Neuroimmunology
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Acute necrotizing hemorrhagic leukoencephalitis …
- Updated 06.18.2024
- Released 01.24.1996
- Expires For CME 06.18.2027
Acute necrotizing hemorrhagic leukoencephalitis
Introduction
Overview
Acute hemorrhagic leukoencephalitis of Weston Hurst is at the extreme end of the spectrum of demyelinating diseases. It typically follows a viral upper respiratory infection and evolves rapidly to coma and death. "Ball and ring" hemorrhages appear in the centrum semiovale of the brain, associated with mononuclear and neutrophil infiltrates, surrounded by demyelination spreading out from fibrin-filled venules. In this article, the author addresses these issues and suggests that IL-17, a cytokine that attracts neutrophils, may be important in pathogenesis. Hemorrhages, neutrophils, and the cytokine profile differentiate it from ADEM.
Key points
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• Acute necrotizing hemorrhagic leukoencephalitis is a devastating disorder that often follows a virus or mycoplasma infection. | |
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• COVID-19 infection induces acute necrotizing hemorrhagic leukoencephalitis. | |
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• Lesions are hemorrhagic, with fibrinoid necrosis and polymorphonuclear neutrophil infiltration that is associated with demyelination. | |
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• The devastating immune response may be from excess sensitization to one or more unknown antigens. | |
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• Therapy is difficult, and most of those affected will die. Several therapies are suggested to deactivate the immune response. |
Historical note and terminology
E Weston Hurst was the first to clearly define acute necrotizing hemorrhagic leukoencephalitis and to suggest that it was a demyelinating disease (23). He described the abrupt onset of neurologic symptoms following a nonspecific upper respiratory infection in three patients: a 43-year-old housewife, a 33-year-old munitions worker, and a 37-year-old accountant. Death occurred in several days, and autopsies of two of these patients showed identical hemorrhagic lesions in the white matter. Other authors, such as Gayet, Leyden, Strümpell, Bückler, Leichtenstern, Brie, Oppenheim, de Faro, Baker, Levy, Adams, and Crawford described similar encephalitic conditions with petechial hemorrhage and inflammation, as early as 1875 (31).
Clinical manifestations
Presentation and course
The onset of acute hemorrhagic leukoencephalitis is abrupt and sometimes violent. It appears from 2 days to 2 weeks after a 3- to 5-day premonitory illness. It is most common in fall and winter. Viral upper respiratory infections are the most common antecedent (33%), but there is sometimes no prodrome (18%) (13; 18). In one third of cases, the upper respiratory infection may be followed by a symptom-free period of several days, but neurologic symptoms then suddenly appear. Patients with acute myeloid leukemia in hematologic remission may be particularly susceptible (2%) to this rare condition (40). The most common ages are 20 to 40 years, but children and sexagenarians have been affected. Two thirds are male. Twelve percent have preexisting autoimmune diseases (18).
The course is brief and usually ends in death or disability. Fever up to 106°F, headache, photophobia, neck stiffness, meningeal irritation, confusion, and lethargy last several days and are followed by a progressively deepening coma over 4 to 10 days (31). A biphasic course over several weeks is possible. In one case of biphasic disease, high-dose steroids were withdrawn before the second episode (44), likely leading to recrudescence. Neurologic signs are protean because of the diffuse and massive necrosis of CNS white matter. Visual field disturbances, gaze preferences, pseudobulbar palsy, aphasia, or mutism suggest a cortical disturbance but actually arise from undercutting of the cortical connections by the white matter lesions. Progressive motor and sensory disturbances and incontinence appear early. Reflexes are usually hyperactive and toes are upgoing. Fifty percent of patients have hemiparesis. A smaller percentage has seizures or status epilepticus, involuntary movements, and dysarthria (13; 16; 20). Papilledema from increased intracranial pressure is present in one third (13). Death results from brain swelling with herniation. Rarely, patients have a subacute course and rarely, recover completely. CSF pleocytosis resolves after several weeks (32), and clinical symptoms improve over weeks to months.
Prognosis and complications
Most patients (68%) die within a week of onset of neurologic symptoms (13). Survivors usually have severe deficits, including seizures, psychiatric symptoms, and mental deterioration. A few patients have recovered completely (50; 32; 49).
Clinical vignette
A 28-year-old life insurance salesman had an upper respiratory infection that resolved after four days. One week later, he developed a stiff neck, fever to 102°F, headache, and confusion. Left arm and leg weakness was followed by bilateral paresis, incontinence, dysarthria, and lethargy over the next two days. He was diffusely hyperreflexic and had bilateral papilledema.
His complete blood count showed 38,000 cells/mm3 with neutrophilia. Serum C-reactive protein and ferritin were elevated. There was a suggestion of diffuse hypodensity of the right hemisphere on CT scan. Spinal fluid showed an opening pressure of 345 mm H2O, 150 RBC/mm3, 3000 WBC/mm3 (largely polymorphonuclear leukocytes), total protein of 200 mg/100 ml, normal glucose, and no oligoclonal bands.
The symptoms and signs worsened over the next four days, and the patient became comatose five days after the onset of symptoms. Despite intravenous mannitol and high dose glucocorticoids, the patient expired three days later from herniation.
