Magnetic resonance image at 5 weeks after the onset of neurologic symptoms in the patient described in this report. Hyperintensities (arrowheads) on fluid-attenuated inversion recovery involving the left cerebellar hemisphere (A), bilateral pons (B), bilateral midbrain peduncles (C), and extending up into the thalami bilaterally (D).
A, Luxol fast blue-periodic acid–Schiff and hematoxylin-eosin staining of the central pons showing bilaterally symmetric areas of demyelination (original magnification ×10). B, Optic nerve tissue immunostained for myelin basic protein, showing reduced immunoreactivity and disruption of myelin structure (arrowheads) (original magnification ×40). C, CD68-immunoreactive macrophages infiltrating the optic nerve (original magnification ×20). D, High-power magnification showing macrophages with phagocytosed myelin (arrowheads). E, Neurofilament immunostaining of the pons showing myelin phagocytosis by macrophages (arrowhead) (original magnification ×40). F, Neurofilament immunostaining of the optic nerve showing occasional axonal retraction bulbs (arrowhead) (original magnification ×40).
Kromm JA, Power C, Blevins G, Larratt L, van Landeghem FKH, Rempel J. Rapid Multifocal Neurologic Decline in an Immunocompromised Patient. JAMA Neurol. 2016;73(2):226-231. doi:10.1001/jamaneurol.2015.2658
A man in his early 70s with a diagnosis of chronic lymphocytic leukemia and being treated with prednisone, fludarabine, cyclophosphamide, and rituximab presented with progressive multifocal neurologic decline. The patient died 2 months after the onset of this decline despite extensive clinical and laboratory investigation and a trial of methylprednisolone therapy. The approach to the immunosuppressed patient with progressive neurologic decline, neuropathologic findings, and final diagnosis are discussed.
A man in his early 70s with a diagnosis of chronic lymphocytic leukemia (CLL) was otherwise healthy and had no significant family history of disease or recent exotic travel. He reported that he did not use drugs or alcohol and remained highly active for 4 years after the diagnosis of CLL.
Treatment with prednisone and cyclophosphamide was initiated for CLL-induced autoimmune hemolytic anemia. Two years later, his disease worsened, prompting treatment with prednisone, fludarabine, cyclophosphamide, and rituximab. His response after 4 cycles of such treatment was suboptimal. His chemotherapy was discontinued and a splenectomy was planned, for which the patient received the appropriate vaccinations. Four and a half months after this, the patient experienced a decline in neurologic function.
Neurologic assessment disclosed pyramidal weakness with decreased reflexes and ataxia in the patient’s left arm, a reduced pinprick sensation in both arms, and a wide-based gait. Four weeks later, his deficits had progressed and included multimodal neurocognitive deficits, evidence of bilateral optic neuropathies, abnormal eye movements, spastic dysarthria, and quadraparesis worse on the left than on the right side, with increased reflexes and bilateral extensor plantar reflexes. He reported a band of dysesthesia at the T8 level, with impaired vibration and proprioception bilaterally, and had axial and appendicular ataxia affecting all of his limbs.
An empirical trial of methylprednisolone had no effect on the patient’s condition. After discussion with the patient’s family, his care was transitioned to comfort measures and he died 2 months after the onset of his first neurologic symptom.
Routine investigations consistently failed to contribute to clarifying the reason for the patient’s neurologic decline during the last 3 months of his life (Table). Findings from blood cultures for bacteria and fungi and tests for anti–human immunodeficiency virus types 1 and 2, anti–hepatitis B surface antigen, and anti–hepatitis C antibodies were negative. Test results for antinuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibody, extractable nuclear antigen antibodies, and anti–Hu/Yo/Ri antibodies were also negative.
