Idiopathic myelopathies with white matter vacuolation in non-acquired immunodeficiency syndrome patients

Postmortem examination of 21 patients showed a vacuolar myelopathy resembling that associated with the acquired immunodeficiency syndrome. Underlying diseases included six cases of leukemia or lymphoma, five of carcinoma, three of systemic lupus erythematosus, two of chronic lung disease, and one each of cadaveric renal transplant, cirrhosis, diabetes, hemophagocytic syndrome, and viral encephalitis. Fourteen patients were on long-term steroid therapy and 10 of these also had immunosuppressive chemotherapy. No patient had the acquired immunodeficiency syndrome, although one received blood transfusions in 1978. Signs and symptoms consistent with myelopathy included paraparesis in seven patients, ataxia in one, and bilateral extensor plantar reflexes in one. Microscopic examination showed vacuolation in spinal cord white matter primarily located in posterior and lateral columns. Lipid-laden macrophages and axonal changes were proportional to the severity of the vacuolation, which was severe in five patients, moderate in 10, and mild in six. Eight patients had coexistent viral diseases elsewhere in the central nervous system, but viral-associated antigens or genomic material was not found in regions of vacuolated spinal cord white matter. Although the etiology of these myelopathies is unknown, their association with immune suppression and coexistent viral infection of the central nervous system suggests that an opportunistic viral infection may be important.     

Fate of reactive axonal swellings induced by head injury

The fate of those reactive axonal swellings seen following head injury was assessed in cats subjected to mild to moderate fluid-percussion head injury. To allow for the ready visualization of any traumatically induced reactive axonal change at both the light and electron microscopic level, the anterograde axonal transport of wheat germ agglutinin conjugated to horseradish peroxidase was employed over a 21-day posttraumatic period in selected cerebral and cerebellar efferents coursing through the brain stem. At the designated posttraumatic survival time, the animals were perfused with aldehydes, processed for the light and electron microscopic visualization of the peroxidase reaction product, and examined for any evidence of reactive axonal change. At the 3rd and 4th posttraumatic days, peroxidase-laden swellings could be identified. Some reactive swellings were packed with organelles and were either encompassed by a distended myelin sheath or lacked myelin investment. Other reactive swellings demonstrated either lobulation or increased electron density with macrophage accumulation, all of which indicated degeneration. Wallerian change occurred distal to the reactive swellings; however, with the exception of these changes the related brain parenchyma and vasculature demonstrated no significant abnormality. With continued survival, reactive swellings comparable to those just described were consistently observed; however, now regenerative responses were also seen. At the 5th and 7th days, reactive sprouts were observed originating from reactive swellings which displayed a reduction both in size and in organelle content. By the 9th and 14th posttraumatic days, some sprout-containing swellings demonstrated several robust extensions. These regenerative changes were seen in both myelin- and nonmyelin-invested swellings and persisted through the 21st day, occurring in concert with lobulated, electron dense, and unchanged, swollen reactive axons. This study suggests that head injury elicits axonal swelling that may persist unchanged, degenerate, or undergo a regenerative response. The sustained regenerative responses are considered intriguing and may have relevance both for head-injured humans and for future studies of central nervous system regeneration.     

Neuropathology of the acquired immunodeficiency syndrome

This review attempts to assess critically the literature on the neuropathology of acquired immunodeficiency syndrome in light of our experience with 172 patients with acquired immunodeficiency syndrome who underwent extensive postmortem examinations of the central and peripheral nervous systems. The neuropathologic manifestations of the disease can be divided into three categories: (1) primary or putative/indirect effects of the human immunodeficiency virus, (2) opportunistic infections, and (3) neoplasms. We discuss the known etiologic agents and postulated pathogenetic mechanisms responsible for the broad range of neurologic diseases observed in patients with acquired immunodeficiency syndrome.     