Biological basis
Etiology and pathogenesis
Most cases follow or overlap with a banal upper respiratory tract infection; 35% were found in a series of 43 biopsy-proven cases (18). Other prodromes occasionally lead to acute hemorrhagic leukoencephalitis: viral pneumonia, chickenpox, COVID-19, mRNA vaccine, cytomegalovirus, dengue, Epstein-Barr virus infection, HSV, VZV, HHV-6, measles, influenza H1N1, mumps, mycoplasma pneumonia, tuberculosis, minor operations, dental extraction, skin burns, snake bite, chronic nephritis, relapses of ulcerative colitis (08; 02), or vaccinations such as typhus, smallpox, cholera, COVID-19, dysentery, hepatitis B (27), human papilloma virus, tetravalent inactivated influenza, and pneumococcal polysaccharide. Note, case reports do not indicate causality, and primary virus infections are much more likely to case pathology than vaccination. Scattered reports attribute a kindred disease to toxins and drugs (arsphenamine) (17). Three cases have followed treatment of tuberculosis (09). This suggests that components of mycobacterium tuberculosis activated the immune system, just as when mycobacterium tuberculosis is used to create complete Freund adjuvant for induction of experimental autoimmune diseases.
COVID-19 triggers this disorder. Two years after the pandemic started (in January 2022), there were 25 reports of acute hemorrhagic leukoencephalitis; eight were reliable (15; 41; 65; 42; 61; 57; 51). Seventeen other reported cases were likely acute disseminated encephalomyelitis, acute necrotizing encephalopathy, or hypoxic damage, likely misclassified due to lack of biopsy and the less rigorous vetting of COVID-related publications during the pandemic. Importantly, acute hemorrhagic leukoencephalitis, disseminated encephalomyelitis, and acute necrotizing encephalopathy are all precipitated by viruses, and all three have somewhat overlapping MRI and pathological findings. COVID binding to ACE2 of brain endothelial cells or activation for other CNS viruses may amplify hemorrhagic pathology in all of these disorders. This spectrum of inflammatory brain diseases suggests that host factors retarget the response to COVID in different ways. In untreated multiple sclerosis, 8800 genes are dysregulated in peripheral blood mononuclear cells (11), attesting to the complexity of immune-CNS-virus interactions, and that therapy of these COVID-induced CNS inflammatory disorders may differ.
White matter of the cerebral hemispheres is involved on MRI in 65%, usually asymmetrically, and often with visible hemorrhage (18). Fifteen percent have isolated lesions in the cerebellum, brainstem, and spinal cord. Cerebrospinal fluid (CSF) almost always shows increased protein. CSF white blood count is elevated in 65%; 50% of cases are mainly mononuclear and 40% polymorphonuclear; eosinophils are sometimes present. Despite hemorrhagic lesions on biopsy, CSF red blood cells are elevated in only 39% (18).
At autopsy, the brain is edematous and swollen. The tissue is pink or yellow-gray, with diffuse petechial hemorrhages and congested vessels, and may approach a state of liquefaction (23; 31; 13; 58). The centrum semiovale is the main area affected, often asymmetrically.
The brainstem, the cerebellar peduncles, and even the spinal cord are sometimes involved (28). There are signs of hippocampal and tonsillar herniation and flattened gyri. The gray matter, U fibers, and basal ganglia are spared.
Microscopic changes include diffuse edema, widespread areas of demyelination and eosinophilic fibrinoid necrosis.
There is perivenous inflammation around blood vessels in the brain and in the meninges, with microglial foci and infiltrating polymorphonuclear cells and smaller numbers of activated mononuclear cells, including monocytes and cytotoxic T cells. There are minimal microglial nodules and no immunoglobulin deposition on perivascular cells (47). Some areas show myelin vacuolation and decompaction. Astrocytes, both protoplasmic and fibrous, are swollen, especially in their perivascular end-feet and parenchymal processes. Degenerating astrocytes are dystrophic with “beaded” processes. Swollen astrocytes and their remnants are immunoreactive for AQP4 and AQP1 (47). Small hemorrhages abound in the centrum semiovale, but massive hemorrhage is atypical. The pons and cerebellar peduncles also sometimes contain small hemorrhages. These ball and ring hemorrhages affect gray and white matter throughout supra- and infratentorial areas.
The sequence of events begins with swollen endothelial cells, continues with plasma leakage into the CNS, and is followed by cellular infiltrate (first neutrophils, then macrophages, and finally lymphocytes). Capillaries are disrupted with a surrounding hemorrhagic ball that forms a ring (“ball and ring”) around a bloodless center that sometimes contains a fibrin clot.
The walls of venules are impregnated or replaced with fibrin, often extending into the perivascular space and brain tissue. This is not a necrotizing angiitis because there is no initial inflammation of the vessels, and small venules instead of arterioles are involved. It would be better termed an angiopathy. The cause of the endothelial cell necrosis is unknown, but possible etiologies include antibody-antigen-complement, toxic cytokines, or reactive oxygen intermediates (58).
Demyelination predominates around small vessels that are surrounded by neutrophils. Some lymphocytes and lipid-filled macrophages are present, but most importantly, a neutrophilic infiltrate characterizes acute necrotizing hemorrhagic leukoencephalitis. Demyelinated areas contain activated microglia. Meninges may be infiltrated with lymphocytes (02). Axonal damage is also dramatic. Beta-amyloid precursor protein, a marker for acute axonal damage, is present in axons and neuronal cell bodies surrounding inflamed veins but only rarely beyond 0.25 mm from the wall of the inflamed vessels (14). Macrophages are located in areas of axonal damage, suggesting macrophages cause the damage.
Cerebral white matter is the target. Early investigators implicated infection, toxins, and acquired sensitivity of brain tissue to a circulating antigen (31). However, no infection or toxin is consistently associated, and pathogens are not present in the CNS.
