Rare neurological diseases

Rare neurological diseases may be inherited, postinfectious, iatrogenic, or of unknown etiology. They can affect the brain, spinal cord, or peripheral nerves. Symptoms range from mild tremors to significant motor and cognitive impairment. Therapy is often supportive.

• Definition: a rare X-linked neurological disease usually seen in young men
• Inheritance: X-linked recessive disorder
• Epidemiology
  • Rare
  • Most often manifests in young boys
• Pathophysiology: mutation of the ABCD1 gene (located on chromosome X), which encodes a peroxisomal ATP-binding cassette (ABC) transporter protein
  • Impaired transport of very long chain fatty acids (VLCFA) into peroxisomes
  • Impaired β-oxidation of VLCFA results in accumulation of VLCFA in the adrenal glands, testes, and white matter.
  • Neuron demyelination and destruction of adrenal and Leydig cells.
• Clinical features
  • Cognitive impairment
  • Progressive vision, hearing, and motor deterioration
  • Dementia
  • Adrenal insufficiency
  • Coma
  • Death
• Diagnostics
  • Increased concentration of VLCFA in plasma
  • Decreased adrenal function (↑ ACTH and ↓ cortisol)
  • Brain MRI: occipitoparietal white matter demyelination
  • Mutation analysis
• Treatment
  • Dietary therapy: VLCFA restriction and Lorenzo's oil; )
  • Adrenal insufficiency: corticosteroid replacement therapy
  • Early cerebral adrenoleukodystrophy: allogeneic hematopoietic stem cell transplantation

The name adrenoleukodystrophy means dystrophy (tissue wasting) of the adrenals and the white matter (leuko) of the nervous system.

• Definition: a conjugate, bilateral, limitation of the eye movements in upgaze and/or downgaze
• Etiology: tumors (e.g., pinealoma), multiple sclerosis, encephalitis, and cerebral infarction → damage of cranial nerves or superior colliculi in the midbrain
  • The most common pinealoma in children is a germinoma, which often secretes β-hCG
• Clinical features
  • Conjugate vertical gaze palsy
  • Mydriasis
  • Poor pupillary constriction to light but intact constriction with accommodation
  • Hydrocephalus (due to obstruction of cerebrospinal fluid outflow pathways)
  • Ataxia (due to cerebellar involvement)
  • If germinoma in boys: potentially precocious puberty
• Treatment: treat the underlying condition
  • If pinealomas: focal radiation or chemotherapy.

• Definition: a rare behavioral syndrome that results from bilateral damage to the medial parts of the anterior temporal lobes (amygdala, hippocampus)
• Etiology
  • Infection (e.g., HSV-1 encephalitis)
  • Head trauma
  • Stroke
  • Malignancy (e.g., brain metastases)
  • Neurodegenerative disease (e.g., Alzheimer disease)
• Pathophysiology: bilateral damage to the medial parts of the anterior temporal lobes (amygdala, hippocampus)
• Clinical features
  • Disinhibited behavior
    • Hyperorality: excessive chewing, sucking, lip-smacking, and examination of objects with the mouth
    • Hyperphagia
    • Hypersexuality (e.g., increased libido, sexually suggestive speech and gestures)
  • Placidity
  • Hyperdocility (e.g., excessive obedience, loss of the ability to resist commands)
  • Cognitive dysfunction (e.g., memory loss, distractibility, amnesia, aphasia)
  • Visual agnosia
  • Seizures
• Treatment
  • Symptomatic and psychotropic medications
  • Acyclovir if active HSV infection is suspected

References:^[1][2]

• Description
  • Considered a radiologic finding rather than a clinical condition
  • A small and flat pituitary gland within the sella turcica on MRI (empty sella)
• Epidemiology: occurs most often in obese women with hypertension
• Etiology
  • Primary form: idiopathic
  • Secondary form: associated with idiopathic intracranial hypertension, pituitary gland surgery, radiation therapy, trauma, or infarction (e.g., Sheehan syndrome)
• Pathophysiology
  • Primary form: enlargement or malformation of the sella turcica, which surrounds the pituitary gland → CSF leaks in and partially or completely fills the sella turcica → compression and/or atrophy of the pituitary gland
  • Secondary form: small pituitary gland due to, e.g., surgical removal of a pituitary tumor or increased intracranial pressure
• Clinical features
  • Often asymptomatic
  • Symptoms of hypopituitarism in severe cases
• Treatment: in hypopituitarism, hormone replacement

References:^[3]

Acute posthypoxic myoclonus ^[4]

• Definition: generalized myoclonus that typically manifests within hours of a hypoxic episode
• Etiology: hypoxic brain injury
• Clinical features
  • Typically, generalized myoclonus
  • Other possible features include:
    • Multifocal myoclonus
    • Upward eye deviation
    • Periodic eye opening
    • Swallowing movements
    • Flexion of the neck and trunk
• Diagnosis
  • Clinical diagnosis
  • EEG: The following findings are usually seen in affected individuals, but one or more may be absent.
    • Spike-wave activity (continuous or intermittent)
    • Burst suppression
    • Diffuse slow background and waves
    • Alpha coma
• Treatment
  • Anticonvulsants
  • If ineffective: anesthetic agents

