Progressive Multifocal Leukoencephalopathy (PML);
Acquired Immunodeficiency Syndrome (AIDS);
Prurigo Nodularis
Patient #21 presented with a non-dominant parietal syndrome with some interesting twists. The characteristic features of the syndrome in this patient include hemineglect, anosagnosia, dressing apraxia, apathy, extinction on the left to double simultaneous stimulation, and constructional apraxia. These features are all part of an underlying dysfunction in directed attention - one of the major tasks of the non-dominant parietal lobe. The degree of hemineglect in this patient was mild, consistent with a non-dominant parietal origin. Frontal, thalamic, and basal ganglionic lesions generally result in more profound hemineglect than was seen in this patient. In addition, the dressing apraxia (consisting of dressing one-half of the body) is most consistent with a non-dominant parietal lesion rather than bilateral lesions that result in an inability to dress either side of the body. Features not present in this patient, but frequently seen in patients with non-dominant parietal lobe damage, include astereognosis and agraphaesthesia in the contralateral hand and geographical disorientation.
Other features suggesting involvement of areas outside the non-dominant parietal lobe in this case include the memory disturbance, weakness, hyper-reflexia, hypertonia, homonymous hemianopsia, bradyphrenia, and ideomotor apraxias. This degree of memory impairment does not occur with isolated parietal injury. And the pattern of memory loss—inability to recall that is improved with cues (the problem lies not in registration or storage but only in recall) —is consistent with diffuse subcortical damage. In particular, this pattern is seen with bilateral frontal subcortical white matter involvement and is most likely due to a disconnection syndrome. Bradyphrenia and bradykinesia are commonly seen in this form of memory loss. Ideomotor apraxias are not commonly seen with non-dominant parietal damage but imply, rather, an insult in the dominant inferior parietal, temporal, or frontal lobes. The lesion may be cortical or subcortical, and is due to a disconnection between language comprehension and motor output. Rarely, injury to the non-dominant pre-frontal cortex will cause ideomotor apraxias in the contralateral hand. The homonymous hemianopsia implies a lesion involving the optic radiations in the subcortex of the parietal and temporal lobes, or occipital cortex. Macular involvement places the lesion in the optic radiations. A single parietal insult would be expected to produce only an inferior quadrantanopsia. The face, arm and leg weakness with increased reflexes and hypertonia implies a lesion in the subcortical white matter (internal capsule or corona radiata) subserving motor function.
The overall picture in this case, then, is of a diffuse process largely affecting the non-dominant parietal lobe and/or parieto-occipital junction, with both cortical and subcortical features. The differential diagnosis includes several entities that diffusely affect white matter tracts including MS, ADEM, dysmyelinating diseases (ALD, MLD, etc.) presenting in the adult, PML, multiple subcortical infarctions, and CNS vasculitis (either isolated CNS granulomatous angiitis or a systemic rheumatologic condition, such as SLE). One might also consider an unusual presentation of a butterfly glioma or other CNS tumor, such as lymphoma.
This patient also complained of generalized pruritis which may be seen in several conditions, including hyperthyroidism, diabetes mellitus, carcinoid syndrome, lymphoma, leukemia, abdominal cancer, some CNS tumors, multiple myeloma, mycosis fungoides, drug ingestion, scabies, onchocerciasis, ascariasis, chronic renal failure, polycythemia vera, paraproteinemia, cholestasis, pregnancy, psychogenic states, and HIV infection. The coexistence of generalized pruritis and focal (largely subcortical) neurological compromise effectively limits the possible diagnoses to lymphoma, CNS tumors, polycythemia vera with multiple infarctions, and HIV infection with one of its attendant complications. The patient was subsequently discovered to be HIV+. The diagnosis most consistent with the clinical features and widespread demyelination seen on MRI is PML, which has a predilection for the white matter of the parietal and occipital lobes.
When confronted with his diagnosis, the patient revealed that he engaged in unprotected sex with several prostitutes in Southeast Asia on his trip six years previously. His family have since been tested, and all are HIV-. While neurological disease existed long before the AIDS pandemic, one must now consider HIV-related disease in many differential diagnoses. AIDS has been likened to the variable presentations seen with syphilis in previous centuries. Because the HIV virus may result in neurological disease at virtually all steps of the neuraxis, with the exception of the neuromuscular junction, one may consider it a potential cause of disease in most patients. However, routine testing for HIV is not necessary, as most patients with HIV-related neurological disease will have known risk factors. Only when other diagnostic avenues are unrewarding and clinical suspicion exists should HIV testing be performed in the patient without known risk factors.
