REVIEW
Treatable Causes of Cerebellar Ataxia Biller, MD, FACP, FAAN, FANA, FAHA2 Adolfo Ramirez-Zamora, MD,1* Warren Zeigler, MD,1 Neeja Desai, MD,1 and Jose 1 Albany Medical Center, MC- 70 Department of Neurology, Albany, New York, USA Loyola University Chicago, Stritch School of Medicine, Department of Neurology, Maguire Center, Maywood, Illinois, USA
2
ABSTRACT:
The cerebellar ataxia syndromes are a heterogeneous group of disorders clinically characterized by the presence of cerebellar dysfunction. Initial assessment of patients with progressive cerebellar ataxia is complex because of an extensive list of potential diagnoses. A detailed history and comprehensive examination are required for an accurate diagnosis and hierarchical diagnostic investigations. Although no cure exists for most of these conditions, a small group of metabolic, hereditary, inflammatory, and immunemediated etiologies of cerebellar ataxia are amenable to
Initial evaluation of patients with progressive cerebellar ataxia is challenging because numerous acquired, hereditary, paraneoplastic, toxic, and neurodegenerative conditions need to be considered in the differential diagnosis. Sporadic cerebellar ataxias represent the most common forms of new-onset cerebellar ataxia in adulthood.1 In spite of considerable advances in gene discovery and our understanding of the pathophysiology of cerebellar ataxia, management remains supportive and symptomatic. However, a limited group of heterogeneous progressive ataxic conditions may improve with disease-specific treatments if instituted early. Initial evaluation requires a complete assessment of the patient’s neurological and non-neurological features. Currently, more than 60 distinct neurogenetic
------------------------------------------------------------
*Correspondence to: Adolfo Ramirez-Zamora, MD, MC- 70 Department of Neurology, 47 New Scotland Avenue, Albany, NY 12208, E-mail: [email protected] Funding agencies:
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 17 July 2014; Revised: 9 December 2014; Accepted: 29 December 2014 Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26158
disease-modifying, targeted therapies. Over the past years, disease-specific treatments have emerged. Thus, clinicians must become familiar with these disorders because maximal therapeutic benefit is only possible when done early. In this article, we review disorders in which cerebellar ataxia is a prominent clinical feature requiring targeted treatments along with specific manC 2015 International Parkinagement recommendations. V son and Movement Disorder Society
K e y W o r d s : ataxia; treatment; cerebellar syndrome
conditions are known to cause primary cerebellar ataxia, and a multitude of genetic/metabolic conditions include cerebellar ataxia as a prominent clinical feature. A comprehensive assessment is critical in elucidating important clinical keys, including rate of onset/progression, family history, specific diagnostic signs, and brain magnetic resonance imaging (MRI) abnormalities. The presence of associated neurological features can be useful for differentiating ataxic etiologies and dictating additional investigations (Table 1). The initial diagnostic evaluation of an ataxic patient should include an in-depth assessment for potential acquired causes, with hierarchical selection of laboratory testing with focus on conditions amenable to treatment. If a detailed screening for acquired causes is unrevealing, the diagnostic evaluation can then be directed toward hereditary or genetic etiologies (Tables 2, 3). In this review, we focus on disorders in which ataxia is a prominent clinical sign amenable to disease-specific treatment, whereas traditional metabolic encephalopathies and endocrine and genetic disorders in which ataxia is part of a more complex syndrome are not discussed. Chronic cerebellar injury secondary to alcohol, or other commonly used drugs, is treated with removal of the offending drugs. The most relevant drugs associated with ataxia are lithium,2 phenytoin,3 amiodarone,4 toluene,4 5-fluorouracil, and cytosine arabinoside,5 as
Movement Disorders, Vol. 00, No. 00, 2015
1
R A M I R E Z - Z A M O R A
E T
A L
