1. Case Study 29
Julia Kofler, M.D.

2. Question 1
A 27 year old male was admitted with several days to weeks of diffuse lower abdominal pain, dizziness and a 50 pound weight loss over an uncertain period of time. Shortly after admission, he started to complain of chest tightness and dyspnea and experienced episodes of supraventricular tachycardia, ST depression over precordial leads on EKG and a rise in troponin levels. The patient also exhibited deteriorating levels of consciousness and diffuse, generalized slowing on EEG. Describe the abnormal findings on the following representative T2 flair MRI images.

5. Answer
T2 flair hyperintensities in the medial thalamus, bilaterally, and periaqueductal gray of the midbrain

6. Question 2
What is your differential diagnosis?

7. Answer Metabolic/toxic process Infectious/inflammatory process
Ischemic process unlikely given the distribution of the lesions

8. Question 3
Despite multimodal therapy, the patient’s neurologic condition did not improve. He died ~2 weeks after admission following withdrawal of care. Gross examination of the brain revealed mild diffuse edema. The hypothalamus appeared slightly enlarged. Transverse sections of the brainstem revealed multifocal areas of brown discoloration. No other gross abnormalities were noted. Microscopic examination revealed lesions in the mamillary bodies, hypothalamus, thalamus, periaqueductal gray, inferior colliculi and subventricular zone of pons and medulla. Describe the major pathologic features in the following slides of hypothalamus (including mamillary body) and brainstem at the transition of midbrain to pons: Click here to view slide.

9. Answer
Circumscribed lesions in the medial hypothalamus, mamillary body, periaqueductal gray and inferior colliculi
Prominent endothelial hypertrophy and capillary proliferation
Accumulation of abundant foamy macrophages
Occasional perivascular cuffs of mononuclear inflammatory cells
Rare petechial hemorrhages, hemosiderin deposits and dystrophic calcifications

10. Question 4
What are the round eosinophilic structures that can be seen focally within the lesions (see attached images)?

13. Answer
Axonal spheroids

14. Question 5
What is the pathophysiologic process underlying the development of axonal spheroids? Name a few conditions where you can see axonal spheroids.

15. Answer
Spheroids are axonal swellings due to impaired anterograde axonal transport
They are composed of neurofilaments, organelles and other material that is normally transported along the axon
Spheroids are a feature of axonal damage by diverse insults including trauma and infarcts
Axonal swellings can also be seen in metabolic disorders (e.g. Nieman-Pick disease) and nutritional deficiencies (vitamin E deficiency)

16. Question 6
Name a few stains which are commonly used to highlight astrocytes, neurons and axons in tissue sections.

17. Answer Astrocytes: Glial fibrillary acid protein (GFAP) stain
Neuronal cell bodies: Nissl stain (Cresyl violet); NeuN (nuclear reactivity) and neurofilament immunohistochemical stains
Axons: Neurofilament stain, Silver impregnation techniques  

18. Question 7
Describe the findings in the following immunohistochemical stains for GFAP and NeuN? Click on the following links to view slides: GFAP; NeuN

19. Answer
Marked reduction of GFAP reactivity within the core of the lesions with significant loss of astrocytes
Reactive astrocytes in peripheral rim surrounding the lesions
Neuronal loss in the more central portions of the lesions
Preservation of neuronal cell bodies in the peripheral portions of the lesions
Relative sparing of neurons compared to loss of astrocytes

20. Question 8
What is your diagnosis?

21. Answer
Wernicke’s encephalopathy

22. Question 9
What is the cause of this disease?

23. Answer
Thiamine deficiency

24. Question 10
What are the classical symptoms of Wernicke’s encephalopathy?

25. Answer
Classical triad: Gaze palsies (ophthalmoplegia), ataxia and confusion/delirium
Sometimes associated with Korsakoff’s psychosis with amnesia and confabulations