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Show Journal of Clinical Neuro-ophthalmology 7(4): 244-249, 1987. Neuronal Intranuclear Hyaline Inclusion Disease Associated with Premature Coronary Atherosclerosis Joseph c. Parker, Jr., M.D" Michael L. Dyer, M.D., and William A. Paulsen, M.D. © 1987 Raven Press, Ltd., New York Neuronal intranuclear hyaline inclusion disease (NIHID) has been recognized in 14 patients. It usually occurs in the first and second decades but has been seen in the sixth. Both sexes are affected by this sporadic multisystem degenerative disorder that has involved the central and peripheral nervous systems with fibrillar and granular intranuclear inclusions. NIHID appears to be several variants of a multisystem degenerative disease as illustrated by the combination of a spontaneous, degenerative central and peripheral nervous system disorder with neuronal intranuclear inclusions and severe atherosclerotic coronary artery disease in a 23-year-old white man. Beginning at 11 years of age, this patient had experienced diffuse muscle spasms, dysarthria, dysphagia, tremors, ataxia, oculogyric crises, progressive muscle weakness, and atrophy. At autopsy, neuronal intranuclear hyaline inclusions and neuronal loss were seen in his brain, brainstem, cerebellum, spinal cord, bowel, bladder, and esophagus. These fibrillary and granular Cowdry type A and Bintraneuronal inclusions were consistent with the diagnosis of NIHID associated with severe coronary atherosclerosis. Key Words: Neuronal intranuclear hyaline inclusion disease-Neurodegenerative disorder-Premature coronary atherosclerosis. From the Departments of Medical Biology, Pathology O.c.P.), Medicine (W.A.P.), University of Tennessee Memorial Research Center and Hospital and Department of Pathology (M.L.D.), Fort Sanders Regional Medical Center, Knoxville, Tennessee. Address correspondence and reprint requests to Dr. Joseph c. Parker, Jr., Department of Pathology, University of Mis$ ouri-Tr\Jman Medical Center, Kansas City, MO 64108, U.s.A. 244 Neuronal intranuclear hyaline inclusion disease (NIHID) was proposed by Sung et al. (1,2) to describe a slowly progressive neurodegenerative disorder involving the central, peripheral, and autonomic nervous systems, with eosinophilic intranuclear neuronal inclusions. These inclusions have been found throughout the central nervous system (CNS) involving neurons and glia and in ganglion cells in the bowel, bladder, and esophagus (1-13). The current case (8) is the first reported patient with NIHID associated with premature coronary atherosclerosis. CLINICAL DATA This 23-year-old white man had a chronic neurologic illness since 11 years of age. He was born at full-term to normal parents. There was no family history of neurological disease, and the perinatal period was uneventful. His developmental milestones were normal. At 11 years of age, the patient developed dysarthria, dysphagia, drooling, and a change in temperament characterized by nervousness and emotional lability. He steadily deteriorated both mentally and physically and experienced poor school performance. Twelve months after the onset of his problems, he had episodes of oculogyric crises lasting from minutes to an hour. At rest, a tremor and cogwheel rigidity were evident. His deep tendon reflexes were brisk in all limbs. When walking, he had no arm swing on both sides with accentuation of dystonic posturing in his left arm. His handwriting was small. Results of routine blood and urine sample determinations including copper and ceruloplasmin studies were normal. No Kayser-Fleischer rings were noted on slit lamp examination. Pneumoencephalogram, electroencephalogram, and spinal NEURONAL INTRANUCLEAR HYALINE INCLUSIONS 245 fluid studies were normal. At that time, a diagnosis of juvenile parkinsonism (14,15) was made, and he was treated with levodopa. He tolerated 4.5 g/d. After 4 to 6 months of therapy, he showed some improvement with disappearance of his dysarthria, drooling, and cogwheel rigidity. Approximately 2 years after onset, the patient developed progressive muscle weakness and ataxia. These features along with dysphagia, slowly progressed