Differential Diagnosis in Neurology

13.5. Non-Vascular Cerebellar Disease

An Overview of Non-Vascular Cerebellar Disease

The major drug group that affects the cerebellum is the anticonvulsants. Characteristic of all in excess are lethargy, nystagmus (usually gaze evoked, but rarely spontaneous) due to interference with "hold neurons" of the visual system that foveate the target. Dilantin has been noted to cause ophthalmoplegia as well as a slowly progressive peripheral neuropathy usually limited to decreased ankle jerks. Phenobarbital in addition to nystagmus may cause severe dysarthria and reversible decortication and decerebration.

5-flurouracil is the usual anti-cancer agent encountered that causes a mild cortical cerebellar deficit. Notable is absent peripheral neuropathy which is characteristic of most of the other CNS toxic anti-neoplastic drugs. Cisplatinum affects the dorsal root ganglion with loss of large proprioceptive neurons and posterior column deficits. The intention tremor is throughout all thirds of movement and the patients are dramatically affected unless they have visual compensation.

Cyclosporin and lithium have cerebellar features and render patients ataxic, but their seminal features are myoclonus, depressed cognition and hyperreflexia. Hypnotic sedatives cause ataxia both of gait and limb, but dysarthria, lethargy, depressed reflexes and psychiatric problems predominate.

The primary deficiency states with cerebellar dysfunction as a core symptom are B12 and Vitamin E deficiency. The former is dominated by spasticity, an active peripheral neuropathy (paresthesias) an ebullient mental status, optic atrophy and cranial nerve I dysfunction. Trauma, Kallmann's syndrome, Hencken's syndrome, and Foster–Kennedy syndrome are also considered when cranial nerve I is involved. Vitamin E deficiency from either α-Tocopherol transporter or deficiency deficits has very prominent dorsal column dysfunction. Acute B12 deficiency involving all signs and symptoms may be induced by nitrous oxide anesthesia. Pantothenic acid deficiency is commonly associated with chronic alcoholism and may be partly responsible for its associated ataxia.

Alcohol is by far the most serious toxin worldwide. Its pattern of expression is appendicular in the lower extremities with imbalance and an anterior vermian deterioration. The patients have a stiff legged gait ("Martinet" gait) without the usual cerebellar modulation of both the stance and swing phase. There is minimal dysarthria, nystagmus or upper extremity dysmetria.

The usual patterns of toxic involvement that affects the CNS are:

• Optic neuritis (always occurs with methyl alcohol poisoning); centrocecal scotomata
• Dorsal column dysfunction with acute vibratory and position sense impairment-longest fibers involved first
• Spasticity as a late consequence
• Frontal lose cognitive deficits

This is seen with toluene n-ethyl toluene and paint solvents. Glue sniffing affects the frontal lobes and causes euphoria and lethargy. Huffer's syndrome (gasoline sniffing) has prominent frontal lobe depression. Paint sniffing (silver paint, SW of the USA) causes cerebellar deficits that are overshadowed by pronounced mental status depression. Thallium is recognized by euphoria, ataxia and hair loss. Mercury poisoning is distinguished by mental changes, dystonia and choreoathetosis in addition to ataxia.

Endocrine induced ataxia is usually secondary to hypothyroidism. This is minimal and is most often accompanied by VIIIth nerve deficits, proximal myopathy (pseudohypertrophy or Hoffmann's syndrome) bilateral carpal or tarsal tunnel syndrome, and failure to make ear wax or sweat normally.

Severe liver disease is associated with ataxia which is often due to degeneration of the anterior vermis (lingula, culmen and centralis) from alcohol abuse. The caudate and putamen may be hyperintense on T2 weighted images and the patients may demonstrate acquired hepatolenticular degeneration. This consists of subcortical dementia, severe dysarthria, extrapyramidal signs and falling backwards.

