Neurology

Cerebellar disease

Cerebellar Structure and function

  • The cerebellum contains as many neurones as the entire cerebrum. Its primary role is the coordinating motor function with other parts of the brain.
  • It is composed of a core of white matter surrounded by grey matter.
  • Anatomically it is closely related to the IVth ventricle and contains 4 deep nuclei called the dentate, emboliform, globose and fastigial. (Easily memorable as the DEFG nuclei)
  • The cerebellum receives sensory input as well as input from the motor and premotor cortex and returns feedback to these same centres.
  • The cerebellar hemispheres receive input from the contralateral motor and premotor cortices by fibres which have decussated in the pons and enter the cerebellum via the middle cerebellar peduncle.
  • As such the cerebellar hemispheres deal with ipsilateral movement and function.
  • Histologically the important functional cell is the Purkinje cell which lies between the molecular and deep granular layer of cells. The purkinje cells communicate with the deep cerebellar nuclei.
  • The cerebellum is composed of a midline vermis and two lateral cerebellar hemispheres. It is composed of anterior and posterior lobes and flocculomodular lobe. The vermis is concerned with midline and truncal position and receives input from the spinal cord. Dysfunction is noted by postural instability and gait ataxia. Cerebellar hemispheres communicate via inferior, middle and superior cerebellar peduncles. The Inferior peduncle is mostly composed of afferent input. The large middle peduncle brings input from pontine nuclei. The superior peduncle carries efferent fibres to other centres.
  • Processing occurs in the cerebellar hemisphere and output is via the superior cerebellar peduncle which decussates in the midbrain and whose fibres pass to the motor nuclei of the thalamus and from there back to the motor and premotor cortex. As ever in neuroscience this is a simplification of what happens but clinically good enough for now.

Clinical Symptoms

Testing Cerebellar Function

  • Ask patient to touch their nose with index finger and then follow and touch your finger which should be almost at the distance away of their outstretched hand. Look for accuracy and overshooting and signs described below.
  • Listen to speech - ask them to say the usual 'West register street' and 'Baby hippopotamus' and they should have scanning monotonus speech
  • Examine eye movements looking for Nystagmus
  • Test for tone which may be decreased
  • Analyse gait and look for unsteadiness and ataxia

Clinical signs of the cerebellar disease

  • Truncal ataxia - unsteadiness on standing and falls to the affected side. There is a corresponding wide based stance. This is seen more so with midline cerebellar disease
  • Dyschonometria - abnormal rate of stopping and starting movements
  • Dysmetria - abnormal rate of amplitude of movements
  • Dyssynergia - abnormal combining of single movements
  • Dysdiadochokinesia - impaired ability to do fast alternating movements.
  • Nystagmus - fast component to the side of the lesion and worse on looking to side of lesion
  • Hypotonia - decreased muscle tone.
  • Scanning speech - long pauses between words and syllables.
  • An Intention tremor

Causes of Cerebellar Dysfunction

  • Vascular
    • Stroke: Easily the commonest with both ischaemic and haemorrhagic strokes causing acute onset of a cerebellar syndrome usually on one side (same side as stroke).
    • Global Hypoxic injury: Purkinje cells are fragile and susceptible to hypoxia which may be related to cardiorespiratory arrest or other brain insult. Other vulnerable areas include the cells of the hippocampus. MRI - atrophy Variable improvements with time
  • Demyelination
    • MS commonly affects cerebellum and its brainstem and other connections.
  • Drug Induced Cerebellar ataxia
    • Drugs: Phenytoin toxicity can lead to a more prolonged cerebellar syndrome, Others - 5 FU and cytosine arabinoside Cerebellar atrophy with prolonged phenytoin. Usually reversible on drug withdrawal
    • Alcoholic cerebellar degeneration: Direct toxin or nutritional. Males > females, Scanning speech and nystagmus unusual, Gait ataxia and postural instability more evident than the other cerebellar signs seen with more lateral cerebellar disease. There may also be an associated alcoholic neuropathy. There is more degeneration of midline vermis structures than cerebellar hemisphere
  • Tumours
    • Primary tumours: Medulloblastoma (below) and Cerebellar astrocytomas (pilocytic which are benign)
    • Ependymoma: seen in childhood usually at level of IVth ventricle
    • Haemangioblastomas: seen in those Von Hippel Lindau(AD) secrete EPO
    • Metastases: Lung breast, myeloma can spread to the cerebellum which should be differentiated from paraneoplastic cerebellar syndromes
    • Paraneoplastic: with small cell lung cancers but also breast and ovarian cancer. Positive antineuronal antibodies seen only in 50% and so absence does not exclude diagnosis. There is a loss of purkinje cells
  • Multiple system atrophy: Cerebellar also known as Oliviopontocerebellar atrophy. There is Neuronal loss in inferior olives, pontine nuclei and cerebellum. Oligodendrocyte glial intracytoplasmic inclusions (MSA) MRI - Atrophy of cerebellum, pons and middle cerebellar peduncle. Degeneration of Onuf's nucleus leads to abnormal denervation of anal sphincter assessed by EMG
  • Idiopathic: late onset cerebellar ataxia is common but a Diagnosis of exclusion
  • Hypothyroidism: Seen with some cases of hypothyroidism and usually responds to therapy - Ataxic cerebellar gait , Rx Thyroid replacement
  • Coeliac disease: May be cerebellar atrophy and loss of purkinje cells at post mortem - Progressive ataxia and myoclonus, Exclude nutritional deficiency
  • Selective Vitamin E deficiency: Seen with cystic fibrosis or cholestasis. A highly fat soluble vitamin and absence for whatever reason can cause a spinocerebellar ataxia, Clinically resembles Friedreich's ataxia with progressive symptoms and altered sensation, loss of reflexes, skeletal problems and cardiomyopathy. MRI may be needed to exclude differentials. Rx Vitamin supplementation
  • Post infectious
    • EBV, HIV
    • Chicken pox can cause an acute childhood cerebellar ataxia during the acute illness which usually is followed by a complete recovery
  • Inherited
    • Friedreich's ataxia (AR)
    • Ataxia telangiectasia (AR)
    • Abetalipoproteinaemia (AR)
    • Refsum's disease (AR)
    • Autosomal dominant Spinocerebellar ataxias

