MOC Exam Topic: Acute Hemorrhagic Leukoencephalopathy

First recognized as a discrete entity by Weston Hurst in 1941, acute hemorrhagic leukoencephalopathy (AHL) is a usually fatal disease characterized clinically by an abrupt onset of fever, neck stiffness, and neurological deficits, often progressing rapidly to seizures and coma. The presenting clinical picture is similar to that of acute disseminated encephalomyelitis (ADEM) but with a more fulminant course. At autopsy, the brain is swollen with multiple petechial hemorrhages centered in the white matter. Large foci of necrosis with cavitation may be present. The cerebral cortex and basal ganglia usually appear intact. Histologically, perivascular demyelinating lesions consist of ball or ring hemorrhages surrounding necrotic venules. There are cuffs of mononuclear cells and neutrophils. There is also substantial axonal injury in the affected areas. The lesions are indistinguishable from ADEM, but the extent of microvascular damage and therefore hemorrhage is is greater. An allergic mechanism is postulated.

FIGURE 3. A (H&E, 100×), B (LFB/PAS, 100×), and C (HAM-56 IHC, 400×). Light microscopic studies revealed thin sleeves of pallor surrounding small-caliber parenchymal blood vessels (A) which correspond to areas of demyelination on special stain (B). Macrophages stain strongly positive for macrophage marker HAM-56 (C). From Lann MA, et al. Am J Forensic Med Pathol. 2010 Mar;31(1):7-11.

MOC Exam Topic: More on Aquaporin-4

My last post elicited two important comments on aquaporin-4. Since not all readers necessarily look at the comments, I am publishing them as a separate post here:

 Maria said...

Worth mentioning that [aquaporin-4] is the most well known target in Neuromyelitis Optica (NMO) and NMO spectrum disorders, since about 80% of patients with this syndrome will have circulating anti-aquaporin 4 antibodies. The IHC is useful when considering active NMOSD on a biopsy specimen by showing loss of staining (Neurology. 2015 Jan 13;84(2):148-58)

Agent86 said...

And one can only get so far without mentioning the glymphatic pathway..

Genetic knock-out of the gene encoding the astroglial water channel aquaporin-4, which is importantly involved in paravascular interstitial solute clearance, exacerbated glymphatic pathway dysfunction after TBI and promoted the development of neurofibrillary pathology and neurodegeneration in the post-traumatic brain. These findings suggest that chronic impairment of glymphatic pathway function after TBI may be a key factor that renders the post-traumatic brain vulnerable to tau aggregation and the onset of neurodegeneration.

Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, Singh I, Deane
R, Nedergaard M. Impairment of glymphatic pathway function promotes tau pathology
after traumatic brain injury. J Neurosci. 2014 Dec 3;34(49):16180-93.

Treatable Neurological Disorders Misdiagnosed as Creutzfeldt-Jakob Disease

A case of primary CNS angiitis thought to be sCJD

Dr. Mark Cohen and a team of workers at Case Medical Center in Cleveland, Ohio have published an important article in the Annals of Neurology entitled Treatable Neurological Disorders Misdiagnosed as Creutzfeldt-Jakob Disease (Ann Neurol 2011;70:437–444). Why is this article important? Well, because mistaking a survivable, treatable disorder for a fatal, non-treatable disorder is not optimal. Cohen's team reviewed the pathologic diagnoses of 1,106 patients who were referred for potential prion disease to the National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University from 2006 to 2009. About one-third of the cases did not have prion disease, with Alzheimer disease and vascular disease being the most common conditions accounting for dementia. Further, about one-quarter of the non-prion cases had treatable diseases, including immune-mediated disorders, neoplastic disorders such as lymphoma, as well as infectious and metabolic disorders. The immune-mediated disorders included primary angiitis of the CNS, acute disseminated encephalomyelitis, limbic encephalitis, neurosarcoidosis, paraneoplastic cerebellar degeneration, and one case of Wegener granulomatosis. Of note, more than half of patients with a treatable dementia had a positive CSF 14-3-3 protein test, highlighting the danger of relying too heavily on this test in making a diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). It turns out that the most specific test for distinguishing CJD from other diseases was magnetic resonance imaging. Drs. David Perry and Michael Geschwind, in a review of this study in the September 2011 issue of Nature Reviews Neurology, (Perry, D. C. & Geschwind, M. D. Nat. Rev. Neurol. 2011:7, 479–480) write: "The fact that many of the non-prion diagnoses in the present study were potentially treatable RPDs [rapidly progressive dementias] should prompt thorough diagnostic testing in patients who are suspected of having sCJD, in order to rule out mimics. The use of CSF testing, contrast-enhanced MRI, and autoimmune antibody screening is supported by this study."