In general, tumors of the cerebellum are age specific. Children and young adults may have an ependymoma of the fourth ventricle. This tumor is suggested by vertigo with change of head position, nystagmus and papilledema. Projectile vomiting (pressure on the vomit center) is common in the morning. Ataxia, headache and hydrocephalus are prominent. The origin of a medulloblastoma is the superior medullary velum of the IVth ventricle. The symptoms and signs are similar to those of an ependymoma but the spinal cord is seeded with this tumor. Cystic and solid astrocytomas may be hemispheric or vermian. In the later, axial symptoms are more prominent than appendicular. These tumors frequently distort the IVth ventricle and put pressure on the pons and medulla. Headache, vomiting, and bilateral VIth nerve palsy occurs if there is an acute change of pressure (trapped under the petroclinoid ligament in Dorello's canal). Any mass in the IVth ventricle may cause down beat nystagmus accentuated by lateral gaze. Tumor's involving the floccular nodular lobe cause hypermetric saccades and rotary nystagmus with a contralateral torsional component. Rarely, oligodendrogliomas are found in the cerebellum. Most of the tumor is benign, but there usually is one section that is malignant. Hemangioblastomas are most common in the hemisphere of an adult, but tend to be midline in younger patients. They bleed intermittently which is evident by new blood (4–8 days) noted as increased signal on T2 weighted images on MRI in the center of the lesion with a surrounding hemosiderin ring (old bleed). These cause symptoms by location. There are three major tumors of the cerebellopontine angle that often involve the cerebellum by pressure. A Schwannoma presents with tinnitus and hearing loss. Meningiomas often compress the Vth nerve and present with facial pain. Epidermoids have high signal on T2 weighted images (keratin) and may present with pain radiating to the inner ear, ataxia or cranial nerve involvement. A ganglioneuroma is benign and may present with vermian or hemispheric symptoms. It does not enhance strongly with gadolinium.

The cerebellum is a major destination for metastatic lesions in adults. The hemispheres are more involved than the vermis. Squamous cell carcinoma of the lung is most common, followed by breast and the G.I. tract. Prostate metastasis reach the posterior fossa by means of the valveless paravertebral veins (Batson's) plexus. This tumor may specifically metastasize to the petrous apex. Lymphomas in HIV patients are often necrotic and occasionally involve the cerebellum.

Cholesterol granulomatosis (usually very bright T2 weighted image) at the petrous apex occasionally compress the cerebellum. Meningiomas of the tentorium (enlarged feeding artery from the meningohypophyseal trunk Bernasconi–Cassinari) produce headache, referred pain to the inner ear (IX nerve) and ataxia.

Rarely a cerebrotendinous xanthoma and amyloidoma may be seen compressing the cerebellum from the tentorium.

Paraneoplastic disease of the cerebellum is primarily associated with tumors of the female genitalia, primarily those of the ovary. Anti-Yo antibodies are sought. The ataxia may be of sudden onset rather than gradual as would be expected. Breast cancer that induces anti-Ri antibodies presents with the myoclonus opsoclonus syndrome of "dancing eyes". The same clinical picture is caused by neuroblastoma (VMA should be sought in the urine) and rarely by lung tumors.

Hyperosmolar syndromes from sodium excess (dehydration) or diabetes (glucose > 3000 mg/dl) may cause severe ataxia. Most often segmental myoclonus predominates. Too rapid correction of a low serum sodium (>12 mm/hr) may induce pontine and extrapontine myelinolysis. The ataxia occurs from destruction of the pontine crossing fibers that constitute the majority of the middle cerebellar peduncle. A recent case of hypernatremia has been reported as a cause of osmotic myelinolysis.