Investigations

  • CT scan may show a cerebellar haematoma but
  • MRI is best for stroke and demyelination and degeneration
  • Genetic studies if there is a family history suggestive
  • Drug levels - e.g. phenytoin
  • TFTs - hypothyroid Raised TSH Low T4
  • CXR - lung cancer
  • LFTS - alcohol
  • LP - Oligoclonal bands (MS)
  • Paraneoplastic - Tumour markers, Autoantibodies - Yo etc, Anti TTG
  • Coeliac disease - e.g. Anti-endomysial IgA, Anti transglutaminase IgA
  • Varicella Zoster titres if diagnosis uncertain in paediatric
  • Vitamin E levels

Von Hippel Lindau(VHL)

An autosomal dominant condition with multiple complications
  • Polycythaemia as secretes EPO
  • Renal cell carcinomas - renal mass and haematuria
  • Phaeochromocytomas - hypertensive crises
  • Liver/pancreatic cysts - abdominal pain
  • Cerebellar Haemangioblastomas which causes a cerebellar syndrome

Medulloblastoma

About
  • This is a a malignant primitive neuroectodermal tumour (PNET).
  • Posterior fossa tumours are seen more commonly in children especially the Medulloblastoma.
  • It is the commonest tumour in children.
  • It may spread through CNS and very rarely metastasise to bone.

Clinically

  • Hydrocephalus, cerebellar signs such as ataxia and nystagmus and falls.
  • There may be spread to spinal cord.
  • Disease is often midline so present with midline features of gait and truncal ataxia and nystagmus

Investigations

  • CT shows hyperdense lesions
  • MRI scan shows isointense on T2
  • CSF cytology may be needed for staging and can spread by CSF.
Management
  • Surgical excision, Radiation, Chemotherapy. Recurrence is possible

Paraneoplastic cerebellar degeneration

About
  • A cause of non metastatic cerebellar disease in those with small cell lung cancers. Also seen with breast and ovarian cancer. Autoimmune aetiology but positive antineuronal antibodies seen only in 50% and so absence does not exclude diagnosis. Histologically there is a loss of purkinje cells

Clinically

  •   Cerebellar syndrome may predate diagnosis of underlying malignancy e.g. Small cell lung cancer, Ovarian, Hodgkin's lymphoma

Investigations

  • MRI with gadolinium to exclude metastases and which can show mild cerebellar atrophy MRI seen late.
  • There may be raised CSF White cells.
  • Look for antibodies to Purkinje cells, Anti - Yo (Breast/Ovarian), Anti - Tr (Hodgkins disease), Anti - Hu (small cell)

Management

  • Treat the underlying tumour

Arnold Chiari Malformation

About
  • This occurs when there may be partial herniation of brainstem and cerebellar tonsils through the foramen magnum which can block CSF flow
  • It can cause pressure on the brainstem and is potentially life threatening.
  • It may be associated with development of a syrinx and development of clinical features of syringmyelia

Classification details worsening extent of herniation:

