NEURQDEGENERATiVE DISORDERS

Neurodegenerative disorders (NDD) is a collective term to denote broad spectrum of heterogeneous disorders, all characterized by Progressive deterioration or regression of neurological functions, e.g.

Classification: NDD may be classified according to etiology, age of onset and biochemical defects, though most useful is the classification based on primary site of lesion that helps in clinical diagnosis (Table 18.36).

Etiologically, these disorders may be inherited due to genetic biochemical defects or acquired following chronic viral infections, toxic encephalopathies and idiopathic brain injury.

Metachromatic leukodystrophy is the commonest hereditary NDD in Indian children, while subacute sclerosing panencephalitis (SSPE) due to slow measles virus infection is the commonest acquired NDD.

Almost all hereditary NDDs are autosomal recessive, except x-linked recessive adrenoleukodystrophy and Menkey (kinky hair) disease.

Pathologically, NDDs include storage and non-storage disorders. Storage disorders are characterized by

TABLE 18.36: Common neurodegenerative disorders

• Gray matter degeneration

- Storage disorders (Sphingolipidoses):

GM1 gangliosidoses (Infantile and juvenile)

GM2 gangliosidoses (Tay-Sachs disease, Sandhoff disease) Neuronal ceroid lipofuscinoses

Others: Gaucher disease, Niemann-Pick disease

- Non-storage disorders

Subacute sclerosing panencephalitis (SSPE)

Menkes Kinky hair disease

• White matter degeneration

- Leukodystrophies

Metachromatic Leukodystrophies

Adrenoleukodystrophies

- Demyelinating diseases

Multiple sclerosis (Neuromyelitis optica)

Schilder disease

• Spinocerebellar degeneration

Friedreich's ataxia

Ataxia telangiectasia Abetalipoproteinemia Refsum disease

• Basal ganglia degeneration

Wilson disease

Huntington chorea Hallervorden-Spatz disease Dystonia musculum deformans

excessive intracellular storage of either normal or abnormal lipid component of cell membrane, due to some inherited enzymatic defect in their catabolism.

Clinical manifestations: Early development is characte­ristically normal in NDDs, till the onset of disease. Age of onset and early clinical manifestations vary according to the site and type of lesion, though end-stage clinical picture is often similar with crippling loss of intellect, voluntary motor activity and severe impairment of vision, hearing and speech. Among hereditary defects, children with complete absence or severe deficiency of causative enzyme present at birth/infancy, while those with moderate or mild deficiencies present as juvenile or adult variants.

Gray matter disorders generally begin with regression of mental milestones, intellectual dysfunction, seizures and visual/hearing impairment. Motor dysfunction is a late feature in these disorders.

White matter disorders usually present with early pyramidal tract signs, e.g. regression of motor milestones, spasticity or hypotonia, gait disturbances and feeding difficulties due to pseudobulbar palsy. Intellectual impairment and seizures are usually late manifestations in these conditions.

Diagnosis requires—(a) precise history and clinical examination including fundus examination specially for cherry-red spot, (b) neuroimaging with MRI (CT scan is not very useful), and (c) specific biochemical tests to identify enzyme deficiency or storage substance.

Molecular studies on leukocytes or skin fibroblasts to identify genetic defect in index case and carrier-detection are essential for genetic counseling in hereditary NDDs and prenatal diagnosis is possible for many diseases. Management of NDDs is largely supportive and most patients succumb to illness after variable period of time. Some important NDDs are discussed as follows: Subacute sclerosing panencephalitis (SSPE) or Dawson encephalitis is the commonest acquired NDD in India, due to the slow virus infection of CNS after many years of measles disease or vaccination.

Incidence of SSPE is estimated to be ~8 per million clinical cases and lt;1 per million vaccinations of measles.

Clinically, these cases present by late childhood, after 4-5 years of measles attack, with:

• Personality changes, e.g. emotional instability and deterioration in school performance (earliest features).

• Myoclonic seizures followed by tonic-clonic seizures, hypertonia, choreoathetoid movements and deve­lopmental regression with decerebrate posturing.

• Ophthalmic signs, e.g. papilledema, optic atrophy, chorioretinitis or macular pigmentation in late stages of most cases.

Diagnosis is established by—(a) past history of measles ~4-5 years back, (b) typical clinical progression, (c) presence of measles antibodies in CSF, and (d) characteristic EEG with repeated bursts of high voltage slow wave complexes. Post-mortem brain biopsy may confirm the diagnosis on histology and viral culture.

Management is supportive and antiviral therapy is not effective. Some drugs, e.g. intraventricular interferon -2B and isoprinosine have been tried with unproven benefit. Most cases die within 2-3 years of onset.

Metachromatic leukodystrophy (MLD) is the commonest hereditary NDD in India, characterized by Arylsulfatase-A deficiency, leading to accumulation of cerbroside sulfate in the myelin sheaths.

Classic MLD presents at 1-2 years of age, with gait disturbances, inability to walk/stand, hypotonia and hyporeflexia followed by gradual intellectual impairment, dysarthria and loss of vision (optic atrophy). MRI reveals diffuse symmetrical hyperintensities in the deep white matter, while sparing the subcortical U-fibres. Most cases die by 5-6 years due to aspiration Bone marrow transplant is only promising therapy for MLD, still in experimental stage.

Other variants present similarly but at a later age, i.e. 5-10 years (Juvenile MLD) or adults (Adult MLD).

