2017 NPB-11

This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

The patient was first seen at age 77 for upper extremity weakness, loss of range of motion, and decreased dexterity. He reported having mild head injury from multiple falls recently as well as several horseback riding falls and two remote car accidents that involved moderate head injury. Several of these incidents caused loss of consciousness but with no skull fractures or known hemorrhages, and none required surgery. Physical therapy was not improving his symptoms, and neuroimaging showed severe cervical stenosis. He had C4/C5 surgery, and after surgery he started having worsening upper limb weakness. Both electromyography and neurological exam showed lower motor neuron dysfunctions and, to a lesser extent, upper motor neuron signs. He was diagnosed with amyotrophic lateral sclerosis (ALS) at the time and started on Riluzole. His disease progressed over the next several months with prominent dysphagia for which he had a percutaneous endoscopic gastrostomy tube placed. Over the next year he developed progressive motor weakness requiring a wheel chair. Cognitive testing was not performed, but his family members reported that he was becoming withdrawn and having some memory problems. He became ill with pneumonia and died. An autopsy was performed.

Tissue Site
Brain and spinal cord

The whole slide image provided is a Tau IHC stained slide from autopsy.

Virtual slide used with permission from Dr. Juan Troncoso. Johns Hopkins University.

The diagnosis in this case is chronic traumatic encephalopathy (CTE) and amyotrophic lateral sclerosis (ALS). The brain weighed 1,360 grams and showed no gross neuropathological abnormalities. Specifically, no focal or diffuse atrophy or findings of remote contusion or infarct were seen. The spinal cord showed mildly atrophic ventral nerve roots but no other abnormalities. The frontal, temporal, and occipital lobes showed preservation of cortical cytoarchitecture. No inflammation or gliosis were noted. The centrum semiovale was unremarkable. The cerebral motor cortex showed preserved Betz cells (upper motor neurons). The midbrain, pons, and medulla displayed normal cranial nerve nuclei and fiber tracts with the exception of the hypoglossal nucleus that showed a few Bunina bodies (small, densely eosinophilic cytoplasmic inclusions) in neurons. The cerebellum was normal. The cervical spinal cord showed moderate loss of lower motor neurons and gliosis in anterior horn. The lumbosacral spinal cord showed similar neuronal loss and severe gliosis. Luxol fast blue H&E stain showed no or minimal loss of myelinated fibers in the lateral and anterior corticospinal tracts (Image A). Ascending tracts were also preserved. Motor nerve roots were atrophied compared to sensory nerve roots. Skeletal muscle tissue showed grouped atrophy.

Immunostain for phospho-TDP-43 showed many glial and neuronal cytoplasmic aggregates highlighted in affected spinal cord areas (Image C), but not in the cerebral motor cortex. Immunostain for p-tau (PHF-1) of the frontal cortex, hippocampus, entorhinal cortex, and amygdala showed rare amyloid plaques and scattered neurofibrillary tangles (Image B). In addition, cytoplasmic PHF-1 immunoreactivity was seen in scattered neurons and glia around vessels (Image D), and often at the depth of cortical sulci (Image E).

This represents a complex case, characteristic of many cases of CTE. Autopsy findings provide evidence for multiple neurodegenerative conditions including ALS and CTE. The ALS findings are primarily those of lower motor neuron degeneration with loss of motor neurons and pathological inclusions of phospho-TDP-43. It is unclear why degenerative changes in upper motor neurons and corticospinal tracts were not apparent in this case. CTE changes are moderate with cytoplasmic inclusions of p-tau in glia and neurons of frontal and temporal cortices. Based on the proposed staging system for CTE this case would be CTE stage II or III. Pathologic findings of other neurodegenerative diseases are sometimes seen in reported cases of CTE, but their relationship has not been causally established.

The term “chronic traumatic encephalopathy” emerged in the 1960’s and, more recently, was used to describe several cases of US professional football players who developed neurodegeneration characterized by excess p-tau deposits. Eighty years prior, a series of boxers were described to have sustained multiple concussions and later developed “intoxicated, punch drunk” symptoms and central nervous system neuropathological changes - so-called “dementia pugilistica.”

A full understanding of the clinical development, pathophysiology, and breadth of neuropathological sequelae of CTE is currently lacking. Currently, the only way to diagnose definite CTE is autopsy. Clinically, patients have a history of usually repeated concussive or subconcussive head injuries, often associated with their professions (ie, athlete or soldier). However, there are also CTE case reports on individuals with only a few serious remote head injuries. The symptoms of CTE are described as “insidious, first manifested by deteriorations in attention, concentration, and memory, as well as disorientation and confusion, and occasionally accompanied by dizziness and headaches. With progressive deterioration, additional symptoms, such as lack of insight, poor judgment, and overt dementia, become manifest.” Other symptoms that have been described include dysarthria, dysphagia, ocular abnormalities (eg, ptosis), a progressive slowing of muscular movements, gait abnormalities, mask facies, impeded speech, tremors, vertigo, and deafness.

The predominant neuropathological findings of CTE are that of a tauopathy with perivascular accumulation of abnormally phosphorylated tau in neurons and astrocytes distributed in an irregular fashion with a propensity for sulcal depth of the cerebral cortex. Widespread brain regions have been found to be affected. Other pathological changes seen in advanced disease include abnormal cellular deposits of phospho-TDP-43, neuroinflammation, beta amyloid plaques, neuronal loss, and white matter degeneration. CTE neuropathology has been reported in individuals as young as 17 and as old as 98 years. A variety of neurodegenerative diseases are often found accompanying CTE (including ALS, Alzheimer disease, Parkinson disease, and frontotemporal lobar degeneration), although the relationships between CTE and these diseases are not understood.

Recently, a National Institute of Neurological Disorders and Stroke (NINDS) consensus group has established a four-tier pathological staging scheme for CTE. In stage I, p-tau is found in few small foci of the cerebral cortex with perivascular p-tau-positive neurons and astrocytes. In stage II, these are more numerous and often concentrated at the depth of sulci. In stage III, the p-tau deposits are moderately widespread throughout neocortex and limbic system, and neurofibrillary tangles become more evident in these locations as well. In stage IV, there is widespread severe p-tau pathology affecting most regions of the cerebral cortex and the medial temporal lobe. Gross pathological changes are generally seen in stages III and IV with decreased brain weight, frontotemporal concentrated atrophy, thinning of the corpus callosum, dilation of the ventricular system, a cavum septum pellucidum and/or septal fenestrations, thalamic/hypothalamic atrophy, and depigmentation of the substantia nigra and locus ceruleus.

Identifying reliable imaging and serological biomarkers, establishing better epidemiology of CTE, and performing larger numbers of neuropathological evaluation are all actively being pursued to better understand this neurological disease.

• CTE, first described nearly 100 years ago, is a neurological disease associated with prior history of usually multiple head injuries and often found associated with other neurodegenerative diseases.
• The pathognomonic lesion of CTE is cytoplasmic deposition of phosphorylated tau within astrocytes and neurons, often in perivascular and deep sulcal distributions.
• Identifying reliable imaging and serological biomarkers, establishing better epidemiology of CTE, and performing larger numbers of neuropathological evaluation are all essential before we can better diagnose and treat this progressive neurodegenerative disease.

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