1096

(33-34A) Sagittal T1WI in a 64y woman with visual agnosia, left cortical blindness shows striking atrophy of parietal , occipital lobes.

(33-34B) Axial FLAIR shows normal frontal lobes, atrophic left parietal , occipital lobes characteristic of posterior cortical atrophy.

CREUTZFELDT-JAKOB DISEASE

Pathology and Etiology

•Most common human transmissible spongiform encephalopathy

•CJD is a prion disease

○Proteinaceous particles without DNA, RNA

○Misfolded isoform PrP(Sc) of normal host PrP(C)

○Propagated by conformational conversion of PrP(C) to PrP(Sc)

•4 CJD types recognized

○Sporadic (sCJD) (85%)

○Genetic/familial (gCJD) (5-15%)

○Iatrogenic (iCJD) (2-5%)

○Variant ("mad cow" disease, vCJD) (< 1%)

Clinical Issues

•Peak age = 55-75 years

•Rapidly progressive dementia, death in sCJD within 4 months

Imaging

•T2/FLAIR hyperintensity

○Basal ganglia, thalami, cortex

○"Pulvinar" sign: posterior thalami

○"Hockey stick" sign: posteromedial thalami

○Occipital cortex in Heidenhain variant

•Restricted diffusion

Posterior Cortical Atrophy

Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by insidious onset and selective, gradual decline in visuospatial and visioperceptual skills with relative sparing of other cognitive domains such as memory and language.

Some investigators consider PCA an atypical ("visual variant") form of AD, whereas others define it a separate neurodegenerative syndrome. In contrast to AD, neuropathologic studies of PCA report that the highest density of neurofibrillary tangles and senile plaques is in the parietooccipital regions, while the frontal lobes are relatively less involved. Mixed, multiple (e.g., PCA-AD), or variant pathologies are common.

PCA typically presents in the mid-50s or early 60s and primarily affects the parietal, occipital, and occipitotemporal cortex with relative sparing of the frontal and inferomedial temporal lobes. Biparietal (dorsal), occipitotemporal (ventral), and primary visual (caudal) variants have been described within the PCA spectrum of disease.

Occipito-parietal or occipito-temporal atrophy on MR is typical (33-34) although not all patients with PCA demonstrate discernible volume loss. Asymmetric involvement is common. FDG PET/SPECT shows hypometabolism in the parietooccipital lobes and both frontal eye fields.

The major imaging differential diagnosis of PCA is the occipital (Heidenhain) variant of CJD. Although the clinical and histopathologic features of both diseases overlap, PCA demonstrates greater right parietal with less left medial temporal and hippocampal atrophy. Other clinical considerations include Alzheimer disease, dementia with Lewy bodies, and corticobasal degeneration.

Degenerative Disorders

(33-34C) Compared with age-matched control, the patient shows abnormal left parietal (green) and occipital lobes (red/orange, yellow).

In this section, we consider a range of brain degenerations. Although some (such as Parkinson disease, PD) can be associated with dementia, most are

not. Because PD occurs more often as a movement disorder than a dementing illness, it is discussed with other degenerative diseases.

The use of deep brain stimulators (DBSs) in treating patients with disabling akinetic-rigid PD is increasingly common, so a brief review of the dopaminergic striatonigral system and its relevant anatomy will be helpful before we discuss PD.

Basal Ganglia

The basal ganglia are part of the complex neuronal circuits that play a key role in the integration and execution of motor, cognitive, and emotional function. The subthalamic nucleus (STN) and globus pallidus interna (GPi)—both targets in DBS—are components of a large segregated corticalsubcortical network of white matter fibers.

Advanced diffusion imaging techniques enable detection of multiple fiber orientations in complex neuroanatomical regions that can be used to map white matter connectivity between the STN and the GP. As PD is increasingly being viewed as a circuit disorder, visualizing the inhibitory pallidosubthalamic fibers that project from the GP pars externa (GPe) to the STN and excitatory subthalamo-pallidal fibers that project from the STN to the GPi and the GPe may become clinically relevant in DBS placement.

Dopaminergic Striatonigral System

Dopaminergic neurons are found throughout the brain, but by far the largest collections lie in the midbrain. Here dopaminergic neurons are located in three specific areas: the ventral tegmental area (VTA), the pars compacta of the substantia nigra (SNPc), and the retrobulbar field. Neurons in the VTA project to the frontal cortex and ventral striatum, whereas SNPc neurons project to the putamen and caudate nuclei. Mesencephalic dopaminergic neurons help regulate voluntary movement and influence reward behavior.

Dopamine transporter (DaT) scans are used to differentiate essential tremor from the presynaptic dopaminergic degeneration in PD. Striatal loss of dopamine transporters occurs in the various parkinsonian syndromes and cannot be used to differentiate between PD and other disorders such as multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).

1097

(33-35) Graphic of midbrain depicts substantia nigra , red nuclei , pars compacta , and CN3 nuclei and tracts .

(33-36) 9-T MR shows subthalamic nuclei between red nuclei , substantia nigra . (Courtesy T. P. Naidich, MD, B. N. Delman, MD.)

Relevant Gross Anatomy

The striatonigral system consists of the basal ganglia (caudate nucleus, putamen, and globus pallidus), the substantia nigra (SN), and the subthalamic nucleus (STN). The gross and imaging anatomy of the basal ganglia is discussed in Chapter 32.

The SN lies in the midbrain tegmentum between the cerebral peduncles and red nuclei (RN). The SN consists of pigmented gray matter that extends through the midbrain from the pons to the subthalamic region. The SN has two parts: the pars compacta (which contains dopaminergic cells) and the pars reticularis (which contains GABAergic cells). The RN is a round gray matter formation that lies medial to the SN and serves as a relay station between the cerebellum, globus pallidus, and cortex (33-35).

The STN is a small lens-shaped structure that measures approximately 100125 mm³ in total volume. The SN envelopes the anterior and inferior borders of the STN (33-36). The STN lies just inside the internal capsule, 1-2 mm from the anterolateral edge of the RN.

The superior border of the STN is formed by the lenticular fasciculus while the lateral aspect of the STN abuts the internal capsule. The medial border of

(33-37) Axial 3-T T1WI in a normal patient shows approximate locations of GPe (green), GPi (red), and STN (orange).

(33-38) Axial diagram shows midbrain atrophy with narrowing and depigmentation of the substantia nigra (SN) in Parkinson disease (top) relative to normal anatomy (bottom, STN ). Note narrowing of pars compacta between red nuclei, SN.

the STN is formed by a band of subthalamic white matter—the zona incerta (ZI)—that lies between it and the RN

(33-38).

The STN is currently the preferred target for both direct (imaging-based) and indirect (atlas-based) stereotactic DBS electrode placement in the treatment of movement disorders. Recent studies have demonstrated that both STN volumes and neuron numbers decrease with age, which might influence the efficacy of DBS in a geriatric population.