A single report shows marked lymphocyte proliferation to myelin basic protein, similar to that seen in acute disseminated encephalomyelitis (05). The kinetics of the antimyelin basic protein response have not been studied. This group also used passive transfer of white blood cells from a patient with acute hemorrhagic leukoencephalitis to induce experimental allergic encephalomyelitis in monkeys (06).
The pathology of the disease is reminiscent of hyperacute experimental allergic encephalomyelitis, provoked by vaccination with spinal cord homogenate in complete Freund's adjuvant followed by pertussis toxin. Experimental allergic encephalomyelitis becomes hyperacute and similar to acute hemorrhagic leukoencephalitis when animals are exposed to intravenous meningococcal toxin (ie, when a Shwartzman reaction is superimposed on the response) (60). This suggests that sensitization to CNS antigens is enhanced by endotoxin. In support of this hypothesis, acute hemorrhagic leukoencephalitis can be provoked by Gram-negative septicemia that is associated with acute tubular necrosis and disseminated intravascular coagulation (17). Perhaps related, there are high levels of clostridium perfringens epsilon toxin in multiple sclerosis (33).
In another relevant model, C57BL/6 mice are normally resistant to Theiler virus-induced demyelination because of their strong antiviral responses. However, if the target protein is injected after seven days of controlled virus infection, the blood-brain barrier opens, and there is demyelination and microhemorrhages (45).
The predominance of neutrophils in acute hemorrhagic leukoencephalitis argues for elevated levels of interleukin-17 (IL-17). The proinflammatory IL-17 cytokine raises levels of IL-6 and granulocyte-colony stimulating factor that stimulate granulopoiesis in bone marrow, and induces chemokines (IL-8) that attract neutrophils. IL-17 is secreted by CD8 T cells and by a subset of CD4 memory T cells that are a separate lineage from Th1 and Th2 cells. IL-6 plus transforming growth factor-beta generate Th17 cells from naive CD4 cells. IL-4, and also interferon-gamma and interferon-beta, inhibit IL-17 production. Bacterial infection, lipopolysaccharide, and cytokines induce IL-17.
Th17 cells amplify CNS inflammation. They increase during multiple sclerosis exacerbations and are higher in CSF than serum (35). IL-17 is increased in plaques, CSF, and serum in neuromyelitis optica (24). In acute hemorrhagic encephalomyelitis, there is a cytokine storm, with pronounced elevation of Th1 cytokines (TNF-alpha, IFN-gamma, CCL3, CXCL8/IL-8, CXCL9, CXCL10, G-CSF), Th2 and Treg cytokines (IL-1 receptor antagonist, IL-4, IL-10, IL-13, CCL2, CCL4, CCL17, CXCL11), Th17 cytokines (IL-17A, IL-23), and IL-6 and interferon-alpha, but no B cell cytokines (59). CSF cytokine levels are higher than in acute disseminated encephalomyelitis, where B cell cytokines are increased. A monoclonal antibody directed at IL-17 could block the immune activation. Type I (alpha and beta) and II (gamma) interferons inhibit generation of IL-17-producing cells (22), so interferon-beta is a potential therapeutic agent, at least at the early stages of disease.
Two unrelated pediatric patients of Filipino descent with a partial complement factor I deficiency had upregulation of complement C3, membrane attack complex, and IL-1 in the brain during hemorrhagic leukoencephalitis (07). They improved after treatment with anti-IL-1 antibody. F1 is a serine protease that inactivates C3b and C4b. Thus, complement and IL-1 may play a role in Hurst disease.
Epidemiology
Most early reports were from the United Kingdom and Australia. Subsequent descriptions originated in the United States, Belgium, France, Germany, Eastern Europe, Turkey, and Japan. Men are affected twice as frequently as women (13). Approximately 100 case reports describing this rare disease are in the literature.
Prevention
No means of prevention are known.
Differential diagnosis
Other types of encephalitis can be confused with acute hemorrhagic leukoencephalitis. It must be separated from diseases that cause multiple petechial hemorrhages or multiple areas of demyelination.
Demyelinating disorders.
Acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis also follows upper respiratory infections, and the inflammation is perivascular. However, hemorrhagic necrosis is not present or is minimal, the peripheral white blood cell count is lower, and polymorphonuclear cells are not a feature of acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis lesions are random fluffy white mater lesions and do not form large foci; cerebral edema is uncommon, and there is less axonal damage (14). T cells are sensitive to myelin basic protein in acute disseminated encephalomyelitis (55). In the CSF, lymphocytes predominate (not neutrophils), and there are fewer immune cells. Protein is less elevated and opening pressure is lower, and oligoclonal bands are absent. Argument persists whether these are two separate entities or part of a spectrum, with acute hemorrhagic leukoencephalitis being the most rapidly developing form, and acute disseminated encephalomyelitis being a later form where recovery is much more likely (32). They are separate entities with different disease mechanisms and perhaps different treatments.
Acute disseminated encephalitis is more common in children and is less fulminant and less fatal. In a large series of Turkish children, one third had one or more relapses after the initial event. Prognosis was good; 71% recovered completely (03). In 84 Argentinean children, MRI showed four subgroups of acute disseminated encephalomyelitis with small lesions (62%), with large lesions (Schilder disease, 24%), with predominant bithalamic involvement (acute necrotizing encephalopathy, 12%), and acute hemorrhagic encephalomyelitis (2%) (54). On T2 MRI, acute disseminated encephalomyelitis lesions are usually fluffy and localized to white matter throughout the brain and range from small to large. Lesions of acute hemorrhagic leukoencephalitis are larger, more confluent, and more edematous, and they often spare the basal ganglia (29).
