Ataxia: Pathophysiology and clinical syndromes

Degenerative ataxia

MSA is likely the most common disorder, certainly in adults ( ; ). In the large series from Japan, of the sporadic ataxias, 64.7% were MSA ( ). In addition to ataxia, patients have parkinsonism and autonomic dysfunction (including impotence). The disorder also has been called olivopontocerebellar atrophy or MSA-C when the emphasis is on ataxia, striatonigral degeneration, or MSA-P when the emphasis is on bradykinesia and rigidity, and Shy–Drager syndrome when the emphasis is on autonomic dysfunction. Early falls are a prominent feature. Variable clinical features include pyramidal signs, tremor, dysarthria, dystonia, and mild dementia. There is typically a poor response to levodopa, but clearly at times there is some response, and this can be confusing. Responses are rarely dramatic and typically unsustained. The pathologic hallmark of the disorder, in addition to neuronal cell loss, is the glial cytoplasmic inclusion (GCI) ( ). Although common, MSA is often misdiagnosed. A study of 134 clinically diagnosed patients found that 68% were correctly diagnosed ( ). MSA is described in detail in Chapter 9 .

Laboratory findings of value include autonomic abnormalities ( ). Studies include the skin sympathetic response, the Valsalva maneuver, and heart rate variation. Rectal sphincter electromyography (EMG) shows denervation, but this test must be performed with caution. Women who have been through childbirth may have denervation secondary to their delivery. The specificity of this finding has been called into question. Magnetic resonance imaging (MRI) can show cerebellar and pontine atrophy. The hot-cross bun sign in the pons is due to degeneration of corticocerebellar fibers. Magnetic resonance spectroscopy (MRS) can show decreased N-acetyl aspartate signal in the cerebellum, and positron emission tomography (PET) can show decreased cerebellar metabolism.

Another degenerative cause is progressive myoclonic epilepsy because ataxia is typically a part of this syndrome. Often myoclonus and ataxia become difficult to separate. These syndromes are described in Chapter 18 .

Strokes

A variety of strokes can produce ataxia. These can be due to lesions of the cerebellum or the cerebellar pathways ( ).

Ataxic hemiparesis is characterized by both weakness and incoordination. Lesions can be in the thalamus and posterior limb of the internal capsule, upper basis pontis and cerebral peduncle, parietal lobe, and (debated) anterior internal capsule and frontal lobe.

Hemisensory loss and hemiataxia is typically the result of a thalamic lesion.

Isolated gait ataxia can be seen with a lesion of the pontomedullary junction.

Ataxia (hemiataxia and/or gait ataxia) with variable cranial nerve involvement can be seen with involvement of several arteries. The superior cerebellar artery affects the upper pontine tegmentum; the anterior inferior cerebellar artery leads to damage of the lateral pontomedullary junction; and the posterior inferior cerebellar artery gives rise to the well-known lateral medullary syndrome.

Tumors

The tumors commonly affecting the cerebellum are listed in Table 20.2 .

Toxic and metabolic

Toxic damage to the cerebellum can be caused by alcohol, both acute and chronic ( ; ). The acute effects of alcohol appear to cause a true ataxia as measured by physiologic studies. In the chronic state, there can be irreversible cerebellar damage, particularly to the cerebellar vermis, leading to particular difficulties with stance and gait. There is also a characteristic prominent anterior-posterior sway when standing.

Hypoxia damages the cerebellum with a particular propensity for the Purkinje cells. These patients may also get myoclonus. Hyperthermia is another cause for Purkinje cell loss.

The childhood hyperammonemias are a cause of intermittent ataxia.

Although it remains somewhat controversial, ataxia can be a gluten-related disorder, that is, a consequence of the ingestion of gluten, a component of wheat ( ; ; ). Celiac disease or sprue, the best-known gluten-related disorder ( ), is an enteropathy with malabsorption and has been long known to sometimes be associated with ataxia and possibly also myoclonus ( ). It is now considered that there are three main forms of autoimmunity to gluten, celiac disease, gluten ataxia, and dermatitis herpetiformis ( ; ); however, there continue to be reports of antibodies associated with a variety of neurologic diseases, even including amyotrophic lateral sclerosis ( ). The different manifestations likely arise from different spectra of antibodies. Celiac disease can be treated with a gluten-free diet. The ataxia in the setting of celiac disease may persist despite a good diet ( ).