Imaging Anatomy

On thin-section 1.5- or 3.0-T T2-weighted MR scans, the STNs are seen as hypointense almond-shaped structures that are obliquely oriented in all three standard planes. In the axial plane, the STN lies between the SN anterosuperiorly and the RN posteromedially. The hypointensity of the STN blends imperceptibly into that of the SN, but medially the white matter of the ZI separates the STN from the RN.

The midpoint of the STN lies between 9.7-9.9 mm lateral to the midline. Its position (and the correct location of the tip of a DBS) can thus be estimated on CT scans by finding the upper cerebral peduncles and measuring 9-10 mm from the midline.

Parkinson Disease

(33-39) Autopsied sections compare normal midbrain (L) to one affected by Parkinson disease (R). Note midbrain volume loss in PD, abnormal pallor of the substantia nigra . (Courtesy R.

Hewlett, MD.)

When PD is accompanied by dementia, it is referred to as

Parkinson disease dementia (PDD). When PD is combined with other clinical signs, it is called "Parkinson plus," an overarching term that includes multiple system atrophy and progressive supranuclear palsy (see below).

PD is classified clinically as a neurodegenerative disorder, histopathologically as a Lewy body disease, and immunohistochemically as a synucleinopathy.

Etiology

General Concepts. Although a number of environmental factors have been implicated, aging is the most significant known risk factor for PD.

In PD, degeneration of dopaminergic neurons in the SNPc reduces dopaminergic input to the striatum. Neuronal degeneration is relatively advanced histopathologically before it becomes apparent clinically. By the time clinical symptoms develop, over 60% of dopaminergic neurons are lost and 80% of striatal dopamine is already depleted.

The death of dopaminergic neurons in PD is regional and very selective with neuronal loss centered mainly in the SNPc. The precise mechanisms underlying the susceptibility of dopaminergic neurons and regional propensity for cell death in the SNPc are poorly understood.

Terminology

Parkinson disease (PD) is a multisystem neurodegenerative disorder that affects diverse neural pathways and several neurotransmitter circuits. The constellation of resting tremor, bradykinesia, and rigidity is often termed parkinsonism. PD accounts for approximately 75% of all cases of parkinsonism.

Genetics. The vast majority of PD cases are genetically complex. Nearly two decades ago, mutation in the α-synuclein locus was the first gene identified in PD. To date, genomewide association studies have identified 26 PD risk loci. Approximately 5-10% of patients have a monogenic form of PD, with autosomal-dominant mutations in SNCA, LRRK2, and VPS35 and autosomal-recessive mutations in PINK1, PARK7,

(33-40) Axial FLAIR (top) and T2* GRE (bottom) in a 61y man show mild midbrain volume loss with narrowed SNPc, especially on the right side , where it is difficult to delineate the border between the substantia nigra and red nucleus.

and Parkin, cause the disease to manifest with high penetrance. Between 10-20% cases of PD are familial, but most are sporadic.

Pathology

Gross Pathology. The midbrain may appear mildly atrophic with a splayed or "butterfly" configuration of the cerebral peduncles (33-38). Depigmentation of the substantia nigra is a common pathologic feature of PD and is related to loss of neuromelanin (33-39).

Microscopic Features. The most devastating effects of PD are seen in the dopaminergic striatonigral system. The two histopathologic hallmarks of PD are (1) severe depletion of dopaminergic neurons in the SNPc and (2) the presence of Lewy bodies (LBs) in the surviving neurons. Immunohistochemistry shows that the LBs stain positively for ubiquitin and α-synuclein.

Staging, Grading, and Classification. PD is divided into six (Braak) stages, which correlate clinical symptoms with the distribution of LBs. LBs begin to accumulate well before diagnosis. The disease process in the brainstem generally pursues an ascending course.

Stages 1 and 2 are preclinical. In stage 1, the LBs are confined to the medulla and the olfactory system. As the disease progresses, LBs spread into the upper brainstem and forebrain. At Braak stage 3, numerous LBs are present in the SN, loss of dopaminergic neurons is evident, the forebrain cholinergic system is involved, and the first clinical symptoms begin to emerge.

(33-41) DaT scan (top) shows normal uptake in caudate, putamen in an 83y man with tremor. The double "commashaped" configuration is a classic normal finding. (Bottom) Fused PET CT in the same case is negative for Parkinson disease.

In Braak stage 4, the limbic system becomes involved. In the most advanced stages (Braak stages 5 and 6), LBs are distributed throughout the entire neocortex.

Clinical Issues

Epidemiology and Demographics. PD is both the most common movement disorder and the most common of the Lewy body diseases. Its distribution is worldwide, and the estimated overall prevalence is 150-200:100,000. There is a slight male predominance.

Peak age at onset is 60 years; PD onset under 40 years is uncommon. Rarely, PD occurs as a juvenile-onset autosomaldominant dystonia.

Presentation. PD diagnosis depends on a constellation of symptoms. The three cardinal clinical features of PD are (1) resting tremor, (2) rigidity, and (3) bradykinesia (slowness in executing movements). An expressionless face, sometimes termed "masked" or "stone" face, is a common manifestation of bradykinesia.

Other classic symptoms are "pill-rolling" tremor, "cogwheel" or "lead pipe" rigidity, and postural instability with shuffling gait. Rigidity occurs in both agonist and antagonist muscles, affects movements in both directions, and can be elicited at very low speeds of passive movement.

Dementia eventually develops in 40% of PD patients. Other less common features of PD include autonomic dysfunction, behavioral abnormalities, depression, and sleep disturbances.

Natural History. PD typically follows a slowly progressive course with an overall mean duration of 13 years. Falls and "gait freezing" eventually become a major cause of disability.

(33-42A) DaT scan in a 78y man with clinical diagnosis of Parkinson disease shows normal uptake in the heads of both caudate nuclei , absence of uptake in the right putamen , and markedly reduced uptake in the left putamen .

Treatment Options

Medical Treatment. A number of medications are available to control PD symptoms. Levodopa was introduced more than 40 years ago and remains the most efficacious treatment, especially in young patients. As SNPc dopamine-secreting neurons are lost, striatal dopamine levels become increasingly dependent on peripherally administered levodopa. Motor complications of levodopa such as "wearing off," dyskinesias, and "on-off" phenomena are common.

Emerging disease-modifying therapies such as adenosine A2A antagonists, MAO-b inhibitors, and dopamine agonists are under consideration, as is gene therapy to enhance in vivo dopamine production.

Surgical Options. High-frequency stimulation of deep brain structures is now preferred to ablative/lesional therapy. Deep brain stimulation (DBS) has become the preferred technique for treating a gamut of advanced PD-related symptoms.

The STN is considered one of the most optimal DBS targets. Electrodes are inserted via burr holes 25-30 mm lateral to the sagittal sutures, 20-30 mm anterior to the coronal sutures, and angled approximately 60% from the horizontal plane of the anterior-posterior commissure line. Electrode positions are determined from preoperative MR or by using standard computerized atlases.

The distance of the STN from the midline varies somewhat from individual to individual. As the STN is often difficult to identify on standard MR, many neurosurgeons identify the red nucleus and position the DBSs slightly anterolateral to it. Recent studies indicate that some patients—those with a socalled dominant STN—may do as well with one DBS as with bilateral electrodes.

