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To describe the characteristics of multiple sclerosis (MS) presenting with severe cognitive impairment as its primary disabling manifestation.
Retrospective case series.
Tertiary referral center.
Patients were identified through the Mayo Clinic data retrieval system (1996–2008) with definite MS (McDonald criteria) and severe cognitive impairment as their primary neurological symptom without accompanying significant MS-related impairment or alternative diagnosis for cognitive dysfunction. Twenty-three patients meeting inclusion criteria were compared regarding demographics, clinical course and radiological features.
Demographic, clinical, and radiological characteristics of the disease.
Twelve patients were men. The median age of the first clinical symptom suggestive of CNS demyelination was 33 years, and severe MS-related cognitive impairment developed at a median of 39 years. Cognitive impairment could be dichotomized as subacute fulminant (n=9) or chronic progressive (n=14) in presentation, which corresponded to subsequent relapsing or progressive MS courses. Study patients commonly exhibited psychiatric (65%), mild cerebellar (57%) and cortical symptoms and signs (e.g. seizure, aphasia, apraxia) (39%). Fourteen of 21 (67%), where documented, smoked cigarettes. Brain MRI demonstrated diffuse cerebral atrophy in 16 and gadolinium enhancing lesions in 11. Asymptomatic spinal cord MRI lesions were present in 12 of 16 patients (75%). Immunomodulatory therapies were generally ineffective in improving these patients.
We describe patients with MS whose clinical phenotype is characterized by severe cognitive dysfunction and prominent cortical and psychiatric signs presenting as a subacute fulminant or chronic progressive clinical course. Cigarette smokers may be over represented in this phenotype.
Cognitive dysfunction is a common feature of multiple sclerosis (MS), affecting approximately 40–60% at some time in their disease course (1). Cognitive impairment often manifests as deficits in recent memory, attention, information-processing speed, executive functions, and visuospatial perception (1). The type and degree of cognitive dysfunction is not highly associated with disease course (i.e. relapsing-remitting, primary or secondary progressive) (2). Even seemingly minor cognitive dysfunction may be troubling and impair employment and daily living (3, 4) however it typically does not cause severe disability until late in the disease course when other co-existent neurological impairment also becomes prominent.
MS rarely presents primarily as debilitating cognitive dysfunction, without accompanying disability in motor, sensory or cerebellar function. When this presentation occurs, it is referred to as “cortical” or “cerebral-type” MS (5) and it presents a diagnostic dilemma, particularly in differentiating primary neurodegenerative dementias, infectious, or metabolic disorders. Treatment is challenging in these patients as symptomatic therapies aimed at MS cognitive impairment is of limited benefit (5). Earlier case series describe some of the characteristics of this presentation (6, 7) however the phenotype remains poorly described. Furthermore, risk factors that may predispose patients to primary cognitive forms of MS have not been elucidated. We present 23 patients with predominant, severe cognitive presentations of MS.
The study was approved by the Mayo Clinic Institutional Review Board (IRB #06-003613). The Mayo Clinic (Rochester, MN) patient database was queried for diagnostic coding of both MS, central nervous system (CNS) demyelinating disease (and related terms) plus cognitive impairment (and related terms) between January 1, 1996, and June 27, 2008. Study patients had definite MS by the revised Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis (8) and MS clinical course was classified by the criteria of the National Multiple Sclerosis Society (USA) Advisory Committee (9). Patients had severe cognitive impairment as their primary impairing neurological symptom, great enough to impair instrumental activities of daily living. Cognitive impairment was formally assessed by the Kokmen Short Test of Mental Status (STMS) a brief 38-point cognitive screening test assessing orientation, attention, learning and recall, calculation, abstraction, construction, and knowledge (normal value of 33.1 +/− 3.3 for patients older than 60). A score of 31/38 or less for patients under 50 years old yields a specificity of 93.5 and sensitivity of 86.4 for dementia (10). In selected patients comprehensive neurocognitive testing was employed, which evaluated for dementia, intelligence, memory, language, visual spatial learning, attention, problem solving, and depression.
Exclusion criteria were: 1) significant impairment in other neurological domains (as determined by the formal Mayo Clinic neurology records), 2) alternative diagnoses explaining the cognitive impairment (e.g. degenerative dementing diseases such as Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, inherited and sporadic leukodystrophies, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), metabolic disturbance or infection). Serological investigations performed, where indicated, included antinuclear antibody, rheumatoid factor, angiotensin converting enzyme, antibody to extracted nuclear antigen, cyclic citrullinated peptide, erythrocyte sedimentation rate, anti-endomysial antibody, thyroid stimulating hormone, thyroperoxidase antibody, vitamin B12, heavy metals, vitamin E, lactate, pyruvate, ceruloplasmin, copper, liver function tests, c-and p- anti neutrophil cytoplasmic antibodies (ANCA), myeloperoxidase, proteinase 3 antibody, antiphospholipid antibodies, skin biopsy for CADASIL, paraneoplastic antibody panel, arylsulfatase A, galactosylceramide beta-galactosidase, very long chain fatty acids, hexosaminidase A and infectious screens for syphilis, HIV, hepatitis, rubella, rubeola, JC virus, parvovirus, Lyme disease, Whipple’s disease, cryptococcus, toxoplasmosis, West Nile virus, EBV, HTLV, and equine encephalitis.