TABLE 1. Helpful diagnostic signs and disease-specific considerations in patients with cerebellar ataxia Sign
Condition
Myelopathy with ataxia Vertical supranuclear palsy Xanthomas Severe autonomic dysfunction Early cognitive impairment Dysphonia, palatal myoclonus, and dentate calcification Visual loss Oculomotor apraxia Seizures and ataxia Retinitis pigmentosa Chorea/dystonia Parkinsonism Tremor Sensory neuronopathy Sensorimotor polyneuropathy
Alexander’s disease, ARSACS, adult-onset Friedreich’s ataxia, SCA 3 NPC CTX MSA CJD; anti-GAD syndrome; POLG mutations, Ataxic variant of SREAT, SCA 17 SCA 20 AVED, SCA 7, mitochondrial disease AOA1, AOA2, Whipple’s disease, AT SCA 10, CoQ10 deficiency AVED, vitamin E deficiency, Refsum’s disease, SCA 3, SCA 17, DRPLA, HD, AT, NPC, GLUT-1 deficiency SCA 3, SCA 2, MSA FTAX, Wilson’s disease, SCA 12 FRDA (brisk jaw reflex), SCA 2, AOA1, AVED Late-onset Tay–Sachs disease (axonal), CTX (axonal, demyelinating, or mixed) AT (axonal), AOA2 (axonal), ARSACS (axonal or demyelinating), Refsum’s disease (demyelinating) POLG mutations (demyelinating), SCA 1, SCA 2, SCA 3, SCA 4, SCA8, SCA12, SCA18, SCA 23, SCA 25 (all axonal)
Abbreviations: ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; FRDA, Friedreich’s ataxia; NPC, Niemann-Pick disease type C; CTX, cerebrotendinous xanthomatosis; MSA, system atrophy; CJD, Creutzfeldt-Jakob disease; GAD, glutamic acid decarboxylase ataxia; POLG, DNA polymerase gamma; SREAT, steroid-responsive encephalopathy associated with autoimmune thyroiditis; SCA, spinocerebellar ataxia; AVED, ataxia with vitamin E deficiency; CoQ10, coenzyme Q 10; AOA, ataxia with oculomotor apraxia type 1 and 2; AT, ataxia-telangectasia; HD, Huntington’s disease; DRPLA, dentatorubralpallidoluysian atrophy; GLUT-1, glucose transporter type 1 deficiency; FTAX, fragile X–associated tremor/ataxia syndrome.
well as heavy metals, including organic-lead compounds, mercury, and thallium.6
Inherited/Metabolic Conditions Ataxia with Vitamin E Deficiency Ataxia with vitamin E deficiency (AVED) is an autosomal recessive disease caused by mutations in the alpha tocopherol transfer protein (TTPA gene) on chromosome 8q13.1 It presents as a slowly progressive spino-cerebellar ataxia syndrome resembling Friedreich’s (FRDA) ataxia. Some of the shared features
of AVED and FRDA include ataxia, loss of muscle stretch reflexes, vibratory and sensory disturbances, muscle weakness, dysarthria, and upper motor neuron signs. Cardiomyopathy is less common in AVED, whereas head titubation and dystonia are more specific for AVED.7 Patients with AVED also have a slower course, with mild neuropathy compared with patients with FRDA. Age at onset of AVED for most patients is before age 20. Daily, divided, high doses of vitamin E (800 mg/d) typically lead to cessation of disease progression and to neurological improvement, although recovery may be slow and incomplete.8 The results of vitamin E supplementation also seem to be
TABLE 2. Recommended primary evaluation for acquired causes of ataxia in an adult patient Primary Laboratory Testing
Serum electrolytes and complete blood count, ammonia Erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), Ds-DNA Abs, rheumatoid factor (RF), SSA/Ro and SSB/La, Rapid plasma reagin/fluorescein treponema antibody (RPR/FTA) Vitamin B12 methylmalonic acid Homocysteine Thyroid-stimulating hormone Vitamin E levels Ceruloplasmin, urine, and serum copper Creatine kinase (CK) Lactate and pyruvate Serum/urine protein electrophoresis (SPEP/UPEP) Electromyogram (EMG)/nerve conduction velocities (NCVs) Brain MRI
2
Movement Disorders, Vol. 00, No. 00, 2015
Condition
Metabolic abnormalities and lymphoproliferative disorders Inflammatory or autoimmune conditions, vasculitis including systemic lupus erythematosus (SLE)/rheumatologic disease Neurosyphilis Subacute combined degeneration Hyperthyroidism/hypothyroidism Vitamin E deficiency, AVED Copper deficiency, Wilson’s disease Myopathy Mitochondrial cytopathies Lymphoproliferative disorders Evaluation for polyneuropahty (axonal vs demyelinating) Vascular disease, superficial CNS siderosis, neoplasms, multiple sclerosis, leukodystrophies, Creutzfeldt–Jakob disease, assess for brainstem and cerebellar atrophy.
