Loulwah Mukharesh, Intern
Neurology Rotation (April 2012)
Causes
Acquired
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Head trauma
Stroke
TIA
CP
MS
Chicken pox
Paraneoplastic
syndromes
• Tumor
• Toxic reaction
• Prions
Hereditary
(AD)
• Spinocerebellar
ataxia
• Episodic ataxia
Hereditary (AR)
• Friedreich’s ataxia
• Ataxiatelangectasia
Paraneoplastic syndrome
 A heterogeneous group of neurologic disorders associated
with systemic cancer and caused by mechanisms other
than metastases, metabolic and nutritional deficits,
infections, coagulopathy, or side effects of cancer
treatment.
 Paraneoplastic cerebellar degeneration is an uncommon
disorder that can be associated with any cancer; the most
commonly associated are lung cancer (particularly small
cell lung cancer (SCLC)), gynecologic and breast cancer,
and lymphoma (particularly Hodgkin disease). The
neurologic symptoms frequently precede the diagnosis of
cancer, sometimes by an interval of years
Pathogenesis
 The cerebellum is a frequent target of paraneoplastic
autoimmunity. All paraneoplastic antibodies have
been reported in association with PCD. Some of these
autoantibodies are associated with specific clinical
settings that may help focus the search for an
underlying occult malignancy. Only two antibodies,
anti-Yo and anti-Tr, predominantly associate with
cerebellar dysfunction; the other paraneoplastic
antibodies often associate with symptoms involving
other areas of the nervous system.
Antibodies
 The most common among the associated antibodies,
anti-Yo antibodies (also called Purkinje cell
antibody type 1 or PCA-1) primarily occur in patients
with PCD who have breast cancer or tumors of the
ovary, endometrium, and fallopian tube. Rare cases of
anti-Yo associated PCD have been described in men
with adenocarcinoma. The target antigens of anti-Yo
antibodies are the cdr proteins that are expressed by
Purkinje cells and ovarian and breast cancers. A
cytotoxic T cell response against cdr2 has also been
identified in these patients.
Antibodies
 Anti-Hu antibodies (also called antineuronal
nuclear antibody, type 1 or ANNA-1) are prevalent in
patients with small cell lung cancer (SCLC) and PCD.
In one report of 57 such patients, 44 percent had a
high titer of anti-Hu antibodies. These patients are
more likely to have multifocal neurologic disease and
severe disability than other patient groups.
Antibodies
 Anti-P/Q type calcium channel antibodies were
the second most commonly associated antibody (seen
in 24 percent) in the above series of patients with
SCLC and PCD. These antibodies were present in all
patients who also had Lambert-Eaton myasthenic
syndrome (LEMS), as well as in some patients with
cerebellar dysfunction without LEMS. Antitumor
treatment did not alter the course of the cerebellar
degeneration, but it did improve the myasthenic
symptoms. Lambert-Easton myasthenic syndrome is
discussed separately.
Antibodies
 Anti-Tr antibodies, directed against a cytoplasmic
antigen of Purkinje cells, appear to be specific for
cerebellar degeneration associated with Hodgkin
disease (HD) and less commonly non-Hodgkin
lymphoma. In some patients, these antibodies are
detectable in the CSF but not in serum. In contrast to
other clinical settings, PCD often develops after the
diagnosis of HD or when the patient is in remission.
Antibodies
 Anti-Ri (ANNA-2) antibodies have been associated
with PCD, primarily in patients with breast,
gynecologic cancers, and SCLC. Multifocal disease also
occurs in this group with associated encephalitis
and/or opsoclonus myoclonus occurring in more than
half.
Antibodies
 Anti-CV2 antibodies, directed against a cytoplasmic
antigen in some glial cells, and against peripheral nerve
antigens, have been associated with several syndromes,
including PCD as well as limbic encephalitis,
encephalomyelitis, peripheral neuropathy, and optic
neuritis. The most common tumors are SCLC and
thymoma.
 Antibodies to Ma proteins, which are selectively
expressed in brain, testis, and some tumors can occur in
patients with paraneoplastic brainstem and cerebellar
dysfunction associated with a variety of tumors arising in
the testes (germ-cell tumors), breast, colon, and parotid
gland, among others.
Antibodies
 Antibodies to the Zic4 have been described in
patients with neurologic disorders including cerebellar
dysfunction and SCLC. These patients often have
concurrent anti-Hu or CRMP5 antibodies. Patients
with isolated Zic4 antibodies are more likely to
develop cerebellar dysfunction than those with
concurrent immunities.