Five patients underwent brain biopsy for diagnostic purposes, three of which confirmed demyelinating disease while two showed non-specific gliosis without other diagnostic abnormalities. In the two patients with non-diagnostic biopsies, an MS diagnosis was made by clinical history, radiological and cerebrospinal fluid (CSF) findings, and serological exclusion of alternative diagnoses.
Broadly screening for MS, CNS demyelinating disease, and cognitive impairment or dementia identified 549 patients with 172 having severe cognitive impairment attributable to MS (Figure 1). Twenty-three met our strict criteria for this study with the others excluded because of co-existent impairing MS neurological signs and symptoms. All selected patients had either minimal or no impairments in non-cognitive neurological domains (pyramidal, cerebellar, brainstem, sensory, bowel/bladder, or visual). Medical records from the Mayo Clinic were abstracted for the following: demographics, MS clinical course, associated neurological and psychological signs and symptoms, smoking history, neuropsychometric testing, laboratory analyses, neuroimaging studies, and treatment responses. Ten patients were seen at Mayo Clinic for one visit. In these cases, the clinical course was abstracted entirely from their history and outside medical records. The remaining 13 patients were seen at Mayo Clinic multiple times and had a median of 2 years follow-up (range 0.5–10).
Statistical analysis was performed using JMP or Microsoft Excel statistical software. Data were analyzed with either the two-tailed Student’s t-test (parametric data) or Fisher’s exact test (non-parametric data).
Twelve patients (52%) were male and the patients had a median age of 33 years (range 20–56) at first onset of symptoms of CNS demyelination (Table). The median age at onset of debilitating cognitive impairment was 39 years (range 20–56). Cognitive impairment was the initial presentation in 17 (74%) patients. with the remaining 6 patients presenting with optic neuritis (1), paresthesias (2), seizures (2), or mild leg weakness (1). Nine MS patients had a relapsing remitting course, 11 primary progressive, and 3 secondary progressive.
Associated signs and symptoms of cortical or psychiatric dysfunction were common (Table). Cortical signs and symptoms were present in 9 of 23 patients including seizures (6), aphasia (4) and apraxia (3). Thirteen (57%) patients had mild cerebellar ataxia. Psychiatric abnormalities were present in 15 of 23 patients with a combination of depressive (13/23) or psychotic (3/23) symptoms.
Fourteen of 21 patients (67%) had a history of tobacco use (2 not documented). Twelve were current smokers, with a median 30 pack-year history (range 2.5–80) in the eleven patients where this was clearly documented.
Twenty-one of 23 patients were assessed by Kokmen STMS with a median score of 25 (range 3–33). Comprehensive neuropsychometric testing was performed in 14 patients and all had results confirming disabling cognitive impairment and dementia not attributable to either depression or non-MS diagnosis.
In 14 patients (61%), cognitive dysfunction evolved in a progressive fashion, eventually leading to significant disability. In the remaining 9 patients (39%), cognitive dysfunction occurred in an attack-related subacute and fulminant manner. Four of these patients had multiple, recurrent attacks of cognitive or psychiatric dysfunction, whereas the remaining five had a single severe cognitive attack without full resolution. All 9 patients with a subacute and fulminant onset of cognitive dysfunction developed relapsing-remitting MS, whereas the MS patients with progressive cognitive dysfunction developed was primary progressive MS in 11 and secondary progressive MS in 3.
Neuroimaging was performed at differing time points in presentation given the retrospective nature of the study; therefore limited analysis was performed. Brain MRI reports were reviewed in all patients and spinal cord MRI in 16. Neuroimaging review was limited to a median of 2 (range 1–6) brain scans per patient and those assessed were performed a median of 2 years following onset of cognitive impairment (range: 0–13 years). The scans showed no consistently defining abnormalities despite the clinical presentation (Figure 2) with all patients having numerous typical T2 lesions and 11 having gadolinium enhancing lesions on at least one scan. Twelve of sixteen patients with spinal cord MRI available revealed at least one typical small, ovoid, T2 hyperintense lesion consistent with MS. Brain MRI demonstrated diffuse cerebral atrophy in 10 patients with accompanying cerebellar atrophy in 6 further patients.
CSF analysis was available in 20 of 23 patients and showed abnormalities consistent with MS in 19/20 (95%). Fourteen had elevated immunoglobulin G (IgG) index, 16 had elevated unique CSF oligoclonal bands and 11 had both abnormalities.
