AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Onset is most commonly in late childhood or early adolescence, but cases with adult onset have been described (Jankovic, 1985). The disease can be familial or sporadic. When familial, it is inherited recessively and has been linked to chromosome 20 (Taylor, 1996). Recently, a mutation in the pantothenate kinase (PANK2) gene on band 20p13 has been described in patients with typical HSD (Zhou, 2001).

Hallervorden and Spatz first described the disease in 1922 as a form of familial brain degeneration characterized by iron deposition in the brain. Recently concerns have been raised regarding reports of Hallervorden and Spatz's association with Nazi activities in Germany, and some even suggested changing the name of the syndrome to neuroaxonal dystrophy (Harper, 1996). The term "neurodegeneration with brain iron accumulation type1" (NBIA-1) has been used in more recent publications (Neumann, 2000).

Pathophysiology

The exact pathophysiology of the disease is not known. One suggestion states that abnormal peroxidation of lipofuscin to neuromelanin and deficient cysteine dioxygenase lead to abnormal iron accumulation in the brain. While portions of the globus pallidus and pars reticulata of substantia nigra (SN) have high iron content in healthy individuals, individuals with HSD have excess amounts of iron deposited in these areas. However, the exact role of iron in the pathogenesis of this disease remains unknown. Also, whether the deposition of iron in basal ganglia in HSD is the cause or consequence of neuronal loss and gliosis is not clear. Decreased activity of the enzyme cysteine dioxygenase was demonstrated in one affected child (Perry, 1985). This was postulated to lead to accumulation of cysteine in the basal ganglia, since cysteine can chelate iron and thus result in its deposition. However, these findings were not confirmed in adult patients.

Recently, a role for mutation in the PANK2 gene (band 20p13) in the pathogenesis of the disease has been proposed. Deficiency of pantothenate kinase may lead to accumulation of cysteine and cysteine-containing compounds in the basal ganglia. This causes chelation of iron in the globus pallidus and free radical generation as a result of rapid auto-oxidation of cysteine in the presence of iron (Hayflick, 2001).

Pathologic evaluation reveals characteristic rust-brown discoloration of the globus pallidus and SN pars reticulata secondary to iron deposition (Swaiman, 1991; Halliday, 1995). Generalized atrophy of the brain may be noted, with the caudate nuclei, SN, and tegmentum decreased in size. Microscopically, the characteristic changes include the following:

• Variable loss of neurons, myelinated fibers, and gliosis in globus pallidus and SN, which may appear spongiotic when severe
• Widely disseminated rounded or oval nonnucleated structures known as spheroids, also known as axon schollen or neuroaxonal dystrophy; these represent swollen axons with vacuolated cytoplasm and are found most abundantly in the pallidonigral system but also in cerebral cortex
• Accumulation of pigment, mostly containing iron
• Ceroid lipofuscin and neuromelanin containing iron in the areas mainly affected as mentioned above

Iron deposition may be found both intracellularly and extracellularly and frequently is centered on vessels. These changes are found to a lesser degree in other parts of the brain and in the spinal cord. Presence of spheroids suggests a link between HSD and infantile neuroaxonal dystrophy. However, no clinical or genetic relationship has been reported between the 2 diseases. Tau-positive neurofibrillary tangles and alpha-synuclein–positive Lewy bodies may be found in cortical and subcortical regions in patients with a prolonged clinical course (Neumann, 2000).

Frequency

United States

The exact frequency of HSD is not known.

Mortality/Morbidity

HSD is relentlessly progressive. The course is characterized by progressive dementia, corticospinal signs (eg, spasticity, hyperreflexia), and extrapyramidal signs including rigidity, dystonia, and choreoathetosis. Affected individuals typically die in the second or third decade. The course of the disease usually proceeds over 10-12 years, but case reports describe patients surviving 30 years (Saito, 2000; Hickman, 2001).

Race

No particular race is more susceptible than others to HSD. The disease is rare and has been reported in all races.

Sex

The disease is equally common in both sexes.

