Motoneuron Disease with Coexistent Demyelinating Disease (Possible Multiple Sclerosis)
This 55 year old female presented with a clinical course dominated by progressive bulbar dysfunction with both lower and upper motoneuron features. Clinical, electromyographic, and muscle biopsy evidence suggested generalized motoneuron disease with lower motoneuron involvement of the head, arms, and legs. There was also evidence of upper motoneuron involvement on clinical examination of the head and arms, all the more striking in view of the patient's past history of difficult-to-elicit tendon reflexes. In addition to these findings, however, several features of this patient's case are highly atypical for a diagnosis of isolated motoneuron disease. The unexplained episode of leg stiffness and cramping beginning 11 years prior to the onset of the present illness, together with the findings of an unexplained reduction in visual acuity in the right eye, suggest the possibility of an additional CNS process. In addition, the mild evidence for cerebellar dysfunction on examination was felt by the clinical team to exceed any dysfunction attributable solely to weakness. The signal abnormalities on MRI, read as more typical for demyelination than ischemic changes, and the increased CSF immunoglobulin synthesis with oligoclonal banding, suggest a multifocal, immune-inflammatory or demyelinating process, possibly multiple sclerosis. (Note: if a second process producing upper motoneuron signs is being entertained as a diagnosis, it will be difficult to unequivocally attribute all of the upper motoneuron signs evident on examination to the motoneuron disease process).
Coexistence of motoneuron disease and suspected demyelinating lesions has a limited, but interesting, differential diagnosis. Radiation injury can produce MRI T2 signal changes suggestive of demyelination, focal lower motoneuron degeneration, and upper motoneuron signs below the level of the injury, but would not be consistent with the clinical history and presentation of this patient. Several hereditary syndromes have been described with combinations of late-onset paraparesis, optic atrophy, and amyotrophy, but none well fitting the apparently sporadic and rapidly progressive bulbar disease encountered in this patient. Prion diseases, including Creutzfeldt-Jakob disease, may present with amyotrophy and bulbar dysfunction (reviewed in Worrall et al., 2000), as well as oligoclonal bands on CSF studies, but anatomic findings typically reflect spongiform changes rather than demyelination. Furthermore, cases of prion-related amyotrophy have nearly always occurred in a clinical context suggesting prion disease (e.g., advancing dementia), which was not observed in this patient. Motoneuron disease and lesions suggesting CNS demyelination have been reported in HIV disease as well as HTLV-1 associated myelopathy; the role of opportunistic infections is not always clear in reports of the former. Lyme disease (neuroborreliosis) can be associated with a motoneuron disease phenotype as well as with CNS demyelinating lesions. This patient had not traveled to Lyme-endemic areas, and had no other history suggestive of exposure to Borrelia spp.; thus this possibility was considered unlikely. Syphilis has been reported in association with motoneuron disease in rare cases, perhaps by producing meningeal vasculopathy with ischemia of nerve exit zones; in one small series, penicillin treatment was reported to produce improvement in clinical features of syphilis-associated motoneuron disease (el Alaoui-Faris et al., 1990). Neurosyphilis has also been associated with intrathecal immunoglobulin synthesis and MRI T2 signal abnormalities which could be mistaken for a primary demyelinating disease. However, syphilis serologies did not suggest this diagnosis. Mycoplasma infection has been associated with CNS demyelination, bulbar syndromes, focal motoneuron disease of the upper extremities, and acute motor axonal neuropathy (e.g., Pellegrini et al., 1996). However, reported cases of postinfectious CNS involvement have typically occurred within weeks to months following a mycoplasma infection, rather than the decade elapsed since mycoplasma infection in this patient. Rare cases of paraneoplastic syndromes with associated motor neuron disease and CSF oligoclonal banding have been reported (e.g., Ferracci et al., 1999). However, this patient had no evidence of an associated malignancy on screening to explain her present illness, and the decade which elapsed since the occurrence of her earlier neurologic symptoms make it extremely unlikely that a paraneoplastic syndrome could provide a unifying diagnosis. Sjögren's syndrome may present as a multiple sclerosis-like syndrome (Alexander et al., 1986) and