Acute necrotizing encephalopathy (ANE). Acute necrotizing encephalopathy of childhood is described in children from the Far East (Japan, Korea, and Taiwan) and occasionally in the Occident (Turkey, Greece, Germany, and Canada) (37; 66). It causes bilateral, multifocal, symmetric destruction of thalamus, sometimes with a target appearance on MRI. In some cases there are also symmetric lesions in internal capsule, brainstem tegmentum, and cerebellum. These lesions do not typically contain inflammatory cells. Encephalopathy and seizures are typical. There are reports of several Japanese adults with this disorder. It is often preceded by viral infections (especially influenza A, H1N1; possibly HHV6, parainfluenza, and reovirus) by only 0.5 to 3 days, differentiating it from post-infectious encephalomyelitis, which typically develops 10 to 14 days after the infection. Cases have similar courses with or without antecedent influenza. Cytokine storm was reported in one patient. Another case associated with hemophagocytic lymphohistiocytosis suggests there is excessive immune system and macrophage activation. Many affected children had been treated with antipyretics. Steroids may be helpful.
Occasional cases have mutations in the nuclear pore protein Ran binding protein 2 (RANBP2) involved in neuronal energy metabolism and mitochondrial function. It binds to COX11 to allow hexokinase activation, perhaps neurotrophic (19). There may be a family history of similar recurrent events (“ANE1”) (39; 63). Lesions are more widespread and can include spinal cord lesions. Sodium channel alpha1 subunit (SCN1A) mutation was present in one case. Influenza also causes encephalopathy with cortical lesions, such as hemorrhagic shock and encephalopathy (HSES), acute brain swelling (ABS), and febrile convulsive status epilepticus (FCSE). A patient with multiple sclerosis for 14 years, treated with glatiramer acetate and then interferon-beta, developed severe, biopsy-proven severe hemorrhagic necrosis, diagnosed as acute hemorrhagic encephalitis of Weston Hurst that symmetrically involved the thalami and basal ganglia, but was similar to acute necrotizing encephalomyelitis (64).
This monophasic disorder is associated with seizures (40%), acute encephalopathy with decreased consciousness (30%), and vomiting (20%). Within 24 hours, diencephalic and upper brainstem damage causes spasticity, decerebrate posturing, miotic pupils, and coma. Liver enzymes are elevated by the second hospital day, but serum ammonia is normal. There are no infiltrating inflammatory cells, nor CSF pleocytosis. Lesions are usually symmetric. They are often hemorrhagic and cavitary and are found in the thalamus (essential for diagnosis), internal capsule, basal ganglia, brainstem tegmentum, and cerebral and cerebellar white matter. On T1-weighted MRI, bilateral thalamic lesions have a hyperdense center and a hypodense ring; densities reverse on T2-weighted MRI (38). The apparent diffusion coefficient (ADC) on MRI is decreased, whereas it is high in acute disseminated encephalomyelitis. The outcome is poor to grave.
Myelin-oligodendrocyte glycoprotein–associated disease (MOGAD) has been associated with acute hemorrhagic leukoencephalitis in one biopsy-proven report (04). MOGAD is seldom as severe, but 30% of adults and 45% of children present with fever. Multifocal white matter lesions on MRI are common, but they are not hemorrhagic.
Multiple sclerosis. Multiple sclerosis is seldom this fulminant and is less widespread in the brain. The reaction to myelin basic protein in multiple sclerosis is absent or minimal, in contrast to the strong response to myelin basic protein that is common in acute disseminated encephalomyelitis and which is also occasionally seen in acute hemorrhagic leukoencephalitis. Multiple sclerosis is typically recurrent, whereas acute hemorrhagic leukoencephalitis is monophasic, with the exception of one report (30). There are case reports of an association of hemorrhagic leukoencephalitis with Crohn disease or ulcerative colitis. Association with muscle and nerve damage may be from intensive care inflammatory neuropathy/myopathy.
Infections.
Bacterial meningitis. Bacterial meningitis causes an early fall in CSF glucose. Polymorphonuclear cells are present in the spinal fluid, but red cells are not as common as hemorrhagic leukoencephalitis. Abundant bacteria are usually detected on Gram stain. Asymmetric changes in the white matter are uncommon. It is critical to differentiate meningitis from acute hemorrhagic leukoencephalitis because glucocorticoids are used to treat leukoencephalitis, but antibiotics are used for meningitis.
Bickerstaff brainstem encephalitis. Sometimes caused by autoantibodies.
Brain abscess. Brain abscess is usually focal and is easily diagnosed with CT or MRI.
Epidural empyema. Epidural empyema is relatively rare. It is usually caused by sinus infection or trauma to the cranium that allows bacterial ingress.
Eastern equine encephalitis. Eastern equine encephalitis is a rare disease seen mostly in infants and children during late summer. It causes diffuse encephalitis with blood and spinal fluid pleocytosis.
Hemorrhagic encephalitis of Baker. The so-called hemorrhagic encephalitis of AB Baker did not follow upper respiratory infections, and not all of the white matter lesions were hemorrhagic. These distinctions seem trivial, and the condition is probably identical to acute hemorrhagic leukoencephalitis.
Herpes simplex encephalitis. Herpes simplex encephalitis is often focused in the temporal lobes. It evolves over days to a week. The peripheral white blood cell count is not as markedly elevated as in hemorrhagic leukoencephalitis, and the CSF infiltrate is lymphocytic instead of polymorphonuclear. Bloody CSF can be seen in both. Petechial hemorrhages are early in hemorrhagic leukoencephalitis, but appear later in herpes encephalitis. CT and MRI changes predominate in the temporal lobes and may enhance with contrast, and white and gray matter are both involved in herpes encephalitis, rather than predominantly white matter. EEG changes are also common in the temporal lobes with herpes infection.