Age

Age of onset is usually in early adolescence; however, presentations in adulthood and infancy have been reported (Jankovic, 1985; Grimes, 2000; Cooper, 2000). The classic presentation is in the late part of the first decade or early part of the second decade, when the individual is aged 7-15 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Clinical manifestations vary from patient to patient.

• The symptoms usually begin in the first decade with a motor disorder of extrapyramidal type and gait difficulty. Symptoms including rigidity of extremities, slowness of movement, dystonia, choreoathetosis, and tremor dominate the clinical picture.
• In some patients, extrapyramidal dysfunction may be delayed for several years, as spasticity and dysarthria may be the presenting symptoms.
• Dystonia is a prominent and early feature.
• Significant speech disturbances can occur early on.
• Dysphagia is common and is due to rigidity and corticobulbar involvement.
• Dementia is present in most individuals with HSD.
• Visual impairment from optic atrophy or retinal degeneration is not uncommon and can be the presenting symptom of the disease, although this is rare.
• Seizures have been described (Swaiman, 1991).

Physical

Physical examination reveals signs consistent with extrapyramidal and corticospinal dysfunction. In addition to rigidity, dystonia, and chorea, patients may experience spasticity, brisk reflexes, and extensor plantar responses.

• Based on the common clinical features, the following diagnostic criteria for HSD have been proposed (Swaiman, 1991). All of the obligate findings and at least 2 of the corroborative findings should be present. None of the exclusionary factors should be present.
• • Obligate features
    • Onset during the first 2 decades of life
    • Progression of signs and symptoms
    • Evidence of extrapyramidal dysfunction including one or more of the following: dystonia, rigidity, choreoathetosis
  • Corroborative features
    • Corticospinal tract involvement
    • Progressive intellectual impairment
    • Retinitis pigmentosa and/or optic atrophy
    • Seizures
    • Positive family history consistent with autosomal recessive inheritance
    • Hypointense areas on MRI involving the basal ganglia
    • Abnormal cytosomes in circulating lymphocytes and/or sea-blue histiocytes in bone marrow
  • Exclusionary features
    • Abnormal ceruloplasmin levels and/or abnormalities in copper metabolism
    • Presence of overt neuronal ceroid lipofuscinosis as demonstrated by severe visual impairment and/or seizures that are difficult to control
    • Predominant epileptic symptoms
    • Severe retinal degeneration or visual impairment preceding other symptoms
    • Presence of familial history of Huntington chorea and/or other autosomal dominantly inherited neuromovement disorders
    • Presence of caudate atrophy on imaging studies
    • Deficiency of hexosaminidase A
    • Deficiency of ganglioside monosialic acid-1 (GM1)-galactosidase
    • Nonprogressive course
    • Absence of extrapyramidal signs

Causes

No single risk factor is known to predispose individuals to HSD. The role of genetic factors has been proposed on the basis of known familial cases. By homozygosity mapping, a gene for the disease has been localized to band 20p12.3-13, raising the possibility of a future genetic test for the disease (Taylor, 1996).

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

The differential diagnosis includes other diseases presenting with extrapyramidal-pyramidal-dementia complex.

Wilson disease usually presents with tremors, rigidity, dementia, and pseudobulbar features and has an autosomal recessive mode of inheritance. Slit-lamp examination of the eye may reveal a Kayser-Fleischer ring. MRI exhibits the characteristic changes consisting of high-intensity lesions in the basal ganglia, thalami, and mid brain. The normal low intensity of red nuclei and SN surrounded by abnormal high signal intensity in the tegmentum of mid brain gives rise to the typical "face-of-the-giant panda" sign. Serum ceruloplasmin and copper studies are usually abnormal and help confirm the diagnosis. Neurological symptoms are reversible if treated early with copper chelation therapy; hence, early diagnosis is important.

The juvenile form of Huntington disease may be confused with HSD. Patients with the juvenile form of Huntington disease can have a predominantly akinetic-rigid syndrome (ie, Westphal variant). The differentiating features include autosomal dominant mode of inheritance and presence of caudate atrophy on MRI.