The notion of gluten ataxia arose after finding a higher than expected incidence of antigliadin antibodies in patients with sporadic ataxia. Curiously, it is now clear that up to 40% of patients with sporadic ataxia have antigliadin antibodies, but no sign of celiac disease ( ; ; ; ; ). This has been supported by a 2018 meta-analysis ( ). In some of these patients, there are abnormalities of the white matter and prominent headache; at least a few of these patients have some symptomatic response to a gluten-free diet ( ). Antibodies to gangliosides were found in 64% of patients with mixed ataxias, suggesting that the increase in antigliadin antibodies may not be specific ( ). In gluten-associated ataxia, there also can be antibodies directed to tissue transglutaminase, either type 2, which is expressed in the gut ( ), or, likely more specifically, type 6, which is expressed in neural tissue ( ). In a series of 100 patients with sporadic ataxia, 35 of 48 (73%) who had antigliadin antibodies had antibodies to transglutaminase type 6, whereas the antibodies were present in 21 of 65 (32%) patients without antigliadin antibodies ( ). In that same series, neurologic controls had 5% incidence of the antibodies. Antigliadin antibodies in patients with ataxia also bind to the neural antigen synapsin I ( ), giving another autoimmune pathway to neurologic damage.

Some patients have symptoms of celiac disease but no demonstrable enteropathy, called nonceliac gluten sensitivity (NCGS). In a study of 228 patients with celiac disease and 334 with NCGS, there was about 40% ataxia in both groups and a similar high incidence of transglutaminase type 6 antibodies and a similar response to a gluten-free diet ( ).

There is open-label evidence that a gluten-free diet ( ; ) may benefit patients with antigliadin antibodies, but still no double-blind study. Additionally, magnetic resonance spectroscopy (MRS) of the cerebellum can improve on a gluten-free diet ( ). Intravenous immunoglobulin (IVIG) has improved the ataxia in three patients with overt celiac disease and ataxia ( ). IVIG therapy has been observed to help two patients and two other patients with anti-GAD antibodies (see later for discussion of this entity), suggesting a role for immunotherapy ( ).

A patient has been reported with long-standing slowly progressive ataxia who developed palatal tremor, and hence the syndrome of progressive ataxia with palatal tremor (PAPT) ( ). She had antigliadin antibodies. On a gluten-free diet, the palatal tremor resolved and the ataxia stabilized. Additionally, there was, typically, hypertrophy of the inferior olivary nuclei, and this regressed to some extent when on the diet.

There is a large report of 68 neurologic patients with celiac disease biomarkers that found that most had a strong alternative cause identified, some with other autoimmunity ( ). Hence, it might be that antigliadin antibodies are a frequent bystander and not often directly pathogenic.

Vitamin deficiencies can cause cerebellar dysfunction, including thiamine (vitamin B ₁ ), vitamin B ₁₂ , and vitamin E. Zinc deficiency also may be a culprit of cerebellar dysfunction.

In the endocrine area, hypothyroidism, hypoparathyroidism, and hypoglycemia (insulinoma) have been associated with ataxia.

Toxic drugs include thallium, bismuth subsalicylate, methyl mercury, methyl bromide, and toluene. Drugs include phenytoin, carbamazepine, barbiturates, lithium, cyclosporine, methotrexate, and 5-fluorouracil. Ataxia can be a component of the serotonin syndrome, from selective serotonin reuptake inhibitors (SSRIs).

Paraneoplastic

The paraneoplastic causes are very important to keep in mind ( ; ; ; ; ). The clinical syndrome is often rapidly progressive over a relatively short period and then plateaus. What appears to be happening in most cases is a rapid destruction of Purkinje cells. Even if the cancer is found and successfully treated, the disorder may not improve because the cells are irreversibly damaged. Nevertheless, it is clearly important to treat the cancer.

In many cases, there will be detectable antibodies in the serum ( Table 20.3 ). These antibodies are markers of the cancer and are not specific for cerebellar syndromes. Some cases of paraneoplastic ataxia have no defined associated antibody, so the disorder should not be ruled out just because one of the known antibodies is not found.

A number of the antibodies react against intracellular neuronal antigens, and many of those are specific to the Purkinje cell. These include anti-Yo (also called PCA1), seen with ovary and breast cancers; anti-Tr, seen with Hodgkin disease; and anti-PCA2, seen with small cell lung cancer. Two antibodies can be seen with or without neoplasms. These are anti-GAD ( ), which can be seen with thymoma or renal cell carcinoma, and anti-mGluR1, which can be seen with Hodgkin disease. Anti-mGluR2 antibodies have now also been found in two patients with tumors ( ).

There are antibodies directed against neurons, not specific to the Purkinje cell. Anti-Hu (ANNA-1) can be seen with small cell lung or neuroendocrine tumors. Because the antibody may have a wide impact, other neurologic conditions may occur, such as encephalomyelitis. Anti-Ri (ANNA-2) is found with tumors of the breast and small cell lung cancer. Patients might also have brainstem encephalitis.

Antibodies to Zic4 are directed mostly to cerebellar granule cells and are seen with small cell lung cancers.

An antibody directed to a neuronal cell surface antigen is the anti–voltage-gated calcium channel (VGCC), which is also seen with small cell lung cancers.