Rasmussen encephalitis. Rasmussen encephalitis has a much longer and slower course and is often unilateral.
Other viruses. Other viruses linked to this disorder include Epstein-Barr and influenza.
Vascular disorders.
Brain purpura. Brain purpura (pericapillary encephalorrhagia) is a noninflammatory condition with multiple small petechial hemorrhages and hyaline or fibrin clots obliterating the lumens of pre-capillary arterioles in the white matter (23). Patients develop stupor and coma, usually without focal signs. The CSF is normal. Its etiology is obscure, but it is sometimes associated with Gram-negative infections or with arsenic or phosgene poisoning. A combination of brain purpura and acute disseminated encephalomyelitis, perhaps the superimposition of one condition on the other, may be the etiology of acute hemorrhagic leukoencephalitis.
Cerebral venous thrombosis. Cerebral venous thrombosis causes seizures and focal cortical signs, especially from gray matter damage, in contrast to the centrum semiovale lesions in acute hemorrhagic leukoencephalitis.
Subarachnoid hemorrhage. Subarachnoid hemorrhage is explosive in onset and is associated with a severe headache and stiff neck. Focal or generalized neurologic signs can progress to death within hours to days.
Toxic disorders.
Acute lead encephalitis. Acute lead encephalitis may develop abruptly and sometimes generates focal signs and elevated CSF protein. Lead lines in the shafts of the long bones and a history of pica are common, usually in young children who ingest paint that contains lead.
Arsphenamine encephalitis. Arsphenamine encephalitis has a similar pathology (01).
Central pontine myelinolysis. Abrupt electrolyte fluctuations cause central pontine myelinolysis. The BBB is altered from endothelial shrinkage after rapid correction of hypotonicity with hyperosmolar solutions. Osmotic stress is followed by early lesions with astrocytic damage and loss of AQP4 and AQP1 (47). It causes demyelination with sharp borders, axonal damage, plus edema, macrophage inflammation, and astrocytosis. The axonal retraction bulbs and beta-amyloid precursor staining are not perivenular and the damaged axons are of larger diameter than in acute hemorrhagic encephalomyelitis (14). Macrophage location does not correlate with axonal damage as would be expected with a metabolic, compared to an inflammatory, insult.
Toxic spongiform encephalopathy. Reversible toxic spongiform encephalopathy can follow inhalation of heated heroin vapor, or “chasing the dragon.” There is cerebellar ataxia, motor restlessness, and apathy. This is associated with bilaterally symmetric MRI lesions in cerebellar nuclei and white matter, deep cerebral white matter, and brainstem.
Reye syndrome. Reye syndrome is a mitochondrial disorder in children that follows use of aspirin during viral infections. Acute brain swelling is associated with protracted vomiting and hepatic damage.
Subacute leukoencephalopathy. Chemotherapy can cause subacute leukoencephalopathy.
Wernicke encephalopathy. In alcoholics, ataxia, ophthalmoparesis, and encephalopathy often with thiamine deficiency can have acute or subacute onset.
Diagnostic workup
The peripheral white blood cell count is markedly elevated, which is a rare finding in most other demyelinating conditions. Neutrophils predominate and range from 11,000 to 120,000 cells/mm3. The sedimentation rate is occasionally elevated.
The CSF is normal in 10%, usually early in the disease. Intracranial pressure is increased up to 350 mm H2O. CSF pleocytosis is from 10 to 4000 cells/ml, and rarely up to 20,000. There is usually a marked polymorphonuclear cell pleocytosis. Xanthochromia and red blood cells are often present and up to 150 cells/ml. The CSF total protein is elevated (one fourth have levels over 200), but the glucose is almost always normal. CSF myelin basic protein can be elevated from devastating damage.
CT scans show low density in the white matter and can show small hemorrhages. The abnormalities are relatively symmetric and are associated with mass effect from the early edema. Changes appear within 18 hours of onset of neurologic symptoms (48). There is sometimes gyral enhancement with contrast, but the white matter does not enhance (62). Later scans in survivors show hypodensity.
MRI is more sensitive than CT. It shows numerous nonenhancing lesions with increased signal intensity in the centrum semiovale and deep white matter, including frontal and temporal lobes and the corpus callosum (10; 46; 12). One 23-year-old Belgian woman, 10 days after a measles eruption, had confluent bilateral thalamic and subcortical white matter lesions on MRI and biopsy showing hemorrhagic lesions and neutrophil (PMN) infiltration (56), but this may have been acute necrotizing encephalomyelitis. Lesions are hyperintense on T2 MRI, and mixed hypo- and hyperintense on diffusion-weighted and apparent diffusion coefficient imaging, and they change with time. They are often bilateral but can be asymmetric. Serial MRI shows focal non-hemorrhagic lesions, followed by much larger white matter lesions and later necrosis. Susceptibility-weighted (SWI) MRI imaging (T2*), which detects paramagnetic blood and iron deposits, shows low-signal large hemorrhages as well as petechial hemorrhages, along with nondisplaced medullary veins (26). MRI evidence of small hemorrhages could obviate brain biopsy.
The EEG is abnormal in 90% of these patients. It shows diffuse slowing that may be lateralized.
Management
This disease resembles hyperacute experimental allergic encephalomyelitis in animals, a disease ameliorated by glucocorticoids or ACTH, which has additional nonsteroidal anti-inflammatory effects. Half of patients treated with high doses of glucocorticoids survive, and one sixth of survivors are asymptomatic (13). Too-rapid steroid withdrawal may provoke recurrence (44).