Autoimmune induced cerebellar dysfunction is most prominent with demyelinating diseases such as MS. In general, it is accompanied by frontal lobe mental changes, intranuclear ophthalmoplegia, spasticity and optic nerve inflammation. A poor prognosis for patients has been suggested if there are infratentorial lesions early in the course of the illness (particularly the MCP). Acute disseminated encephalomyelitis frequently evolves into MS. A distinguishing feature is that all lesions are of the same age. In acute hemorrhagic encephalomyelitis, all lesions are on the left side. Post viral and vaccination syndromes almost always have an autoimmune component that causes an acute hemispheric and vermian syndrome. It should be suspected 10–14 days following an infection or vaccination. There may be periventricular lesions in post viral patients and larger lesions in the centrum semiovale occur after vaccination. The latter may be accompanied by a transverse myelitis. The white matter lesions most suggestive of MS are in the corpus callosum, optic nerve and periventricular white matter (Dawson's fingers).

There is an overlap between central and peripheral myelin antigenic epitopes. There are many patients with GBS or CIDP that have central inflammatory white matter lesions due to this overlap.

Anoxic lesions of the cerebellum are suggested by metronomic eye movements, oscillations in which the eyes remain at the end of their complete excursion prior to oscillating to the opposite extreme.

Enzyme Defects with Major Cerebellar Symptoms

• Phenylketonuria (phenylalanine dehydrogenase)
• Tryptophane dehydrolase (Hartnup's disease)
• Pyruvate dehydrogenase deficiency (complex IV)
• Multiple carboxylase deficiency
• Hyperornithinemia (transcarboxylase deficiency)
• Arginase deficiency
• Arginosuccinate deficiency
• Glucocerebrosidosis (Niemann Pick's)
• Galactosyl cerebrosidoses (Fabry's)
• Hexosaminidase A (Tay-Sach's disease)
• Mannosidosis
• Fucosidosis
• 3-methyl-glucoconic aciduria
• Gamma-glutamyl-cysteine synthetase deficiency
• Triosephosphate isomerases deficiency

Progressive Treatable Ataxia

• Vitamin E deficiency
• Wilson's disease
• Galactosemia
• Coenzyme Q deficiency
• Refsum' disease
• Thyroid failure

Episodic Ataxia

• Episodic ataxia type I (ETA-1)
• Episodic ataxia Type II (ETA-2)
• Multiple carboxylase deficiency (biotin)
• Ornithine transcarboxylase deficiency (male heterozygote)
• Krebs-Henseleit (liver cycle) enzyme defects

Congenital Disorders

• Congenital ataxia with episodic hyperpnea, abnormal eye movements and mental retardation (Joubert's syndrome)
• Congenital ataxia with mental retardation and spasticity (includes ponto-cerebellar hypoplasia type I and II)
• Congenital ataxia and mental retardation (granule cell hypoplasia)
• Congenital ataxia with mental retardation and partial aniridia (Gillespie syndrome)
• Lhermitte Duclos (dysplastic gangliocytoma)
• X-linked recessive ataxias with spasticity and mental retardation (Paine's syndrome)

Ataxic Disorders with Known Metabolic or Other Causes

• Metabolic disorders
  • With hyperammonia:
    • Ornithine transcarbamylase deficiency
    • Arginosuccinate synthetase deficiency
    • Arginosuccinate deficiency
    • Arginase deficiency
    • Hyperornithinemia
  • Aminoacidurias without hyperammonemia:
    • Intermittent branch chain ketoaciduria
    • Isovaleric acidemia
    • Hartnup disease
  • Disorders of Pyruvate and Lactate Metabolism
    • Pyruvate dehydrogenase deficiency (Complex IV)
    • Pyruvate decarboxylate deficiency (Complex IV)
    • Leigh's disease
    • Multiple carboxylase deficiencies

Progressive Unremitting Ataxic Syndromes

• Abetalipoproteinemia
• Hexosaminidase A deficiency
• Cholestanol (cerebrotendinous xanthomatosis)
• Mitochondrial diseases
• Glutamate dehydrogenase deficiency
• Partial hypoxanthine guanine phosphoribosyl transferase deficiency (Lesh Nyhan disease)

