Introduction
Lesions of multiple cortical tracts have not been described in patients with HIV infection. However, isolated motoneuron disease associated with HIV infection has been described [1–3] and usually occurs in the AIDS stage. Motoneuron disease may be reversible under treatment with HAART [1]. In general, motoneuron disease is difficult to diagnose in the early stage of the disease, as a whole spectrum of opportunistic infections and syndromes must be considered in a patient with HIV infection. The combination of lesions of the auditory, visual and corticospinal tract has been described in rare hereditary or sporadic diseases, but never as a consequence of HIV infection.
Case report
A 37-year-old man presented with dysarthria and a clumsy right hand in our Neuro-AIDS outpatient clinic. HIV infection had been diagnosed 5 years before. He was in the CDC A1 stage of the disease [CD4+ cell counts 720 cells/μl, viral load under the limit of detection in the serum and the cerebrospinal fluid (CSF)]. Numerous laboratory tests, including examination of the CSF, tests for metabolic changes and opportunistic infections including PCR were unremarkable [CSF cell counts 2 lymphocytes/μl, total protein 449 mg/l, immunoglobulin G (IgG) 24 mg/l, three oligoclonal bands in the CSF, one oligoclonal band in the serum, glucose 77.5 mg/dl, lactate 2.03 mmol/l, no intrathecal synthesis of immunoglobulins, normal antibody tests and indices for cytomegalovirus, Epstein Barr virus, herpes simplex virus, varicella zoster virus, human T-lymphotropic virus 1 and 2, JC-polyomavirus, rubella, rubeola and mumps virus, and Treponema pallidum).
MRI of the brain showed hyperintense lesions in the T2-weighted and diffusion weighted images in the pons (Fig. 1a), the medulla oblongata and the pyramidal tract, the internal capsule, the crura cerebri (frontopontine and cerebrospinal fibers, Fig. 1b) and the optic tract, more on the left side than on the right (Fig. 1a and b). The apparent diffusion coefficient was reduced in these tracts representing a restricted diffusion. There was no contrast enhancement except of one of the lesions located in the left paramedian pons that showed nodular contrast enhancement. Additionally, diffusion tensor imaging (DTI) was performed. DTI is a noninvasive MRI technique for the detection of macrostructural and microstructural impairments of fiber integrity on the basis of normal values for the fractional anisotropy. A reduction of the fractional anisotropy represents a destruction of fiber integrity, as demonstrated in our patient in the pyramidal tract (Fig. 1c and d, fractional anisotropy reduction is green and blue; normal fractional anisotropy of the tract is red. Right in the conventional MRI corresponds to the left on DTI).
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Fig. 1: Degeneration of the corticospinal tract in a T2-weighted MRI sequence. MRI of the brain showed hyperintense lesions in the T2-weighted images in (a) the pons and (b) the crura cerebri on the left more than on the right side. Reduced fractional anisotropy on diffusion tensor imaging, color coded. Red areas represent normal fractional anisotropy values, green and blue to violet areas represent reduced fractional anisotropy values (c and d). R, right.
The symptoms were rapidly progressive in the next 5 months. Finally, the patient suffered from a spastic tetraparesis with painful muscle cramps, severe dysarthria, blindness, dysphagia and intermittent hearing loss on the right more than on the left ear. HAART (nevirapine, zidovudine and lamivudine) did not stop the progressive course of the disease. Different treatments with steroids, cidofovir and different antibiotics in order to treat any kind of infectious, autoimmune or inflammatory disease did not result in any amelioration or deterioration. Steroids were only started when infections were excluded. In the course of the disease, the CD4+ blood counts decreased to 437 cells/μl, but the viral load remained under the limit of detection in the blood plasma and in the CSF. The patient died 5 months after the onset of the first symptoms.
On postmortem examination, the formalin-fixed brain weighted 1662 g with mild edema. Coronal sections of the brain and parasagittal section of the cerebellum were unremarkable. The transversal section of medulla oblongata and cervical spinal cord showed bilaterally sharply demarcated lesions within the pyramidal tract (HE-overview, Fig. 2a). The upper cervical spinal cord was examined as well; here the lesion extended to the corticospinal and dorsal tracts. Gross examination of the body was not performed.
Fig. 2: Immunohistochemistry. The transversal section of medulla oblongata and cervical spinal cord showed bilaterally sharply demarcated lesions within the pyramidal tract (hematoxylin and eosin-overview, Fig. 2a). Histological examination revealed a vacuolar degeneration of the pyramidal tracts with destruction of the myelin (KlĂ¼ver–Barrera staining, Fig. 2b). Mild reactive astrogliosis was present in the adjacent brain parenchyma (glial fibrillary acidic protein (GFAP) staining, Fig. 2c). Numerous CD68-positive invading foamy macrophages typically for Wallerian degeneration could be detected (Fig. 2d).