Adrenoleukodystrophies (ALD) include a group of NDDs associated with adrenal cortical deficiency.

Other variants include Neonatal ALD, presenting in newborns or early infancy with severe hypotonia, psychomotor retardation, optic atrophy and seizures; and Adrenomyeloneuropathy in adults beyond 3-4^th decade of life.

Krabbe disease (KD) is a rare autosomal recessive (GALC gene) disease with severe myelin loss and the presence of globoid bodies in white matter due to deficiency of a lysosomal enzyme galactocerebroside ^-galactosidase.

Clinically most cases present in early infancy with excessive cry, hyperpyrexia, vomiting and diffi­culty feeding followed by development of seizures, rigidity, blindness (optic atrophy) and deafness. Most patients die by 2 years of age. Late-onset KD may present in older children or adolescents with ataxia, progressive rigidity and blindness, often confused with adrenoleukodystrophy.

MRI and MR spectroscopy clinch the diagnosis and stem-cell transplant may be useful in early stages. Prenatal diagnosis is possible by enzyme assay in chorionic villi/amniotic fluid cells.

Gangliosidoses are multiple autosomal recessive disorders of ganglioside catabolism (a normal lipid in cell membranes) due to various enzyme deficiencies, leading to its accumulation within the neuronal cells.

Presence of cherry-red spot over macula (Fig. 27.1D) is highly suggestive of all gangliosidoses, except in juvenile GM₂ gangliosidsis.

a. Infantile disease, presenting since birth with marked developmental retardation, seizures, coarse features and hepatosplenomegaly;

b. Juvenile disease, presenting at ~1 year with progressive ataxia, spasticity and seizures, but without coarse features or hepatosplenomegaly.

c. Adult disease with further late presentation.

GM₂ gangliosidoses (Hexoaminidase deficiency) also has three variants:

a. Tay-Sach disease (Hex A deficiency) is more common in Jews and presents at 5-6 months of age with hyperacusis (exaggerated startle response), develop­mental regression, spasticity, seizures and blindness;

b. Sandhoff disease (Hex A and B deficiency) with similar presentation but with splenomegaly;

c. Juvenile or adult GM₂ gangliosidoses, presenting in mid-childhood or later, with progressive ataxia and spasticity. Visual and intellectual functions are relatively preserved and cherry-red spot is uncommon.

Neuronal ceroid lipofuscinoses (NCL) are commonest NDDs in western children, characterized by storage of an autofluorescent substance in neurons and other tissues.

Of three variants, all autosomal recessive, commonest is late infantile NCL, presenting at 2-4 years with myoclonic seizures, progressive dementia, ataxia and loss of visual acuity. Brown/black retinal pigmentation with optic atrophy and abnormal visual evoked potential studies are typical.

Other variants include early infantile NCL, presenting by one year of age and juvenile NCL, with onset at 5-10 years.

Multiple sclerosis is a common chronic remitting NDD in adults with multiple white lesions in brain due to inflammatory demyelination and axonal degeneration. Less than 1% of these cases present in childhood.

Menkes (kinky hair) disease, an X-linked recessive disorder of copper metabolism, presents with myoclonic seizures in early infancy, failure to thrive, severe mental retardation, optic atrophy and typical sparse, colorless and brittle hair.

Rett syndrome, due to mutation in MECP2 gene is most commonly seen in girls and present with develop­mental regression from 1-2 years of age, followed by development of typical autistic behavior, peculiar sighing respiration with intermittent apnea and Loss of purposeful hand movements with repetitive hand­wringing movements (hallmark features). Seizures are common. Most cases survive till late adolescence.

Friedreich ataxia, an autosomal recessive disorder due to expansion of a GAA trinucleotide repeat region, is the commonest NDD with spinocerebellar degeneration, presenting in late childhood or adolescence with:

• Posterior spinal column involvement with loss of position and vibration sense,

• Pyramidal tract involvement with spasticity and extensor planter response,

• Spinocerebellar tract involvement with ataxia, nystagmus and dysarthria,

• Peripheral neuropathy with areflexia, and

• Coexisting skeletal deformities, e.g. Pes cavus.

Extensor planter response (pyramidal tract lesion) with absent ankle jerk (peripheral neuropathy) is a useful indicator of Friedreich ataxia.

Hallevorden Spatz disease, a rare recessive NDD with iron accumulation in the brain, presents in childhood with progressive dystonia, rigidity, choreoathetosis and dysarthria. Mental deterioration and spasticity develops in adolescence with death in early adulthood. Neuropathology reveals accumulation of iron-containing pigment in globus pallidus and substantia nigra, which may be visible on MRI as eye-of the-tiger sign in globus pallidus.

Dystonia musculorum deformans is a rare autosomal dominant disorder, more common in Ashkenzi Jews.

Clinical manifestations generally begin in mid-childhood with intermittent attacks of unilateral leg dystonia with abnormal gait (tip-toe walking), aggravated by stress. Gradually, the attacks become more persistent, involving all extremities, face and trunk, with severe postural deformities and feeding/speech difficulties.

Diagnosis is clinical and severe cases may benefit from large doses of trihexyphenidyl, carbamazepine, levodopa or diazepam.

Some other important NDDs - ataxia telaniectasia, Wilson disease and Huntignton chorea, have been discussed elsewhere in Ch 15.8, 18.9 and 18.14 respectively.

18.16