Eight patients received corticosteroids during their disease course (7-subacute, 2-chronic), and two patients with subacute severe cognitive attacks subsequently received plasmapheresis. Chronic immunomodulatory treatment was initiated in 13 patients (with some patients receiving more than one treatment): beta interferons 11, glatiramer acetate 4, and mitoxantrone 3. One patient with a subacute fulminant course and multiple cognitive exacerbations had improvement of cognitive impairment after initiation of mitoxantrone therapy (as documented by two neuropsychometric evaluations 5 years apart). There was no marked improvement in MS related dementia in the remaining patients despite therapy. Whether chronic immunomodulatory therapy prevented a more severe decline in cognition or other MS related neurological impairment could not be determined.
A 43-year-old man without prior history of neurological disease developed subacute memory impairment, aphasia, and apraxia over the course of two weeks. Gait and other neurological functions were normal. Brain MRI (Figure 2: A, B) showed T2 lesions consistent with MS, many of which enhanced following gadolinium administration. CSF revealed elevations in both immunoglobulin (Ig) G index and oligoclonal bands. Extensive serological evaluations for connective tissue diseases, vasculitis, paraneoplastic disease, and infectious etiologies were negative. Brain biopsy was performed at an outside institution given the atypical clinical course, and demonstrated active demyelination with relative axonal sparing. Acute treatment was initiated with intravenous corticosteroids and subsequent plasma exchange, with only mild and gradual improvement over six months. Despite treatment with interferon beta-1b he continued to have clinical relapses and two years later he was impaired with dementia and coexisting mild depression.
A 57-year-old woman was found wandering following the nursing home placement of her mother with whom the patient had been living. She had no history of acute neurological disease but had a long history of depression and cigarette smoking. She was cognitively impaired but entirely alert and had only minor imbalance on tandem walking on neurological examination. Head MRI demonstrated extensive T2 signal abnormalities within the hemispheric white matter and central pons with moderate diffuse cerebral atrophy without associated restricted diffusion or gadolinium enhancement (Figure 2: C,D). MRI spinal cord demonstrated two focal T2 hyperintensities within the cervical cord without enhancement consistent with MS and a normal thoracic cord. CSF showed elevated IgG index, twelve unique oligoclonal bands, and mildly elevated protein (68 mg/dL). Investigations for infection, metabolic disease and skin biopsy for CADASIL were negative. Formal neurocognitive testing was consistent with dysfunction typically seen in MS, including reduced speed of information processing, compromised complex attention, reduced nonverbal reasoning, complex learning efficiency and reduced novel problem-solving. Informed decision-making was so impaired that appointment of a guardian and placement in a nursing home was required.
The patients described here represent an uncommon MS clinical presentation characterized by severe cognitive impairment in the relative absence of significant co-existent MS- related impairment. These hallmark features are often accompanied by signs of cortical dysfunction (seizures, apraxia, aphasia) that are infrequent in prototypic MS patients. Patients may present with either subacute fulminant or insidiously progressive cognitive impairment, which corresponded to their subsequent MS clinical course of relapsing and progressive disease respectively. Over time, the majority of patients continue to have predominantly cognitive disability with little disability in other neurological spheres. Cognitive dysfunction (particularly when severe) is poorly represented by the EDSS, especially at higher levels of disability where ambulation is the primary determinant of score.
We confirmed prior findings of significant co-existent psychiatric symptoms (most commonly depression) in this cohort (7). An intriguing finding was the apparent high proportion of cigarette use in these patients, which in theory could represent a modifiable risk factor. Sixty-seven percent of our cohort had a history of smoking, 93% of which was active at the time of disease onset. These compare with the self-reported North American Research Committee on Multiple Sclerosis (NARCOMS) registry (n=8983 patients) rates of ever-smokers (54.2%) and current-smokers (17.3%) (11) and a study of Rhode Island MS patients where a current smoker rate of 15.2% was found (12). The smoking rate of the US population is approximately 19.8% (13). Additionally, cigarette smoking has been associated with both an increased risk of developing MS (14) and subsequent cerebral atrophy in MS patients (15).
Although subcortical MS pathology may produce cortical type symptoms (16), cortical MS lesions may also contribute to the clinical phenotype seen in our patients. Recent neuropathological studies have confirmed that cortical demyelination may be extensive in progressive MS (17) and does not correlate with white matter lesion burden (18, 19). Although conventional brain MRI techniques do not adequately identify MS lesions within the cortical ribbon, more recent novel techniques and sequences are being developed to enhance in vivo detection (20).
Limitations of this study include its retrospective nature. Follow-up was limited in some patients and investigations and therapies were inconsistently applied. Prospective evaluation of a similar cohort would be ideal in better defining the natural history, treatment response, and clinical outcome of this phenotype.
Our study illustrates the importance in considering multiple sclerosis as a cause of acute or progressive severe cognitive impairment even with relative sparing of other neurological deficits. Therapy appears challenging in these patients and functional evaluation by traditional outcome measures such as EDSS underestimate the severity of their functional impairment.