Histological examination revealed a vacuolar degeneration of the pyramidal tracts with destruction of the myelin (KlĂ¼ver–Barrera staining, Fig. 2b). Mild reactive astrogliosis was present in the adjacent brain parenchyma (glial fibrillary acidic protein, GFAP staining, Fig. 2c). Numerous CD68-positive invading foamy macrophages typically for Wallerian degeneration could be detected (Fig. 2d). Loss of myelin was shown using an antibody directed against myelin basic protein (MBP). Within the cytoplasm of the macrophages, MBP-positive myelin degradation products were detected. Stainings for neurofilaments demonstrated a marked reduction of axons as well as the presence of axonal spheroids, a typical hallmark of acute axonal damage. Immunohistochemical stainings for the detection of JC-polyomavirus or toxoplasma were negative.
Discussion
Herein the first case description of a rapidly progressive disease with degeneration of the auditory, visual and corticospinal tract in the early stage of a HIV infection is presented. Intensive investigations showed no sign of metabolic changes or an opportunistic infection. Even treatment with HAART, steroids, cidofovir and different antibiotics as possible salvage therapy could not stop the dramatically rapid course of the disease. There was no detectable HIV load in plasma or CSF, the CD4+ blood count was normal, and the symptoms occurred in CDC A1 stage of HIV infection. Histologically, the findings suggest a severe and disseminated form of vacuolar myelopathy and leukoencephalopathy. Clinically, the triad of auditory, visual and corticospinal degeneration is not typical for vacuolar leukencephalopathy in HIV; furthermore, the occurrence in a patient with a good immunological state is unusual for vacuolar myelopathy [4,5].
The triad of auditory, visual and corticospinal tract degeneration has not been described in patients with HIV infection, and it is not known to be caused by any of the therapeutics the patient was treated with. There are a few rare syndromes that lead to the triad of auditory, visual and corticospinal tract lesions.
Adult onset adrenoleukodystrophy [6], an X-linked disorder that involves white matter, the adrenal cortex and testis, is associated with abnormal accumulation of very long chain saturated fatty acids in brain, adrenal gland, red blood cells and plasma. It is caused by a mutation on chromosome Xq28 that codes for a peroxisomal membrane protein. A severe childhood form and a mild adult form exist. Matching our patient, the disease causes spasticity, dysarthria, weakness of legs and a demyelination on MRI in the corticospinal, auditory and optic tract. Histologically, the disease results in myelin loss, mild gliosis and many PAS-positive cells. Our patient did not show any peripheral nerve involvement, signs of adrenal insufficiency, bladder and bowel disturbance, dementia or demyelination of the corpus callosum. Vacuolar degeneration is not typical for the disease. Adult onset adrenoleukodystrophy progresses slowly over decades.
Brown–Vialetto–van Laere syndrome [7] is a syndrome of unknown cause with progressive pontobulbar palsy associated with sensorineural deafness, lower and upper motor neuron signs and other symptoms. Fifty-eight cases have been described in the last 100 years. Like in our patient, the syndrome causes upper motor neuron limb signs, deafness, slurring of speech and optic tract degeneration. It affects mostly male patients and presents with a sporadic onset in 50% of the cases. MRI shows atrophy of the brainstem and cerebellum or hyperintensities in the brainstem nuclei, cerebellar peduncles, internal capsule or subcortical white matter. Unlike the syndrome in our patient, the disease also involves lower cranial nerves and other cranial nerves, and lower motor neuron involvement is common. The age of onset varies from childhood to the third decade, and the clinical course is variable with sometimes abrupt periods of worsening, but death within a few months in an adult patient has not been described.
Madras motor neuron disease [8] is occurring predominantly in southern India. Its clinical features are pyramidal dysfunction, wasting and weakness of distal muscles, facial and bulbar muscles and hearing impairment, and there is a variant with optic atrophy. A familial form and a sporadic form can be distinguished. Like in our patient, it results in sensorineural hearing loss, weakness of limbs, visual disturbance, dysphagia and dysarthria. Histologically, the brain shows gliosis and demyelination. Unlike our patients, the mean duration of the illness is 59 months, muscle wasting is typical, as well as facial palsy, and there were no relatives from Asia in our patient.
Intoxication with a methanol-containing solvent mixture as a cause for a motoneuron disease with optic neuropathy has been described [9]. However, our patient was not exposed to any toxic agent, and there was no amelioration, but deterioration after controlled hospital conditions without exposure to other than the prescribed drugs or to toxic agents.
To summarize, none of the above-described syndromes can be the cause of the rapidly progressive disease of our patient. It is very likely that it is associated with the HIV infection of our patient, even if he was in an extremely good immunological state. It is shown that this triad of auditory, visual and corticospinal tract lesions has to be considered in patients with concordant symptoms and HIV infection, and may present a first, early manifestation of Neuro-AIDS, even in the early stages of the infection with a good immunological state. Even after more than 30 years of experience with HIV, physicians have to be alert to unexpected syndromes associated with HIV infection.
Acknowledgements
Description of the role of each of the authors in the study reported.
I.K. was responsible for writing the report, literature and data collection and research on the topic.
H.W. contributed essentially to the data collection.
W.S. and M.D. were responsible for acquiring and interpreting the MRI data.
K.K. and T.K. were responsible for the gross examination and microscopic description of the brain.
I.H. was responsible for the interpretation of the findings, the initiation of the autopsy and, as a specialist for Neuro-AIDS, as a supervisor of this case report.
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