Clinics in diagnostic imaging (191)

CASE PRESENTATION

A 49-year-old Chinese man with no significant past medical history was evaluated for a two-year history of progressive uncoordinated movements, dysphagia and urinary symptoms. According to his wife, he had given up badminton over a year ago and was increasingly unsteady on his feet. Faced with an extended leave of absence from work, he sought the attention of a neurologist. Clinical examination confirmed marked gait and limb ataxia as well as significant orthostatic hypotension and slightly garbled speech. What do the magnetic resonance (MR) images (Fig. 1) show?

Fig. 1

(a) Axial T2-W; (b) axial T2-W fluid-attenuated inversion recovery; and (c) sagittal T1-W multi-sequence, multi-planar MR images.

IMAGE INTERPRETATION

Axial T2-weighted (Fig. 1a) and T2-weighted fluid-attenuated inversion recovery (Fig. 1b) MR images at the level of the cerebellum demonstrate a cruciform pattern of hyperintensity within the pons, representing a hot cross bun sign. Enlargement of the fourth ventricle, with atrophy of the cerebellum and ventral flattening of the pons, is best demonstrated on the sagittal T1-weighted sequence (Fig. 1c).

DIAGNOSIS

Multiple system atrophy-cerebellar type (MSA-C).

CLINICAL COURSE

Once diagnosed, the patient was subsequently referred to occupational and physical therapy for outpatient neurorehabilitation. His clinical symptoms of neurogenic bladder, recurrent urinary tract infections and orthostatic hypotension were managed by the neurology department to provide symptomatic relief. The patient continued to deteriorate over the next seven years, eventually becoming bedbound and fully dependent on home care for activities of daily living. He eventually passed away from aspiration pneumonia.

DISCUSSION

MSA-C, also referred to as sporadic olivopontocerebellar atrophy, is a rare and unfortunately fatal neurodegenerative disease. According to Fanciulli and Wenning, the combined prevalence of both MSA-C and MSA-P (multiple system atrophy with Parkinson’s subtype) is only around 4.4 cases in 100,000.(1) The peak incidence typically occurs in the sixth decade of life, with no known gender predilection. There are no proven environmental risk factors for MSA-C, although exposure to pesticides, organic solvents and metal dust are classically thought to be associated with the disease.(1) The accumulation of alpha-synuclein glial cytoplasmic inclusions in the pons, cerebellum and inferior olives is thought to result in dysfunction of neurons and oligodendrocytes, which ultimately leads to cellular death.(2) The precise mechanism behind the increase in alpha-synuclein remains unknown, although mutations in several genetic loci, including the COQ2 and GBA genes, have been investigated.(3)

The disease typically manifests with prodromal autonomic symptoms, including urinary incontinence, sexual dysfunction and orthostatic hypotension; cerebellar symptoms typically occur later in the disease course. As the disease progresses, patients typically develop limb and gait ataxia, action tremor and abnormal posturing. Dysarthria, dysphagia and drooling generally characterise more advanced disease.(3) MSA-C may also be associated with sleep breathing disorders and rapid-eye movement sleep behavioural disorder. Ultimately, a definitive diagnosis of MSA requires histopathology and is often only obtained post-mortem. The diagnostic criteria for probable and possible MSA-C are shown in Table I. Supporting features may include additional clinical and radiological findings from the second consensus statement on the diagnosis of MSA by Gilman et al.(4) Nevertheless, even with consensus criteria, the clinical presentation of MSA-C (i.e. adult-onset ataxia with autonomic symptoms) can remain a diagnostic challenge, requiring consideration of toxic causes, vitamin deficiency, infectious states, immune-mediated pathology and other neurodegenerative disorders.(5) Clinical history to determine the chronicity of symptoms, family history, a full neurologic examination and autonomic function testing, including tilt-table testing, are essential. Laboratory investigations should be guided by history and physical findings, but may include testing for Vitamin B1, E or B12, alcohol levels, complete blood count, renal function, liver function tests, human immunodeficiency virus, venereal disease research laboratory or select autoantibodies depending on the clinical picture.