over the next 5 years. By 20 years of age, he had severe ataxia, muscle weakness in his lower and upper extremities, bowel and bladder incontinence, decreased deep tendon reflexes, intention tremor, and pes cavus. The patient was evaluated at that time at another institution, and a diagnosis of olivopontocerebellar atrophy was made. He was hospitalized on several occasions because of paralytic ileus and became unable to walk or control his bladder and bowel habits. His serum lipid studies were normal, and there was no family history for diabetes mellitus, strokes, vascular disease, or hyperlipidemias. Other than the oculogyric crises, no eye abnormalities were noted during his numerous examinations. At 23 years of age, he expired from aspiration pneumonia. POSTMORTEM FINDINGS The body was that of a severely cachectic man with muscle wasting, contractures, and bilateral pes cavus. Brown atrophy of the liver and heart was observed. His lungs were heavy and showed organizing and acute aspiration pneumonia, which was felt to be the terminal event. Severe coronary atherosclerosis was characterized by focal, 75% subocclusive atheromatous plagues in the left anterior descending coronary artery (Fig. 1). His scalp, skull, dural sinuses, and meninges were normal. The brain weighed 1,240 g. The circle of Willis was complete and had no atherosclerosis or congenital anomalies. The cranial nerves and spinal cord were normal. There was severe diffuse atrophy of the cerebellum (Fig. 2). Serial coronal sections of the cerebral hemispheres revealed barreling of the third ventricle and mild enlargement of the lateral ventricles. The cerebellum and brainstem sections showed marked atrophy of the cerebellum especially in the vermis. Reduced neuromelanin was seen in the substantia nigra and loci cerulei. The basis pontis was normal. Histologic sections demonstrated severe neuronal loss (Fig. 3) in the loci cerulei, substantia nigra, basal nuclei, cerebrum, hypoglossal nuclei, Purkinje cell layer (Fig. 4), and anterior horn cells FIG. 1. Cross-section of left anterior descending coronary artery showing atherosclerosis (hematoxylin and eosin stain. x 67). (Fig. 5). Reduced to absent ganglion cells were found in the esophagus, bowel, and bladder. Astrogliosis was observed in the dentate nuclei, basal ganglia, anterior horn cells, frontal cortex, FIG. 2. Whole mount sagittal cerebellar section showing atrophy (hematoxylin and eosin stain, x 100). I Gill Nell ro-0l'hthalIllO! , V,,/. 7, No.4, 1987 FIG. 4. Sections of cerebellum with Purkinje cell loss FIG. 3. Central nervous system sections showing (Hematoxylin and eosin stain, x 235). areas (dots) with severe neuronal loss. 246 J. c. PARKER ET AL. ,l ". , .. • • ,1 • .~ r . ... .~ .. ~ ... .- ... ." '" .. .. •. • inferior olives, hypoglossal nuclei, hippocampus, substantia nigra, and posterior columns of the spinal cord and optic chiasm. Diffuse demyelination was seen in the posterior and anterior lateral columns of the spinal cord. Slight demyelination was evident in the optic chiasm. Sections of the proximal and distal skeletal muscles revealed severe neurogenic atrophy with fibrosis and fatty infiltration. Degenerative changes and demyelination in the peripheral nerve bundles were observed. A remarkable marker was the eosinophilic intranuclear neuronal inclusions of the Cowdry type A and B (Fig. 6). These were observed in the thalamus, hypothalamus, basis pontis, dentate nuclei, anterior horn cells, loci cerulei, inferior olives, hypoglossal nuclei, substantia nigra, and hippocampus (Fig. 7). The greatest concentration was in the loci cerulei and substantia nigra. They were also noted in ganglion cells in the bowel, bladder, and esophagus. The cardiac conduction system including the sinoatrial and atrioventricular nodes was not sampled. Electron microscopy of these intranuclear neuronal inclusions showed nonmernhrane- bound nsmophilic, 8-nm straight fibrils without periodicity (Fig. 8). Structures resembling viral particles were not seen. The neuronal cytoplasm was unremarkable. COMMENT The patient presented here had a slowly progressive, primary neurodegenerative disorder involving