rarely as a motoneuron disease (Salachas et al., 1998), but this patient did not exhibit clinical features of keratoconjunctivitis, xerostomia, or parotid abnormalities typical of this disorder, and the patient's mildly positive ANA titer was not considered by the clinical team as sufficiently elevated to suggest a systemic rheumatic disease. Likewise, lupus erythematosus, which may produce CNS lesions with a demyelinating appearance, rarely occurs in association with motoneuron disease, and in any event is not suggested by this patient's history or findings. Multiple sclerosis may occasionally present with asymmetric atrophy of distal arm muscles, which together with upper motoneuron signs could raise the possibility of motoneuron disease early in the course (Fisher et al., 1983; Shefner et al., 1992), in describing a series of patients with multiple sclerosis and asymmetric hand muscle atrophy, speculated that demyelination in the region of the ventral root exit zone may produce collateral damage to axons, mimicking the clinical and electrical findings of focal motoneuron disease. However, this patient's rapidly progressive course of bulbar dysfunction with evidence of generalized lower motoneuron involvement would be difficult to explain solely by a diagnosis of multiple sclerosis. We have occasionally observed motoneuron disease complicated by concomitant cerebrovascular events (for which this patient did have risk factors), but the clinical course and patterns of radiographic involvement, together with evidence of ongoing CSF immunoglobulin production, argue against this possibility.
Holmes-Adie syndrome, or tonic pupil with generalized loss of tendon reflexes, may be associated in some cases with clinical signs of sensory or autonomic dysfunction. The pathology of this syndrome has been suggested to arise as a ganglionitis involving the ciliary body and dorsal root ganglia, accompanied by a relatively selective loss of central projections of Ia afferent fibers onto alpha-motoneurons. A single report of Adie's pupils appearing with rapidly evolving sensory neuropathy, upper motoneuron signs, and anterior horn cell degeneration, which developed shortly after the onset of sicca symptoms (probable Sjögren's syndrome), has been published (Katz et al., 1999). However, the course of symptoms in this patient's case is not suggestive of such a temporal association, and I am not aware of any evidence suggesting that Adie syndrome itself predisposes to the later development of motoneuron disease.
If the diagnosis of concomitant motoneuron disease and multiple sclerosis is correct, did this coincidence result from mere chance association, or might common factors underlie the occurrence of both diseases in this patient? Animal models indicate that both motoneuron disease and demyelinating disease can potentially result from the same inciting cause; some Theiler's murine encephalomyelitis virus variants (e.g., Lipton, 1975) as well as transgenic overexpression of the cytokine interleukin-3
In summary, this case illustrates the need for careful and thorough examination of patients presenting with neurologic dysfunction, with particular attention to features atypical for the initially suspected diagnosis. Electromyography is not performed routinely in the evaluation of suspected multiple sclerosis, and neither is lumbar puncture performed routinely at most centers in the evaluation of suspected motoneuron disease; thus careful clinical evaluation is absolutely necessary if concomitant disease is not to be overlooked. Over 80% of responders to this case, as of this writing, identified motoneuron disease or multiple sclerosis as likely diagnoses; however, only 12% of responders suggested the coexistence of both disorders.
This case also calls attention to the reality that even at the end of the millenium, both motoneuron disease (amyotrophic lateral sclerosis) and multiple sclerosis are clinically diagnosed as syndromes (identification of characteristic features, and exclusion of alternative causes), rather than by measuring biological markers unique to these diseases. Thus, without postmortem confirmation, diagnostic certainty for research purposes can generally be classified as no higher than "probable" whenever syndromes with potentially overlapping diagnostic criteria are believed to coexist in the same patient.
Shortly after her initial diagnostic evaluation, the patient was readmitted for percutaneous gastrostomy placement to manage her progressive dysphagia. She remains ambulatory with assistance, although her limb weakness has also progressed. Discussions regarding further management, including the possibility of empiric immunotherapy, are ongoing at this time.
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