T R E A T A B L E
C A U S E S
O F
C E R E B E L L A R
A T A X I A
TABLE 3. Secondary investigations for evaluation in patients with adult-onset ataxia Recommended Secondary Laboratory Testing
Cerebrospinal fluid (CSF) analysis (cell count, protein, glucose, cultures, Venereal Disease Research Laboratory (VDRL), IgG synthesis, oligoclonal bands, cytology, lactate, 14-3-3 protein, paraneoplastic antibodies Antigliadin antibodies, transglutaminase 2 and 6 antibodies Fasting lipid profile, including apoprotein B levels Paraneoplastic panel (Table 4) Anti-GAD65 antibodies Urine heavy metals Thyroperoxidase and thyroglobulin antibodies
Additional secondary investigationsa
Muscle biopsy Serum cholesterol levels and urinary bile alcohol levels. Serum phytanic acid levels Erythrocyte glucose uptake assay or CSF glucose concentration CoQ10 in skeletal muscle by high performance liquid chromatography Consider testing for the more common hereditary ataxiasb Consider clinical exome sequencing if other genetic etiologies are negative
Condition
CJD, encephalitis, immune-mediated polyneuropathy, inborn errors of metabolism, mitochondrial disease, multiple sclerosis, neoplasm, neurosyphilis, paraneoplastic cerebellar ataxia, Whipple’s disease Gluten ataxia AVED, cholesterol metabolic disorders Paraneoplastic cerebellar degeneration Glutamic acid decarboxylase (GAD) ataxia Heavy metal toxicity Inflammatory conditions, ataxic variant of steroid-responsive encephalopathy associated with autoimmune thyroiditis
Condition
Mitochondrial disease Cerebrotendinous xanthomatosis Refsum disease Glucose transporter type 1 deficiency Ataxia associated with coenzyme Q10 deficiency. FRDA, SCA1, SCA2, SCA3, SCA6, SCA8, and SCA17 Multiple pathogenic gene variants
FRDA, Friedreich’s ataxia; CJD, Creutzfeldt-Jakob disease; SCA, spinocerebellar ataxia; AVED, ataxia with vitamin E deficiency. a The selection of tests to perform should be directed toward the patient’s phenotype, neurological features, and previous diagnostic evaluation. Additional testing for other SCA should be individualized based on clinical evaluation. b Testing for the less common hereditary ataxias should be individualized and may depend on factors such as clinical phenotype. If no acquired cause of the ataxia is identified, the probability is 13% that the affected individual has SCA1, SCA2, SCA3, SCA6, SCA8, SCA17, or FRDA.76
most beneficial if started in patients with less than 15 years of disease duration; the sooner after diagnosis the supplementation is begun, the better.
