Ataxic disorders

Patients with ataxia show an impairment of coordination in the absence of muscle weakness (Table 29.1). The cause of this relates to one or both of the following:

Table 29.1

Clinical features of ataxia

Core clinical features (variably present according to etiology)

Impaired balance: patients often show a swaying movement of the trunk while standing and have a wide-based stance with a wide-based, often staggering gait

Clumsy limb movements: movements lack proper timing with the trajectory and force being misjudged (dysmetria). On clinical testing there is inability to perform rapidly alternating pronation and supination of the hands (dysdiadochokinesis)There is also poor coordination on the heel–shin test

Tremor: characterized by worsening on movement (intention tremor) seen clinically in the finger–nose test as jerky over-shooting of the finger as it approaches the nose or examiners finger

Dysarthria: often described as scanning speech

Disturbance of eye movements: characterized by nystagmus and jerky pursuit movements on examination

Muscle hypotonia

Associated clinical features (only seen in some cases and may help in establishing a direction for diagnosis)

Impaired proprioception, painful distal neuropathy, pyramidal signs, macrocytic anemia – B12 deficiency

Weight loss, diarrhea, abdominal pain, arthritis – Whipple’s disease

Shooting limb pains, areflexia in the lower limbs, Argyll–Robertson pupils, optic atrophy – syphilis

Early onset, recurrent respiratory tract infections, cutaneous telangiectasia – ataxia telangiectasia

Early onset, sensory neuropathy, pyramidal tract involvement (extensor plantar response), diabetes mellitus, optic atrophy, cardiomyopathy – Friedreich’s ataxia

Pigmented retinal degeneration, parkinsonism, peripheral neuropathy, cognitive decline – hereditary autosomal dominant cerebellar ataxia

Late onset, tremor, cognitive impairment, high signal in the cerebellum on MRI (T2) – FXTAS

Late onset, parkinsonism, autonomic dysfunction – multiple system atrophy (MSA)

Time-course of progression can help with predicting a cause, as follows:

Acute onset of severe ataxia: typically associated with an acquired ataxia caused by a focal pathology (hemorrhage, neoplasm, infarct, demyelination). Drug- and toxin-related acquired ataxias are also possible causes. Less commonly, a patient can present in this manner with an episodic ataxia syndrome

Subacute ataxia becoming progressively worse over several days: typically linked to an acquired ataxia due to an infective, autoimmune, or inflammatory cause including demyelination. Mass lesions in the posterior fossa can also lead to a gradually progressive ataxia

Chronic ataxia with gradual progression over months to years: causes of acquired ataxia would usually have been investigated in such patients, especially toxic causes such as alcohol. Having excluded an acquired etiology, the most important causes to consider are inherited ataxias, metabolic causes, and neurodegenerative disease such as MSA-C or less commonly a prion disease. If all investigations do not establish a cause then a diagnosis of sporadic adult-onset ataxia of unknown etiology (SAOA) is appropriate

Disease of the cerebellum and/or afferent/efferent tracts leading to failure of cerebellar cortical function (cerebellar ataxia).

Disease of peripheral nerves, dorsal root ganglia or ascending tracts in the spinal cord leading to failure of proprioceptive inputs (sensory ataxia).

Patients with ataxia can be considered in three main groups classified according to etiology as follows:

Acquired ataxia: there are many secondary causes of cerebellar disease (i.e. toxic, nutritional, metabolic, inflammatory, infective, ischemic, and paraneoplastic; Table 29.2) and the pathology of these conditions is dealt with in the relevant chapters elsewhere in this book.

Table 29.2

Classification of ataxic disorders

Acquired ataxias

Creutzfeldt–Jakob disease (Chapter 32)

Mass lesion (tumor or abscess)

Toxins and drugs

Ethanol

Anti-epileptic drugs

Lithium

Antibiotics (isoniazid, metronidazole)

Heavy metals (lead, mercury)

Autoimmune disease

Celiac disease

Paraneoplastic syndromes (anti-Hu, anti-Ma, anti-mGluR1, anti-Tr, anti-Rim anti Yo antibodies)

Anti-GQ1b antibodies (Miller Fisher syndrome)

Infections (Whipple’s disease, Epstein–Barr virus, Varicella–Zoster virus, syphilis)

Superficial siderosis

Vitamin deficiency (B12, B1, E)

Thyroid disease

Hereditary ataxias

Autosomal dominant

Spinocerebellar ataxias (SCA1–36)

Dentatorubropallidoluysial atrophy (DRPLA)

Episodic ataxias (linked to mutation in an ion channel)

Familial British dementia and Familial Danish dementia

Autosomal recessive

Friedreich ataxia

Ataxia with selective vitamin E deficiency

Mitochondrial recessive ataxia syndrome (POLG)

DNA repair syndromes (ataxia telangiectasia, xeroderma pigmentosum)

Spinocerebellar ataxia, autosomal recessive) (SCAR 1–10)

Inherited metabolic diseases and congenital disorders

X-linked

Fragile X-associated tremor/ataxia syndrome (FXTAS)

Congenital disorders

Usually recessively inherited pediatric diseases with cerebellar aplasia

Mitochondrial

MERFF, MELAS, NARP

Non-hereditary degenerative ataxias

Multiple system atrophy (MSA-C)

Sporadic adult-onset ataxia of unknown etiology (SAOA)

Hereditary ataxia: conditions with a range of inheritance patterns (Table 29.2).

