Multiple sclerosis mimickers: Recognizing the underrecognized
For more than 100 years, neuromyelitis optica (NMO), known as Devic's disease, was thought to be a variant of multiple sclerosis (MS), despite observations that acute episodes were restricted to the optic nerve and spinal cord and were more immediately devastating than in MS.
It was not until 1999 — when neurologists and MS specialists Brian G. Weinshenker, M.D., at Mayo Clinic in Rochester, Minn., and Dean M. Wingerchuk, M.D., at Mayo Clinic in Arizona, published a series of 73 cases and identified distinguishing features of NMO — that the disease began to be recognized as an entity distinct from MS.
NMO is perhaps the best known of the MS mimickers, a group of neurological conditions that may share characteristics of MS but are being identified as discrete diseases. Patients may have radiologic findings consistent with MS but have symptoms that are not. Another distinguishing feature of MS mimickers is that standard MS treatments often fail.
Although most such disorders are uncommon, their identification is of obvious clinical utility. Understanding them provides insight into central nervous system (CNS) disease mechanisms shared across disease types. Examples of MS mimickers include:
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
MRI showing multiple punctate perivascular enhancing lesions
Early in his career, B Mark Keegan, M.D., a neurologist at Mayo Clinic in Rochester, saw a patient with signs typical of inflammatory brainstem disease and in whom MS was suspected. The MRI findings, however, showed small focal, gadolinium-enhancing lesions possibly more typical of CNS sarcoidosis but certainly highly atypical of MS.
The condition was responsive to corticosteroids, but, unlike MS, the lesions recurred immediately after the patient was weaned from corticosteroid therapy. "We ran multiple tests, but all of them came back negative for known entities. Fortunately, the neurosurgeon was able to conduct a biopsy of the brainstem, which showed a nonspecific inflammation," Dr. Keegan explains.
Ten years later, neuroimmunology colleague Sean J. Pittock, M.D., brought a patient with similar signs to Dr. Keegan's attention. Other patients with similar symptoms and the typical MRI findings soon followed, including two patients from Belgium. In four of the eight patients who underwent brainstem and cerebellum biopsy, the findings were similar and exclusive of other known diseases.
Drs. Pittock and Keegan and their colleagues have since identified the common radiologic, pathologic, and clinical features of the disease they have labeled chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Their findings were published in the September 2010 issue of Brain.
The symptoms include episodic diplopia or facial paresthesias with subsequent brainstem and, occasionally, myelopathic symptoms that improve with a high dose of corticosteroids and may require long-term immunosuppressive therapy.
Primary intramedullary spinal cord lymphoma and secondary intramedullary spinal cord non-Hodgkin lymphoma
Myelopathies may complicate cancers such as lymphoma, but usually the clinical effect is due to an extramedullary compressive cause. Although rare, intramedullary spinal cord lymphoma can occur and mimic other intramedullary cord lesions, such as MS or NMO, even in the absence of systemic lymphoma, thus making the differential diagnosis difficult.
In a review of 14 such cases, published in the August 2010 issue of Neurology, Dr. Keegan and his colleagues found that patients presented with back pain (64 percent) and constitutional symptoms of fever, chills, malaise, night sweats or weight loss (64 percent). Some had evidence of lower motor neuron involvement (43 percent). The diagnoses that were initially considered included:
- Spinal cord neoplasia
- Infectious myelitis
- Transverse myelitis
- Acute disseminated encephalomyelitis
- Chronic inflammatory demyelinating polyneuropathy
MRI findings showed multifocal, persistent — lasting (two to eight months) — gadolinium-enhancing lesions with spinal cord enlargement, occasionally with extension into the conus medullaris and with accompanying brain lesions. Morbidity rate was high, and treatment was often delayed because the cause remained uncertain. In most patients, definitive diagnosis required brain or spinal cord biopsy.
Leptomeningeal metastases may complicate non-Hodgkin lymphoma (NHL), but intramedullary spinal cord metastases are rare. In a follow-up to the primary intramedullary spinal cord lymphoma (PISCL) study, published in the May 2012 issue of the Journal of Neuro-Oncology, Dr. Keegan and colleagues found direct intramedullary spinal cord infiltration in seven patients with active NHL.
The investigators cautioned that when myelopathy is discovered in a patient with NHL, it is important to exclude other causes, such as myelopathy due to spinal cord compression or of paraneoplastic cause, infection, ischemia from intravascular lymphoma, and hematomyelia from damaged blood vessels and from the effects of irradiation on the spinal cord. Survival was poor in these patients: Median survival was approximately 12 months. Even this survival was far better than in patients with spinal cord metastases from other solid cancers. Their median survival rate was approximately 3 months).