Abetalipoproteinemia Abetalipoproteinemia is a rare metabolic disease caused by mutations in the gene for the large subunit of microsomal triglyceride transfer protein (MTTP gene), located on chromosome 4q22-24. When MTTP is mutated, plasma apolipoprotein B containing lipoproteins are absent, which in turn leads to the compromise of fat and fat-soluble vitamins. Vitamin E deficiency leads to muscle stretch hyporeflexia, reduced proprioception and vibratory sense, muscle weakness, and spino-cerebellar ataxia similar to FRDA. Symptoms typically begin before age 20. Retinitis pigmentosa also may occur. The definitive, “gold standard” diagnostic test is molecular testing by sequencing the MTTP, but specific laboratory investigations include blood smear showing acanthocytosis, and a lipid profile revealing nearly absent low-density lipoprotein C (
Treatable Causes of Cerebellar Ataxia Biller, MD, FACP, FAAN, FANA, FAHA2 Adolfo Ramirez-Zamora, MD,1* Warren Zeigler, MD,1 Neeja Desai, MD,1 and Jose 1 Albany Medical Center, MC- 70 Department of Neurology, Albany, New York, USA Loyola University Chicago, Stritch School of Medicine, Department of Neurology, Maguire Center, Maywood, Illinois, USA
2
ABSTRACT:
The cerebellar ataxia syndromes are a heterogeneous group of disorders clinically characterized by the presence of cerebellar dysfunction. Initial assessment of patients with progressive cerebellar ataxia is complex because of an extensive list of potential diagnoses. A detailed history and comprehensive examination are required for an accurate diagnosis and hierarchical diagnostic investigations. Although no cure exists for most of these conditions, a small group of metabolic, hereditary, inflammatory, and immunemediated etiologies of cerebellar ataxia are amenable to
Initial evaluation of patients with progressive cerebellar ataxia is challenging because numerous acquired, hereditary, paraneoplastic, toxic, and neurodegenerative conditions need to be considered in the differential diagnosis. Sporadic cerebellar ataxias represent the most common forms of new-onset cerebellar ataxia in adulthood.1 In spite of considerable advances in gene discovery and our understanding of the pathophysiology of cerebellar ataxia, management remains supportive and symptomatic. However, a limited group of heterogeneous progressive ataxic conditions may improve with disease-specific treatments if instituted early. Initial evaluation requires a complete assessment of the patient’s neurological and non-neurological features. Currently, more than 60 distinct neurogenetic
------------------------------------------------------------
*Correspondence to: Adolfo Ramirez-Zamora, MD, MC- 70 Department of Neurology, 47 New Scotland Avenue, Albany, NY 12208, E-mail: [email protected] Funding agencies:
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 17 July 2014; Revised: 9 December 2014; Accepted: 29 December 2014 Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26158
disease-modifying, targeted therapies. Over the past years, disease-specific treatments have emerged. Thus, clinicians must become familiar with these disorders because maximal therapeutic benefit is only possible when done early. In this article, we review disorders in which cerebellar ataxia is a prominent clinical feature requiring targeted treatments along with specific manC 2015 International Parkinagement recommendations. V son and Movement Disorder Society
K e y W o r d s : ataxia; treatment; cerebellar syndrome
conditions are known to cause primary cerebellar ataxia, and a multitude of genetic/metabolic conditions include cerebellar ataxia as a prominent clinical feature. A comprehensive assessment is critical in elucidating important clinical keys, including rate of onset/progression, family history, specific diagnostic signs, and brain magnetic resonance imaging (MRI) abnormalities. The presence of associated neurological features can be useful for differentiating ataxic etiologies and dictating additional investigations (Table 1). The initial diagnostic evaluation of an ataxic patient should include an in-depth assessment for potential acquired causes, with hierarchical selection of laboratory testing with focus on conditions amenable to treatment. If a detailed screening for acquired causes is unrevealing, the diagnostic evaluation can then be directed toward hereditary or genetic etiologies (Tables 2, 3). In this review, we focus on disorders in which ataxia is a prominent clinical sign amenable to disease-specific treatment, whereas traditional metabolic encephalopathies and endocrine and genetic disorders in which ataxia is part of a more complex syndrome are not discussed. Chronic cerebellar injury secondary to alcohol, or other commonly used drugs, is treated with removal of the offending drugs. The most relevant drugs associated with ataxia are lithium,2 phenytoin,3 amiodarone,4 toluene,4 5-fluorouracil, and cytosine arabinoside,5 as