the pyramidal, extrapyramidal, and peripheral nervous systems, with neuronal intranuclear inclusions. Similar findings have occurred in individuals from 3 to 68 years of age and have included 6 men and 8 women (1-13) (Table 1). The name, neuronal intranuclear hyaline inclusion disease (NIHID) proposed by Sung et a1. (2), was used to describe a slowly progressive neurodegenerative disorder with eosinophilic intranuclear neuronal inclusions, yet similar inclusions have been found in glia, Schwann cells, muscles, pituitary, and other tissues (1-13). Just as in the present patient, intraneuronal inclusions have been noted to be distributed widely in the central and peripheral nervous systems, including ganglion cells in the bowel, bladder, and esophagus (1-13). The unique feature of our case is the severe premature coronary atherosclerosis in a young man without known risk factors. NEURONAL INTRANUCLEAR HYALINE INCLUSIONS 247 FIG. 5. Horizontal section of lumbar spinal cord showing loss of anterior horn cells (hematoxylin and eosin stain, x 100). FIG. 6. Neuron with eosinophilic Cowdry type A intranuclear neuronal inclusion (arrow) (hematoxylin and eosin stain, x 385). FIG. 7. Sections of nervous system showing areas (dots) with Cowdry type A and B intranuclear neuronal inclusions. FIG. 8. Intranuclear neuronal inclusion composed of 8-nm thick straight filaments (x 9,045). I Cllll NCllro'l'l'hthailllo!, Vol. 7. No. 4, 1987 248 J. c. PARKER ET AL. TABLE 1. Overview of 15 patients with neuronal intranuclear hyaline inclusion disease In 1978, Schuffler et al. (10) reported two siblings with a generalized neurological degenerative disease that presented as intestinal psuedo-obstruction. Neurons were reduced and had intranuclear eosinophilic inclusions involving the cerebrum, brainstem, dorsal root ganglia, spinal cord, and myenteric plexi of the bowel. In 1979, Janota (4) reported a patient with spinal degeneration with intraneuronal inclusions and noted the similarity of these inclusions to Marinesco bodies by light microscopy. With electron microscopy, the granular Marinesco bodies (16) were distinguishable from these fibrillary intranuclear inclusions (I), which were evident within neurons in the central and peripheral nervous systems. Michaud and Gilbert (6) reported the case of an I8-year-old woman with a pronounced neurodegenerative disease since 9 years of age. Intranuclear inclusions were observed in the neurons of her central and peripheral nervous systems. In this case, the inclusions were not found in the autonomic neurons of the intestine. Munoz-Garcia and Ludwin (7) have described NIHID in patients in the 5th and 6th decades. Based on reports of 15 patients (1-13 and the present case) NIHID is considered a unique sporadic disorder occurring equally in men and women and beginning between 3 and 56 years of age (Table 1). Death usually occurs within 20 years after onset. Clinical manifestations involve mentation, emotions, and motor and autonomic functions. Features recognized most frequently have Features Age at onset Age at death Sex Ocular alterations Cerebellar deficits Pyramidal deficits Extrapyramidal deficits Seizures Autonomic/peripheral dysfunction Altered mentation Neuronal intranuclear inclusions B Data from references 1-13. Findings 3-56 yr (mean 17 yr) 6-68 yr (mean 32 yr) 6 males 9 females 8 patients (53%): ptosis, altered movements, optic atrophy, altered pupillary reactions, oculogyric crises, nystagmus 8 patients (53%): ataxia 9 patients (60%): muscle atrophy, weakness, hyperreflexia 15 patients (100%): tremors, cogwheel rigidity, dysarthria 5 patients (30%): grand mal 5 patients (30%): constipation, pes cavus 8 patients (53%): altered memory 15 patients (100%), CNS; 11 patients (73%), PNS been mental deterioration, ataxia, choreoathetosis, dysarthria, dysphagia, dysphasia, seizures, tremors, upper and lower motor signs, reduced sensations, and altered eye movements and pupillary reactions. The intranuclear hyaline i~clusio.ns characteristic of the disease have not stamed WIth periodic acid-Schiff, Bodian, oil red a, methyl green pyronin, or acid-fast methods (7). Ultrastructurally, ill-defined fibrils