 0.07 to 4.1 ng/ml) [17
Computed tomography (CT) is readily obtained in most community hospitals and is the initial imaging modality in the evaluation of persons presenting for evaluation of altered mental status, particularly when rapid imaging is required not only for diagnosis but also as a pre-requisite to lumbar puncture. Diffuse hypodensity of white matter, particularly if unexpected (for example in a younger individual) can be strongly suggestive of acute demyelination. Prior scans for comparison (such as those at initial presentation) can be confirmatory if they demonstrate that the more recent finding is new. Otherwise, supplemental magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) sequences may be necessary.
The MRI findings of DPHL are nearly pathognomonic. Among individuals with this condition, diffuse hyperintensity of cerebral white matter will be present on T2-based sequences, particularly in the region of the dorsal frontal and parietal lobes known as the centrum semiovale. In contrast, posterior reversible encephalopathy syndrome usually has a predilection for the white matter regions supplied by posterior cerebral arteries. Inhaled heroin, in reports, can cause spongiform leukoencephalopathy that is associated with a pattern of T2 hyperintensity involving dorsal hemispheric white matter, posterior limb of the internal capsule, cerebellum, and brainstem corticospinal tracts. It characteristically spares the ventral frontal and temporal lobar white matter, anterior limb of the internal capsule, and cerebellar dentate nuclei [24
The predictive value of early neuroimaging on DPHL is uncertain. One reported case had mild T2 hyperintensity of white matter within the first 24 hours following the hypoxic event (drug overdose), becoming more pronounced following onset of neuropsychiatric symptoms [28
]. MRI with diffusion weighted imaging (DWI) sequences can clarify extent of brain injury and hence provide some prognostic information. An apparent diffusion coefficient (ADC), calculated from the T2-based DWI sequence, is used to create an image that reflects the rate of diffusion of water molecules. Neuronal death under hypoxic conditions is accompanied by a failure of ATP-dependent ion channels. The resulting loss of ion gradients and translocation of water from extracellular to intracellular compartments causes restricted movement of molecules. This is reflected as a low ADC, known as “diffusion restriction” [29
]. Abnormalities in deep grey matter structures are common in CO poisoning. Globus pallidus, which exists at arterial border zones is usually affected, but thalamus or midbrain can also be involved. T2 hyperintensity and diffusion restriction (reflecting cytotoxic edema) in these grey matter regions appears within 48 hours after the initial hypoxic insult [30
]. Similar to cytotoxic edema following a stroke [32
], this early diffusion restriction usually resolves within 7-10 days. Restricted diffusion in white matter has a different origin, because axons and oligodendroglia are largely spared in DPHL [4
]. ADC in affected white matter gradually declines, reaching a nadir at about 7 weeks [33
]. More data is required to confirm, but it appears that homogeneous prolonged restriction may portend a worse prognosis than patchy restriction with early resolution [17
There are potential explanations for the longer duration of diffusion restriction of cerebral white matter in DPHL. First, it may be due to trapping of water molecules within areas of defective myelin (dysmyelination.) Persistent diffusion restriction of the same white matter tracts is seen with metachromatic leukodystrophy (MLD) [37
]. MLD is a progressive leukodystrophy in which autosomal recessive deficiency of arylsulfatase-A (an enzyme required for metabolism of sulfatides in myelin turnover) causes dysmyelination. Second, oligodendrocyte apoptosis or other inflammatory changes have been proposed to occur [33
While clinical history and distribution of white matter changes are generally sufficient to make a diagnosis of DPHL once alternative differential diagnoses have been excluded, MR-spectroscopy (MRS) and diffusion tensor imaging (DTI) are of interest for purposes of research. The classic finding on MRS is a choline peak which indicates increased lipid turnover (as seen in acute demyelination) [12
]. A fall in the neuronal marker n-acetyl-aspartate may reflect a gain of non-neuronal cells (astrocytes and macrophages) known to occur [15
]. An elevated lactate peak, suggesting a shift from aerobic to anaerobic metabolism within affected white matter, has also been reported [15
]. DTI has shown that severe disruption of axonal function and structural integrity in these regions gradually resolves over a period of 5 months [15
DPHL can generally be diagnosed when the clinical history, laboratory assessments, and neuroimaging features are concordant with those described above. Alternative diagnoses should be considered if white matter lesions are non-continuous, enhancing, extend to overlying cortex, and are accompanied by seizures or constitutional symptoms. In rare circumstances, brain biopsy may be necessary in order to guide therapy if alternate diagnoses such as progressive multifocal leukoencephalopathy, neoplasm, or autoimmune phenomena (such as CNS vasculitis or acute disseminated encephalomyelitis) are suspected.