Table I

Diagnostic criteria for probable and possible multiple system atrophy-cerebellar type (MSA-C).(4)

Magnetic resonance (MR) imaging and, infrequently, positron emission tomography (PET) are the primary neuroimaging modalities when MSA-C is suspected. As expected for a disease affecting gait and limb ataxia, multi-sequence MR imaging typically reveals atrophy of the cerebellum, but may also involve selective atrophy of the ventral pons, putamen, middle cerebellar peduncles (MCPs) and inferior olives.(6) Most characteristic for this entity is a cruciform pattern of T2 hyperintensity within the pons (hot cross bun sign), which is seen in up to 96% of probable MSA-C cases (Fig. 2);(7) this radiologic pattern is the result of selective degeneration of the myelinated transverse pontocerebellar fibres and pontine neurons, with conservation of the craniocaudally oriented corticospinal tracts.(1,7) Increased signal on the apparent diffusion coefficient map within the MCPs, cerebellum, pons and putamen may also aid in the diagnosis of MSA-C.(8) Furthermore, PET imaging may also reveal fluorodeoxyglucose hypometabolism within the cerebellum and MCPs.(9)

Fig. 2

Multi-sequence multi-planar MR images from a 59-year-old man with chronic alcohol abuse. (a) Axial T2-W; (b) axial T1-W; and (c) sagittal T1-W images show atrophy of the cerebellum (white arrow) with relative sparing of the pons (black arrow). In contrast, the pons in an MSA-C patient is typically flattened. No hot cross bun sign is seen on the axial T2-W images in the pons.

The radiologic differential diagnosis of cerebellar atrophy is broad but typically includes more commonly encountered processes such as chronic alcohol ingestion and Dilantin-induced cerebellar atrophy (Fig. 3). These entities will not demonstrate a hot cross bun sign, preferentially result in cerebellar atrophy and typically do not result in pontine flattening.(10) Clinical history is often more helpful in making the diagnosis than imaging. When presented with MR findings suspicious for MSA-C (cruciform T2 hyperintensity of the pons and selective atrophy of the posterior fossa contents), the differential diagnosis is limited to a select few rare entities for which only a handful of cases have been reported in the literature. Spinocerebellar ataxia, in particular Subtypes 2, 3 and 6, can be radiologically indistinguishable from MSA-C.(11) In these instances, genetic testing can help differentiate this inherited neurodegenerative disease from MSA. Additionally, there have been rare case reports of hot cross bun signs occurring in variant Creutzfeldt-Jakob disease (vCJD) and vasculitis, although this is certainly not their typical radiologic presentation. vCJD classically presents with signal abnormality in the posterior thalamus, which is known as the hockey stick sign,(12) while vasculitis may present with supratentorial and infratentorial areas of ischaemia, infarction and vessel wall irregularity.(13) It is important to note that while neuroimaging findings may be highly suggestive of MSA-C, they are ultimately not essential, as the current diagnostic criteria of MSA-C are solely based on clinical findings. As such, neuroimaging may be used in instances of clinical diagnostic uncertainty.

Fig. 3

Multi-planar (a) axial; (b) axial bone window; and (c) coronal CT images in a patient with epilepsy and chronic Dilantin use. There is preferential atrophy of the cerebellum (black arrow in a & c) with relative sparing of the pons (white arrow) and supratentorial brain. Diffuse bone marrow expansion is also seen (white arrowhead), secondary to chronic Dilantin use.

Unfortunately, the prognosis for MSA-C is dismal and includes a slow and progressive period of decline over 5–10 years before death.(14) Interventions are directed at alleviating symptoms and improving quality of life, as there is no effective disease-modifying treatment for its progressive cerebellar ataxia. Medications such as fludrocortisone, oxybutynin and selective serotonin reuptake inhibitors may be used to address commonly encountered symptoms such as orthostatic hypotension, overactive bladder and concomitant depression, respectively.(15)