(33-42B) PET CT with fused DaT scan, NECT in the same case shows absence of uptake in the right putamen and greatly reduced uptake in the left consistent with the clinical diagnosis of Parkinson disease.

Imaging

CT Findings. CT is used primarily following DBS placement to evaluate electrode position (33-43) and to check for surgical complications. Correct positioning in the STN is seen when the tips of the electrodes are approximately 9 mm from the midline and located just inside the upper margin of the cerebral peduncles (33-43). Complications include ischemia (33-44). Transient inflammatory changes may develop around the electrodes (33-45). These typically appear within a few weeks and then gradually resolve.

MR Findings. Conventional MR alone is not sufficiently sensitive in diagnosing and differentiating neurodegenerative parkinsonian syndromes. Mild midbrain volume loss with a "butterfly" configuration can be seen at 1.5 T in some late- stage cases of PD. Findings that may support the diagnosis of PD include thinning of the pars compacta (with "touching" RNs and "smudging" of the SNs) and loss of normal SN hyperintensity on T1WI (33-40).

The STNs are difficult to identify on standard 1.5- and 3.0-T MR scans, as their hypointensity blends in with the hypointensity of the SN. At 7.0 T, the shapes and boundaries of the SN on susceptibility-weighted sequences, which normally appear smooth and arch-like, may become irregular ("serrated" or "lumpy-bumpy") and blurred in PD patients.

Nuclear Medicine. The most sensitive imaging techniques for an early diagnosis of parkinsonian syndromes are SPECT and PET. DaT-SPECT is used to assess integrity of presynaptic dopaminergic nerve cells in patients with movement disorders (33-41). Decreased uptake of I-123 FP-CIT is considered highly suggestive of PD (33-42), but is also seen in other parkinsonian degenerations.

Differential Diagnosis

DaT-SPECT imaging enables differentiation of neurodegenerative causes of parkinsonism from other movement or tremor disorders in which the study is typically normal.

When dementia is present, the major differential diagnosis of PDD is dementia with Lewy bodies. The clinical features overlap and are distinguished by whether parkinsonism precedes dementia by more than a year. If so, the diagnosis is PDD rather than LBD.

PARKINSON DISEASE

Etiology and Pathology

•Degeneration of dopaminergic neurons in SNPc

○Reduced dopaminergic input to striatum

○60% of SNPc neurons lost, 80% striatal dopamine depleted before clinical PD develops

•Substantia nigra (SN) becomes depigmented

•Pars compacta thins

•Lewy bodies develop

○PD is most common Lewy body disease

Clinical Issues

•Peak age = 60 years

•3 cardinal features

○Resting tremor

○Rigidity

○Bradykinesia

Treatment Options

•Medical

○Levodopa (L-dopa), other drugs

•Surgical

○Deep brain stimulation (DBS)

○Electrodes implanted into subthalamic nuclei

Imaging

•Difficult to diagnose on standard MR

○± Midbrain atrophy

○± Thinned, irregular SN

○± "Touching" SN, red nuclei

•Dopamine transporter (DaT) imaging

○PET or SPECT can show decreased uptake

Multiple System Atrophy

Terminology

Multiple system atrophy (MSA) is an adult-onset sporadic neurodegenerative disorder that is one of the more common Parkinsonplus syndromes. Parkinson-plus syndromes exhibit the classic dyskinetic features of PD plus additional deficits that are not present in simple idiopathic PD. Parkinson-plus syndromes include MSA, progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Each will be discussed in turn.

MSA includes three disorders that were previously regarded as separate entities: striatonigral degeneration, olivopontocerebellar atrophy, and ShyDrager syndrome. These disorders are all now recognized as clinical MSA subtypes.

1101

(33-43) Incorrect placement of left DBS (top) superomedial to STN is before repositioned left DBS, new right DBS (bottom) in correct position.

(33-44) NECT shows bilateral DBS placement with complication of midbrain, basal ganglia subacute infarction .

(33-45) NECT 4 wks after bilateral DBS shows leads surrounded by hypodensity . This is transient inflammatory reaction, not infection.

(33-46) Axial T1WI (top) and T2WI (bottom) show changes of MSA-P. Note large ventricles/sulci and thinned, atrophic putamina with an irregular lateral rim of hypoand hyperintensity .

MULTIPLE SYSTEM ATROPHY: TERMINOLOGY, PATHOLOGY, AND CLINICAL ISSUES

Terminology

•Parkinson-plus syndrome

•3 disorders now considered part of MSA

○Striatonigral degeneration

○Olivopontocerebellar atrophy

○Shy-Drager syndrome

Pathology

•MSA-P (parkinsonian)

○Substantia nigra depigmented

○Putamen atrophic, grayish discoloration

•MSA-C (cerebellar)

○"Flat" atrophic pons

○"Beaked" appearance

○Cerebellar peduncles/hemispheres atrophic

•Microscopic features

○Glial (not neuronal!) cytoplasmic inclusions

○Immunohistochemistry (+) for synuclein, ubiquitin

Clinical Issues

•Divided into subtypes by dominant symptoms

○Parkinsonian → MSA-P

○Cerebellar → MSA-C

○Autonomic → MSA-A

•Parkinsonian features in 85-90% of all MSA patients

•Mean onset = 58 years, duration = 5.8 years

MSA subtypes are identified by dominant symptomatology. When parkinsonian (i.e., extrapyramidal) symptoms predominate, the disease is designated MSA-P. If cerebellar symptoms such as ataxia predominate, the disorder is designated MSA-C. When signs of autonomic failure such as

(33-47) (Top) Axial T2WI in a 62y patient with MSA-P shows abnormal putaminal hypointensity . (Bottom) MIP SWI shows shrunken, hypointense putamina with irregular lateral margins. (Images reformatted from Imaging in Neurology.)

orthostatic hypotension, global anhidrosis, or urogenital dysfunction predominate, the condition is designated MSA-A.

Etiology and Pathology

The etiology of MSA is unknown.

Gross pathology shows two distinct atrophy patterns. MSA-P shows depigmentation and pallor of the substantia nigra. The putamen may be atrophic and show a grayish discoloration secondary to lipofuscin pigment accumulation. In MSA-C, marked volume loss in the cerebellum, pons, middle cerebellar peduncles (MCPs), and medulla gives the pons a "beaked" appearance (33-48). MSA-A may demonstrate a combination of these patterns.

Microscopically, MSA is characterized by glial cytoplasmic inclusions that are immunopositive for α-synuclein and ubiquitin.

Clinical Issues

Mean age of onset is 58 years; mean disease duration is 5.8 years.

Parkinson-like features are present in 85-90% of all MSA patients, regardless of subtype. Other symptoms such as dysautonomia, cerebellar ataxia, and pyramidal signs can occur in any combination. Nearly two-thirds of MSA cases are classified as parkinsonian type (MSA-P) and 32% as MSA-C. Some degree of symptomatic dysautonomia is present in almost all patients but is rarely the dominant feature. Less than 5% of MSA patients have MSA-A.