Non-hereditary neurodegenerative ataxia: degenerative conditions in which a genetic or acquired cause if not evident on investigation (Table 29.2).

This chapter will consider the hereditary and non-hereditary neurodegenerative ataxias. Rapid advances in the characterization of genetic causes in the inherited forms of disease usually allow for testing of patients in life and the establishment of a diagnosis. Those patients with a chronic ataxia in which a genetic or acquired cause cannot be found are classed as having sporadic adult-onset ataxia of unknown etiology (SAOA).

NEUROPATHOLOGICAL CHANGES IN DEGENERATIVE CAUSES OF ATAXIA

While there is significant pathological heterogeneity in the degenerative cerebellar ataxias, some common patterns of pathology are seen. Different causes of degenerative ataxia are associated with specific patterns of disease but there are significant overlaps. No pattern of disease pathology can reliably predict the cause of the ataxia.

Loss of neurons from the cerebellar cortex with associated tract degeneration (cerebellar cortical degeneration) (Fig. 29.1).

29.1 Cerebellar cortical degeneration.
(a) Lateral view of the brain from a patient with pathology of a cerebellar cortical degeneration. Note the marked atrophy of the cerebellum in relation to the size of the cerebrum. (b) Slices through the cerebellar hemispheres and vermis of a control brain (top) and a patient with cerebellar cortical degeneration (bottom). Note the reduction in the volume of cortical gray matter and the widening of the cerebellar sulci in the patient’s cerebellum. (c) Patchy loss of Purkinje cells. (d) Severe diffuse loss of Purkinje cells. There is also marked depletion of granule cells and proliferation of Bergmann astrocytes. (e) The Purkinje cell axonal swellings are readily demonstrable by silver impregnation. (f) Note the ‘empty basket’ to the right of the axonal swelling. (g) Several adjacent ‘empty baskets’ in cerebellar cortical degeneration. (h) The degeneration of Purkinje cells is associated with proliferation of Bergmann astrocytes, at the junction of the granular and molecular layers. Note also the moderate loss of myelinated fibers from the white matter. (i) Bergmann astrocytosis accompanied by isomorphic gliosis of the molecular layer.

Loss of neurons from the cerebellar cortex with associated tract degeneration associated with atrophy and neuronal loss from the inferior olivary nuclei (cerebello-olivary degeneration).

Loss of neurons from the cerebellar cortex, pontine nuclei and inferior olivary nuclei (olivopontocerebellar degeneration) (Fig. 29.2).

29.2 Brain stem in olivopontocerebellar atrophy. The genetic subtype was not determined in this case.
(a,b) This case shows degeneration of the pontine nuclei and transverse pontine fibers. (c) There is moderate depletion of neurons from the inferior olives, and loss of the corresponding afferent and efferent fibers from the amiculum (AO) and hilus (HO), which appear abnormally pale. The hilus of the dentate nucleus (HD) and the superior cerebellar peduncle (SCP) are relatively well preserved.

Loss of myelinated axons from cerebellar afferent projections seen in the cerebellar peduncle, including loss of myelinated axons in tracts in the spinal cord (spinocerebellar degeneration)(Fig. 29.3).

29.3 Friedreich’s ataxia.
(a) There is degeneration of the gracile funiculi and spinocerebellar tracts in the upper cervical cord. As is often the case, at this level the pyramidal tracts are relatively spared. (b) Degeneration of the gracile funiculi. (c) Dense clusters of satellite cells (nodules of Nageotte) mark the sites where dorsal ganglion cells have degenerated. Satellite cells have proliferated to a varying extent around several of the remaining ganglion cells. (d) Marked loss of nerve fibers from a posterior lumbar nerve root.

± Loss of neurons from cerebellar dentate nuclei, cranial nerve nuclei, basal ganglia, substantia nigra, or red nucleus.

± Peripheral neuropathy.

± Systems pathology, e.g. retina, cardiac, skeletal muscle.

CEREBELLAR CORTICAL DEGENERATION

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Cerebellar cortical degeneration is characterized macroscopically by atrophy of the cerebellar folia with widening of the intervening sulci and reduction in the amount of white matter (Fig. 29.1). The histologic changes are non-specific and can be seen in diverse diseases that are clinically, metabolically, or genetically distinct. The Purkinje cells are reduced in number and may be absent from large lengths of cortex (Fig. 29.1c,d). There may also be a loss of granule cells, which is sometimes marked (Fig. 29.1d). Surviving Purkinje cells often show axonal swellings (‘torpedoes’). These are visible in the cerebellar granular layer as eosinophilic spheroids, but are better demonstrated by silver impregnation (Fig. 29.1e,f) or immunohistochemistry for neurofilament proteins. At the sites of loss of Purkinje cells, the persisting basket cell fibers form ‘empty baskets’ that can be demonstrated by silver impregnation (Fig. 29.1f,g). With loss of Purkinje cells there is proliferation of Bergmann astrocytes at the junction of the granular and molecular layers (Fig. 29.1 h). Bergmann astrocytes extend processes towards the pial surface in a regular radial pattern termed ‘isomorphic gliosis’ (Fig. 29.1i). Degeneration of Purkinje cells causes some loss of myelinated fibers from the cerebellar folia. In some conditions caused by triplet-repeat expansion within a gene, inclusion bodies can be detected in neuronal nuclei by use of appropriate immunohistochemical techniques, for example with antibody to ubiquitin or P62.