Movement Disorders, Vol. 00, No. 00, 2015
1
R A M I R E Z - Z A M O R A
E T
A L
TABLE 1. Helpful diagnostic signs and disease-specific considerations in patients with cerebellar ataxia Sign
Condition
Myelopathy with ataxia Vertical supranuclear palsy Xanthomas Severe autonomic dysfunction Early cognitive impairment Dysphonia, palatal myoclonus, and dentate calcification Visual loss Oculomotor apraxia Seizures and ataxia Retinitis pigmentosa Chorea/dystonia Parkinsonism Tremor Sensory neuronopathy Sensorimotor polyneuropathy
Alexander’s disease, ARSACS, adult-onset Friedreich’s ataxia, SCA 3 NPC CTX MSA CJD; anti-GAD syndrome; POLG mutations, Ataxic variant of SREAT, SCA 17 SCA 20 AVED, SCA 7, mitochondrial disease AOA1, AOA2, Whipple’s disease, AT SCA 10, CoQ10 deficiency AVED, vitamin E deficiency, Refsum’s disease, SCA 3, SCA 17, DRPLA, HD, AT, NPC, GLUT-1 deficiency SCA 3, SCA 2, MSA FTAX, Wilson’s disease, SCA 12 FRDA (brisk jaw reflex), SCA 2, AOA1, AVED Late-onset Tay–Sachs disease (axonal), CTX (axonal, demyelinating, or mixed) AT (axonal), AOA2 (axonal), ARSACS (axonal or demyelinating), Refsum’s disease (demyelinating) POLG mutations (demyelinating), SCA 1, SCA 2, SCA 3, SCA 4, SCA8, SCA12, SCA18, SCA 23, SCA 25 (all axonal)
Abbreviations: ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; FRDA, Friedreich’s ataxia; NPC, Niemann-Pick disease type C; CTX, cerebrotendinous xanthomatosis; MSA, system atrophy; CJD, Creutzfeldt-Jakob disease; GAD, glutamic acid decarboxylase ataxia; POLG, DNA polymerase gamma; SREAT, steroid-responsive encephalopathy associated with autoimmune thyroiditis; SCA, spinocerebellar ataxia; AVED, ataxia with vitamin E deficiency; CoQ10, coenzyme Q 10; AOA, ataxia with oculomotor apraxia type 1 and 2; AT, ataxia-telangectasia; HD, Huntington’s disease; DRPLA, dentatorubralpallidoluysian atrophy; GLUT-1, glucose transporter type 1 deficiency; FTAX, fragile X–associated tremor/ataxia syndrome.
well as heavy metals, including organic-lead compounds, mercury, and thallium.6
Inherited/Metabolic Conditions Ataxia with Vitamin E Deficiency Ataxia with vitamin E deficiency (AVED) is an autosomal recessive disease caused by mutations in the alpha tocopherol transfer protein (TTPA gene) on chromosome 8q13.1 It presents as a slowly progressive spino-cerebellar ataxia syndrome resembling Friedreich’s (FRDA) ataxia. Some of the shared features
of AVED and FRDA include ataxia, loss of muscle stretch reflexes, vibratory and sensory disturbances, muscle weakness, dysarthria, and upper motor neuron signs. Cardiomyopathy is less common in AVED, whereas head titubation and dystonia are more specific for AVED.7 Patients with AVED also have a slower course, with mild neuropathy compared with patients with FRDA. Age at onset of AVED for most patients is before age 20. Daily, divided, high doses of vitamin E (800 mg/d) typically lead to cessation of disease progression and to neurological improvement, although recovery may be slow and incomplete.8 The results of vitamin E supplementation also seem to be
TABLE 2. Recommended primary evaluation for acquired causes of ataxia in an adult patient Primary Laboratory Testing
Serum electrolytes and complete blood count, ammonia Erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), Ds-DNA Abs, rheumatoid factor (RF), SSA/Ro and SSB/La, Rapid plasma reagin/fluorescein treponema antibody (RPR/FTA) Vitamin B12 methylmalonic acid Homocysteine Thyroid-stimulating hormone Vitamin E levels Ceruloplasmin, urine, and serum copper Creatine kinase (CK) Lactate and pyruvate Serum/urine protein electrophoresis (SPEP/UPEP) Electromyogram (EMG)/nerve conduction velocities (NCVs) Brain MRI
2
Movement Disorders, Vol. 00, No. 00, 2015
Condition
Metabolic abnormalities and lymphoproliferative disorders Inflammatory or autoimmune conditions, vasculitis including systemic lupus erythematosus (SLE)/rheumatologic disease Neurosyphilis Subacute combined degeneration Hyperthyroidism/hypothyroidism Vitamin E deficiency, AVED Copper deficiency, Wilson’s disease Myopathy Mitochondrial cytopathies Lymphoproliferative disorders Evaluation for polyneuropahty (axonal vs demyelinating) Vascular disease, superficial CNS siderosis, neoplasms, multiple sclerosis, leukodystrophies, Creutzfeldt–Jakob disease, assess for brainstem and cerebellar atrophy.