(33-48) MSA-C shows cerebellar atrophy, shrunken middle cerebellar peduncles, and small pons with "hot cross bun" sign. (Courtesy J. Townsend, MD.)

Imaging

General Features. Although there can be some overlap, the imaging findings for the two most common MSA subtypes (MSA-C and MSA-P) are somewhat different.

CT Findings. NECT scans in MSA-C show cerebellar atrophy with the hemispheres more severely affected than the vermis. A small flattened pons and an enlarged fourth ventricle are common associated findings. Cortical atrophy—especially involving the frontal and parietal lobes—may be present. Findings in MSA-P are less obvious; NECT may demonstrate shrunken putamina with flattened lateral margins.

MR Findings

MSA-P. In patients with MSA-P, the putamina appear small and hypointense on T2WI and often have a somewhat irregular high signal intensity rim along their lateral borders on 1.5-T scans ("hyperintense putaminal rim" sign) (33-46). This finding is nonspecific, as it can be seen in some cases of CBD as well as in over one-third of normal patients.

T2* (GRE, SWI) scans show significantly higher iron deposition in the putamen compared with both age-matched controls and patients with PD (33-47). DTI shows decreased FA in the pons and middle cerebellar peduncle.

MSA-C. T1 scans in MSA-C show a shrunken pons and medulla, symmetric cerebellar atrophy, small concave-appearing MCPs, and an enlarged fourth ventricle.

T2/FLAIR scans demonstrate a cruciform hyperintensity in the pons termed the "hot cross bun" sign (33-49). The "hot cross bun" sign results from selective loss of myelinated transverse pontocerebellar fibers and neurons in the pontine raphe.

(33-49) (L) T2WI and (R) FLAIR in MSA-C show severe pontine, cerebellar atrophy with distinct hyperintense "hot cross bun" sign .

DWI shows elevated ADC in the pons, middle cerebellar peduncles, cerebellar WM, and dentate nuclei.

DTI demonstrates decreased volume of fiber bundles and reduced FA in the degenerated transverse pontocerebellar fibers. Corticospinal tract involvement is often inapparent on standard T2WI but can be demonstrated clearly with DTI.

Nuclear Medicine. 123I-Ioflupane SPECT (DaT) scans are usually normal in MSA.

MULTIPLE SYSTEM ATROPHY: IMAGING AND DDx

Imaging

•MSA-P

○Small shrunken, hypointense putamina on T2/FLAIR

○± T2/FLAIR hyperintense lateral rim

○Increased putaminal iron deposition on T2*

•MSA-C

○Cerebellar atrophy

○Small, concave middle cerebellar peduncles

○Shrunken "beaked" pons, "hot cross bun" sign

○Reduced FA in transverse pontocerebellar, corticospinal tracts

•MSA-A

○No distinctive imaging findings

Differential Diagnosis

•Parkinson disease

•Atypical parkinsonian syndromes (progressive supranuclear palsy, corticobasal degeneration)

•Spinocerebellar ataxia

•Hypoglycemia (transient MCP hyperintensity)

The major differential diagnosis of MSA is Parkinson disease. Clinical findings often overlap. Imaging shows that the width of the middle cerebellar peduncles is diminished in MSA-C but not PD. Putaminal iron deposition appears earlier and is more prominent in MSA-P compared with PD. DTI also shows decreased FA in the middle cerebral peduncles in MSA-P.

Atypical parkinsonian syndromes (e.g., progressive supranuclear palsy and corticobasal degeneration) can also be difficult to distinguish clinically from MSA, but regional ADC values and MCP widths are normal.

Spinocerebellar ataxia can look identical to MSA-C, demonstrating atrophic, hyperintense middle cerebellar peduncles and a "hot cross bun" sign. Hypoglycemia can cause transient hyperintensity and acutely restricted diffusion in the MCPs and pyramidal tracts.

Progressive Supranuclear Palsy

Terminology

Progressive supranuclear palsy (PSP)—also known as Steele- Richardson-Olszewski syndrome—is a neurodegenerative disease characterized by supranuclear gaze palsy, postural instability, and mild dementia.

Etiology and Pathology

Unlike Lewy body disease, Parkinson disease (PD), and multiple system atrophy (MSA) (which are synucleinopathies), PSP is a tauopathy. When tau protein is fibrilized, it becomes less soluble, and its microtubule-stabilizing properties are reduced. PSP shares many clinical, pathologic, and genetic features with other tau-related diseases, such as corticobasal degeneration (CBD) and tau-positive frontotemporal lobar degeneration (FTLD).

The major gross pathologic findings are substantia nigra and locus ceruleus depigmentation with midbrain atrophy. Variable atrophy of the pallidum, thalamus, and subthalamic nucleus together with mild symmetric frontal volume loss may also be present (33-50) (33-51).

Pathologic heterogeneity is common in PSP. Histologic findings consistent with other coexisting neurodegenerative diseases, such as Alzheimer disease or diffuse Lewy body disease, are present in the majority of cases.

PSP is characterized histopathologically by neuronal loss and astrocytic gliosis. Tau-immunoreactive cellular inclusions accumulate within both neurons and glia (in "tufted" or starshaped astrocytes). The distribution of tau inclusions is predominantly subcortical with the globus pallidus, STN, substantia nigra, and brainstem most severely affected. Cortical involvement is common.

Epidemiology and Demographics. PSP is the second most common form of parkinsonism (after idiopathic PD) and is the most common of the so-called Parkinson-plus syndromes.

The prevalence of PSP is age dependent and estimated at 6- 10% that of PD.

Presentation and Natural History. PSP symptom onset is insidious, typically beginning in the sixth or seventh decade. Peak onset is 63 years, and no cases have been reported in patients under the age of 40.

Two PSP phenotypes are recognized: Richardson syndrome (PSP-RS) and parkinsonian-type PSP (PSP-P). PSP-RS is the classic, more common presentation with lurching gait, axial dystonia, and early ocular symptoms. Vertical supranuclear gaze palsy is the definitive diagnostic feature but typically develops years after disease onset.

One-third of patients exhibit the PSP-P phenotype. Parkinsonism dominates the early clinical picture with bradykinesia, rigidity, normal eye movements, and transient response to levodopa.

Although disease course is variable, PSP is a progressive neurodegenerative process. Neuropsychiatric symptoms develop in over half the patients within two years of disease onset. In 15-30% of cases, cognitive decline and behavioral changes are the presenting complaints and can remain the only clinical feature throughout the disease course.

Imaging

CT Findings. NECT scans show variable midbrain volume loss with prominent interpeduncular and ambient cisterns. Mild to moderate ventricular enlargement is common.

MR Findings. Sagittal T1and T2-weighted images show midbrain atrophy with a concave upper surface (the

"penguin" or "hummingbird" sign) (33-52). Volumetric calculations show that the sagittal midbrain is less than 70 mm³ and that the midbrain:pons ratio is less than 0.15, only half that of normal controls.