Diffuse axonal injury in infants with nonaccidental craniocerebral trauma: enhanced detection by beta-amyloid precursor protein immunohistochemical staining

OBJECTIVE: Accurate identification of diffuse axonal injury is important in the forensic investigation of infants who have died from traumatic brain injury. beta-Amyloid precursor protein (beta-APP) immunohistochemical staining is highly sensitive in identifying diffuse axonal injury. However, the effectiveness of this method in brain-injured infants has not been well established. The present study was undertaken to assess the utility of beta-APP immunohistochemistry in detecting diffuse axonal injury in infants with either shaken baby syndrome or blunt head trauma. MATERIALS AND METHODS: Archival formalin-fixed, paraffin-embedded blocks from infants (<1 year old) with shaken baby syndrome (7 cases) and blunt head trauma (3) and blocks from 7 control cases that included nontraumatic cerebral edema (1), acute hypoxic-ischemic encephalopathy (1), and normal brain (5) were immunostained for beta-APP. A semiquantitative assessment of the severity of axonal staining was made. Corresponding hematoxylin-eosin-stained sections were examined for the presence of axonal swellings. RESULTS: Immunostaining for beta-APP identified diffuse axonal injury in 5 of 7 infants with shaken baby syndrome and 2 of 3 infants with blunt head trauma. Immunoreactive axons were easily identified and were present in the majority of the sections examined. By contrast, hematoxylineosin staining revealed axonal swellings in only 3 of 7 infants with shaken baby syndrome and 1 of 3 infants with blunt head trauma. Most of these sections had few if any visible axonal swellings, which were often overlooked on initial review of the slides. No beta-APP immunoreactivity was observed in any of the 7 control cases. CONCLUSIONS: Immunostaining for beta-APP can easily and reliably identify diffuse axonal injury in infants younger than 1 year and is considerably more sensitive than routine hematoxylin-eosin staining. We recommend its use in the forensic evaluation of infants with fatal craniocerebral trauma.     

Late onset distal axonal swelling in YFP-H transgenic mice

Axonal swellings, or spheroids, are a feature of central nervous system (CNS) axon degeneration during normal aging and in many disorders. The direct cause and mechanism are unknown. The use of transgenic mouse line YFP-H, which expresses yellow-fluorescent protein (YFP) in a subset of neurons, greatly facilitates longitudinal imaging and live imaging of axonal swellings, but it has not been established whether long-term expression of YFP itself contributes to axonal swelling. Using conventional methods to compare YFP-H mice with their YFP negative littermates, we found an age-related increase in swellings in discrete CNS regions in both genotypes, but the presence of YFP caused significantly more swellings in mice aged 8 months or over. Increased swelling was found in gracile tract, gracile nucleus and dorsal roots but not in lateral columns, olfactory bulb, motor cortex, ventral roots or peripheral nerve. Thus, long-term expression of YFP accelerates age-related axonal swelling in some axons and data reliant on the presence of YFP in these CNS regions in older animals needs to be interpreted carefully. The ability of a foreign protein to exacerbate age-related axon pathology is an important clue to the mechanisms by which such pathology can arise.     

Acquired immunodeficiency syndrome with disseminated toxoplasmosis presenting as an acute pulmonary and gastrointestinal illness

Encephalitis due to the protozoan Toxoplasma gondii has emerged as a common cause of central nervous system disease in patients with acquired immunodeficiency syndrome. Extraneural disease is less common and more difficult to diagnose. We report a case of widely disseminated toxoplasmosis that presented as acute gastrointestinal and pulmonary disease in a patient without a prior diagnosis of acquired immunodeficiency syndrome. The diagnosis of toxoplasmosis was made only at autopsy. Antemortem diagnosis of disseminated T gondii infection requires a high degree of clinical suspicion and the prompt utilization of appropriate diagnostic testing. Since toxoplasmosis is a potentially treatable opportunistic infection, diagnosis allows the swift institution of anti-Toxoplasma therapy.     

Human T-lymphotropic virus type I-associated myelopathy in patients with the acquired immunodeficiency syndrome.