T R E A T A B L E
C A U S E S
O F
C E R E B E L L A R
A T A X I A
TABLE 3. Secondary investigations for evaluation in patients with adult-onset ataxia Recommended Secondary Laboratory Testing
Cerebrospinal fluid (CSF) analysis (cell count, protein, glucose, cultures, Venereal Disease Research Laboratory (VDRL), IgG synthesis, oligoclonal bands, cytology, lactate, 14-3-3 protein, paraneoplastic antibodies Antigliadin antibodies, transglutaminase 2 and 6 antibodies Fasting lipid profile, including apoprotein B levels Paraneoplastic panel (Table 4) Anti-GAD65 antibodies Urine heavy metals Thyroperoxidase and thyroglobulin antibodies
Additional secondary investigationsa
Muscle biopsy Serum cholesterol levels and urinary bile alcohol levels. Serum phytanic acid levels Erythrocyte glucose uptake assay or CSF glucose concentration CoQ10 in skeletal muscle by high performance liquid chromatography Consider testing for the more common hereditary ataxiasb Consider clinical exome sequencing if other genetic etiologies are negative
Condition
CJD, encephalitis, immune-mediated polyneuropathy, inborn errors of metabolism, mitochondrial disease, multiple sclerosis, neoplasm, neurosyphilis, paraneoplastic cerebellar ataxia, Whipple’s disease Gluten ataxia AVED, cholesterol metabolic disorders Paraneoplastic cerebellar degeneration Glutamic acid decarboxylase (GAD) ataxia Heavy metal toxicity Inflammatory conditions, ataxic variant of steroid-responsive encephalopathy associated with autoimmune thyroiditis
Condition
Mitochondrial disease Cerebrotendinous xanthomatosis Refsum disease Glucose transporter type 1 deficiency Ataxia associated with coenzyme Q10 deficiency. FRDA, SCA1, SCA2, SCA3, SCA6, SCA8, and SCA17 Multiple pathogenic gene variants
FRDA, Friedreich’s ataxia; CJD, Creutzfeldt-Jakob disease; SCA, spinocerebellar ataxia; AVED, ataxia with vitamin E deficiency. a The selection of tests to perform should be directed toward the patient’s phenotype, neurological features, and previous diagnostic evaluation. Additional testing for other SCA should be individualized based on clinical evaluation. b Testing for the less common hereditary ataxias should be individualized and may depend on factors such as clinical phenotype. If no acquired cause of the ataxia is identified, the probability is 13% that the affected individual has SCA1, SCA2, SCA3, SCA6, SCA8, SCA17, or FRDA.76
most beneficial if started in patients with less than 15 years of disease duration; the sooner after diagnosis the supplementation is begun, the better.
Abetalipoproteinemia Abetalipoproteinemia is a rare metabolic disease caused by mutations in the gene for the large subunit of microsomal triglyceride transfer protein (MTTP gene), located on chromosome 4q22-24. When MTTP is mutated, plasma apolipoprotein B containing lipoproteins are absent, which in turn leads to the compromise of fat and fat-soluble vitamins. Vitamin E deficiency leads to muscle stretch hyporeflexia, reduced proprioception and vibratory sense, muscle weakness, and spino-cerebellar ataxia similar to FRDA. Symptoms typically begin before age 20. Retinitis pigmentosa also may occur. The definitive, “gold standard” diagnostic test is molecular testing by sequencing the MTTP, but specific laboratory investigations include blood smear showing acanthocytosis, and a lipid profile revealing nearly absent low-density lipoprotein C (