Paraneoplastic isolated myelopathy
Paraneoplastic myelopathies occur most commonly with cancer of the lung or breast. A Mayo Clinic retrospective review of 31 cases of paraneoplastic isolated myelopathy, published in the June 2011 issue of Neurology, found that the disorder typically occurred in the context of other neurological disorders, including encephalopathy, peripheral neuropathy and cerebellar dysfunction. An interesting spinal MRI finding that should alert physicians to the possibility of paraneoplastic myelopathy is symmetrical, longitudinally extensive tract or gray matter changes, called tractopathies.
Sporadic and hereditary leukoencephalopathy with spheroids
Neuroaxonal leukodystrophy is a rare cause of progressive leukoencephalopathy, the primary symptom of which is dementia. The most frequently cited cases are those that are inherited and occur in childhood. When neuroaxonal leukodystrophy has an adult onset and occurs sporadically, the severe, progressive cognitive and motor impairments can be confused with other progressive dementias and primary movement disorders. It can also be confused with MS because of the presence of asymmetrical, diffuse, nonenhancing subcortical white matter lesions on MRI. See "Sporadic adult-onset leukoencephalopathy with neuroaxonal spheroids mimicking cerebral MS" in the March 2008 issue of Neurology.
Sporadic and hereditary diffuse leukoencephalopathy with spheroids (HDLS) is another CNS white matter disease that can present with dementia. Other signs include personality changes, depression, parkinsonism and seizures. This autosomal dominant inherited disease mimics other neurodegenerative diseases, including Parkinson's disease (PD) and MS.
Elizabeth A. Shuster, M.D., a neurologist and MS specialist at Mayo Clinic in Florida, saw a patient two years ago with signs of demyelinating disease whose mother had a similar white matter disease. Because some of the clinical features were similar to PD, Dr. Shuster consulted her neurology colleague Zbigniew K. Wszolek, M.D., an expert in movement disorders who has a particular interest in neurodegenerative disease genetics. He had seen other patients with similar disorders.
Working together with a team led by Mayo geneticist Rosa Rademakers, Ph.D., they were able to uncover the gene CSF1R, the loss of which appears to play an important role in HDLS. Their findings were published in the February 2012 issue of Nature Genetics. CSF1R is considered a key mediator of microglial proliferation and differentiation in the brain, which suggests that microglial dysfunction is a critical mechanism in HDLS pathology.
As Dr. Shuster points out, identifying MS mimickers helps to clarify disease commonalities. MS and many other neurological conditions have both degenerative and inflammatory features. She notes that interest is growing, including among Mayo Clinic researchers, about the neurodegenerative aspects of MS and whether or not it shares common features with other neurological disorders. As a step in this research process, she and Dr. Wszolek are looking for links between the neurodegenerative aspects of PD and those of MS.
Neuromyelitis optica update
After the seminal paper on NMO in 1999, a Mayo team of neurologists and autoimmunity researchers had, by 2006, identified the NMO antibody (NMO-immunoglobulin, Ig, G) and its target, aquaporin-4, and had developed a diagnostic blood test that reliably distinguished NMO from MS. Now, NMO is recognized around the world as a distinct disease.
Dr. Wingerchuk notes that the laboratory test for NMO-IgG helped to galvanize the MS community to recognize NMO as a unique disease and that it is not uncommon now for Mayo to receive referrals specifically for NMO evaluation. Treatment strategies for NMO differ from those used for MS. Mayo Clinic investigators are studying the benefits of various new approaches for NMO.
For patients with a severe relapse that is unresponsive to corticosteroids, plasma exchange is widely used as a rescue therapy. To investigate the value of plasma exchange as a preventive NMO therapy, Drs. Wingerchuk and Keegan have established a prospective registry of patients who are being treated with maintenance plasma exchange as part of their routine care. The observational study will help determine how quickly and completely the antibody is depleted, how well that depletion is maintained, and whether maintenance plasma exchange successfully prevents relapses and disability.
In addition, Drs. Pittock and Wingerchuk are heading up a clinical trial of eculizumab for NMO treatment. Eculizumab is a monoclonal antibody that targets complement, an immune system component thought to be a key early activator of inflammation in NMO relapses. Study results are expected later this year.
Finally, Drs. Weinshenker and Wingerchuk are leading an international panel to revise and refine the diagnostic criteria for NMO. Mayo Clinic in Arizona is also participating with two other medical centers in developing a clinical consortium to facilitate multicenter collaboration for NMO research.