Metabolic Disorders in which Ataxia Occurs as a Minor Feature

• Sphingomyelin disorders
• Metachromatic leukodystrophy
• Multiple sulphate deficiency
• Late onset globoid cell leukodystrophy (Krabbe's disease)
• Adrenoleukodystrophy
• Adrenomyeloneuropathy
• Ceroid lipofuscinosis
• Sialidosis type I

Disorders Characterized by Defective DNA Repair and Ataxia

• Ataxia telangiectasia
• Xeroderma pigmentosa
• Cockayne's syndrome

Early Onset Cerebellar Ataxias (less than 20 years)

• Friedreich's ataxia
• Early onset ataxia with retained reflexes
• With hypogonadism; deafness and/or dementia
• With myoclonus (Ramsay-Hunt)
• With pigmentary retinal degeneration; mental retardation and/or deafness
• With optic atrophy and mental retardation (Behr's disease)
• With cataracts and mental retardation (Marinesco Sjögren)
• With childhood onset deafness and mental retardation
• With congenital deafness and mental retardation
• With extrapyramidal features
• X-linked recessive ataxias
• With ocular apraxia (EOA1)
• With ocular apraxia (EOA2)

Late Onset Cerebellar Ataxias (greater than 20 years)

• ADCA1 (associated with optic atrophy, ophthalmoplegia, extrapyramidal features, and amyotrophy)
• ADCA 2–pigmentary retinal degeneration, and ophthalmoplegia and/or extrapyramidal feature
• ADCA 3 – pure primarily cerebellar hemispheric disease
• ADCA 4 – ataxia with myoclonus and deafness
• ADCA5 – ataxia with essential tremor

AD Cerebellar Ataxias

• SCA 1–25

Autosomal Recessive Ataxias

• Friedreich's ataxia
  • Variant with early onset and retained reflexes
• Ataxia telangiectasia
  • Njemien and Berlin variants
• Cockayne's syndrome
• Vitamin E deficiency (alpha tocopherol transporter deficiency)
• Holmes disease (hypogonadotrophic hypogonadism)
• Ramsay Hunt (progressive myoclonus)
• Infantile onset with spinocerebellar ataxia
• Marinesco Sjögren (MR, cataracts, immune deficits)
• Behr's disease (optic atrophy, seizures, scoliosis)
• Associated with childhood deafness
• Associated with extrapyramidal signs
• Wilson's disease (dysarthria, flapping tremor, Kayser–Fleischer ring)
• Refsum disease (cataract, deafness, intermittent neuropathy)
• Batten–Kornsweig disease (abetalipoproteinemia, acanthocytosis, neuropathy)

Paraneoplastic Cerebellar Degeneration

• Anti-Yo
  • Gynecological breast cancer
  • Cerebellar degeneration with ataxia
  • Ab to cytoplasm of Purkinje cells (62 kD)
• Anti-Ri
  • Breast, gynecological, small cell lung cancer
  • Cerebellar ataxia with opsoclonus
  • Neuronal nuclei of CNS (55,80 kDa size)
• Anti-Ta
  • Hodgkin's lymphoma
  • Cerebellar degeneration
  • Cytoplasm of neurons; Purkinje cell dendrites
• Anti-Ma
  • Testicular germ cell tumors primarily
  • Limbic, brainstem encephalitis, and cerebellar degeneration
  • Nuclear and cytoplasmic antigens (37, 40 kDa)
• Anti-CV2
  • Encephalomyelitis; cerebellar degeneration
  • Glial cells (66 kda antibody)

