Contributed by Pasquale Strianoa, Cameron A. Ackerleyc, Mariarosaria Cervasiod, Jean-Marie Girarde, Julie Turnbullf, Maria Laura Del Basso-De Carod, Salvatore Strianob, Federico Zaraa, and Berge A. Minassiane, f
aMuscular and Neurodegenerative Disease Unit, Institute G. Gaslini, Genova, Italy; bEpilepsy Center, Department of Neurological Sciences, Federico II University, Napoli, Italy, Italy; cDepartment of Pathology and Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada; dHuman Anatomopathology Unit, Federico II University, Napoli, Italy; eDivision of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada; fProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
A 22-year-old girl presented with convulsive status epilepticus and a previous history of recurrent seizures, myoclonus, ataxia and impaired cognitive functions. Testing revealed severe metabolic acidosis, elevated transaminases and creatine kinase, and respiratory insufficiency. After intubation and ventilation, thiopental was introduced but the patient's condition worsened dramatically with death after a few hours. The parents gave permission for autopsy.
Born of healthy unrelated parents the patient had developed normally until the age of 16 years, when she suffered tonic-clonic seizures and visual hallucinations. Some months prior to seizure onset, her parents had noted erratic jerks of the upper limbs, personality changes, and decline in school performance. An electroencephalographic (EEG) recording had shown spikes over the occipital regions and photosensitivity. Therapy with valproate had decreased the frequency of seizures. However, progressive worsening of cognitive and motor functions occurred within a few months. In addition, sudden and brief episodes of loss of contact were reported. Neurological examination had shown ataxia due to severe myoclonus at rest and action-induced myoclonus, pyramidal signs, and opposition hypertonia. She could not tandem walk, and deep tendon reflexes were barely detectable. EEG showed diffusely slow background activity with superimposed generalized, high- voltage, paroxysmal abnormalities. Brain MRI displayed diffuse cerebral and cerebellar atrophy. Neuropsychological testing demonstrated a full-scale IQ of 70 (verbal 75; performance 60). Adjunctive therapy with clonazepam and zonisamide significantly reduced the intensity of myoclonus. In the following years, mental decline continued unabated resulting in severe dementia, disorientation, akinesia, marked rigidity with opposition hypertonia, and inability to feed, which was her clinical state prior to her admission for status epilepticus and death.
MICROSCOPIC AND ULTRASTRUCTURAL FINDINGS
Histochemical analysis revealed that the CNS was diffusely replete with intracellular inclusions (Figs 1, 2, 3, 4, 5) which were highlighted by positive periodic acid-Schiff (PAS) staining (figures 6, 7). The inclusions were most plentiful in the thalamus, cerebellum, and brainstem, and in lesser numbers in the frontal and occipital cortices. The inclusions were absent in subcortical white matter but were abundant in the spinal cord gray matter. Two types of inclusions could be distinguished: type I, punctate structures present in neuronal processes (Figure 6;bar=50 Ám, and type II, large structures found in neuronal cell bodies usually apposed to the nucleus and often so large as to occupy the entire soma (Figure 7; bar=10 Ám). All sections were ubiquitin-negative.
Electron microscopy showed that the inclusions consisted of accumulations of a fibrillar material in the dendrites but not in the axon terminals, recognized through their synaptic vesicles (SV) (Figures 8, 9; bar=500 nm). Additional ultrastructural images show the filamentous nature (Figures 10, 11) In addition, the same inclusions were present in clinically unaffected organs too, especially skeletal and cardiac muscle, and the liver. In the apocrine sweat gland of skin (Figure 12; bar=50 Ám) pathological inclusions (arrows) were clearly distinguishable from normal PAS-positive, diastase-resistant secretory material of the gland (asterisks).