Magnetic resonance imaging (MRI) of the patient’s brain at 3 weeks after his symptoms began showed subtle hyperintensities on fluid-attenuated inversion recovery images in the central pons symmetrically. Findings from the MRI of his cervical spine were normal. Two weeks after this, a subsequent MRI of the patient’s brain showed increased signal in his pontine lesions and new hyperintensities in fluid-attenuated inversion recovery images and T2-weighted images extending bilaterally through the cerebral peduncles into the thalami, with new lesions noted in the left cerebellar hemisphere, middle cerebellar peduncles, and rostral medulla. Findings from the MRI of the patient’s thoracic spine showed a heterogeneous T2-hyperintense lesion extending from T7 to T9. Findings from a follow-up MRI of the patient’s brain done 3 weeks later revealed progression of his lesions (Figure 1).
Analyses of cerebrospinal fluid (CSF) specimens collected on 2 separate occasions separated by 1 week revealed a mild lymphocytic pleocytosis (7 × 106/L), with no red blood cells, a normal glucose concentration, and an increased protein concentration of 0.12 g/dL (to convert to grams per liter, multiply by 10.0). A normal IgG to serum albumin index was identified with absent oligoclonal bands. The findings on cytologic examination on the patient’s CSF were unremarkable. Findings from the stains and cultures of the patient’s CSF for bacteria were negative, including those for acid-fast bacilli. Findings from the stains for fungi were negative, as was a test for cryptococcal antigen. Polymerase chain reactions for herpes simplex virus types 1 and 2, varicella zoster virus, enterovirus, parechovirus, and cytomegalovirus were negative. Testing with the polymerase chain reaction for JC polyomavirus (JCV), human herpesvirus–6, and BK polyomavirus gave negative results on both occasions of sampling of the patient’s CSF. Testing for paraneoplastic antineuronal nuclear antibodies types 1, 2, and 3; anti–glial nuclear antibody-1; Purkinje cell antibody types 1 and 2; amphiphysin; and CRMP-5 yielded negative results.
The differential diagnosis of disease in an elderly patient undergoing chemotherapy for CLL and presenting with progressive multifocal neurologic deterioration is broad and includes disorders likely to occur in an immunosuppressed patient. Central nervous system (CNS) involvement by CLL or neurologic complications related to its treatment is often underrecognized, but autopsy series estimate involvement by CLL of the brain, dura, and leptomeninges to be 7%, 21%, and 8%, respectively.1
On the basis of the findings on neuroimaging and the CSF profile of the patient in the present case, consideration should be given to infections causing rhomboencephalitis. Opportunistic infections develop in 80% of patients with CLL and cause up to 60% mortality, although not all infections in patients with CLL affect the nervous system.1 A CSF profile showing mononuclear pleocytosis, a moderately elevated protein concentration, and a normal glucose concentration directs the differential diagnosis toward viral encephalitis, granulomatous infection, or a parameningeal infection. Tests of CSF from the patient in the present case for herpes simplex virus types 1 and 2, varicella zoster virus, and cytomegalovirus were negative. An assay of CSF IgM antibody to varicella zoster virus is helpful in cases of presumed varicella zoster virus encephalitis, in which polymerase chain reaction can be negative. Bacterial infections of the patient in the present case were ruled out with blood and CSF cultures. Findings from blood cultures were negative for Candida, Cryptococcus, and Aspergillus species, as were stains of CSF for fungal agents. In patients who have traveled to areas endemic for various microbial infections, further tests should be done. Toxoplasma gondii, an opportunistic parasite, should be considered in immunocompromised patients with neurologic and ocular signs and symptoms because it can cause encephalitis and necrotizing retinochoroiditis in this population. However, the patient in the present case did not have clinical or radiologic features typical of toxoplasmic encephalitis.