Chronic posthypoxic myoclonus (Lance-Adams syndrome)

• Definition: a syndrome characterized by multifocal myoclonus following hypoxic brain injury (e.g., due to cardiac arrest)
• Etiology: hypoxic brain damage
• Clinical features
  • Multifocal myoclonus exacerbated by muscle activation (action myoclonus) or intention to move (intention myoclonus)
  • Possible additional features
    • Seizure
    • Dysarthria
    • Dysphagia
    • Ataxia
    • Cognitive deficits
• Diagnosis
  • Clinical diagnosis
  • EEG: typically focal EEG discharge over the corresponding sensorimotor cortical area
  • EMG: short EMG discharge typically (≤100 ms) accompanied by near-synchronous EMG discharges in agonists, antagonists, and contiguous muscle segments
• Treatment: anticonvulsants

• Definition: a state of nearly continuous myoclonus that lasts > 30 minutes ^[5]
• Etiology
  • Epilepsy syndromes
    • Juvenile myoclonic epilepsy
    • Dravet syndrome
    • Lennox-Gastaut syndrome
  • Patients without a history of epilepsy
    • Toxic-metabolic encephalopathy (e.g., uremia, exposure to heavy metals, adverse effect of medications such as pregabalin, cefepime, and olanzapine)
    • Infection
    • Neuroinflammation
    • Neurodegeneration (e.g., progressive myoclonic epilepsy)
    • Anoxic encephalopathy
• Clinical features
  • Bilateral myoclonus of the trunk, limbs, and facial muscles
  • Periodic eye opening and upward deviation of the eyes
• Diagnosis
  • Detailed history to identify cause
  • Laboratory studies
    • Basic metabolic panel
    • Urine and serum toxicology
    • Cerebrospinal fluid analysis if either autoimmune or neuroinflammatory cause is suspected
  • Imaging
    • EEG (jerk-locked back-averaged EEG): spikes located over the contralateral primary motor cortex precede myoclonus
    • EMG and/or EEG with somatosensory evoked potentials test to identify the neuroanatomic origin
• Treatment: valproate, levetiracetam, intravenous benzodiazepines
• Prognosis: depends on underlying cause
  • MSE due to a reversible cause (e.g., uremia): good prognosis
  • Anoxic MSE: poor prognosis

• Definition: a syndrome of unknown etiology that is characterized by unilateral periorbital headache and palsy of one or more oculomotor nerves
• Etiology: unknown
• Pathophysiology: granulomatous inflammation in the area of the cavernous sinus or the superior orbital fissure
• Clinical features
  • Severe retro-ocular pain
  • Eye muscle paresis (ophthalmoplegia)
• Treatment: prednisone

• Definition: a rare, slowly progressive, chronic neurologic disease that is associated with HTLV-1
• Epidemiology: seen in tropical regions
• Etiology: infection with human T-cell lymphotropic virus type I (HTLV-1) → immunologic response in the CNS → chronic CNS inflammation and neurodegeneration
• Clinical features
  • Similar to multiple sclerosis or amyotrophic lateral sclerosis, with the addition of:
    • Arthritis
    • Uveitis
    • Alveolitis
    • Polymyositis
• Treatment: supportive

References:^[6]

Diseases caused by prion infection. Prion diseases affect both animals and humans. Creutzfeldt-Jakob disease (CJD) and variant CJD are discussed in a separate card.

Kuru ^[7][8]

• Definition: a rapidly lethal prion infection
• Etiology: acquired through ritualistic cannibalism
• Pathophysiology: neuronal loss, gliosis, and spongiform degeneration of cerebral gray matter
• Clinical features
  • Cerebellar ataxia
  • Muscle tremors
  • Pathological laughter
• Treatment: supportive

Gerstmann-Sträussler-Scheinker syndrome ^[8]

• Definition: a rapidly lethal prion infection
• Pathophysiology: deposition of amyloid plaques, mainly in the cerebellum
• Clinical features
  • Cerebellar ataxia
  • Dysarthria
  • Nystagmus
  • Late-onset dementia
• Treatment: supportive

• Definition:
  • An inherited neurological disorders, in which iron accumulates in the brain
  • Formerly known as Hallervorden–Spatz disease
• Epidemiology: usually manifests in childhood
• Etiology: mutation in PANK2 gene (encodes the enzyme pantothenate kinase 2)
• Pathophysiology: pantothenate kinase 2 deficiency → iron accumulation in the brain (mainly the basal ganglia)
• Clinical features
  • Rigor
  • Tremor
  • Choreoathetosis
  • Dystonia
  • Dementia
  • Pyramidal tract signs (e.g., Babinski sign)
• Treatment: symptomatic (i.e., anticholinergics, benzodiazepines, and anti-spasticity drugs such as baclofen)