Juvenile neuronal ceroid lipofuscinosis may be difficult to distinguish from HSD. It is an inherited disorder characterized by storage of ceroid and lipofuscin in neuronal and other tissues. The symptoms start in early childhood with vision loss, retinitis pigmentosa, dementia, rigidity, and dystonia. In contrast to the infantile and late-infantile forms of the disease, generalized tonic-clonic seizures and myoclonic seizures are not very common. The diagnosis can be made on the basis of clinical presentation, electrophysiologic studies, and skin biopsy findings. The electroretinogram reveals markedly reduced amplitude, and visual and somatosensory evoked responses are increased. The characteristic fingerprint inclusion bodies are identified easily in eccrine sweat glands and in circulating lymphocytes.

Machado-Joseph disease is inherited as an autosomal dominant trait, and the clinical disease usually has its onset when the individual is older than 20 years. Ataxia and other signs of spinocerebellar dysfunction are predominant. Some affected children may have extrapyramidal features, but prominent ataxia and the inheritance pattern should help differentiate Machado-Joseph disease from HSD.

Neuroacanthocytosis is characterized by onset of prominent orofacial dyskinesia, chorea, dystonia, and cognitive changes in the third or fourth decade. Other features include self-mutilation, peripheral neuropathy, and seizures. Recognition of acanthocytes (red blood cells with irregular spine on the cell surface) in the peripheral smear can lead to the diagnosis. HARP syndrome, which is characterized by hypoprebetalipoproteinemia, acanthocytes, retinitis pigmentosa, and pallidal degeneration, is another form of neuroacanthocytosis. Clinically it presents with dyskinesias, dystonia, and progressive dementia. The lipoprotein electrophoresis reveals absence of prebeta fraction, and MRI exhibits hypointense signal intensities in the globus pallidus.

Rare metabolic disorders such as GM1 and GM2 gangliosidoses in children sometimes can have features similar to HSD, but they have other clinical features and lab abnormalities and are differentiated readily.

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• No biochemical markers have been found in HSD.
• Levels of copper, ceruloplasmin, lipids, amino acids, and acanthocytes typically are measured in the blood to exclude other conditions.
• Radionuclide scan reveals increased uptake of iron by the basal ganglia (Vakili, 1977).
• Cultured skin fibroblasts have been reported to accumulate iron 59Fe transferrin, but the isotope is no longer available for human use.
• Increased platelet monoamine oxidase B activity has been reported (Zimmerman, 1981).
• Bone marrow histiocytes and peripheral lymphocytes may demonstrate the presence of abnormal cytosomes including fingerprint, granular, and multilaminated bodies (Swaiman, 1983; Alberca, 1987). The characteristics of the material suggest the presence of ceroid lipofuscin.

Imaging Studies

• CT imaging is not very helpful but may exhibit hypodensity in the basal ganglia and some atrophy of the brain. Calcification in the basal ganglia in the absence of any atrophy also has been described.
• MRI has increased the likelihood of antemortem diagnosis of HSD (Felciani, 1994; Shah, 1999).
• • The typical MRI appearance is of bilaterally symmetric hyperintense signal changes in anterior medial globus pallidus with surrounding hypointensity in the globus pallidus on T2-weighted images (see Image 1). These imaging features are fairly diagnostic of HSD and have been termed the "eye-of-the-tiger" sign (Sethi, 1988).
  • The hyperintensity represents pathologic changes including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is due to loss of signal secondary to iron deposition.
• Iodine 123 (¹²³I)-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (CIT) single-photon emission computed tomography (SPECT) and (¹²³I)-iodobenzamide (IBZM)-SPECT also have been used in making the diagnosis of HSD (Hermann, 2000).

Histologic Findings

See the microscopic description in Pathophysiology.

TREATMENT

Section 6 of 11  

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Medical Care

Treatment remains directed toward symptomatic findings. Systemic chelating agents such as desferrioxamine have been used in an attempt to remove excess iron from the brain, but these have not proved beneficial.