Axial scans show a widened interpeduncular angle and abnormal concavity of the midbrain tegmentum. However, PSP, CBD, MSA, and Lewy body disease may all exhibit increased cerebral peduncle angle.

In addition to a small midbrain, enlarged third ventricle, and prominent perimesencephalic cisterns, the quadrigeminal plate is often thinned. Cerebellar atrophy is common, and the superior cerebellar peduncles also frequently appear atrophic.

DTI indices (FA, mean diffusivity, etc.) demonstrate widespread WM abnormalities that are often mild or inapparent on T2/FLAIR. WM changes are more severe in PSPRS.

Nuclear Medicine. FDG PET shows glucose hypometabolism in the midbrain and along medial frontal regions. Dopamine transporter (DaT) radioligands show uniformly decreased dopamine nerve terminals in both the caudate nuclei and

putamen. Tau-PET accumulation is markedly distinct compared with that of amyloid burden in aging and Alzheimer disease.

Differential Diagnosis

The major differential diagnosis includes other tauopathies, such as CBD and some forms of FTLD. All share common molecular mechanisms and are therefore probably part of the same disease spectrum. Alzheimer disease, PD, and MSA-P usually do not exhibit severe atrophy of the superior colliculi that is seen with PSP.

PROGRESSIVE SUPRANUCLEAR PALSY

Etiology and Pathology

•Abnormal tau protein ("tauopathy")

•Substantia nigra depigmented

•Prominent midbrain atrophy

Clinical Issues

•Second most common cause of parkinsonism

•Insidious onset (sixth, seventh decades)

•Neuropsychiatric symptoms develop in 50%

Imaging

•Midbrain volume loss

○"Penguin" or "hummingbird" sign on sagittal T1WI

○Quadrigeminal plate thinned (especially superior colliculi)

○Adjacent cisterns increased

•Midbrain, medial frontal hypometabolism

Differential Diagnosis

•Other tauopathies

○Corticobasal degeneration

○Some forms of FTLD

•Alzheimer, PD, MSA-P

○No disproportionate atrophy of midbrain, superior colliculi

Corticobasal Degeneration

Terminology

Corticobasal degeneration (CBD) is an uncommon sporadic neurodegenerative and dementing disorder whose characterization continues to evolve. Once thought to represent a distinct clinicopathologic entity, CBD has multiple clinical phenotypes and different associated syndromes. The umbrella terms corticobasal syndrome (CBS) and CBS/CBD have been used to acknowledge the clinicopathologic heterogeneity of CBD.

Etiology

CBD, PSP, and the FTD-tau subset of frontotemporal dementia are all characterized by tau inclusions in neurons and glia. These tauopathies have overlapping mutations, largely through the MAPT clade.

Pathology

The most common gross features of CBD are asymmetric frontoparietal atrophy, especially in the motor and sensory areas. The temporal and occipital cortex are relatively spared. Striatonigral degeneration is seen with striking atrophy and discoloration of the substantia nigra. The putamen, pallidum, thalamus, and hypothalamus are affected to a lesser degree.

1105

(33-50) Sagittal graphic (L) and high-resolution T2WI (R) together show normal midbrain and pons.

(33-51) PSP with frontotemporal atrophy , depigmented SN , locus ceruleus , small superior cerebellar peduncles (R. Hewlett).

(33-52) PSP shows small midbrain with upper concavity and "penguin" or "hummingbird" sign, tectal atrophy , and concave midbrain .

(33-53) Axial T2WI in a 72y woman with corticobasal degeneration (CBD) shows the hyperintense putaminal rim characteristic of CBD. This finding can also be seen in some cases of MSA-P and in 35-40% of normal patients.

Microscopically, CBD is characterized by neuronal achromasia (pale ballooned neurons) and tau-positive cytoplasmic inclusions in astrocytes within the atrophic cortex.

Clinical Issues

CBD typically affects patients 50-70 years of age. Its onset is both insidious and progressive. CBD can be associated with a broad variety of motor, sensory, behavioral, and cognitive disturbances. Levodopa-resistant, asymmetric, akinetic-rigid parkinsonism and limb dystonia (usually affecting an arm) are classic findings. Rigidity is followed by bradykinesia, gait disorder, and tremor. "Alien limb phenomenon" occurs in 50% of cases.

Variable cortical features of CBD include cognitive decline with impaired language production (nonfluent aphasia) and symptoms such as visuospatial dysfunction that mimic posterior cortical atrophy. Learning and memory are relatively preserved.

Imaging

Conventional imaging studies show moderate but asymmetric frontoparietal atrophy, contralateral to the side that is more severely affected clinically. The dorsal prefrontal and perirolandic cortex, striatum (33-53), and midbrain tegmentum are the most severely involved regions. FLAIR scans may show patchy or confluent hyperintensity in the rolandic subcortical WM (33-54).

SPECT and PET demonstrate asymmetric frontoparietal and basal ganglia/thalamic hypometabolism. Studies using striatal dopamine transporter imaging are sometimes helpful in

(33-54) CBD is in a 66y woman with spastic left arm. The temporal and occipital lobes appear normal. Note asymmetric atrophy, thin cortex, and hyperintense WM in the right perirolandic region .

differentiating CBD from other neurodegenerative disorders such as Parkinson disease.

Differential Diagnosis

CBD is a member of the parkinsonian group of disorders. The clinical differential diagnosis of CBD therefore includes

Parkinson disease, progressive supranuclear palsy, and multiple system atrophy. In patients with cognitive dysfunction, symptoms can also mimic dementia with Lewy bodies or one of the frontotemporal lobar degeneration syndromes.

Amyotrophic Lateral Sclerosis

Terminology

Amyotrophic lateral sclerosis (ALS) is also known as motor neuron disease (ALS/MND) or Lou Gehrig disease.

Etiology

General Concepts. Upper motor neurons (UMNs) in the primary motor cortex send axons inferiorly along the corticospinal tract (CST) to pass through the brainstem, decussate at the cervicomedullary junction, and travel into the spinal cord. There, they synapse with anterior horn cells [lower motor neurons (LMNs)].

ALS is characterized by progressive degeneration of motor neurons in both the brain and spinal cord. Whether the degeneration is a neuronopathy (i.e., begins in the cell body and proceeds in an anterograde fashion) or an axonopathy with retrograde degeneration is unknown.

(33-55) Axial T2WI in a patient with ALS shows prominent hyperintensity along the course of the CSTs . Remember that the CSTs are typically slightly hyperintense on T2WI, especially at 3 T. (From Imaging in Neurology.)

As is the case with many other neurodegenerations, it is now recognized that ALS is a heterogeneous condition associated with more than one pathogenic mechanism and with different clinical manifestations and trajectories.

Genetics. Mutations in several genes appear to be associated with familial ALS: C9orf72, SOD1, TARDBP, and FUS.

Pathology

Gross Pathology. Evidence of widespread muscle atrophy affecting limb and intercostal muscles and the diaphragm is typical at autopsy. Macroscopically, the brain is generally unremarkable, but mild focal atrophy of the precentral gyrus can be seen in some cases.