Anti-CV2 (CRMP5) antibody is associated with a syndrome of ataxia often together with retinal or optic nerve symptoms ( ; ). It has been seen with small cell lung carcinoma. The CV2 antigen is expressed by oligodendrocytes. This is one syndrome in which improvement has been seen with removal of the tumor.

Antibodies directed to a serum protein, Ma1, have been found in patients with testicular and other tumors ( ; ). A related antibody is anti-Ma2 (or anti-Ta). These patients more likely will have limbic or brainstem encephalitis. Ma1 is a phosphoprotein highly limited to brain and testis.

Antibodies directed to amphiphysin are rarely associated with a cerebellar syndrome ( ; ). This is often a marker for small cell lung carcinoma.

Tests that are currently commercially available include Hu, Ma, Ta, Yo, Ri, amphiphysin, Zic4, and CV2. Guidelines for screening have been published by the European Federation of Neurologic Societies (EFNS) ( ).

In a series of 50 patients with paraneoplastic cerebellar degeneration out of 137 with any neurologic syndrome, 19 had anti-Yo, 16 anti-Hu, 7 anti-Tr, 6 anti-Ri, and 2 anti-mGluR1 ( ). Whereas 100% of patients with anti-Yo, anti-Tr, and anti-mGluR1 antibodies had ataxia, 86% of anti-Ri and 18% of anti-Hu patients had paraneoplastic cerebellar degeneration. In 42 patients (84%), a tumor was detected; the most common were gynecologic and breast cancer (anti-Yo and anti-Ri), lung cancer (anti-Hu), and Hodgkin lymphoma (anti-Tr and anti-mGluR1). All patients received antitumor therapy, and 7 had some neurologic improvement. The functional outcome was best in the anti-Ri patients, with 3 of 6 improving neurologically; 5 were able to walk at the time of last follow-up or death. Survival was worse with anti-Yo and anti-Hu compared with anti-Tr and anti-Ri.

In relation to treatment, it is critical to move as rapidly as possible. In addition to removing the tumor, immunologic therapy might be considered ( ).

Autoimmune

Ataxia can be associated with antibodies not related to an underlying cancer ( ). As noted earlier, one such antibody is anti-GAD ( ; ; ; ; ) (although it can be cancer related [ ]). There can be a pure ataxia syndrome and one with an associated peripheral neuropathy. In one series of 14 patients, 13 were women and 11 had late-onset diabetes ( ). Another series had 34 patients, 28 were women and 13 had diabetes ( ). Anti-GAD antibodies are better known for association with stiff-person syndrome, but why one patient has one disorder or the other is not clear. It could be that the pathologic process is actually mediated by subtypes of GAD65-specific CD4(+) T cells, and the anti-GAD antibodies are only a marker ( ; ). In the series by Arino and colleagues (2014), 9 of the 34 also had stiff-person syndrome. In one case with antibodies in the cerebrospinal fluid, the antibody blocked GABAergic transmission in the rat cerebellum ( ). As with stiff-person syndrome, patients can exhibit other forms of autoimmunity. IVIG or other immunotherapy may be useful ( ; ; ).

Patients also have been described with autoimmunity directed to the metabotropic glutamate receptor type 1 (mGluR1) ( ). The symptoms and settings were highly variable.

Autoimmunity in general is a bad prognostic finding; guidelines for diagnosis have been suggested ( ). The presence of one or more systemic, nonneuronal antibodies correlates with a faster evolution and shorter survival ( ). On the other hand, in anti-GAD ataxia, prompt recognition and immunotherapy led to long-term improvement in 35% ( ). General guidelines have been suggested for treating immune-mediated ataxias ( ; Mitoma et al., 2021). In a series of 118 patients with various types of autoimmunity, a number of patients did respond well, particularly those with GAD65 or plasma membrane protein (PMP) autoimmunity ( ).

Infectious and postinfectious

Infectious causes include rubella and Haemophilus influenzae ( ). Ataxia is also common in neurocyticercosis ( ). Acute postinfectious cerebellitis is generally a childhood condition, most common after varicella. Creutzfeldt–Jakob disease may have an ataxic form. Acute cerebellitis can be due to SARS-CoV-2 ( ).

Demyelinating

Ataxia is common in multiple sclerosis. A patient with leukoencephalopathy with neuroaxonal spheroids (LENAS), a rare disease of cerebral and cerebellar white matter, had a 14-year course of progressive neurologic decline consistent with a clinical diagnosis of probable MSA, with prominent cerebellar dysfunction and dysautonomia ( ).

Other

Other syndromes include Chiari malformation, abscess, hydrocephalus, and superficial central nervous system hemosiderosis ( ). Ataxia can be a feature of high-altitude cerebral edema ( ).

Ataxia of noncerebellar origin

What looks like cerebellar ataxia can come from dysfunction outside the cerebellum. Most common causes include neuropathies such as the Miller Fisher form of Guillain–Barré syndrome ( ; ; ) and spinocerebellar tract lesions.