Contributed by Kate McFadden, MD and Clayton Wiley, MD, PhD
Published on line in August 2005
The patient was a normally developing boy who noted hand tremors at 7.5 years of age, approximately 3 weeks after his last mumps, measles and rubella vaccine. One month later, he exhibited difficulty walking, leg pain and weakness. His gait became stiff legged with the right leg rotated outwards. He was found to have significant action and sustention tremor, bilateral lower leg weakness (tibialis anterior), decreased deep tendon reflexes and pes planus. He also exhibited impaired speech articulation.
Despite continued neurological progression, extensive clinical evaluation over the next year demonstrated limited abnormalities. Nerve conduction studies showed slowing of motor and sensory conduction velocities. Electron myography showed giant motor unit potentials suggestive of previous denervation followed by reinnervation. Sural nerve biopsy showed mild axonal degeneration and regeneration suggesting neuroaxonal dystrophy. A skin biopsy was unremarkable. Laboratory values for copper, ceruloplasmin, creatine kinase, lactate, erythrocyte sedimentation rate, anti-nuclear antibody, Lyme serology, thyroid panel, lipoprotein electrophoresis, lysosomal enzymes and complete Charcot-Marie-Tooth Disease DNA panel were normal. Urine amino acids were normal. An EKG was normal. CSF showed 60 leukocytes (99% mononuclear), 0 RBC, protein 31, glucose 56 and lactic acid 1.0. Brain MRI showed mild enlargement of cerebellar sulci and vermian atrophy.
He became wheelchair bound by 9 years of age and was unable to produce speech or control secretions. His tremor became coarser and tongue fasciculations, extensor plantar reflexes and oculogyric crises were noted. Cognitive function remained intact and there was no discernible abnormality of sensation, vision or hearing. A trial of L-dopa produced no noticeable improvement of symptoms. Amantadine was initiated with marked albeit temporary improvement. At 13 years of age, he developed an intercurrent respiratory infection and died of respiratory failure.
Significant findings were generalized muscle atrophy and emaciation, bilateral pulmonary lobar consolidation and pericardial effusion. The fresh brain weighed 1425 grams. Examination of the fixed hemisected brain was unremarkable except for mild atrophy of the cerebellar hemisphere and vermis. The substantia nigra was not grossly pigmented. Mild atrophy of the ventral roots of the spinal cord was evident. Multiple cross sections of the spinal cord showed no other gross abnormalities.
Microscopic examination of H&E stained sections revealed round, eosinophilic intranuclear inclusions in the majority of neurons in all neocortical areas sampled (Figure 1). There was no obvious neuronal loss or gliosis. The deep white matter was well myelinated. Glial inclusions were not seen. Neurons of the striatum and globus pallidus showed fewer neuronal intranuclear inclusions (NII). The thalamus exhibited numerous NII and mild gliosis particularly in the subthalamic nucleus. The hippocampus showed moderate to severe numbers of NII but no discernible neuronal loss within the CA1 region, subiculum and entorhinal cortex. The lateral geniculate bodies and nuclei of the mid-brain, pons and medulla (Figure 2) likewise exhibited numerous NII. The substantia nigra neurons showed severe neuronal loss with NII in the majority or remaining neurons. The cerebellar cortex showed massive Purkinje cell loss with attendant Bergmann gliosis (Figure 3). NII were seen in the majority of rare remaining Purkinje cells. The granular cell layer exhibited moderate neuronal loss but no discernible NII. The dentate nucleus showed moderate neuronal loss with numerous inclusions in remaining neurons. The spinal cord revealed abundant neuronal loss with frequent intranuclear inclusions in the rare remaining anterior horn cells. Review of H&E stained sections from the systemic autopsy demonstrated intranuclear inclusions in dorsal root ganglia neurons and autonomic neurons of Auerbach' s plexus (Figure 4) as well as adrenal medulla (Figure 5).
NII in the cortex demonstrated rim-like immunoreactivity for ubiquitin (Figure 6). In all regions of the brain and spinal cord NII demonstrated intense immunostaining for SUMO-1 throughout the inclusion (Figure 7). Immunocytochemical stains for SUMO-1 were substantially more intense than those for ubiquitin. Immunofluorescence for polyglutamine expansion was negative in inclusions (Figure 8: polyglutamine green, SUMO-1 red). Electron microscopy showed NII to be non-membrane bound collections of randomly oriented filaments and electron dense granular material, distinct from the nucleolus (Fig. 9). Immunohistochemical stains for GFAP confirmed mild to moderate astrocytosis in areas of neuronal loss.