We describe two cases of serologically confirmed human T-lymphotropic virus type I (HTLV-I)-associated myelopathy involving North American men coinfected by the human immunodeficiency virus type 1. Our first patient suffered from a gradually progressive spastic paraparesis for 10 years prior to presenting with Kaposi's sarcoma, while our second patient developed subacutely progressive spastic paraparesis in the setting of full-blown acquired immunodeficiency syndrome. Autopsy examination of the spinal cords from these two cases revealed widespread axonal loss and demyelination principally involving the lateral columns of case no. 1 and the lateral and anterior columns of case no. 2. Vascular sclerosis and hyalinization were prominent in both cases, but in neither was there a conspicuous inflammatory component. In case no. 2, HTLV-I mRNA was not detected by in situ hybridization, but HTLV-I proviral DNA sequences were detected in this case by polymerase chain reaction. Neither case exhibited multinucleated cell (human immunodeficiency virus type 1) myelitis, vacuolar myelopathy, or evidence of HTLV-II infection by polymerase chain reaction assay.     

Legal liability for transfusion injury in the acquired immunodeficiency syndrome era

The emergence of the acquired immunodeficiency syndrome has wrought changes that have affected not only medicine and science, but many aspects of our social and political structures. In 1983 when it clearly became evident that acquired immunodeficiency syndrome could be transmitted by transfusions of blood components and products, blood banks became the focus of intense scrutiny by the public as well as by the mass media. Suddenly it was known that people could contract acquired immunodeficiency syndrome even though they had not engaged in activities known to place them at increased risk for acquiring infection with the human immunodeficiency virus type 1. In many ways the general fear evoked was, and remains, disproportionate to the risks posed by transfusions. This fear coupled with a general distrust of blood banks may also be reflected in the legal response to people infected with human immunodeficiency syndrome type 1 through transfusions. Further, whether the fault system of our tort law is an appropriate way to determine compensation for people injured by transfusion has been brought into question. For those people injured prior to our recognition of acquired immunodeficiency syndrome, the failings of the current system are most obvious.     

Congenital giant axonal neuropathy

Giant axonal neuropathy (GAN) is a distal sensorimotor neuropathy, characterized by neurofilamentous axonal swellings, with usual onset at 2 to 3 years of age. We report a case of congenital GAN with hypotonia at birth. At 7 months of age, nerve conduction studies showed almost complete lack of sensory and motor responses in the lower extremities. A sural nerve biopsy specimen disclosed absence of myelinated axons. Autopsy, following death at 15 months of age, revealed axonal swellings in peripheral nerves and distal degeneration of long spinal cord tracts. The neurofilamentous content of the axonal swellings was confirmed by Glees-Marsland staining and immunoperoxidase reaction with antibodies to neurofilaments. Axonal swellings did not stain with periodic acid-Schiff and were not seen in the cerebral cortex or brain stem, distinguishing this process from infantile neuroaxonal dystrophy. This patient illustrates congenital GAN with subsequent rapid progression.     

Diagnostic pathology in the acquired immunodeficiency syndrome. Surgical pathology and cytology experience with 67 patients

We report the pathologic findings in specimens submitted for histologic and cytologic evaluation from 67 patients with the acquired immunodeficiency syndrome. A wide variety of opportunistic pathogens were identified in 41 patients. Mycobacterium avium-intracellulare evoked only a mild host response: granulomas, if present, were poorly formed. Biopsy specimens showing cytomegalovirus gastroenteritis required sections at multiple levels to demonstrate inclusions. Combined histologic and cytologic evaluation can increase the diagnostic yield in pulmonary and esophageal infections. Kaposi's sarcoma was found in biopsy specimens from 29 patients. Early lesions were often extremely subtle, yet distinct from, benign vascular proliferations in involuted lymph nodes. Malignant lymphoma was diagnosed in ten homosexual men who were suspected of having the acquired immunodeficiency syndrome. The lymphomas were characterized by B-cell origin, a diffuse pattern, frequent extranodal presentations, and an aggressive clinical course with prominent central nervous system involvement.     

Review of the central nervous system cytopathology in human immunodeficiency virus infection

The human immunodeficiency virus (HIV) is a neurotropic retrovirus capable of producing a wide spectrum of central nervous system changes. Nearly 40% of HIV-infected patients demonstrate neuropathy ranging from dementia to the opportunistic infections and neoplasia seen in the acquired immunodeficiency syndrome (AIDS). Dramatic increases in the numbers of AIDS cases have allowed for the cytotechnologist and cytopathologist to become acquainted with the various pathologic manifestations of HIV infection. In this review, we are reporting the HIV-related diseases in the central nervous system and the role of diagnostic cytology.     

