Clinical Reasoning: A 34-year-old man with headache, diplopia, and hemiparesis

SECTION 1

A 34-year-old right-handed man awoke with lethargy, headache, diplopia, bilateral facial numbness, mild right hemiparesis, and right arm numbness. A few weeks prior, he had received vaccines for influenza and hepatitis. His history was significant for chronic sinusitis. Family history was negative for neurologic and autoimmune disease.

On examination, the patient was afebrile and normotensive. He exhibited left abducens and partial left oculomotor palsies. MRI of the brain showed an extensive area of fluid-attenuated inversion recovery (FLAIR) hyperintensity involving the brainstem bilaterally and a few smaller lesions in the left parietal lobe (figure 1). There was no enhancement or abnormal diffusion.

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Figure 1 MRI brain (January 2009)

Axial fluid-attenuated inversion recovery (FLAIR) MRI demonstrates an extensive area of hyperintensity involving the pons bilaterally (A); this also involved the left medulla and extended into the midbrain bilaterally. Additional FLAIR hyperintensities are noted in the subcortical white matter of the left and, to a lesser degree, right parietal lobes (B).

Lumbar puncture revealed normal leukocytes (3 × 10⁶/L), protein, and glucose. CSF oligoclonal bands were absent. Serum studies revealed normal erythrocyte sedimentation rate (ESR) (18 mm/h) and C-reactive protein. Markers of systemic inflammation were normal.

Diplopia resolved over 10 days without treatment. Other symptoms improved within 3 weeks. On follow-up 4 months later, the patient complained only of mild headaches and mild chest tightness, possibly reflecting sensory banding. Examination was normal apart from minimal difficulty with tandem gait.

SECTION 2

The patient presents with an acute polysymptomatic syndrome referable to the midbrain and pons. Though sudden onset would be consistent with a vascular etiology, the subsequent near-complete improvement over 3 weeks would argue against ischemia. Brainstem glioma or CNS lymphoma may present with similar clinical and imaging features, but not typically in such an acute fashion. Hemorrhage into a preexisting neoplasm frequently presents acutely, but hemoglobin breakdown products should be visible on MRI or in CSF. Posterior reversible encephalopathy syndrome may produce similar symptoms and imaging findings, but there was no hypertension and no other risk factors. Venous sinus thrombosis is an important clinical consideration, but the imaging is atypical.

Inflammatory etiologies to consider include multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, Sjögren disease, and neuromyelitis optica spectrum disorder (NMOSD). While multiple sclerosis commonly produces brainstem lesions, they are not usually so confluent. There was no history of oral or genital ulceration to support Behçet disease, which may occur with isolated neurologic manifestations.¹ There was no history of sicca to argue for Sjögren disease. While neurosarcoidosis may produce white matter changes, leptomeningeal disease is more common. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) may produce similar symptoms, but MRI typically reveals punctate enhancement peppering the pons² rather than the more confluent pattern seen in this case. Brainstem encephalitis may cause similar lesions on MRI, but these are typically associated with fever and systemic signs.

The clinical and imaging characteristics are in keeping with ADEM.³ Though unusual in adult patients, this is well-described following immunization or infection.⁴ While diagnostic criteria for ADEM in adults have not been validated, consensus criteria have been published for use in children⁵ (table); these require a polysymptomatic presentation due to presumed inflammatory or demyelinating disease with concurrent encephalopathy. Irritability, lethargy, or other personality changes represent mild encephalopathy.

Acute therapy for ADEM is supportive, though corticosteroids are frequently used. Disease-modifying therapies are not indicated, as patients who recover from the acute episode typically do not experience recurrent symptoms.

Back to the case.

The patient recovered fully over several months. Approximately 1 year after his initial presentation, he returned with subacute headache, confusion, aphasia, diplopia, and unsteady gait. On examination, he was afebrile and normotensive. He was drowsy but able to follow simple commands. There was expressive aphasia. Neurologic examination revealed right abducens palsy, right upper motor neuron facial weakness, and bilateral extensor plantar responses.