Differential Diagnosis of Acute Ataxia from Cerebellar Lesions

• Vascular
  • PICA infarct; inability to walk with cranial nerve IX, X involvement
  • AICA; ataxia of arm > leg; VIIIth nerve deficit; peripheral VII (blood supply of the nerve is from this artery)
  • Superior cerebellar artery; arm and leg ataxia with dysarthria is prominent
• Hemorrhage
  • Severe posterior headache; closure of one eye; head tilt to the side of the lesion; nystagmus, ataxia, quadriparesis not quadriplegia
• Infarcts, if large, may have a pseudotumoral presentation; 4th day from swelling
• Tumor (focal signs with headache)
• Demyelinating disease (associated intranuclear opthalmoplegia) and APD (afferent pupillary defect)
• GBS and other disimmune processes that affect large DRG cells with severe ataxia from (dorsal column demyelination) Richter's variant
• Tick paralysis:
  • Ataxia out of proportion to weakness
  • Tics are found on cold parts of the body
  • Labyrinthitis like attacks
  • Usually the lateral branch of PICA infarction

Acute Ataxia (associated symptoms and signs)

• Metabolic Hypoglycemias
  • CSF sugar < 30–40 mg% (2/3 of serum sugar)
  • Cognitive dysfunction
  • Hyperhidrosis and piloerection
  • Encephalopathy
• Hyponatremia:
  • Lethargy
  • Absent reflexes
  • Seizures if there is an acute drop of Na to <110 mg/dl, "finger print" sign on the skull
• Viral and bacterial infections:
  • Headache and stiff neck
  • Decreased level of consciousness
• Hyperammonia:
  • Related to protein intake
  • Clouded consciousness
  • Increased reflexes
• Biotinidase deficiency
  • Usual presentation 4 weeks to 5 months of age
  • Multiple carboxylase deficiency
  • Erythematous skin rash
  • Alopecia
  • Developmental delay
  • Organic aciduria
  • Sensorineural hearing loss
  • Leukoencephalopathy
• Wernicke encephalopathy
  • Primarily appendicular ataxia
  • Ophthalmoplegia (white >black patients)
  • Areflexia

Infections

Viral

• Sudden onset of headache with stiff neck
• Consciousness maintained much longer than with bacterial infection
• Herpes simplex; coxsackie, HZ are the most common infections
• Post viral acute pancerebellitis 14 days after the acute infection

Bacterial Infection

• Dominated by rapidly decreasing level of consciousness and stiff neck

Brainstem Encephalitis

• Delirium
• Nystagmus
• HZ, listeria monocytogenes, herpes simplex are the most common organisms
• Anti-Hu antibody in association with limbic encephalitis

Toxins

• Delirium
• Optic neuropathy
• Long tract dysfunction (dorsal column system)
• Toluene (associated with hallucinations and peripheral neuropathy)

Deterioration of Chiari Malformation

• Tonsillar herniation
• Head tilt to the side of the lesion
• Acute gait ataxia
• Down beat nystagmus accentuated in lateral gaze

Early Spinal Compressive Lesions

• Gait ataxia and obstipation
• Dominated shortly by bladder involvement, sensory level and weakness

Differential Diagnosis of Episodic Ataxia

• AD episodic ataxia (Type I)
  • Associated myokymia
  • Antibodies to K⁺ channels
• AD episodic ataxia (Type II)
  • Interictal nystagmus
• Paroxysmal kinesigenic choreoathetosis
  • In association with initiation of movement
  • Associated dystonia
  • Attacks are short lived
• SCA 6
  • Associated nystagmus
• Familial hemiplegic migraine
  • Associated CACN genes on chromosome 19
  • Most often hemiplegia rather than migraine headache
  • Hemiplegia same side in all afflicted family members
• Basilar artery migraine (Bickerstaff's)
  • Disease of young women
  • Associated paraesthesias of hands
  • Dysarthria and dysphagia
  • Brief loss of consciousness in some patients
• Post ictal ataxia
  • Associated psychiatric phenomena
• Hartnup's disease
  • Most often noted in alcoholic patients
  • Associated erythematous rash on extensor surfaces
• Hypoglycemia
• Hyperammonia
• Organic acidurias
• Refsum's disease
  • Cataracts
  • Deafness
  • Neuropathy
  • Ichthyosis
• Acute intermittent porphyria
  • Dominated by abdominal pain
  • Psychosis
  • Peripheral neuropathy