Progressive multifocal leukoencephalopathy (PML) caused by JCV should be considered in an immunosuppressed patient with progressive multifocal neurologic deficits.2 This leukoencephalopathy can affect any site within the CNS, and its clinical manifestations are protean. Behavioral and cognitive abnormalities are seen in up to half of all patients with PML.2 Other common clinical findings in the condition include weakness, gait disturbances, visual field deficits, and incoordination. Visual disturbances in PML are caused by leukoencephalopathy of the optic radiations.2 Optic nerve involvement, as evident by the results of the examination of the patient in the present case, has not previously been reported.2 Although spinal cord involvement by PML is rare,2 this patient had a pattern of myelopathic sensory loss on examination, despite indefinite findings on neuroimaging. Findings from the MRI in PML reveals T2-hyperintense and T1-hypointense lesions in affected regions, with minimal gadolinium enhancement. Although PML most often presents with multifocal lesions in the CNS, PML associated with monoclonal antibody treatment commonly causes a single lesion.2 Lesions of monoclonal antibody-induced PML occur predominantly in the frontal and parieto-occipital regions, with rare associated or isolated involvement of the basal ganglia and posterior fossa structures.2 The detection by polymerase chain reaction of JCV in CSF has a sensitivity of 95% to 99% and specificity of 96% for the definitive diagnosis of PML.2 Testing rarely produces a false-negative result in patients with a small viral load, but the patient in the present case had negative results of such testing on 2 occasions. According to the diagnostic criteria for PML outlined by the American Academy of Neurology, this patient could at most be defined as having possible PML, and in such cases if all other diagnostic possibilities are excluded, a brain biopsy for assessing histological features, immunohistochemistry, and in situ hybridization for JCV DNA should be pursued.2
When infections have been ruled out as a source of PML, one should consider the possibility of drug toxicity affecting the CNS. Although the patient in the present case had not received chemotherapeutic agents for 5 months before his neurologic decline, such agents can produce delayed complications. Besides the increased risk of PML associated with therapeutic monoclonal antibodies and fludarabine, these agents have been associated with other CNS-related complications.1 Therapeutic monoclonal antibodies can cause a hyperammonemic encephalopathy, and fludarabine can cause diffuse cerebral leukoencephalopathy as well as toxic effects on the optic nerves.1 Therapeutic monoclonal antibodies and fludarabine, as well as cyclophosphamide, can also cause posterior reversible encephalopathy syndrome.1 Fludarabine-associated leukoencephalopathy generally occurs at doses exceeding 40 mg/m2/d, and is principally defined by a delayed onset (up to 60 days after a last dose of fludarabine) and a progressive clinical course consisting of encephalopathy, seizures, paraparesis, coma, and death.3,4 Neuroimaging reveals diffuse cerebral white matter T2 hyperintensities. Although fludarabine-associated leukoencephalopathy may involve deep brain structures, the areas it predominantly affects are supratentorial.3 The literature contains only a single report of myelopathy associated with fludarabine.4 Presentations of fludarabine-induced ocular nerve damage may consist of blurred vision, amaurosis, monocular scotoma, and blindness.4 Patients receiving immunosuppressive or chemotherapeutic agents and presenting with progressive multifocal or diffuse neurologic deficits should have these agents discontinued, and alternative therapies should be considered once it is deemed medically safe to do so.
Patients with aggressive inflammatory disorders can present with a monophasic subacute decline over periods of weeks to months.5 Acute disseminated encephalomyelitis should be considered in patients, and much more frequently in children and young adults, in whom infection or vaccination is followed by neurologic deterioration, including encephalopathy, seizures, multifocal deficits, and fever (although fever may not be seen in adults with such encephalomyelitis). Neuroimaging in patients with this condition shows an extensive lesion load affecting gray and white matter. The CSF shows a lymphocytic pleocytosis with an elevated protein concentration, generally without oligoclonal bands. Patients with acute hemorrhagic leukoencephalitis develop petechial hemorrhages in affected areas of the brain, manifested on MRI by restricted diffusion, and with CSF manifestations consisting of a neutrophilic pleocytosis, increased protein concentration, and red blood cells. Neuromyelitis optica is a severe inflammatory demyelinating disorder mainly affecting the optic nerves and spinal cord and is mediated by complement-activating antibodies to aquaporin-4. Although neuroimaging may reveal lesions elsewhere in the nervous system of patients with neuromyelitis optica, these lesions are generally asymptomatic.