Neuroaxonal Regeneration is More Pronounced in Early Multiple Sclerosis than in Traumatic Brain Injury Lesions

The extent of irreversible neuroaxonal damage is the key determinant of permanent disability in traumatic and inflammatory conditions of the central nervous system (CNS). Structural damage is nevertheless in part compensated by neuroplastic events. However, it is unknown whether the same kinetics and mechanisms of neuroaxonal de‐ and regeneration take place in inflammatory and traumatic conditions. We analyzed neuroaxonal degeneration and plasticity in early multiple sclerosis (MS) lesions and traumatic brain injury (TBI). Neuroaxonal degeneration identified by the presence of SMI31+ chromatolytic neurons and SMI32+ axonal profiles were characteristic features of leukocortical TBI lesions. Axonal transport disturbances as determined by amyloid precursor protein (APP)+ spheroids were present in both TBI and MS lesions to a similar degree. Neurons expressing growth‐associated protein 43 (GAP43) and synaptophysin (Syn) were found under both pathological conditions. However, axonal swellings immunopositive for GAP43 and Syn clearly prevailed in subcortical MS lesions, suggesting a higher regenerative potential in MS. In this context, GAP43+/APP+ axonal spheroid ratios correlated with macrophage infiltration in TBI and MS lesions, supporting the idea that phagocyte activation might promote neuroplastic events. Furthermore, axonal GAP43+ and Syn+ swellings correlated with prolonged survival after TBI, indicating a sustained regenerative response.     

Neuroaxonal dystrophy in Australian Merino lambs

Neuroaxonal dystrophy (NAD) is a morphological abnormality in man and animals that is characterized by the occurrence of numerous axonal swellings (spheroids) in the nervous system. NAD has been described in Suffolk lambs in the USA, Merino lambs in Australia and several breeds of sheep in New Zealand. This paper describes the clinicopathological changes of only the second occurrence of NAD reported in Merino lambs. There were some features (myelin loss, gliosis and visual impairment) in these Australian cases that have not been reported previously in ovine NAD. Application of immunohistochemical markers of axonal transport suggested that disruption of this transport mechanism contributed to spheroid development.     

Gastric toxoplasmosis in a patient with acquired immunodeficiency syndrome. A case report and review of the literature

Toxoplasmosis is a common opportunistic pathogen in patients with acquired immunodeficiency syndrome (AIDS). It usually presents with ocular, central nervous system, or pulmonary disease. Gastric toxoplasmosis is uncommon in AIDS patients, especially in the absence of central nervous system manifestations. In the few reported cases, patients have presented with abdominal pain and other digestive complaints that usually are attributed to the more common gastrointestinal manifestations of human immunodeficiency virus infection. We describe a 49-year-old man with AIDS who presented with abdominal pain, diarrhea, dry cough, and systemic symptoms and was diagnosed with toxoplasmosis by a gastric biopsy.     

Clinical manifestations of acquired immunologic deficiency syndrome (AIDS)

The acquired immunodeficiency syndrome AIDS is caused by the retrovirus HIV. About 20% develop after the inoculation of the virus an acute clinical picture resembling infectious mononucleosis. Several weeks to months after the infection antibodies can be demonstrated in the serum. Lateron a lymphadenopathy syndrome or AIDS related complex may develop. Most of the patients with LAS or ARC will progress to the full blown picture of AIDS. This is defined as immunodeficiency complicated by Kaposi-sarcoma or central nervous system malignance lymphoma or opportunistic infections. The most common infections are due to certain parasites, c. e. pneumocystis carinii, toxoplasma gondii and cryptosporidia. Fungi, bacteria and viruses can also cause opportunistic infections.     