Interferon-gamma in the Pig PIN

Remember that outbreak of progressive inflammatory neuropathy (PIN) among pig abattoir workers back in 2007? If not, here's my blog post from January '08 summarizing the event. The good Dr. Mark Cohen (pictured at left) forwarded me a recently published article following up on the outbreak. Investigators found no infectious etiology; but they did find higher levels of interferon-gamma among PIN patients. Since elevated levels of interferon-gamma has been associated with both acute and chronic inflammatory demyelinating polyradiculoneuropathy, this finding supports an autoimmune mechanism for PIN.

Jett Travolta's fatal seizure unlikely related to Kawasaki's disease

Everyone has heard about the tragic death of 16-year-old Jett Travolta (pictured with his dad, actor John Travolta) presumably as a result of a prolonged seizure. It's also public knowledge that Jett Travolta suffered from Kawasaki's disease. It's unclear that there was a connection between Kawasaki's disease and his seizure disorder. There's some evidence, however, that there may be a connection between seizures and Jett's possible autistic disorder. The Travoltas reportedly didn't acknowledge the possibility that Jett had autism, perhaps because their faith (Scientology) does not recognize autism as a legitimate entity. An autopsy is being performed, the results of which are unlikely to be released. But I doubt that an autopsy would shed light on any of these questions anyway. An autopsy may show an anatomic substrate for a seizure disorder (cortical heterotopia, hippocampal sclerosis, etc.), but pathologists will not be able to make a firm connection between the seizure problem and Kawasaki's disease. And there is no way an autopsy can confirm autism.

Formerly known as the mucocutaneous lymph node syndrome, Kawasaki's disease is an acute, febrile, multisystem vasculitic disease of children. The cause of Kawasaki disease is still unknown. It is currently the leading cause of acquired heart disease in children in the United States and Japan. Why heart disease? The coronary arteries get inflamed and compromise blood flow to the heart. (Source: Harrison's Principles of Medicine, 17th edition, 2008.) No mention is made in Harrison's textbook of Kawasaki's disease as a cause of seizure; nor have I ever heard of such a connection.

So, there are more questions than answers in this case; and I'm afraid that the pathologists involved will be of little help in answering these questions.

Thanks to my favorite Springfield, Illinois blogger, Marie of Disarranging Mine, for asking about this issue and prompting this post.

PIG PIN

A few weeks ago, I reported on a cluster of atypical inflammatory neuropathy cases among workers at pig processing plants in the midwest.

My colleague, the esteemed Dr. David Stahl, emailed me a link which describes a break in the case.

CNN reports that authorities have figured out how to contain the disease, which they have dubbed Progressive Inflamatory Neuropathy (PIN). They think its an autoimmune phenomenon related to exposure to aerosolized pig brain tissue. Here's the report from CNN:

http://www.cnn.com/2008/HEALTH/conditions/02/28/medical.mystery/index.html

Dr. Sanjay Gupta, CNN's chief medical correspondent, will report on the issue tonight on Anderson Cooper 360 at 9PM central time.

Urgent Bulletin to Neurologists about patients working with the heads of pigs!

The CDC has sent out an urgent notice to be on the lookout for patients who work in pig processing plants complaining of pain, numbness, and tingling in the extremities. In the fall of 2007, clinicians at the Mayo Clinic in Rochester, Minnesota notified the Minnesota Department of Health of an unusual cluster of 12 patients with inflammatory neuropathy among workers at a pork processing plant in Minnesota. An initial investigation has revealed that they all have worked in the same area of the plant where the heads of the pig are processed. Additional patients have been identified in Indiana, among workers in a similar plant. At this point an etiologic agent has not been identified.
The CDC bulletin reads: “neurologists who have diagnosed patients with peripheral neuropathy, myelopathy, or a mixed clinical presentation of peripheral / central (and, more specifically, myelopathic) involvement in persons with exposure to pig butchering or processing during the past year are asked to report this information to their state health department, and contact the CDC at 770-488-7100.”

Primary Angiitis of the CNS: The Elvis Presley of Neurology

Dr. David Hellmann of Johns Hopkins, in the current Clinical Neurology News, is quoted as saying that primary angiitis of the central nervous system (PACNS) “is the Elvis Presley of neurology… CNS vasculitis-like illness is more often thought to be present than actually present”. In fact, he says, CNS vasculitis accounts for only 1% of all biopsy-proven cases of vasculitis. Interestingly, very few patients with PACNS describe a stroke-like presentation. Rather, the most common presentation is insidious cognitive decline with headache. A biopsy is required for diagnosis, and cyclophosphamide without a definitive biopsy-proven diagnosis is not recommended. Yet again, the neuropathologist is the key!