• Dystonia is the most prominent and disabling symptom and responds to a modest extent to dopaminergic agents such as levodopa and bromocriptine (a dopamine agonist).
• • Anticholinergics such as trihexyphenidyl may be used when dopaminergic agents are not helpful. However, these medications bring only transient relief for dystonia, and physical therapy is often of limited benefit.
  • Botulinum toxin can be injected into severely affected muscles to relieve dystonia.
  • Continuous intrathecal baclofen infusion has been tried for refractory generalized dystonia without much success.
  • Stereotactic pallidotomy and bilateral thalamotomy occasionally have been tried for patients with severe dystonia, resulting in partial relief of symptoms (Justesen, 1999).
• Tremor in patients with HSD responds best to dopaminergic agents. The anticholinergic agent benztropine helps both rigidity and tremor.
• Benzodiazepines have been tried for choreoathetotic movements.
• Hypertonia is usually a combination of rigidity and spasticity and may be difficult to treat.
• • Dopamine agonists and anticholinergics may help reduce rigidity.
  • Baclofen in moderate doses relieves the stiffness and spasms and can reduce dystonia.
• Symptoms such as drooling and dysarthria can be troublesome.
  • Treat excessive drooling with a medication such as methscopolamine bromide.
  • Dysarthria may respond to medications used for rigidity and spasticity.
  • Speech therapy also may be useful, and computer-assisted devices may be used in patients with advanced cases.
  • Gastrostomy feeding may be necessary in advanced cases of dysphagia.
• Dementia is progressive, and no treatment has proved clearly beneficial.
• A multidisciplinary team approach involving physical, occupational, and speech therapists may be needed in selected patients with a protracted course to improve functional skills and communication.

MEDICATION

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Medications are tailored to treat specific aspects of the disease (see Medical Care).

Drug Category: Antiparkinson agents

These agents reduce morbidity associated with dopamine deficiency.

Drug Category: Anticholinergics

These agents are thought to work centrally by suppressing conduction in the vestibular cerebellar pathways. They may have an inhibitory effect on the parasympathetic nervous system.

Drug Category: Benzodiazepines

By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Drug Category: Neuromuscular blocker agents

These agents produce symptomatic improvement in strength, autonomic symptoms, or both in some patients.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
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Further Inpatient Care

• Admission for supportive care is occasionally necessary.

Further Outpatient Care

• Referral to a neurologist, particularly a movement disorders specialist, is helpful. Rehabilitation physicians often are consulted to coordinate therapy regimens.

In/Out Patient Meds

• See Medical Care and Medication.

Transfer

• Transfer is seldom necessary.

Prognosis

• The clinical course is variable. In most patients, the disease has a progressive course extending over several years, leading to death in early childhood. Some patients experience rapid deterioration of function secondary to dystonia, rigidity, dysphagia, and respiratory compromise and die within 1-2 years of disease onset. Other patients undergo a slower progression or even plateau for many years and may continue to function into the third decade of life (Hickman, 2001).

Patient Education

• The Web site of the NBIA Disorders Association (formerly Hallervorden-Spatz Syndrome Association) is helpful.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Referral to a neurologist, particularly a movement disorders specialist, is helpful.

MULTIMEDIA

Section 10 of 11  

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• Introduction
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• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  MRI has increased the likelihood of antemortem diagnosis of Hallervorden-Spatz (HSD) disease. The typical MRI appearance is of bilaterally symmetric hyperintense signal changes in anterior medial globus pallidus with surrounding hypointensity in the globus pallidus on T2-weighted images. These imaging features are fairly diagnostic of HSD and have been termed the "eye-of-the-tiger" sign. The hyperintensity represents pathologic changes including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is due to loss of signal secondary to iron deposition.
	View Full Size Image
Media type:  MRI

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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• Swaiman KF, Smith SA, Trock GL, et al. Sea-blue histiocytes, lymphocytic cytosomes, movement disorder and 59Fe- uptake in basal ganglia: Hallervorden-Spatz disease or ceroid storage disease with abnormal isotope scan?. Neurology. Mar 1983;33(3):301-5. [Medline].
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Article Last Updated: Dec 7, 2006