An MRI scan revealed extensive T2/FLAIR hyperintensities throughout the temporal white matter bilaterally, with lesser involvement of the frontal, parietal, and occipital lobes (figure 2) and midbrain. There was no significant enhancement following gadolinium contrast administration.

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Figure 2 MRI brain (December 2009)

Axial fluid-attenuated inversion recovery MRI reveals extensive white matter hyperintensities extending throughout the supratentorial white matter. The anterior temporal lobes are severely involved bilaterally (A), with patchy involvement of bilateral frontal, parietal, and occipital lobes (B). The midbrain is also involved, in a pattern similar to the previous study.

Lumbar puncture revealed pleocytosis (186 × 10⁶/L, initially neutrophil-predominant and later lymphocyte-predominant) with elevated protein (0.78 g/L) and normal glucose (3.0 mmol/L). CSF cultures and PCR were negative. Oligoclonal bands were again absent. CSF flow cytometry revealed a nonspecific, polyclonal population of lymphocytes and monocytes. Repeat investigations for systemic autoimmune disease were negative, including ESR, antinuclear antibodies, extractable nuclear antigen screen, rheumatoid factor, and antineutrophil cytoplasmic antibodies screen. Serum angiotensin-converting enzyme was normal and CT chest was negative for lymphadenopathy.

The patient's symptoms gradually improved with a course of high-dose IV methylprednisolone combined with plasma exchange. Oral prednisone was tapered over 5 months and he made a near-full recovery with a normal neurologic examination. Repeat MRI of the brain was also normal.

SECTION 3

The recurrence of acute, multifocal demyelination causing a polysymptomatic presentation with encephalopathy raises the possibility of multiphasic ADEM. Multiphasic ADEM is conceptualized as a self-limited, transient multiphasic demyelinating disease that does not lead to lifelong, chronic demyelinating disease.⁵ While this is recognized in a subset of pediatric patients with ADEM, many patients who recur subsequently develop a chronic demyelinating disorder.³ Diagnostic criteria for multiphasic ADEM have recently been revised; relapses beyond a second encephalopathic event are now considered suggestive of a chronic demyelinating disorder such as MS or NMOSD.⁶

The principal diagnostic consideration at this time is between multiphasic ADEM and MS. The fulminant nature of the 2 attacks, combined with full resolution, both clinically and radiologically, are more typical of multiphasic ADEM than MS. Significant CSF pleocytosis and absence of oligoclonal bands, present in 85%–95% of patients with MS, also argue against this diagnosis.

Returning to the case.

Disease-modifying therapy was not instituted and the patient was followed with frequent clinical and MRI examinations. He remained clinically and radiologically stable for 2 years before he developed several small, asymptomatic demyelinating lesions consistent with possible MS. He continued to develop additional asymptomatic lesions before a third acute presentation with nausea, vertigo, right facial numbness, right facial weakness, dysarthria, right hemiparesis, and right-sided limb ataxia. MRI revealed large demyelinating lesions involving the right middle cerebellar peduncle and left pons (figure 3) along with a small lesion in the left frontal lobe. Anti–aquaporin-4 channel antibody was not detected in serum.

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Figure 3 MRI brain (January 2014)

Axial fluid-attenuated inversion recovery MRI demonstrates a new large hyperintense lesion occupying the right middle cerebellar peduncle (A) with extension into the right superior cerebellar peduncle and right pontine tegmentum. A second lesion also involves the left pons (B) and cerebral peduncle.

At this point, a clinical diagnosis of MS was made. The development of asymptomatic demyelinating lesions is characteristic of MS and is not seen in ADEM. A third attack of demyelination would not be consistent with revised criteria for multiphasic ADEM.⁶ The patient was started on disease-modifying therapy for MS and has been free of relapse for over 1 year. He had normal results on neuropsychological testing.