  • Chiari I - Herniation of cerebellar tonsils through foramen magnum
  • Chiari II - Herniation of cerebellar tonsils and vermis through the foramen magnum
  • Chiari III- Herniation of entire cerebellum

Clinical

  • Signs of obstructive hydrocephalus
  • Downbeat nystagmus
  • Cranial nerve palsies involving 9,10,12 or signs and symptoms of Syringomyelia

Investigations

  • MRI scan for diagnosis and classification.
Management
  • Usually conservative but in some cases surgery may be indicated usually decompression at the foramen magnum

Dandy Walker syndrome

This is a congenital anomaly where there is an absent cerebellar vermis, hypoplastic cerebellum, enlarged IVth ventricle, hydrocephalus, abnormal corpus callosum

Clinically Hydrocephalus may develop any time after birth

Investigations includes an MRI. It can be diagnosed by prenatal USS and MRI

Friedreich's ataxia

FA is one of the Spinocerebellar ataxias inherited as an autosomal recessive. Post mortem shows degeneration of the spinocerebellar tracts, the dorsal columns and the corticospinal tracts. There is a gene on Chromosome 9 codes which codes for a mitochondrial protein fraxatin. It is due to 200-900 GAA trinucleotide repeats which disturbs production of frataxin. There is no anticipation

Clinically there are progressive problems with walking. Ataxia comes on before puberty There are Pes cavus and scoliosis and progressive cerebellar disease - intention tremor, nystagmus, scanning speech, ataxia. The gait is progressively ataxic with pyramidal signs. There is Optic atrophy, Peripheral neuropathy, cardiomyopathy and fibrosis

Investigations show an abnormal ECG if cardiomyopathy. MRI brain and spine my show atrophy. Genetic analysis for frataxin. Management is supportive and palliative

Ataxia telangiectasia

This is an autosomal recessive inherited disease with many manifestations. There is progressive ataxia, an immunodeficiency and malignancy in children. Increased sensitivity to ionising radiation. It must be differentiated from Friedreich's ataxia.

There is defective DNA repair and thymic hypoplasia with increased risk of Malignancies - T cell leukaemia, ovarian, breast cancer, lymphomas, Hodgkin's disease. Autopsy shows loss of purkinje cells in the cerebellum

Clinical findings include Telangiectasia on Conjunctiva and nose and ears, nystagmus, progressive ataxia and cerebellar signs. There is a defect in cell mediate immunity and at risk of malignancy with Recurrent pulmonary infections

Investigations show a high alpha-fetoprotein 90%, reduced IgA and IgG and IgE. Genetics for ATM gene for serine protein kinase ATM on chromosome 9. Management is supportive with Death before the age of 30

Abetalipoproteinaemia

Autosomal recessive absence of apolipoproteinaemia B containing lipoproteins prevents incorporation of fat soluble vitamins such as A, E and K into chylomicrons.

Clinically starts in infancy with Diarrhoea and gait ataxia, nystagmus, loss of deep tendon reflexes and pigmentary retinal degeneration

Investigations show Low cholesterol, Low TGS, Absent LDLs, Blood film - acanthocytes. Genetic analysis for MTP gene for Microsomal triglyceride transfer protein. Management is replacement of Vitamin E and other fat soluble vitamins

Refsum's disease

Autosomal recessive inherited defect of the alpha-oxidation of phytanic acid resulting in a build up of phytanic acid and its unsaturated fatty acid derivatives in the plasma and tissues.

Clinically causes cerebellar ataxia, retinopathy, deafness, retinitis pigmentosa, ichthyosis, cardiomyopathy

Investigations show high CSF protein but normal cells. Management is a Phytanic acid-restricted diet

Autosomal dominant Spinocerebellar ataxias (SCA)

There is a collection of Autosomal Dominant inherited diseases with cerebellar and pyramidal signs with varying genetic bases. There is often a trinucleotide repeat e.g. CAG leading to an abnormal polyglutamine tracts in the protein. Autopsy shows olivopontocerebellar degeneration with a loss of neurones in inferior olives and pons.

Clinically there are varying types. Onset is typically in early to late adulthood. Family history. Ataxia, dysarthria and ophthalmoplegia. May be divided into those with and without retinal degeneration.Clinical classification.

  • Type 1 - cerebellar ataxia, dysarthria, ophthalmoplegia, bulbar signs, dysphagia, dementia, peripheral neuropathy
  • Type 2 - Cerebellar ataxia, pigmentary macular degenerations, other signs as in Type 1 25
  • Type 3 - Cerebellar ataxia + mild spasticity

Investigations include Genetic analysis, MRI - shows atrophy. Management is to exclude treatable disease and otherwise is supportive. Some forms lead to increasing disability, wheelchair dependence and death from eventual respiratory problems