The patient was treated with triple therapy in an attempt to arrest the underlying cause for his immuno-suppression (AIDS). Reports of improved cognition in patients with HIV encephalopathy after treatment with triple therapy are encouraging. Treatment in patients with PML is less encouraging to date, though there are isolated reports of remission. Even with therapy, this patient's prognosis is dismal.
Progressive Multifocal Leukoencephalopathy (PML) is an uncommon, relentlessly progressive demyelinating disease caused by a polyomavirus infection in immuno-compromised hosts. Until recently, most clinicians considered PML a rare, terminal complication of cancer patients receiving immunosuppressive medications. The AIDS pandemic, however, has introduced a large population of immuno-compromised patients at risk of developing this condition. Even so, PML is still a relatively uncommon complication of HIV infection, as only 4-5% of AIDS patients develop it. Within this population there does not appear to be a predilection for any particular racial or sexual group. A rare case has been described in an otherwise, ostensibly immuno-competent patient.
Astrom, Mancall, and Richardson first described the clinical characteristics of PML in 1958. The following year, Cavanagh provided evidence for a viral etiology when he described intranuclear inclusions. In 1965, two independent groups provided electron microscopic evidence of viral particles resembling members of the popova group, firmly establishing the viral etiology of this disease. To date, three related viruses, JC, SV40, and BK, have been isolated from patients with PML. Pathogenetic evidence for the latter two viruses has been scanty and controversial, and it is currently unclear if they play an active role in disease progression. Virtually all cases described to date are due to infection with JC virus in an immuno-compromised host.
Although the agent responsible for PML is well described, the mechanism by which it causes disease is not. Exposure to the JC virus is nearly universal, usually occurring at a young age. In immuno-competent individuals, the virus remains dormant in renal cells and B lymphocytes of the spleen and bone marrow. In immuno-compromised hosts, however, the virus gains access to the CNS (either by direct hematogenous spread or via transport by mononuclear cells) where it may cause disease. After entry into the CNS, the JC virus preferentially infects oligodendroglial cells - the cells responsible for CNS myelination. There are no apparent cell surface receptors that mediate this tropism. Rather, oligodendroglia express specific nuclear transcription factors that bind JC viral DNA regulatory regions. This interaction provides not only the means for a particular CNS white matter tropism, but also the mechanism for increased viral transcription within these cells. The result of this interaction is progressive CNS demyelination in susceptible hosts. The precise mechanism for the demyelination is not known, but may result from down regulation of the myelin basic protein gene, oligodendroglial death, a generalized disruption of oligodendroglial function, or a yet unknown mechanism.
There are no pathognomonic features of PML. However, one should suspect PML in any immuno-compromised patient with clinical and radiological evidence of isolated white matter disease. The onset is insidious with progressive mental changes combined with symptoms of white matter involvement such as visual deficits, weakness and ataxia. Confusion, personality change, dementia, and language dysfunction are commonly present as well. While posterior fossa and spinal cord structures may be involved, the cerebral hemispheres bear the brunt of damage. Asymmetric involvement is the rule, with a predilection for the white matter of the parietal and occipital lobes. The spinal fluid is typically normal. MRI typically shows signal abnormalities in the subcortical or deep hemispheric white matter. Contrast enhancement is unusual but may occur. Definitive diagnosis may only be made by brain biopsy, though PCR techniques are currently being investigated.
Gross examination shows multiple areas of demyelination. Typical early lesions begin at the gray-white junction, but foci are generally disseminated throughout the white matter. The corpus callosum is frequently affected. Microscopically, oligodendrocytes are swollen and hyperchromatic with enlarged nuclei and intranuclear inclusions. In larger lesions, one typically finds astroglia with unusually large hyperchromatic nuclei, frequently with abnormal mitoses. These cells appear malignant, inviting the conjecture that the JC virus may be oncogenic. In fact, polyomaviruses are oncogenic in rats, and there is evidence that the JC virus can transform human glial cells in culture. The few reported cases of gliomas in with coexistent PML fuel this conjecture.
There is no effective treatment for this condition. Life span after diagnosis is a dismal 6-12 months. One problem in devising treatments is that PML does not occur in isolation, but only in patients with an underlying, progressive systemic illness. Consequently, most therapies are aimed at controlling the underlying immunosuppression rather than the JC virus itself. Attempted therapies include the use of nucleoside analogs, such as cytarabine, splenectomy in association with antiretroviral therapy, and triple therapy in association with ?-interferon. Each has met with limited, anectodal success. No double-blind, placebo-controlled trials have been performed.
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