Choroidal ganglioneuronal hamartoma in an NF1 patient

Thanks to Dr. Ahmed Gilani (pediatric pathology fellow at the University of Colorado) for providing me with slides of an enucleation specimen from a patient with Von Recklinghausen Neurofibromatosis (NF-1). The specimen exhibits a region of choroidal expansion with hamartomatous neuroglial tissue. Distributed throughout this choroidal expansion are non-pigmented ovoid bodies, which have a delicately laminated appearance reflecting the presence of concentric Schwann cell processes. One might conceive of these choroidal expansions as cousins of iridic Lisch nodules.

Choroidal expansion in an enucleation specimen from a child with NF1

Ganglion-like cells within the choroidal expansion

Ovoid body within choroidal expansion

What is amyloid?

The following is adapted from Phenomena, the Phenopath newsletter, Winter 2018 (21:1):

Rudolph Virchow, introduced the term “amyloid” to refer to extracellular deposits in human tissues that exhibited a positive blue-violet staining reaction to iodine and dilute acid. Based on this reaction, Virchow mistakenly identified these aggregates as composed of starch (amylum is Latin for starch).  Subsequent microscopic studies have shown that amyloid deposits exhibit an affinity for Congo red dyes, which also yield a property known as “dichroic birefringence” in which crossed polarizing filters produce apple-green birefringence. In the 20th century, X-ray diffraction analysis revealed amyloid to be composed of fibrils ordered in a beta pleated sheet conformation. Using the criteria of “congophilia,” dichroic birefringence, and fibrillar morphology, more than 30 biochemically distinct forms of amyloid have been identified, many associated with unique clinical syndromes. Examples of protein that can form an amyloid configuration include: immunoglobulin light chain, amyloid A, beta-amyloid, transthyretin, apolipoprotein A-I, lysozyme, and fibrinogen A α-chain. Identification of the amyloid protein can have important diagnostic, prognostic, and therapeutic implications.

Sural nerve in a case of amyloid neuropathy: congophilic amyloid circled

Today's Google Doodle Honors Neurosurgeon Wilder Penfield

Quoted from KN Smith of Forbes:

Today's Google Doodle celebrates the 127th birthday of Canadian neurosurgeon Wilder Penfield, who developed a groundbreaking epilepsy treatment called the Montreal Procedure.

In the 1930s, while working as a neurosurgeon at the Montreal Neurological Institute at McGill University, Penfield had a patient who reported smelling burned toast just before her seizures. He realized that he could use that hallucinatory scent to pinpoint the part of the brain that was seizing - and put a stop to it.

With the patient wide awake, but under local anesthetic, he used electrodes to stimulate parts of her exposed brain, asking her what she felt, saw, heard, or smelled each time. When she declared, "I smell burned toast!" Penfield determined that he must have found the center of her epilepsy. It worked; he removed a small piece of brain tissue from the spot, and the woman never had a seizure again. Penfield and his colleagues published a paper on the method in 1951, and since then it has helped bring relief to many epilepsy patients.

Of course, there are many different kinds of epilepsy, and the Montreal Procedure doesn't work on all of them, but it made a significant difference for a large number of people. And Penfield performed the procedure more times than any other neurosurgeon working at the time. In the process, he assembled a detailed map of where sensory and motor functions happen in the brain, and which areas of the brain receive input from, or send output to, which parts of the body. He also discovered that using an electrode to stimulate the temporal lobes, in particular, can produce very vivid sensory memories - such as the smell of burned toast.

Penfield died in 1976, after a lifetime spent doing what he described as "the best way to make the world a better place."

Endolymphatic Sac Tumor in an Elderly Man

Papillary architecture is typical for this entity

The patient is not known to have Von Hippel Lindau Syndrome, which can be associated with this tumor. According to Expert Path, the differential diagnosis for endolymphatic sac tumor is middle ear adenoma, middle ear adenocarcinoma, metastatic renal cell carcinoma, metastatic papillary thyroid carcinoma, paraganglioma, choroid plexus papilloma, and ceruminous adenoma.

Guest Post from Dr. Mike Lawlor: Audentes Announces Positive Interim Data from First Dose Cohort of ASPIRO, a Phase 1/2 Clinical Trial of AT132 in Patients With X-Linked Myotubular Myopathy

Dr. Mike Lawlor

Regular contributor Mike Lawlor, MD, PhD passed this development along from the X-linked myotubular myopathy clinical research front:

Audentes Therapeutics has released an interim data update on the ASPIRO gene therapy clinical trial for X-linked myotubular myopathy.  In the 4^th quarter of 2017, three patients were given a single dose of an adeno-associated virus containing the human myotubularin gene.  To quote the press release:

"The early AT132 efficacy data observed in our first dose cohort of patients have exceeded our expectations," stated Dr. Suyash Prasad, Senior Vice President and Chief Medical Officer of Audentes. "At the 12-week timepoint, Patient 1 has improved from a severely compromised baseline to achieve a CHOP-INTEND score and maximal inspiratory pressure that are approaching the ranges normally seen in healthy children.  Importantly, Patient 1 has also attained several age-appropriate developmental milestones within this time period, including head-control, rolling over and sitting unassisted.  While still early in the trial, we view these initial efficacy data as a promising indicator of the potential for AT132 to bring meaningful benefit to patients and families living with this devastating disease."

On the safety side of things, Audentes reported a total of six adverse events (AEs) reported in ASPIRO, two of which were determined to be serious adverse events (SAEs). Per the press release, “Both SAEs occurred in Patient 3, the first of which was a hospitalization one week post-administration due to pneumonia and was deemed not treatment-related. Patient 3 was also hospitalized at week 7 post-administration due to a gastrointestinal infection and elevated troponin levels, the latter of which was deemed probably treatment-related and is responding to treatment with intravenous steroid administration and supportive care.”

On the pathology side of things, it will be a while before biopsies are evaluated or analyzed, as the trial design incorporated extensive strategies to keep the study pathologists blinded to timepoint, treatment group, and even whether a given sample belongs to a study patient.  Hopefully I’ll have the opportunity to share some of the pathology data at the 2019 AANP meeting.

The complete press release can be found at: http://investors.audentestx.com/phoenix.zhtml?c=254280&p=irol-newsArticle&ID=2324833