• Definition: an episode of spasmodic upward movement of the eyes that typically lasts for several minutes
• Etiology
  • Drug-induced (i.e., neuroleptics, amantadine, benzodiazepines)
  • Alcohol use, fatigue, and emotional stress
  • Also seen in patients with basal ganglia disorders (e.g., postencephalitic Parkinsonism, Parkinson disease)
• Clinical features
  • Fixed stare, followed by upward eye deviation
  • Restlessness
  • Ocular pain
• Treatment: benztropine and/or diphenhydramine

• Definition: a general peripheral nerve hyperexcitability disorder of unknown etiology
• Clinical features
  • Fasciculations
  • Myoclonus
• Differential diagnosis
  • Benign fasciculation syndrome: a chronic condition characterized by profuse fasciculations without muscle weakness, atrophy, or other neurological abnormalities
  • Neuromyotonia: a rare syndrome associated with VGKC-antibody complexes characterized by continuous fasciculations, muscle stiffness, myokymias, and myotonic appearance of movements after muscle contraction.
• Treatment: supportive

• Definition: a paraneoplastic polyneuropathy usually associated with small cell lung carcinoma
• Clinical features
  • Distal symmetrical paresthesia
  • Disorder of proprioception and autonomous regulation
• Treatment: treat underlying disease (SCLC)

• Definition: a rare type of epilepsy that is similar to status epilepticus but only affects certain parts of the body
• Etiology
  • Brain tumors
  • Encephalitis
  • Traumatic brain injury
• Clinic features: focal motor clonic seizures that may persist for hours, weeks, or even longer
• Treatment: treat the underlying condition

• Definition: an autosomal recessive chronic degenerative neurological disease
• Clinical features
  • Early-onset polyneuropathy
  • Bladder disturbances
  • Constipation
  • Heat intolerance and/or loss of the ability to sweat
• Treatment: supportive
• Prognosis: lethal before the third decade of life

• Definition: a rare, congenital myopathy
• Epidemiology: manifests during childhood
• Clinical features
  • Proximal muscle weakness
  • Kyphoscoliosis
  • Hip dysplasia
  • Developmental delay
• Treatment: symptomatic and supportive

• Definition: a rare neurologic disease characterized by binge eating, hypersomnia, and hypersexuality
• Epidemiology: mainly affects adolescent males
• Etiology: unknown (although viral infections have been implicated)
• Clinical features
  • Recurrent hypersomnia (patients are only awake for 1–2 hours per day)
  • Hypersexuality when awake
  • Binge eating
• Subtype: menstrual recurrent hypersomnia
  • Very rare variant
  • Characterized by recurrent episodes of excessive sleepiness just before or during menses
  • Associated with compulsive eating (65% of cases), depression (35% of cases), and sexual disinhibition (29% of cases)
  • Symptoms sometimes respond to estrogen-containing contraceptives
• Treatment: supportive

• Definition: an infectious syndrome consisting of bilateral lumbosacral radiculitis and myelitis of the lower spinal cord
• Etiology: HSV-2 infection is most common but other viral etiologies (i.e., CMV, EBV, HIV) are possible → sacral myeloradiculitis
• Clinical features: transient urinary retention and other signs of lumbosacral radiculitis
• Treatment: supportive (i.e., urethral catheterization)

• Definition: a severe neurodegenerative disorder caused by administration of clioquinol
• Epidemiology: Most cases were confined to Japan in the 1960's.
• Etiology: iatrogenic (induced by the drug clioquinol)
• Clinical features
  • Progressive paralysis
  • Blindness
• Treatment: reversible (withdraw clioquinol)

• Definition: a rare genetic neurological disorder characterized by progressive degeneration of the white matter
• Epidemiology: incidence is 1:100,000 births ^[10]
• Etiology: mutations of the aspartoacylase (ASPA) gene, which encodes aspartoacylase, the enzyme responsible for the conversion of N-acetylaspartic acid (NAA) to aspartate and acetate
• Pathophysiology: mutation of the ASPA gene → ↑ NAA levels in neurons and oligodendrocytes → neuronal dysfunction and myelin deficiency
• Clinical features: neonatal/infantile and mild/juvenile are the two main disease types.
  • Neonatal/infantile form: normal at birth, symptoms develop by age 3–5 months. ^[10]
    • Macrocephaly
    • Lack of head control
    • Hypotonia
    • Seizures
    • Progressive vision deterioration
  • Mild/juvenile form: delayed development
• Diagnostics: based on clinical and neuroimaging findings
  • Increased levels of NAA in urine samples
  • Neuroimaging
    • Brain MRI: diffuse, symmetrical white matter degeneration in the subcortical areas
    • MR spectroscopy: elevated NAA and NAA:creatine-ratio (pathognomonic finding)
  • Molecular genetic testing ^[11]
• Treatment: supportive (e.g., feeding gastrostomy tube in case of dysphagia, AED to manage seizures, botulinum toxin injections for spasticity)
• Prognosis
  • Neonatal/infantile form: death in the first decade of life
  • Mild/juvenile form: same lifespan as the general population

CaNAAvan disease is caused by the accumulation of NAA.