Antibodies
 Other, less well characterized antibodies have been
reported in patients with PCD. PCA-2 and ANNA-3 are not
syndrome specific and have unknown autoantigens.
Antibodies to a glutamate receptor in the brain, designated
anti-mGluR1, have only been identified in two patients
with PCD and Hodgkin lymphoma as well as one patient
without cancer. Antibodies against the carbonic anhydrase
related protein VIII (CARP VIII) were identified in a
patient with PCD and melanoma. In one patient with
nonSCLC and PCD, immunoreactivity was observed to
protein kinase C, a protein highly expressed in the Purkinje
cells of the cerebellum.
Clinical features
 Dizziness, nausea, and vomiting (acute)  gait instability, oscillopsia,
diplopia, both truncal and appendicular ataxia, dysarthria, and
dysphagia. Worsen for weeks to months before stabilizing. Severe
disability with inability to walk or even sit unsupported, inability to
write or feed oneself, and limited communication secondary to
dysarthria are common, with some patients having a somewhat better
outcome.
 Many of these patients with paraneoplastic syndromes develop
cerebellar dysfunction along with other neurologic signs. As an
example, when cerebellar degeneration occurs with encephalomyelitis,
the underlying tumor is SCLC in approximately 80 percent of cases.
LEMS can occur with PCD in patients with SCLC who have anti-P/Q
type calcium channel antibodies. Even patients with anti-Yo antibodies
and relatively isolated PCD have detectable cognitive deficits
approximately 20 percent of the time.
 Most patients (60 to 70 percent) with PCD do not have a cancer
diagnosis at the onset of their neurologic symptoms
Diagnosis
 DIAGNOSIS — The diagnostic approach to patients with PCD
includes considering and ruling out other diagnoses, confirming
and characterizing the paraneoplastic syndrome, and identifying
the underlying neoplasm, if this is not previously known.
 Differential diagnosis — cerebellar and brainstem metastases,
toxic and metabolic causes, and neurodegenerative causes.
Alcoholism, vitamin deficiency (thiamine, vitamin E,
cobalamin), hypothyroidism, cerebrovascular disease,
demyelination, infectious or postinfectious cerebellitis, MillerFisher syndrome, anti-glutamic acid decarboxylase (GAD)associated cerebellar ataxia, Creutzfeldt Jakob disease, HIV, and
celiac disease should be specifically considered. Medication lists
should also be reviewed for possible contributors.
Investigation
 MRI is usually not helpful for positive diagnosis of PCD but is important to exclude
metastatic and cerebrovascular disease. In rare instances of PCD, contrast enhancement
in the cerebellar folia can be found in acute phases of the disease, and PET may reveal
hypermetabolism. Diffuse cerebellar atrophy develops subsequently.
 Laboratory: TFT, vitamin levels, and other testing (anti-gliadin, anti-GAD antibodies,
HIV serology) in the appropriate clinical setting.
 CSF examination can show inflammatory changes, at least in the early stages of the
illness. A mild pleocytosis (10-50 lymphocytes) and a mild elevation of protein are
characteristic. Some patients with PCD or extensive encephalitis have the 14-3-3 protein
characteristic of Creutzfeldt-Jakob disease (CJD) in the CSF. This might create some
diagnostic confusion if a tumor is not evident because of symptom overlap between
paraneoplastic disease and CJD. It is likely that the 14-3-3 protein in this setting reflects
extensive CNS damage rather than CJD. Immunoblotting reveals the 14-3-3 protein as a
double band (similar to other false positive results) rather than the single band in CJD.
 Paraneoplastic biomarkers. Negative results do not exclude a paraneoplastic or
autoimmune disorder. A sample of a patient’s CSF and serum should be sent to a research
laboratory for examination in these cases.
 Evaluation for occult malignancy. The presence of paraneoplastic biomarkers may
help direct further evaluation if initial screening is negative. Tumors may be small; in
some cases FDG-PET or exploratory laparotomy was the only means of identifying the
underlying lesion. In a minority of patients with PCD, no tumor is identified despite
vigorous investigations. In such cases, serial investigations are advised
Treatment
 Neurologic outcome is often poor, most patients (75 to 80 percent)
become and remain nonambulatory. Treatment of the underlying
tumor is considered essential for neurologic stabilization; clinical
improvement is less likely but can occur.