Among other aggressive inflammatory disorders is the Marburg variant of multiple sclerosis, a rare, aggressive, inflammatory demyelinating syndrome that can present with a clinical trajectory similar to the patient in the present case, but that generally shows numerous, large multifocal inflammatory lesions affecting deep white matter, and usually affects young patients. Concentric sclerosis can rarely present with multifocal symptoms and signs rather than those of a single mass lesion, but MRI in this condition reveals the classic lamellar lesions with alternating zones of intensity. The diagnosis of diffuse myelinoclastic sclerosis, which generally occurs in children and young adults, depends on an MRI showing white matter lesions affecting the centrum semiovale. Neurologic immune reconstitution inflammatory syndrome usually presents in the context of rapid recovery from profound immunosuppression with a concurrent CNS infection. The patient in the present case did not exhibit the typical clinical course of any of these disorders, and in an elderly patient who has recently had immunosuppressive therapy, such as the patient herein, these disorders are unlikely, with the exception of immune reconstitution inflammatory syndrome.
A vasculitic process is unlikely to occur in an elderly patient undergoing immunosuppressive therapy. Neuroimaging in patients with such a process shows multifocal infarcts involving multiple vascular territories. If a vasculitic process is suspected in a patient, further investigations should be done, including a rheumatologic panel and vascular imaging. The patient in the present case did have a broad battery of rheumatologic tests; all test results were negative.
Other, less common neurologic complications of CLL include CLL meningoencephalitis and Richter syndrome.1 Patients with CLL are also prone to developing secondary neoplasms, including gliomas and meningiomas, although these would present as a single mass lesion rather than multiple lesions.1 Metabolic disturbances may occur during CLL with ensuing CNS disorders. Hypercalcemia from the humoral-mediated liberation of calcium from bone can cause altered mental status, headache, confusion, and coma. Hyponatremia of iatrogenic origin or from lymphocyte infiltration of the pituitary gland can cause cerebral edema leading to confusion, seizures, and coma.1 A well-known yet poorly understood complication of derangements in sodium homeostasis is central pontine and extrapontine myelinolysis.6,7 Although the neuroimaging of the patient in the present case did show a pattern suggestive of this disorder, the T2-hyperintense signal in the patient’s MRI was not as robust as expected, and the patient’s repeated blood analyses did not show any fluctuations in sodium concentration.
In this immunocompromised patient previously receiving chemotherapy, an unidentified opportunistic infection or toxic leukoencephalopathy remain the most likely explanation for his presentation.
An autopsy of the patient revealed a grossly normal brain weighing 1475 g. Hematoxylin-eosin and Luxol fast blue staining of brain specimens revealed multifocal symmetric leukoencephalopathy with evidence of active demyelination (Figure 2A). Well-demarcated areas of demyelination were most apparent within the central pons but were also observed in regions including the midbrain, medulla, thalamus, and optic nerves. Immunostaining for myelin basic protein showed reduced immunoreactivity in the optic nerves as well as in the pons, in keeping with the diminished Luxol fast blue staining noted in the brainstem and thalamus (Figure 2B). The borders of the patient’s brain lesions were more distinct than expected for a toxic leukoencephalopathy.
Immunohistochemical staining for CD68 (Figure 2C), CD3, CD4, CD8, and glial fibrillary acidic protein showed macrophage infiltration and phagocytosis with marked reactive astrocytosis, and a paucity of lymphocytes. Inflammatory cells were diffusely disseminated, without the perivascular infiltrates that would be expected in a toxic leukoencephalopathy (Figure 2D). Immunolabeling of neurofilaments disclosed relative preservation of axonal integrity, with axons of varying caliber and occasional axonal spheroids in areas of severe demyelination (Figure 2E and F). No evidence of perivenous or perivascular demyelination, bell-shaped hemorrhages, necrosis, or vessel-wall infiltration was detected, excluding acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, neuromyelitis optica, the Marburg variant of multiple sclerosis, concentric sclerosis, and diffuse myelinoclastic sclerosis.
The results of histochemical staining, including that with Ziehl-Neelsen, periodic acid–Schiff, and Gram stains, were unremarkable. Ultrastructural examination revealed no evidence of viral inclusion bodies. In situ hybridization for JCV DNA was negative.