There are reports of potential benefit of plasmapheresis and intravenous immunoglobulin (50; 25; 21; 32). Plasmapheresis is more effective after infections such as mycoplasma pneumonia. Plasma exchange removes autoantibodies that promote the catastrophic damage. Ten exchanges reversed most symptoms in a severe case following mycoplasma pneumonia infection (49). Two other cases recovered after plasma exchange plus cyclophosphamide (50; 36). However, plasma exchange is not always effective (49). In one series, aggressive therapy in a neurologic intensive care unit improved prognosis.
The inflammation has an IL-17 component. The rationales for therapy with type I interferon and anti-IL-17 are presented above in the section labeled “Pathogenesis and pathophysiology.”
Two pediatric patients with a partial complement factor I deficiency did not improve with glucocorticoids and IVIG but had dramatic resolution with anakinra (anti-IL-1 monoclonal antibody) (07).
Two pediatric patients with a partial complement factor I deficiency and this disease did not improve with glucocorticoids and IVIG but had dramatic resolution with anakinra (anti-IL-1 monoclonal antibody) (07).
Hypertonic fluids may reduce CNS edema, but they have no proven benefit. Intracranial pressure monitors help titrate the hyperosmolar agents used to decrease swelling (34). Surgical decompression relieves swelling and provides tissue for diagnosis. Before 1990, fewer than half of the patients who were decompressed survived, and all had neurologic sequelae (13). At that time, simple supportive care was considered as a treatment option. Two of four patients treated with high-dose steroids plus decompressive craniotomy recovered completely, and two had residual paraplegia without cognitive changes (52; 43; 49).
Hypothermia to 33°C reversed many of the manifestations of acute hemorrhagic leukoencephalitis (53). Hypothermia may affect the blood-brain barrier, cytotoxic edema, or immune function.
Special considerations
Pregnancy
Pregnancy in relation to acute necrotizing hemorrhagic leukoencephalitis has not been studied.
Anesthesia
Anesthesia in relation to acute necrotizing hemorrhagic leukoencephalitis has not been studied.
Media
References
- 01
- Adams RD, Cammermeyer J, Denny-Brown D. Acute necrotizing hemorrhagic encephalopathy. J Neuropathol Exp Neurol 1949;8:1-29. PMID 18108331
- 02
- An SF, Groves M, Martinian L, Kuo LT, Scaravilli F. Detection of infectious agents in brain of patients with acute hemorrhagic leukoencephalitis. J Neurovirol 2002;8(5):439-46. PMID 12402170
- 03
- Anlar B, Basaran C, Kose G, et al. Acute disseminated encephalomyelitis in children: outcome and prognosis. Neuropediatrics 2003;34(4):194-9. PMID 12973660
- 04
- Bang SJ, Kim S, Seok HY. Acute hemorrhagic leukoencephalitis as a new phenotype of myelin oligodendrocyte glycoprotein antibody-associated disease. Neurol Sci 2023;44(10):3741-3. PMID 37178214
- 05
- Behan PO, Geschwind N, Lamarche JB, Lisak RP, Kies MW. Delayed hypersensitivity to encephalitogenic protein in disseminated encephalomyelitis. Lancet 1968;1009-12. PMID 4176341
- 06
- Behan PO, Lamarche JB. Passive transfer of allergic encephalitis from man to primates. Neurology 1969;19:321-2.
- 07
- Broderick L, Gandhi C, Mueller JL, et al. Mutations of complement factor I and potential mechanisms of neuroinflammation in acute hemorrhagic leukoencephalitis. J Clin Immunol 2013;33(1):162-71. PMID 22926405
- 08
- Byers RK. Acute hemorrhagic leukoencephalitis: report of three cases and review of the literature. Pediatrics 1975;56:727-35. PMID 1105376
- 09
- Chetty KG, Kim RC, Mahutte CK. Acute hemorrhagic leukoencephalitis during treatment for disseminated tuberculosis in a patient with AIDS. Int J Tuberc Lung Dis 1997;1:579-81. PMID 9487459
- 10
- Donnet A, Dufour H, Gambarelli D, Bruder N, Pellissier JF, Grisoli F. [Acute Weston Hurst necrotizing hemorrhagic leukoencephalitis] [Article in French]. Rev Neurol 1996;152(12):748-51. PMID 9205699
- 11
- Feng X, Bao RY, Li L, Deisenhammer F, Arnason BGW, Reder AT. Interferon-β corrects massive gene dysregulation in multiple sclerosis: Short-term and long-term effects on immune regulation and neuroprotection. EBioMedicine 2019;49:269-83. PMID 31648992
- 12
- Friedman DP. Neuroradiology case of the day. Unilateral acute hemorrhagic leukoencephalitis (AHL) complicated by venous thrombosis. Radiographics 1998;18:246-50. PMID 9460130
- 13
- Geerts Y, Dehaene I, Lammens M. Acute hemorrhagic leukoencephalitis. Acta Neurol Belg 1991;91:201-11. PMID 1746242
- 14
- Ghosh N, DeLuca CG, Esiri MM. Evidence of axonal damage in human acute demyelinating diseases. J Neurol Sci 2004;222(1-2):29-34. PMID 15240192
- 15
- Ghosh R, Dubey S, Finsterer J, Chatterjee S, Ray BK. SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: a case report. Am J Case Rep 2020;21:e925641. PMID 32799213
- 16
- Gogus S, Yalaz K, Koçak N. Acute hemorrhagic leukoencephalitis. Turk J Pediatr 1991;33(1):49-54. PMID 1844176
- 17
- Graham DI, Behan PO, More IA. Brain damage complicating septic shock. Acute haemorrhagic leucoencephalitis as a complication of the generalised Shwartzman reaction. J Neurol Neurosurg Psychiatry 1979;42:19-28. PMID 762582
- 18
- Grzonka P, Scholz MC, De Marchis GM, et al. R. Acute hemorrhagic leukoencephalitis: a case and systematic review of the literature. Front Neurol 2020;11:899. PMID 32973663
- 19
- Gurney ME, Apatoff BR, Spear GT, et al. Neuroleukin: a lymphokine product of lectin-stimulated T cells. Science 1986;234(4776):574-81. PMID 3020690
- 20
- Hafler DA. Weekly clinicopathological exercises—rash, meningismus, and diplegia. N Engl J Med 1995;333:1485-93. PMID 7477150
- 21
- Hahn JS, Siegler DJ, Enzmann D. Intravenous gammaglobulin therapy in recurrent acute disseminated encephalomyelitis. Neurology 1996;36:1173-4. PMID 8780119
- 22
- Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6:1123-32. PMID 16200070
- 23
- Hurst EW. Acute haemorrhagic leukoencephalitis: a previously undefined entity. Med J Aust 1941;2:1-6.