 Immunotherapy is often used, but does not clearly affect neurologic
outcome. In one larger case series, immunotherapy was not
significantly associated with recovery. However, there are anecdotal
reports of neurologic improvement in patients tried on various
immunological therapies, including plasma exchange, IVIG,
corticosteroids, azathioprine, cyclophosphamide, and rituximab, given
individually or in combination. One literature review of 15 cases found
that treatment with intravenous immune globulin was more likely to be
associated with a good outcome if it was administered between within
three months of symptom onset. There are also rare reports of
spontaneous improvement. Given the overall poor prognosis with
substantial neurologic disability, a trial of immunotherapy seems
reasonable.
Prognosis
 The type of antibody appears to affect neurologic prognosis. Patients with PCD
associated with anti-Hu or anti-Yo antibodies are less likely to recover, while
those with anti-Tr, anti-Ri, or anti-CV2 antibodies may have a somewhat
better chance of neurologic improvement. In some reports, younger age and
less severe disability at diagnosis and intervention appear to favorably affect
prognosis.
 Survival also varies with the type of associated antibody as well as the
underlying neoplasm. In one series, survival was worse in patients with anti-Hu
antibodies (median seven months) and those with anti-Yo antibodies (median
13 months) compared with patients who had anti-Tr or anti-Ri antibodies
(median survival 113 and 69 months, respectively). In another series, median
survival was 11 months in patients with anti-Hu antibodies compared with 48
months in those with anti-CV2 antibodies. Advanced age has a negative impact
on survival.
 While some reports find that neurologic morbidity contributes most
substantively to mortality, others have found that cancer progression was more
important
“A patient with breast cancer and paraneoplastic cerebellar syndrome
associated with anti-Purkinje cell antibodies: Response to CMF
chemotherapy”
 M. Faris et al
 A 41-year-old lady underwent a left mastectomy and
axillary clearance in 1992, for T2N0 breast cancer. She
remained well until December 1995, when she presented
with a rapidly progressive cerebellar ataxia. Full
investigations for metastatic disease were negative. A
clinical diagnosis of paraneoplastic cerebellar degeneration
was confirmed by a high titre of anti-Purkinje cell
antibodies. She was treated with cyclophosphomide,
methotrexate and 5-fluorouracil. The improvement in
neurological symptoms was dramatic and has been
maintained by further hormone manipulation (ovarian
ablation). The patient now leads a normal life without
medication.
“Anti-GAD antibodies in paraneoplastic cerebellar ataxiaassociated with
limbic encephalitis and autonomic dysfunction”
 C. Carra-Dalliere et al.
 A 59-year-old patient, with history of polymyalgia rheumatica and
active smoking, was admitted for subacute cerebellar ataxia and
memory dysfunction explained by limbic encephalitis on brain MRI.
He also presented with orthostatic hypotension and erectile
dysfunction revealing autonomic dysfunction. CSF was inflammatory
and antibodies to GAD were positive. Onconeuronal antibodies
including GABAB receptor antibodies were negative. Patient's condition
quickly improved after intravenous immunoglobulins. A few months
later, a small cell lung carcinoma was diagnosed and precociously
treated.
 Conclusion
 This case report underlines the importance of appropriate studies to
confirm a primitive neoplasia, when confronted with limbic
encephalitis and cerebellar ataxia, even if anti-GAD antibodies rarely
defineparaneoplastic syndromes.
“Clinical presentation of immune-mediated cerebellar ataxia”
 G. Demarquay et al.
 Accumulation of recent clinical evidence indicates that the immune system plays an
important role in some central nervous system diseases usually regarded as
degenerative. The most striking example is paraneoplastic cerebellar ataxia (PCA),
which is characterized by autoimmune cross-reaction between tumoral and
nervous system antigens.
 In the past 20 years, several antibodies directed against neuronal and tumoral
antigens have been described in association with PCA, leading to the description of
different subtypes of PCA based on the associated antibodies, the clinical course
and the type of tumor. In some subtypes, cerebellar ataxia occurs in isolation,
whereas in others, cerebellar ataxia is a syndrome that occurs in conjunction with
extensive nervous system disease. Circulating antibodies have also been described
in patients with non-paraneoplasticcerebellar ataxia (N-PCA), suggesting that the
immune system may be involved in certain cases of sporadic cerebellar ataxia.
 Immune-mediated cerebellar ataxia does not seem to be limited
to paraneoplastic neurological syndromes. Further studies are however necessary to
understand the exact pathophysiology of these disorders and offer effective
treatments.