After discussion with the clinical team and a literature review, a diagnosis was made of central pontine and extrapontine myelinolysis. Fludarabine leukoencephalopathy was excluded on the basis of the patient’s subtoxic dosage of fludarabine, delayed presentation (5 months after his last dose of fludarabine), atypical (nonlobar) distribution of his lesions, lack of indistinct lesion borders, and absence of the perivascular infiltrates typically seen in toxicity-associated leukoencephalopathies.
We describe a patient with progressive and subacute neurologic decline resulting in death, with neuropathologic features of central pontine and extrapontine myelinolysis with optic nerve involvement and myelopathy. Central pontine myelinolysis was described in 1959, but not until 1962 was it realized that the same process occurred as extrapontine myelinolysis.6,7 After this, the inclusive term osmotic demyelination syndrome (ODS) was created for such conditions. Lesions in this syndrome may involve the pons, cerebellum, diencephalon, basal ganglia, cortex, and adjacent white matter. The midbrain, internal capsule, or medulla are affected in less than 10% of cases.6,7 We could find only 1 case report of spinal cord involvement by this syndrome.8 To our knowledge, optic nerve involvement by this syndrome has not been described.
The role of sodium in ODS was not established until 1982, and in the following 3 decades it has become apparent that other risk factors predispose to this condition.7 Notably, the patient in the present case did not exhibit any of the clinically established risk factors for ODS, including hyponatremia with rapid correction, hypokalemia or hypophosphatemia, prior liver transplantation or cirrhosis, severe burns, dialysis, or ethanol abuse.6,7 The patient did not have tumor lysis syndrome, which could have caused electrolyte abnormalities, nor could we find any association between ODS and CLL or ODS and any of the chemical agents to which the patient was exposed. Nonetheless, he experienced dysphagia and exhibited dysarthria as well as progressive paresis and ataxia, a common presentation for ODS.6,7
King and Rosner7 proposed a mechanism for ODS based on fluctuating sodium levels. In a chronically hyponatremic state, the glia and neurons must actively excrete ions and organic solutes to prevent them from swelling throughout a 48-hour period. On rapid correction of this state, the cells must again actively take up ions and produce organic osmolytes, although at a much faster rate than under physiologic conditions. Under conditions of malnutrition, such as in alcohol abuse, hyperemesis gravidarum, cirrhosis, and perhaps with cancer, as with the patient in the present case, glia and neurons fail to be repleted at a sufficiently rapid rate to prevent massive intracellular to extracellular fluid shifts. The resulting cell shrinkage results in a cascade of events leading to demyelination.
Treatment of ODS is challenging; if hyponatremia is present, the risk of its slow correction must be balanced with the risk of ODS during its rapid correction. Recommendations exist for the appropriate rate of electrolyte correction.6 Case reports exist of corticosteroids and plasmapheresis improving patient outcomes,6,7 and the potential benefits of vasopressin receptor antagonists and myoinositol infusions in ODS also have been examined.6,7
The prognosis for patients with ODS has improved substantially since this disorder was first described, with mortality from the syndrome declining from 50% to 90% to 5% to 10%.6,7 Among survivors, 25% have significant disability.6,7
Corresponding Author: Julie Anne Kromm, MD, FRCPC, Division of Neurology, Department of Medicine, University of Alberta, Heritage Medical Research Centre, 6-11, Edmonton, AB T6G 2S2, Canada (email@example.com).
Published Online: December 14, 2015. doi:10.1001/jamaneurol.2015.2658.
Author Contributions: Dr Kromm had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Kromm, Power, Larratt, van Landeghem.
Acquisition, analysis, or interpretation of data: Kromm, Power, Blevins, van Landeghem, Rempel.
Drafting of the manuscript: Kromm, Power, van Landeghem.
Critical revision of the manuscript for important intellectual content: Kromm, Power, Blevins, Larratt, van Landeghem.
Administrative, technical, or material support: Power, Blevins, van Landeghem, Rempel.
Study supervision: Power, Blevins, van Landeghem, Rempel.
Conflict of Interest Disclosures: None reported.