Combined and alternating ganciclovir and foscarnet in acute and maintenance therapy of human immunodeficiency virus-related cytomegalovirus encephalitis refractory to ganciclovir alone

Summary Cytomegalovirus (CMV) causes life-threatening disseminated infections and in particular vision-threatening infections of the retina in patients with the acquired immunodeficiency syndrome. Ganciclovir currently represents the most frequently used therapy for CMV retinitis. However, cases of ganciclovir-resistant CMV strains have been described, in which foscarnet seems to be an effective alternative. Both drugs have serious toxicities, and relapses frequently occur during maintenance therapy. In a patient with CMV encephalitis, we administered a 3-week combination ganciclovir/foscarnet induction therapy (ganciclovir 5 mg/kg every 12 h; foscarnet 60 mg/kg every 8 h), followed by an alternating maintenance administration of both drugs every other day (ganciclovir 5 mg/kg, foscarnet 120 mg/kg) to reduce toxicity and resistance. This regimen was tolerated well and seemed to be more effective than ganciclovir alone in a patient with CMV encephalitis.Abbreviations AIDS acquired immunodeficiency syndrome - CMV cytomegalovirus - CNS central nervous system - CSF cerebrospinal fluid - CT computed tomography - ED50 50% effective dose - ELISA enzyme-linked immunosorbent assay - HIV human immunodeficiency virus - MRI magnetic resonance imaging     

Progressing encephalomyelopathy with muscular atrophy,induced by aluminum powder

The injection of aluminum powder into the cerebrospinal fluid of adult rabbits induced a slowly progressing encephalomyelopathy characterized at first by alteration of posture and then by myoclonic jerks and muscle weakness. N Neurofibrillary degeneration was the hallmark of the disease and involved most of the gray areas. Giant axonal swellings were also numerous, particularly in the proximal axonal segment of neurons of the anterior horns. In the anterior horns the number of neurons with neurofibrillary degeneration decreased with time, while the images of neuronophagia increased in number in the rabbits killed in the second and third month after aluminum injection. In these animals there were also pathologic changes in the peripheral nerves and muscles. The peripheral nerve showed wallerian-like degeneration. Furthermore, in some a animals, the presence of nodal axonal swellings and of paranodal myelin retraction were expression also of a distal axonopathy. Neurogenic muscular atrophy appeared in animals sacrificed in the second and third month after injection.     

Transfer of neuropathogenic simian immunodeficiency virus with naturally infected microglia.

The central nervous system (CNS) is a target for human immunodeficiency virus infection, and, in individuals with acquired immune deficiency syndrome, this can lead to a devastating dementia. Only certain viral variants appear capable of invading the CNS and infecting microglia and brain macrophages. To determine whether the virus entering the brain may be particularly pathogenic to the CNS, we isolated microglia from the brains of simian immunodeficiency virus-infected rhesus monkeys. Serial transfer of these cells into naive animals indicated that productive simian immunodeficiency virus infection could indeed be transferred. Furthermore, CNS infection occurred within a relatively short time span and was associated with viral gene expression in the brain and pathology characteristic of human immunodeficiency virus encephalitis. While demonstrating that neuropathogenic variants partition into the CNS, our approach will allow the dissection of functional neuropathogenic elements present in these viruses.     

Correlation of in situ hybridization with histology and viral culture in patients with acquired immunodeficiency syndrome with cytomegalovirus colitis

Endoscopic colonic biopsy specimens from 34 patients with acquired immunodeficiency syndrome and six patients without acquired immunodeficiency syndrome (3 were human immunodeficiency virus-seropositive and 3 were human immunodeficiency virus-seronegative) were examined by in situ hybridization for evidence of cytomegalovirus colitis and the results were compared with histologic examinations and viral cultures. In situ hybridization was positive in 22 of 25 patients with acquired immunodeficiency syndrome with histologic evidence of cytomegalovirus colitis. By our interpretation, 15 patients without cytomegalovirus colitis histologically all had negative hybridization studies. No correlation was found between in situ hybridization and viral culture results. In situ hybridization is a useful confirmatory test when the histologic changes are suspicious for cytomegalovirus but not considered diagnostic; it will only rarely demonstrate staining in a case considered negative histologically.