and granular material varying from 8 to 18 nm in diameter and of undefined length have been associated with 13- to I7-nm granules. NIHID has variable clinicopathologic expressions and is considered a subgroup of the multisystem atrophies. NIHID differs from olivopontocerebellar atrophy (OPCA), a consideration for the present patient, by the absence of the basis pontis atrophy and the presence of neuronal intranuclear inclusions (17,18). OPCA is usually transmitted as either a dominant or recessive autosomal disorder. NIHID appears sporadic and may mimic other well-defined neurodegenerative diseases including parkinsonism and Friedreich's ataxia. Parkinson's disease, the inital diagnosis for the present patient, shows degenerative disorders involving the extrapyramidal areas, especially the substantia nigra, and possesses eosinophilic intracytoplasmic neuronal inclusions that are not found in NIHID. Friedreich's disease is a spastic hereditary ataxia marked by degeneration of the posterior columns and corticospinal and spinocerebellar tracts. Eosinophilic intranuclear neuronal inclusions are not observed in this disorder. The etiology of NIHID is unknown. It may comprise more than one variant of a multisystem degenerative disease since the reported cases are so different in clinicomorphologic findings. The hyaline intraneuronal inclusions are the common feature for NIHID and have been considered degenerative lesions resulting from accumulation of some protein due to defective nuclear metabolism or accumulation of nuclear products due to defective transport or nuclear membranes. The present case is unique because the neuronal intranuclear hyaline inclusions were associated with premature coronary atherosclerosis without any underlying risk factors. An autosomal recessive trait may lead to altered lipoprotein metabolism in this disorder. Any individual with an otherwise unexplained multisystem neurological disorder involving cranial nerves, cerebellar function, and motor and extrapyramidal systems in concert with dementia and autonomic dysfunction is a candidate for this unusual neurological problem. Even though all 15 recorded patients required a postmortem examination for their diagnosis, identifying neuronal intra- JClin Neuro-ophthalmol, Vol. i, No.4, 1987 NEURONAL INTRANUCLEAR HYALINE INCLUSIONS 249 nuclear hyaline inclusions in a premortem biopsy from the bowel could provide early recognition. REFERENCES 1. Sung JH. Light, fluorescence, and electron microscopic features of neuronal intranuclear hyaline inclusions associated with multi-system atrophy. Acta Neuropatllol 1980;50:11520. 2. Sung JH, Ramirez-Lassepas M, Mastri AR, Larkin SM. An unusual degenerative disorder of neurons associated with a novel intranuclear hyaline inclusion (neuronal intranuclear hyaline inclusion disease). A clinicopathological study of a case. JNeuropathol Exp NeuroI1980;39:107-30. 3. Haltia M, Somer H, Palo J, Johnson WG. Neuronal intranuclear inclusion disease in identical twins. Ann Neurol 1984;15:316-21. 4. Janota I. Widespread intranuclear neuronal corpuscles (Marinesco bodies) associated with a familial spinal degeneration with cranial and peripheral nerve involvement. Neuropathol Appl Neurobiol 1979;5:311-7. 5. Lindenberg R, Rubinstein LJ, Hermann MM, Haydon, GB. A light and electron microscopy study of an unusual widespread nuclear inclusion body disease. Acta Neuropathol (Berf) 1968;10:54-73. 6. Michaud J, Gilbert JJ. Multiple system atrophy with neuronal intranuclear hyaline inclusions. Acta Neuropathol (Berf) 1981;54:113-9. 7. Munoz-Garcia J, Ludwin SK. Adult onset neuronal hyaline inclusion disease. Neurology 1986;36:785-90. 8. Parker JC Jr. Sporadic spinocerebellar degeneration associated with intranuclear neuronal inclusions and arteriosclerotic heart disease. 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The fine structure of the Marinesco body. Arch PatJI011969;88:431-6. 17. Berciano J. Olivopontocerebellar atrophy. A review of 117 cases. JNeurol Sci 1982;253-72. 18. Konigsmark BW, Weiner LP. The olivopontocerebellar atrophies: A review. Medicine, 1970;49:227-41. I Clill Neuro-ophthalm"l, Vol. 7, No.4, 1987 |