- 24
- Ishizu T, Osoegawa M, Mei FJ, et al. Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain 2005;128:988-1002. PMID 15743872
- 25
- Kanter DS, Horensky D, Sperling RA, Kaplan JD, Malachowski ME, Churchill WH. Plasmapheresis in fulminant acute disseminated encephalomyelitis. Neurology 1995;45:824-7. PMID 7723979
- 26
- Kao HW, Alexandru D, Kim R, Yanni D, Hasso AN. Value of susceptibility-weighted imaging in acute hemorrhagic leukoencephalitis. J Clin Neurosci 2012;19(12);1740-1. PMID 22465779
- 27
- Konstantinou D, Paschalis C, Maraziotis T, Dimopoulos P, Bassaris H, Skoutelis A. Two episodes of leukoencephalitis associated with recombinant hepatitis B vaccination in a single patient. Clin Infect Dis 2001;33(10):1772-3. PMID 11595974
- 28
- Kumar RS, Kuruvilla A. Teaching neuroImages: acute hemorrhagic leukoencephalitis after mumps. Neurology 2009;73(20):e98. PMID 19917982
- 29
- Kuperan S, Ostrow P, Landi MK, Bakshi R. Acute hemorrhagic leukoencephalitis vs ADEM: FLAIR MRI and neuropathology findings. Neurology 2003;60(4):721-2. PMID 12601124
- 30
- Lamarche JB, Behan PO, Segarra JM, Feldman RG. Recurrent acute necrotizing hemorrhagic encephalopathy. Acta Neuropath (Berl) 1972;22(1):79-87. PMID 5083841
- 31
- Lander H. Acute haemorrhagic leuco-encephalitis. Aust Ann Med 1958;7:55-68. PMID 13522495
- 32
- Leake JA, Billman GF, Nespeca MP, et al. Pediatric acute hemorrhagic leukoencephalitis: report of a surviving patient and review. Clin Infect Dis 2002;34(5):699-703. PMID 11810602
- 33
- Ma Y, Sannino D, Linden JR, et al. Epsilon toxin-producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege. J Clin Invest 2023;133(9):e163239. PMID 36853799
- 34
- Mastrodimos B, Barnett GH, Awad IA. Intensive care management of acute hemorrhagic leukoencephalitis with favorable neurologic outcome. Cleve Clin J Med 1992;59:549-52. PMID 1468137
- 35
- Matusevicius D, Kivisakk P, He B, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 1999;5(2):101-4. PMID 10335518
- 36
- Markus R, Brew BJ, Turner J, Pell M. Successful outcome with aggressive treatment of acute haemorrhagic leukoencephalitis. J Neurol Neurosurg Psychiatry 1997;63:551. PMID 9343149
- 37
- Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev 1997;19:81-92. PMID 9105653
- 38
- Mizuguchi M, Takashima S. Imaging and pathology in pediatric neurological disorders. Neuropathology 2002;22(2):85-9. PMID 12075940
- 39
- Neilson DE. The interplay of infection and genetics in acute necrotizing encephalopathy. Curr Opin Pediatr 2010;22(6):751-7. PMID 21610332
- 40
- Pagano L, Larocca LM, Vaccario ML, et al. Acute hemorrhagic leukoencephalopathy in patients with acute myeloid leukemia in hematologic complete remission. Haematologica 1999;84:270-4. PMID 10189394
- 41
- Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain 2020;143(10):3104-20. PMID 32637987
- 42
- Perrin P, Collongues N, Baloglu S, et al. Cytokine release syndrome-associated encephalopathy in patients with COVID-19. Eur J Neurol 2021;28(1):248-58. PMID 32853434
- 43
- Pfausler B, Engelhardt K, Kampfl A, Spiss H, Taferner E, Schmutzhard E. Post-infectious central and peripheral nervous system diseases complicating Mycoplasma pneumoniae infection. Report of three cases and review of the literature. Eur J Neurol 2002;9(1):93-6. PMID 11784383
- 44
- Pinto PS, Taipa R, Moreira B, Correia C, Melo-Pires M. Acute hemorrhagic leukoencephalitis with severe brainstem and spinal cord involvement: MRI features with neuropathological confirmation. J Magn Reson Imaging 2011;33(4):957-61. PMID 21448963
- 45
- Pirko I, Suidan GL, Rodriguez M, Johnson AJ. Acute hemorrhagic demyelination in a murine model of multiple sclerosis. J Neuroinflammation 2008;5:31. PMID 18606015
- 46
- Rosman NP, Gottlieb SM, Bernstein CA. Acute hemorrhagic leukoencephalitis: recovery and reversal of magnetic resonance imaging findings in a child. J Child Neurol 1997;12:448-54. PMID 9373802
- 47
- Robinson CA, Adiele RC, Tham M, Lucchinetti CF, Popescu BF. Early and widespread injury of astrocytes in the absence of demyelination in acute haemorrhagic leukoencephalitis. Acta Neuropathol Commun 2014;2:52. PMID 24887055
- 48
- Rothstein TL, Shaw CM. Computerized tomography as a diagnostic aid in acute hemorrhagic leukoencephalitis. Ann Neurol 1983;13:331-3. PMID 6847149
