Difficulty in walking is a common reason for referral to a neurologist. We present a patient with slowly progressive walking difficulties and white matter changes on MRI.
Walking difficulties are a common reason for referral to a neurological outpatient clinic. During the initial assessment it is important to consider whether such difficulties may be due to neurological disease and, if so, whether they reflect damage to the peripheral or the central nervous system.
The clinical examination will determine the subsequent investigations. The most common causes of walking difficulties are (in no particular order) cerebrovascular disease, neurodegenerative disease, inflammatory disease, degenerative processes in the spinal column and polyneuropathies.
The patient thus had late-onset (after 50 years of age) slowly progressive motor symptoms, with asymmetric upper motor neuron signs, most pronounced in the right leg. There was no indication of lower motor neuron involvement, either clinically or electrophysiologically (EMG/NCV).
There was initially discussion as to whether the symptoms could reflect a cortical infarct, possibly a low-grade tumour that was not detected on CT of the brain. A cortical infarct could explain the central nervous system signs, but not the gradual progression of symptoms. The patient smoked but had no further known risk factors for cerebrovascular disease.
The Doppler ultrasound was normal, and the possibility of a tumour or infarct was ruled out by MRI. However, MRI of the brain and spinal cord did reveal hyperintensities in the pons and medulla oblongata, as well as mild atrophy of the latter. Demyelinating inflammation of the type seen in multiple sclerosis was unlikely given the symmetrical elongated MRI signal changes in the brainstem and cerebellum. Multiple sclerosis seldom gives rise to symmetrical signal changes that extend specifically along defined neuroanatomical tracts.
Hyperintensities on T2-weighted MRI and medullary atrophy may occur in hereditary spastic paraplegia (HSP), a group of hereditary diseases marked by gradual degeneration of the pyramidal tract (1 , 2 ). Other conditions that can produce similar MRI changes are leukodystrophies and other leukoencephalopathies; that is, diseases that affect white matter (3 ).
The patient had definite progression of symptoms. As well as increased weakening of the right lower limb, there was new-onset functional impairment with increased muscle tone in the right arm. Clinical assessment was normal with the exception of the MRI, which was unchanged from before, and the AER, which showed a flattened response on the right side.
This was interpreted as evidence that the brainstem was affected, giving rise to a delayed auditory evoked response. Similar findings have been described in patients with leukodystrophy (4 ). The patient had upper motor neuron symptoms and it was concluded that she might have a form of motor neuron disease with slow progression.
The most common symptoms of hereditary spastic paraplegia are gait abnormalities due to spasticity and loss of power, along with corticospinal symptoms, such as hyperreflexia and an inverted plantar reflex. The spasticity is generally symmetrical, and bladder dysfunction is relatively common. Sensory impairments are rare, but loss of vibration sense can occur upon involvement of the dorsal column (2 ).
The patient was diagnosed with probable autosomal recessive hereditary spastic paraplegia on the basis of increasing spastic paresis of the right lower limb and loss of vibration sense in both lower limbs. However, there was no spastic bladder paralysis, impairments were unilateral and she tested negative for the most common mutations in hereditary spastic paraplegia, which argued against the diagnosis.
Figure 1 MRI of the patient’s brain at 70 years of age. T2-weighted images. Abnormalities are asymmetrical and most pronounced on the left, which is consistent with the patient’s right-dominant clinical signs. a) Coronal plane shows hyperintensities along the pyramidal tracts in the pons (white arrow). b) Axial plane shows hyperintensities in the medulla oblongata (black arrow)
After reassessment of the clinical signs, imaging data and results of previous investigations, it was concluded that the condition was reminiscent of late-onset Alexander’s disease.
This is a hereditary disorder caused by mutations in the GFAP gene (which encodes «glial fibrillary acidic protein»). It is characterised by progressive white matter changes and broad and variable neurological signs.
Discussion
Alexander’s disease is one of many leukodystrophies, that is, diseases that affect the white matter of the central nervous system. Leukodystrophies are characterised by defects in the synthesis and maintenance of myelin, the modified plasma membrane produced by oligodendrocytes (in the central nervous system) which protects and insulates the nerve fibres. Alexander’s disease generally presents at a young age, but juvenile and adult variants exist (6 , 7 ). The prevalence is unknown but fewer than 550 cases of the disease have been reported (7 ).
The disease is caused by a mutation in the gene that encodes GFAP, an intermediate filament protein found in mature astrocytes that is rapidly synthesised in response to injury and reactive astrogliosis. The mutations disrupt dimerisation of the GFAP protein, which leads to collapse of the cytoskeleton and abnormal protein aggregation (8 , 9 ).
Alexander’s disease can be familial or sporadic. The familial form is autosomal dominant, which means that the mutation is inherited from one parent and each child has a 50 % risk of the disease. The sporadic form is caused by a new-onset (de novo ) mutation, with no other cases in the family. Juvenile and infantile forms are assumed to result largely from spontaneous mutations, as patients often are unable to have children. The adult form can be the result of a sporadic mutation, but familial forms have also been reported (1 , 10 , 11 ).
Our patient had neither parents, children nor other relatives with the disease, and it is therefore reasonable to assume that she has the sporadic form due to a de novo mutation. Establishing this with certainty would entail showing that the patient’s parents do not possess the mutation, but this was impossible in our case unfortunately as they were no longer alive.
Patients with late-onset Alexander’s disease have a varied clinical profile, which may include brainstem dysfunction (dysphagia, dysphonia, dysarthria), pyramidal signs (spasticity, hyperreflexia, inverted plantar reflex), cerebellar symptoms (ataxia, nystagmus, dysmetria), autonomic dysfunction, sleep apnoea, gait abnormalities, hemiparesis/hemiplegia, possibly quadriparesis/quadriplegia, seizures and/or diplopia (7 ).
MRI characteristics vary with age of onset. Adults typically show marked atrophy of infratentorial structures, most commonly the medulla oblongata, but also other parts of the brainstem, cerebellum and cervical spinal cord (12 , 13 ). MRI signal changes can precede clinical symptoms (14 ). Alexander’s disease is diagnosed clinically and radiologically, while genetic testing can confirm the diagnosis. There is no active treatment but symptomatic treatment is important (7 ).
Our patient has been monitored by the neurology department for 20 years and has shown only slowly progressive motor symptoms in the form of spastic hemiparesis. Her initial clinical symptoms were non-specific and there were numerous differential diagnoses: neoplasia, inflammation/infection, neurodegenerative disorders such as motor neuron disease, and a large and heterogeneous group of hereditary diseases, including hereditary spastic paraplegia and leukodystrophies. MRI data were the deciding factor in this patient’s diagnosis. Bilateral elongated lesions that selectively affect specific tracts in the brainstem/spinal cord strongly suggest a hereditary, metabolic or degenerative disorder.
Hereditary leukodystrophies usually present in childhood and are generally diagnosed by neuropaediatricians. However, there are also several variants with adult onset. These patients can be difficult to diagnose as they often deviate from «textbook descriptions» and have atypical symptoms and signs. Other examples are adult-onset variants of metachromatic leukodystrophy, Krabbe’s disease and adrenoleukodystrophy. It is also important to consider these differential diagnoses in adult patients with white matter disease of unknown aetiology, in whom more common causes such as multiple sclerosis or chronic cerebral ischaemia have been excluded.