Microscopic Features. The major histopathologic change in ALS is loss of motor neurons in the motor cortex, brainstem, and anterior horns of the spinal cord. Demyelination, axonal degeneration, and astrocytosis are typical features.

An RNA-mediated proteinopathy with mutated TARDBP and FUS occurs in both FTLD and ALS. Immunohistochemistry demonstrates the presence of TDP-43 ubiquitinated cytoplasmic inclusion bodies in motor neurons. Extramotor pathology is also commonly found in the frontal cortex and CA4 neurons of the hippocampus.

Clinical Issues

Epidemiology and Demographics. ALS has an incidence of 1- 2 per 100,000 per year and is the most common motor neuron disease, representing approximately 85% of all cases.

(33-56) SWI in a patient with ALS shows blooming hypointensity ("motor band sign") in both precentral gyri. DWI shows symmetric hyperintensities in the posterior limbs of the internal capsules, cerebral peduncles, and medulla.

ALS is mostly sporadic; 10-15% of cases are familial. The average age of onset in familial ALS is 10 years earlier than in sporadic ALS.

Presentation. Signs of both UMN and LMN disease are generally required for the clinical diagnosis of ALS. Evidence of UMN degeneration includes hypertonicity, hyperreflexia, and pathologic reflexes. LMN disease results in muscle fasciculations, atrophy, and weakness.

Although ALS shares the same genetic spectrum with FTLD, muscle weakness is its dominant feature, and dementia rarely—if ever—occurs. Disease onset is typically insidious, as at least 30% of anterior horn cells are lost before weakness becomes clinically apparent.

Natural History. Although median survival from diagnosis to death is between 3 and 4 years, 10% of patients survive beyond 10 years. Death is generally from respiratory failure due to diaphragm weakness.

ALS: PATHOLOGY AND CLINICAL ISSUES

Terminology and Etiology

•Lou Gehrig disease

•Progressive motor neuron atrophy in brain, spinal cord

Pathology

•Brain macroscopically normal

•Loss of motor neurons

Clinical Issues

•Sporadic > familial ALS

•Insidious onset

•Both upper and lower motor neuron symptoms

•Death from respiratory failure

(33-57) Autopsy specimen from a patient with chronic WaD following large left MCA infarct shows volume loss in the left cerebral peduncle and upper pons . (Courtesy R. Hewlett, MD.)

Imaging

MR Findings. Standard MR in many—perhaps even the majority of—ALS patients is normal. Macroscopic atrophy on T1WI is uncommon in ALS. Voxel-based morphometry may demonstrate subtle gray matter atrophy in the precentral gyri.

T2/FLAIR hyperintensity is unusual but can occur anywhere from the subcortical WM through the posterior limb of the internal capsule, cerebral peduncles, pons to the medullary pyramids, and spinal cord. Changes are usually most prominent in the posterior limbs of the internal capsules and cerebral peduncles (33-55). As the CST is normally slightly hyperintense, this finding lacks both sensitivity and specificity as an imaging "biomarker" for ALS.

T2* SWI may demonstrate hypointensity in the precentral cortex, the so-called "motor band sign" (33-56). DWI may show increased diffusivity and reduced FA in the CSTs.

Tractography may demonstrate subcortical truncation or pruning of the CST fibers.

Differential Diagnosis

The major differential diagnosis of ALS is the normal hyperintensity of compact, fully myelinated WM tracts. The CST is typically slightly hyperintense on T2 scans, especially at 3.0 T.

Another diagnostic consideration is primary lateral sclerosis (PLS). PLS is a juvenile-onset autosomal-recessive motor neuron disease that affects only upper motor neurons. Wallerian degeneration can cause T2/FLAIR hyperintensity along the CST but is unilateral.

(33-58) NECT (upper left) and a series of T2 scans demonstrate changes of chronic WaD following major territorial infarction. Note atrophy of the left cerebral peduncle, upper pons, and midbrain .

Other disorders that may demonstrate T2 hyperintensity along the CSTs include demyelinating and inflammatory diseases, metabolic disorders such as acute hypoglycemic coma, and infiltrating neoplasms (most commonly highgrade astrocytomas).

ALS: IMAGING AND DIFFERENTIAL DIAGNOSIS

Imaging

•T2/FLAIR often normal

○CST hyperintensity occurs but uncommon

○Posterior limb internal capsules (ICs), cerebral peduncles

•DTI shows reduced FA

○Tractography shows thinning of one or both subcortical CSTs

•T2* SWI

○"Motor band sign" (hypointensity in motor cortex)

Differential Diagnosis

•Most common: normal!

○CST normally slightly hyperintense

○Especially in posterior limb of IC, peduncles

•Less common

○Wallerian degeneration (unilateral)

○Primary lateral sclerosis

○Demyelinating disease

○Tumor infiltration

Wallerian Degeneration

Axonal degeneration can occur via several mechanisms, the most common being anterograde (or wallerian) and retrograde ("dying back") degeneration. In diseases such as multiple

(33-59) A patient with acute WaD was imaged 3 weeks following left hemisphere tumor resection. MR scans show CST hyperintensity without volume loss.

(33-60) DTI in a patient with chronic WaD after a right basal ganglionic-internal capsule infarct shows marked diminution in the right CST . (Courtesy N. Agarwal, MD.)

sclerosis, inflammation-associated axonal transport disturbances—so-called "focal axonal degeneration"—may precede axonal transection and the ensuing axonal selfdestruction by wallerian degeneration (WaD).

Terminology

WaD is an intrinsic anterograde degeneration of distal axons and their myelin sheaths caused by detachment from—or injury to—their proximal axons or cell bodies.

Etiology

In the brain, WaD most often occurs after trauma, infarction, demyelinating disease, or surgical resection. Descending WM tracts ipsilateral to the injured neurons degenerate—but not immediately. Axons may stay morphologically stable for the first 24-72 hours. The distal part of the axon then undergoes progressive fragmentation that proceeds directionally along the axon stump.

Most forms of acute axonal degeneration involve a stepwise "cascade" of events. After the initial insult, the myelin sheath first retracts from its axon at the nodes of Ranvier, followed by axonal degeneration. The myelin sheath itself then degenerates with breakdown of its protein components and degradation of the lipids. The final result is granular disintegration of the axonal cytoskeleton and volume loss in the affected WM tracts or nerves.

Pathology

Virtually any WM tract or nerve in the brain, spinal cord, or peripheral nervous system can exhibit changes of WaD. The caudally directed motor fiber pathways of the descending

corticospinal tract (CST) are the most common sites of visible brain involvement. Other affected locations include the corpus callosum, optic radiations, fornices, and cerebellar peduncles.

In chronic WaD, midbrain and pons volume loss ipsilateral to a destructive lesion (e.g., a large territorial infarct) are grossly visible (33-57). Microscopic findings include early changes of myelin disintegration and axon breakdown.

Clinical Issues

Imaging abnormalities in WaD (see below) seem to correlate with motor deficits and poor outcome.

Imaging

CT Findings. NECT scans are insensitive in the acute-subacute stages of WaD. Atrophy of the ipsilateral cerebral peduncle is the most common finding in chronic WaD (33-58).