- 49
- Ryan LJ, Bowman R, Zantek ND, et al. Use of therapeutic plasma exchange in the management of acute hemorrhagic leukoencephalitis: a case report and review of the literature. Transfusion 2007;47:981-6. PMID 17524086
- 50
- Seales D, Greer M. Acute hemorrhagic leukoencephalitis. A successful recovery. Arch Neurol 1991;48:1086-8. PMID 1929904
- 51
- Sharma R, Bhagwat C, Suthar R, et al. Acute hemorrhagic leukoencephalitis with COVID-19 coinfection. Indian J Pediatr 2022;1. PMID 35072908
- 52
- Taferner E, Pfausler B, Kofler A, et al. Craniectomy in severe, life-threatening, encephalitis: a report on outcome and long-term prognosis of four cases. Intensive Care Med 2001;27:1426-8. PMID 11511960
- 53
- Takata T, Hirakawa M, Sakurai M, Kanazawa I. Fulminant form of acute disseminated encephalomyelitis: successful treatment with hypothermia. J Neurol Sci 1999;165:94-7. PMID 10426155
- 54
- Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: A long-term follow-up study of 84 pediatric patients. Neurology 2002;59(8):1224-31. PMID 12391351
- 55
- Tselis AC, Lisak RP. Acute disseminated encephalomyelitis. In: Antel J, Birnbaum G, Hartung HP, editors. Clinical neuroimmunology. Malden, MA: Blackwell Science, 1998:116-46.
- 56
- Tshibanda L, Nchimi A, Otte M, Dondelinger RF. [Hurst acute haemorrhagic leukoencephalitis: MRI findings]. [Article in French] JBR-BTR 2007;90:290-3. PMID 17966249
- 57
- Varadan B, Shankar A, Rajakumar A, et al. Acute hemorrhagic leukoencephalitis in a COVID-19 patient-a case report with literature review. Neuroradiology 2021:63(5):653-61. PMID 33575849
- 58
- Vartanian TK. Weekly clinicopathological exercises--fever and an altered mental state (acute hemorrhagic leukoencephalitis). N Engl J Med 1999;340:127-35.
- 59
- Waak M, Malone S, Sinclair K, et al. Acute hemorrhagic leukoencephalopathy: pathological features and cerebrospinal fluid cytokine profiles. Pediatr Neurol 2019;100:92-6. PMID 31376926
- 60
- Waksman BH, Adams RD. Studies of the effect of the generalized Schwartzman reaction on the lesions of experimental allergic encephalomyelitis. Am J Pathol 1957;33:155-73.
- 61
- Walker JM, Gilbert AR, Bieniek KF, Richardson TE. COVID-19 patients with CNS complications and neuropathologic features of acute disseminated encephalomyelitis and acute hemorrhagic leukoencephalopathy. J Neuropathol Exp Neurol 2021;80(6):628-31. PMID 33871008
- 62
- Watson RT, Ballinger WE Jr, Quisling RG. Acute hemorrhagic leukoencephalitis: diagnosis by computed tomography [letter]. Ann Neurol 1984;15:611-2. PMID 6742799
- 63
- Wolf K, Schmitt-Mechelke T, Kollias S, Curt A. Acute necrotizing encephalopathy (ANE1): rare autosomal-dominant disorder presenting as acute transverse myelitis. J Neurol 2013;260(6):1545-53. PMID 23329376
- 64
- Yildiz O, Pul R, Raab P, Hartmann C, Skripuletz T, Stangel M. Acute hemorrhagic leukoencephalitis (Weston-Hurst syndrome) in a patient with relapse-remitting multiple sclerosis. J Neuroinflammation 2015;12:175. PMID 26376717
- 65
- Yong MH, Chan YFZ, Liu JX, et al. A rare case of acute hemorrhagic leukoencephalitis in a COVID-19 patient. J Neurol Sci 2020;416:117035. PMID 32738478
- 66
- Yoshikawa H, Watanabe T, Abe T, Oda Y. Clinical diversity in acute necrotizing encephalopathy. J Child Neurol 1999;14:249-55. PMID 10334400
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Anthony T Reder MD
Dr. Reder of the University of Chicago received honorariums from Biogen Idec, Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant as well as stock options from NKMax America for advisory work and an unrestricted lab research grant from BMS.
See Profile
Patient Profile
- Age range of presentation
-
- 0 month 64 years
- Sex preponderance
-
- male>female, >2:1
- Heredity
-
- none
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Acute disseminated encephalitis: G04.0
- Acute and subacute haemorrhagic leukoencephalitis [Hurst]: G36.1
- Subacute necrotizing myelitis: G37.4
- ICD-11
-
- Other specified acute disseminated encephalomyelitis: 8A42.Y
- Acute haemorrhagic leukoencephalitis: 8A42.0
- Subacute necrotizing myelitis: 8A45.21
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