MR Findings. The development of visible WaD following stroke, trauma, or surgery is unpredictable. Fewer than half of all patients with motor deficits following acute cerebral infarction demonstrate T2/FLAIR hyperintensities or diffusion restriction in the CST that might herald WaD (33-59).

When it does develop, T2/FLAIR hyperintensity along the CST ipsilateral to the damaged cortex may occur as early as 3 days after major stroke onset ("pre-wallerian degeneration") but more typically becomes visible between 3 and 4 weeks later. The hyperintensity may be transient or permanent.

Chronic changes of WaD include foci of frank encephalomalacia with volume loss of the ipsilateral peduncle, rostral pons, and medullary pyramid. Chronic WaD does not

enhance on T1 C+, but acute degeneration may show transient mild enhancement (33-61).

Transient restricted diffusion in the CST may develop in acute ischemic stroke within 48-72 hours. Recent studies show that restricted diffusion can occur beyond the CST. The most commonly reported area is the corpus callosum (primarily the splenium), which should not be mistaken for acute ischemia, as it most likely reflects the early phase of secondary neuronal degeneration.

Other WM tracts can undergo WaD with an insult to their neuronal cell bodies. These include the corticopontocerebellar tract, dentate-rubro-olivary pathway (Guillain-Mollaret triangle), posterior column of the spinal cord, limbic circuit, and optic pathway.

Microstructural changes in WM tracts are especially well demonstrated with DTI (33-60). Chronic hemispheric infarction shows decreased mean diffusivity (MD) and fractional anisotropy (FA) with absence of color in the CST

(33-61).

Differential Diagnosis

The major differential diagnosis of WaD is primary neurodegenerative disease. The T2/FLAIR hyperintensity sometimes seen in amyotrophic lateral sclerosis is bilateral and extends from the subcortical WM adjacent to the motor cortex into the brainstem. High-grade infiltrating primary brain tumors (typically anaplastic astrocytoma or glioblastoma multiforme) infiltrate along compact WM tracts but cause expansion, not atrophy.

Hypertrophic Olivary Degeneration

In order to understand the imaging findings in hypertrophic olivary degeneration (HOD), it is necessary first to understand the underlying anatomy of the medulla and the functional connections between the olives, red nuclei, and cerebellum.

Anatomy of the Medulla and Guillain-

Mollaret Triangle

Two prominent ventral bulges are present on the anterior surface of the medulla: the pyramids and olives. The pyramids are paired structures, separated in the midline by the ventral median fissure of the medulla. The pyramids contain the ipsilateral corticospinal tracts above their decussation.

The olives are a crenulated complex of gray nuclei that are lateral to the pyramids and separated from them by the ventrolateral (preolivary) sulcus (33-62).

The Guillain-Mollaret triangle consists of the ipsilateral inferior olivary nucleus (ION), contralateral dentate nucleus

(DN), and ipsilateral red nucleus (RN) together with their three connecting neural pathways, i.e., the olivocerebellar tract, dentatorubral tract, and central tegmental tract.

Olivocerebellar fibers from the ipsilateral ION cross the midline through the inferior cerebellar peduncle, connecting it with the contralateral DN and cerebellar cortex.

1111

Dentatorubral fibers then enter the superior cerebellar peduncle (brachium conjunctivum) and decussate in the midbrain to connect to the opposite RN. The ipsilateral central tegmental tract then descends from the RN to the ipsilateral ION, completing the Guillain-Mollaret triangle (33-63).

Terminology

HOD is a secondary degeneration of the ION caused by injury to the dentato-rubro-olivary pathway. Interruption of the dentato-rubro-olivary pathway at any point can cause HOD.

Etiology

Unlike other degenerations, in hypertrophic olivary degeneration, the degenerating structure (the olive) becomes hypertrophic rather than atrophic. Cerebellar symptoms and olivary hypertrophy typically develop many months after the inciting event. Understanding the clinical and pathologic underpinnings of HOD as well as its imaging manifestations will help avoid potential misinterpretation of this unusual lesion as an ischemic event, neoplasm, or focus of tumefactive demyelination.

HOD is a transsynaptic degeneration caused by lesions in the Guillain-Mollaret triangle. Lesions in the dentatorubral or central tegmental (rubro-olivary) tracts functionally deafferent the olive and cause HOD more often than lesions located in the olivocerebellar pathway.

The primary causative lesion in developing HOD is often hemorrhage, either from hypertension, surgery, vascular malformation, or trauma. Pontomesencephalic stroke also occasionally causes HOD. Postoperative pediatric cerebellar mutism (POPCMS) is a well-recognized complication that affects children undergoing posterior fossa brain tumor resection. Interruption of the dentato-thalamo-cortical pathway is recognized as its anatomic substrate. The proximal structures of the DTC pathway also form a segment of the Guillain-Mollaret triangle, so bilateral HOD is common in patients with POPCMS.

Some cases of mitochondrial disorders with POLG and SURF1 mutations have been described as causing HOD. Occasionally, no inciting lesion can be identified.

Pathology

Location. Three distinct patterns develop, all related to the location of the inciting lesion. In ipsilateral HOD, the primary lesion is limited to the central tegmental tract of the brainstem. In contralateral HOD, the primary lesion is located within the cerebellum (either the DN or the superior cerebellar peduncle). In bilateral HOD, the lesion involves both the central tegmental tract and the superior cerebellar peduncle.

Approximately 75% of HOD cases are unilateral and 25% bilateral.

Gross Pathology. Olivary hypertrophy is seen grossly as asymmetric enlargement of the anterior medulla. The contralateral RN often appears pale. In chronic HOD, the

(33-62) Axial graphic of the upper medulla shows the medullary pyramids on each side of the ventral median fissure. The olives lie just posterior to the preolivary sulci .

ipsilateral ION and contralateral cerebellar cortex may be shrunken and atrophic.

Microscopic Features. Interruption of the Guillain-Mollaret triangle functionally deafferents the olive. The result is vacuolar cytoplasmic degeneration, neuronal enlargement, and proliferation of gemistocytic astrocytes. The enlarged neurons and proliferating astrocytes cause the initial hypertrophy. Over time, the affected olive atrophies.

HYPERTROPHIC OLIVARY DEGENERATION

Etiology

•Interruption of Guillain-Mollaret triangle

•Usually secondary to midbrain lesion

•Also postoperative pediatric cerebellar mutism

Pathology

•Inferior olives hypertrophy

○Can be unior bilateral

○Ipsior contralateral to primary lesion

Clinical Issues

•Rare; can occur at any age

•Delayed onset

○Usually occurs 4-12 months after insult

•Palatal myoclonus, dentatorubral tumor

Clinical Issues

Epidemiology and Demographics. HOD is rare. It has been reported in patients of all ages, from young children to the elderly. There is no sex predilection.

(33-63) Coronal graphic depicts the Guillain-Mollaret triangle. The triangle is composed of the ipsilateral inferior olivary nucleus (green), the dentate nucleus (blue) of the contralateral cerebellum, and the ipsilateral red nucleus (red).

Presentation and Natural History. The classic clinical presentation of HOD is palatal myoclonus, typically developing 4-12 months following the brain insult.

Imaging

General Features. The development of HOD is a delayed process. Although changes can sometimes be detected within 3 or 4 weeks after the initial insult, maximum hypertrophy occurs between 5 and 15 months. The hypertrophy typically resolves in 1-3 years, and the ION eventually becomes atrophic.

CT Findings. Although NECT scans may demonstrate the primary inciting lesion (e.g., hemorrhage), the HOD is generally not depicted.

MR Findings. T1 scans are usually normal or show mild enlargement of the ION. T2/FLAIR hyperintensity without enlargement of the ION occurs in 4-6 months but may be detectable as early as 3 weeks after the initial insult. Between 6 months and several years later, the ION appears both hyperintense and hypertrophied (33-64) (33-65). Although the hypertrophy typically resolves and atrophy eventually ensues, the hyperintensity may persist indefinitely.

HOD does not enhance on T1 C+.

T2* SWI imaging may detect degeneration of the RN, seen as loss of the normal RN hypointensity; the signal should be similar to that of the substantia nigra.

Nuclear Medicine. PET shows increased metabolic activity in the early stages of HOD, whereas SPECT may demonstrate hyperperfusion.

HOD: IMAGING AND DIFFERENTIAL DIAGNOSIS

Imaging

•Maximum hypertrophy at 5-15 months

○Usually resolves in 1-3 years

○Then ION atrophies

•ION T2/FLAIR hyperintensity

•Does not enhance

Differential Diagnosis

•Common

○MS, neoplasm

○Perforating artery infarct

•Rare but important

○Metronidazole neurotoxicity

1113

Differential Diagnosis

Other lesions with T2/FLAIR hyperintensity in the anterior medulla include demyelinating disease, neoplasm, and perforating artery infarction. Metronidazole neurotoxicity exhibits bilateral, symmetric T2/FLAIR hyperintense lesions in the corpus callosum splenium and RN as well as the caudate, lentiform, olivary, and dentate nuclei.

Spinocerebellar Ataxias

Spinocerebellar ataxias (SCAs), also known as spinocerebellar atrophy/degeneration or inherited olivopontocerebellar atrophy, represent a clinically and genetically heterogeneous group of disorders. An ever-growing number of SCAs have been reported with more than 60 types identified to date.

Most SCAs are inherited and are progressive neurodegenerative disorders. SCAs are grouped into two

1114

subtypes by pattern of inheritance, autosomal-dominant and autosomal-recessive types.

Autosomal-Recessive SCAs

Friedreich ataxia is the most common autosomal-recessive SCA. Autosomal-recessive SCAs typically become symptomatic before the age of 20 years (33-66) (33-68). Extra-CNS involvement is frequent, and peripheral sensorimotor neuropathy is a common feature. Despite early onset, the clinical course is slowly progressive. Imaging typically shows a normal cerebellum with spinal cord and/or brainstem volume loss.

Autosomal-Dominant SCAs

The autosomal-dominant ataxias usually present at an older age with mean onset between the third and fourth decades of life. Gait disorders, abnormal eye movements, and macular

degeneration are common. The course is relentlessly progressive and usually fatal.

Imaging findings in the autosomal-dominant SCAs vary with type (33-67). Brainstem volume loss is generally more prominent than cerebellar atrophy, which often affects the vermis without involving the hemispheres. The pons is atrophic in SCA1, whereas the entire brainstem is small in SCA3. The cerebellum is atrophic in SCA6.

Cerebral Hemiatrophy (Dyke-

Davidoff-Masson)

Terminology and Etiology

Dyke-Davidoff-Masson syndrome (DDMS), also known as cerebral hemiatrophy, is typically caused by an in utero or early childhood cerebral insult, such as an infarct, trauma, or (less commonly) infection.

Lack of ipsilateral brain growth causes the calvaria and diploic space to thicken, whereas the paranasal sinuses and mastoids become enlarged and hyperaerated (33-69).

Clinical Issues

Patients typically present with contralateral hemiplegia or hemiparesis. Seizures, facial asymmetry, and mental retardation are common.

Imaging

General Features. The affected hemisphere demonstrates diffuse volume loss with encephalomalacia and gliosis. Leftsided hemiatrophy is more common (70%) than right-sided hemiatrophy.

CT Findings. NECT scans show an atrophic hemisphere with enlarged sulci and dilatation of the ipsilateral ventricle. The superior sagittal sinus and interhemispheric fissure are often displaced across the midline (33-70).

Bone CT shows variable degrees of calvarial thickening, elevation of the sphenoid wing and petrous temporal bone, and expanded sinuses and mastoids.

MR Findings. T1WI shows hemispheric volume loss with prominent sulci and cisterns. T2/FLAIR scans demonstrate encephalomalacia with shrunken hyperintense gyri and subcortical WM (33-71). The ipsilateral cerebral peduncle is usually small. Atrophy of the contralateral cerebellum is common, secondary to crossed cerebellar diaschisis.

DDMS neither enhances on T1 C+ nor demonstrates restricted diffusion.

Differential Diagnosis

The major differential diagnosis is Sturge-Weber syndrome (SWS). DDMS lacks the enhancing pial angioma, enlarged choroid plexus, and typical dystrophic cortical calcifications of SWS. Rasmussen encephalitis lacks the calvarial changes typical of DDMS and demonstrates more focal encephalomalacia, typically in the medial temporal lobe and around the sylvian fissure.

In hemimegalencephaly, the abnormal hemisphere is enlarged (not small as in DDMS) and has dysplastic-appearing features caused by hamartomatous overgrowth. Large territorial MCA infarcts that occur after the age of 2 or 3 years do not cause the calvarial changes that typify DDMS.

1115

CEREBRAL HEMIATROPHY

Terminology and Etiology

•Also known as Dyke-Davidoff-Masson syndrome

○Others = cerebral hemihypoplasia, unilateral cerebral hypoplasia

•Can be congenital (infantile) or acquired (early childhood)

•In utero, early childhood insult to developing brain

○Infarction (e.g., unilateral ICA or MCA occlusion, aortic coarctation)

○Less commonly, infection, perinatal insult

•Trauma (1st 2 years of life)

•One hemisphere fails to develop or involutes

○Calvarium thickens

○Falx/tentorium, superior sagittal sinus insert offmidline

Clinical Issues

•Contralateral hemiparesis

•With or without facial asymmetry

•Seizures, variable mental retardation

Imaging Findings

•Small, atrophic hemisphere

○Encephalomalacia, gliosis

○Ipsilateral ventricle, sulci enlarged

○Ipsilateral cerebral peduncle usually small

○Contralateral cerebellar hemisphere often atrophic

•Ipsilateral calvarial thickened

○Paranasal sinuses prominent

○Greater sphenoid wing elevated

○Petrous temporal bone often enlarged, overpneumatized

•Falx inserts off-midline

Differential Diagnosis

•Sturge-Weber syndrome

•Rasmussen encephalitis